A study of street heroin lots for the presence of the hepatitis B surface antigen. Hepatitis B surface antigen (HBsAg) of subtype ay predominates among narcotic addicts infected with hepatitis B virus (HBV) in Europe, Australia and the United States. However, the ad subtype predominates among the non-addict carriers of HBsAg. We investigated the possibility that heroin lots were contaminated with HBV at a source of opium production, the Middle East, a geographical region where HBsAg/ay predominates in the general population. One hundred and nine lots of street heroin were assayed for HBsAg by radioimmunoassay. None of the lots tested was reproduceably HBsAg positive. These results suggest that the heroin itself is not responsible for the high incidence of HBV infection or for the predominance of HBsAg/ay in the addict population. The predominance of HBsAg/ay among addicts in Europe and Australia as well as the United States might be due to extensive needle sharing among a mobile population of drug abusers, although such worldwide dissemination of one subtype by these means is unlikely.


Correlates of methadone patients' lengths of stay for first and second admissions. Product moment correlations were calculated between 17 psychosocial characteristics of 216 heroin addicts and their lengths of stay for first and second admissions to the dame methadone maintenance program. None of the variables which were related to retention during the first admission was associated with retention during the second admission. The conclusion was drawn that the relationships between addict characteristics and length of stay vary according to admission, and it would be unwise to use addicts' former treatment experiences to predict latter responses.


The quantitative assessment of physical dependence on opiates. A procedure for administering naloxone to narcotic-dependent individuals and a technique for quantitating the ensuing acute withdrawal syndrome have been developed to assess the degree of physical dependence. Successive injections of increasing doses of naloxone produce a controlled increase in severity of withdrawal signs and symptoms as measured by a subjective and an objective assessment battery. There is good agreement between the subjective and objective assessments and a global reting of withdrawal severity. The objective measures are, however, most sensitive and produce a withdrawal syndrome score related to the duration of the current cycle of drug abuse. Hand tremor, trapezius electromyogram and heart rate are the most sensitive signs of withdrawal and can be used in combination to form the basis of a simplified and shortened antagonist assessment test for physical dependence.


Use and abuse of non-narcotic analgesics. The definition of abuse and dependence of non-narcotic analgesics should take into consideration the interaction of drug and personality. Usually, definitions are based on qualitative aspects of the risk-benefit ratio in the use of psychotropic drugs. By means of modern research methods in epidemiology and clinical psychology, quantitative aspects might be integrated in the process of defining persons and drugs when evaluating their risk of abuse or dependence. In a prospective field study with working housewives of northwestern Switzerland who showed objective evidence of intake of non-narcotic analgesics and a control group, the interaction of drug use and personality features has been investigated. There was significant evidence that heavy use of non-narcotic analgesics was paralleled with a high risk of depression, emotional liability and disturbance in sexual identity. Using urine analysis, the study group was divided into two subgroups showing low or high intake of drugs, respectively. Special attention was focused on persons shifting from the study group into the control group and vice versa.


[Drug side-effects in patients treated by their general practitioner (author's transl)]. Drug side-effects were registered in 50 of 2688 patients on the day of admission to hospital. These were severe in 52%, moderate in 18% and mild in 30%. Three deaths were clearly related to drug side-effects. Side-effects of cytostatic treatment were not included. Cardiac glycosides and anticoagulants were the drugs with the highest incidence of side-effects (50%).


[Hyperbaric oxygen treatment in gas gangrene (author's transl)]. Among 100 patients with proven gas gangrene surgical treatment was undertaken in 34 who also received 30--60 mega-units of penicillin, in addition to appropriate shock treatment. Since 1967, additional treatment in a hyperbaric chamber was undertaken in 66 patients. There was no clear-cut advantage of hyperbaric oxygenation as far as the death-rate was concerned. There was merely a moderate decrease in the amputation rate after limb injuries. Wide incision of the wound and radical surgical excision of all tissue affected by gas gangrene continues to be an essential form of treatment.


[Treatment of urinary-tract infections with netilmicin (author's transl)]. Netilmicin, a half-synthetic aminoglycoside, was given to 22 patients with urinary-tract infections at a dose of 2 mg/kg body weight twice daily intramuscularly for 7--9 days. Pharmacokinetics (in ten patients), efficacy and tolerance to the drug were analysed. Mean serum peak concentrations on the first and last days of treatment, was 8.7 microgram/ml at 45 min after injection, 9.5 microgram/ml after 60 min. After 12 hours the level had fallen to 0.8 microgram/ml and 1.2 microgram/ml, respectively. Mean half-life was 3.08 hours for the first and 3.57 hours for the last day. The corresponding mean values for plasma clearance were 53.6 ml/min and 42.4 ml/min, respectively. Within 12 hours an average of 77.6% and 78.0%, respectively, of the netilmicin dose were eliminated in the urine. The causative organism was eliminated in 12 of 16 patients with chronic or reccurent and in all six with acute urinary infections. There were two re-infections and two failures. Superinfection did not occur. Local and general tolerance was good and there were no signs of renal or inner-ear toxicity.


[Long-term results of immunosuppressive treatment of chronic aggressive hepatitis (author's transl)]. Long-term treatment with prednisone and azathioprine gives satisfactory results in chronic aggressive (chronic active) hepatitis. Of 18 patients treated between 1966 and 1976 for an average of 2.9 years the disease became inactive clinically, biochemically and histologically in 13; merely two continued to have minimal activity histologically. These patients have not required any treatment for two years (on average). In one patient there are still definite signs of activity and immunosuppressive treatment is being continued. Four patients died of cirrhosis of the liver: two of them had not taken the drugs conscientiously. Death occurred on average two years after the diagnosis had been made. Of the 18 patients five were positive for hepatitis-B antigen.


[Prevention of re-occlusion after recanalisation of occluded arteries by the catheter method (author's transl)]. In a double-blind study, prevention of re-thrombosis was tested on 101 patients in whom stenosis or segmental occlusion of a large artery of the lower limbs had been successfully removed by the intraluminal catheter method. The combination of 75 mg dipyridamol and 330 mg acetylsalicylic acid, three times daily by mouth, proved to be slightly more effective than acetylsalicylic acid alone at the same dosage. In the group with the combined treatment 84% of the arteries remained open, compared with 70% on acetylsalicylic acid alone.


[On informing in-patients, and the problem of hospitalism (author's transl)]. Sixty-seven in-patients, admitted to neurological or surgical wards of an acute hospital, were repeatedly interviewed during an average stay of 15 days to test their need for information about their illness, their satisfaction with information received and their knowledge about their illness. Parallel to these interviews psychometric tests were performed on the second, seventh and penultimate day of the hospital stay, in the evening, to assess the extent of any disturbance in their subjective condition. Independent of the initial state, there were consistently less favourable results in those patient groups which (using several indicators) had a deficit in subjective information. These group-specific differences were in part statistically significant. An intervening influence of 12 personality dimensions was not definitely established. These findings support the hypothesis that deficient instruction and information of in-patients represents an important stress component which in the majority of these patients can give rise to an objectifiable psychosocial hospitalism.


[Radiotherapeutic aspects of testicular tumours: results and problems (author's transl)]. The five-year survival rate of patients with seminoma (61 cases) of all stages was 81% (seven-year survival rate 67%). Within this group the T1-2N0M0 stage had a five-year survival rate of 100%. Patients with tumours other than seminoma (52 cases) of all stages had a five-year survival rate of 54% (seven-year survival rate 47%). These results and those reported by others are the basis for not advocating routinely total radiation of the lymphatic pathways in the early tumour stages.


Early postnatal growth evaluation in full-term, preterm and small-for-dates infants. Postnatal growth patterns of weight, length/height and head circumference in full-term (FTI), preterm (PTI) and small-for-dates (SFDI) infants, are described by using distance and velocity data together with the concept of growth per unit of body weight. The study was performed in 112 healthy Caucasian infants, of a similar socioeconomic status, in Montevideo, Uruguay. Median growth velocity (MGV) and median growth velocity per unit (MGVU) of body size are defined. The authors stress that: (a) growth velocity is related to body mass, (b) a useful evaluation of growth is made by using two consecutive measures with a certain time interval independently of birthweight and gestational age, and (c) expressing growth per day per unit relates well to daily nutritional and other requirements.


Early mother--infant interaction and somatic growth. This study tests the proposition that selected behaviors of both mother and infant during feeding are predictors of weight gain during the 1st mth of life. 40 normal mother--neonate pairs were studied, and the target behaviors were examined using an adaptation of the techniques developed by Brown and Bakeman [18]. Aggregate scores of 4 specific maternal and infant behaviors accounted for over 32% of the variance in total weight gain. These findings indicate that the availability of nutrients is not, in itself, a sufficient condition to meet the infant's nutritional needs. Implicit in these findings are the possibilities that infants at risk of failure-to-thrive can be identified, and measures to prevent this syndrome can be introduced.


Plasma somatomedin activity in an infant with Beckwith Wiedemann syndrome. Plasma growth hormone levels and somatomedin activity were determined in a child with Beckwith--Wiedemann syndrome at birth and at 8 mth of age. Birthweight and length were above the 97th centile. Somatomedin activity in the cord plasma was elevated (2.8 U/ml) compared with controls (0.15--1.3 U/ml; n = 15). Growth hormone was also high (76 ng/ml compared with control group range of 5.5--42.1 ng/ml, n = 26). At 8 mth of age both somatomedin activity and plasma growth hormone had fallen to normal levels and weight and length were on the 75th centile. It is suggested that the high somatomedin activity may have been a contributing factor in the excessive fetal growth of this child.


Germinal centers in the spleens of neonates and stillbirths. Sections of spleens from 235 stillbirths and 227 babies who died between the ages of 1 and 35 days were examined. None of the stillbirths showed any germinal centres, neither did the spleens of any of the babies who died between the ages of 1 and 14 days. From the age of 15 days onwards, the germinal centres started to appear in varying numbers. The appearance of germinal centres in the spleen is further delayed in infants born before 37 wk gestation. Germinal centres in the spleen in neonates do not appear to be related to the presence of inflammatory changes elsewhere in the infant.


Variability of reproductive casualty in maternal phenylalaninemia. A biochemical survey of 4,000 parents of mentally retarded children did not identify any mothers with elevated phenylalanine blood levels. This finding and an analysis of nearly 100 reported cases of maternal phenylalaninemia suggest a low risk of reproductive casualty in phenylalaninemic mothers who somehow escaped the usual effects of phenylketonuria. Recent observation on cases of maternal phenylalaninemia who were detected through unselected screening indicate that the reproductive risk associated with the condition may have been overstimated in the past. This risk is concentrated in mothers who had been affected themselves. Mental level appears to be a stronger predictor of reproductive outcome in phenylalaninemic women than the degree of phenylalaninemia. Selective prenatal intervention based on maternal mental level is not possible, however, where the natural history of the condition has been altered. This is the case in phenylketonuric girls who has been treated during childhood. These girls are now reaching child-bearing age in fast growing numbers, as a result of screening for phenylketonuria. Prenatal intervention is appropriate for all of them until predictors are established that can identify those at risk of reproductive casualty.


Clinical assessment of gestational age at birth: the effects of sex, birthweight, and weight for length of gestation. During studies on different aspects of fetal growth rate infants who were small-for-dates (SFD) large-for-dates (LFD) or within the normal range of birthweight for length of gestation (AFD) were examined within 48 h of birth. Gestational age was clinically assessed by the Dubowitz method. Among 140 AFD infants boys had higher mean values than girls for total and external scores, but there was no difference in neurological scores. Multiple regression of the score for external criteria on gestation, birthweight and sex, showed a significant contribution for birthweight and sex in addition to gestation; whereas gestation was the only singificant explanatory variable in the regression of the score for neurological criteria. When infants in the three weight groups were matched for length of gestation an sex, the SFD group had significantly lower mean total and external scores than the AFD group. The mean scores for the LFD group were not significantly higher than the AFD group. The neurological scores did not differ in the three groups. Maturation of external characteristics is related to weight as well as gestation. When assessment is made after birth by a clinical examination which includes these characteristics, the length of gestation of some SFD infants will be underestimated. The sex of the infant should also be borne in mind.


A study of the role of air trapping in the establishment of the functional residual capacity by analysis of pressure/volume and flow/volume loops. Pulmonary mechanics were measured in 22 normal, full-term babies as soon as quiet, regular breathing was established. The method included construction of tidal resistance profiles, by which it was demonstrated that 'air trapping' is probably not the major factor in establishing and maintaining the functional residual capacity immediately after birth.


Somatomedin activity in human cord plasma and relationship to birth size, insulin, growth hormone, and prolactin. Somatomedin activity was determined by a rabbit chondrocyte bioassay in cord plasma from babies of between 37 and 41 wk gestation. A positive correlation (P less than 0.001) was found between plasma somatomedin activity and birthweight. The mean somatomedin activity in infants whose birthweights were within 1 SD of the mean (3293 g) was 0.76 +/- 0.27 U/ml. Mean somatomedin activity in infants whose weight was (a) greater than the mean weight +1 SD was 1.3 +/- 0.17 U/ml, and (b) less than the mean weight -1 SD was 0.48 +/- 0.15 U/ml. Plasma somatomedin activity was also correlated with placental weight, P less than 0.02 and gestational age, P less than 0.05. No correlation was found between plasma somatomedin activity and birth length, OFC, most measurements of skinfold thickness, cord plasma, growth hormone, prolactin or insulin.


Fetal loss, gravidity, and pregnancy order. An investigation of the reproductive history of 3068 women doctors showed that the risk of fetal loss at a given pregnancy order varied with their gravidity--that is, the total number of pregnancies that has occurred before the survey. Fetal loss rates in even the first pregnancy varied with eventual gravidity in a J-shaped manner. They fell from 12.4% in women with only one pregnancy at the time of the study, to 5.7% in women with two, and then increased steadily to 36.8% in those with six pregnancies. This variation in risk remained when allowance was made for the incomplete nature of some of the reproductive histories. When gravidity was held constant, fetal loss rates decreased with each successive pregnancy. This finding conflicts with previous suggestions that the risk of fetal loss increase with pregnancy order and age.


Soluble fibrinogen--fibrin complexes in intrauterine growth retardation. Soluble fibrinogen--fibrin complex levels were found to be significantly higher in plasma samples from pregnant women with babies suffering from intrauterine growth retardation, when compared with levels found in normal pregnancy. As soluble fibrinogen--fibrin complexes are formed following activation of the coagulation pathway in vitro and in vivo these findings may reflect the increased local intravascular coagulation within the placenta demonstrated histologically in pregnancies complicated by growth retardation. The use of more sensitive methods for detecting alterations in coagulation, fibrinolysis and platelet function may prove useful in the diagnosis of intrauterine growth retardation antenatally.


The contributions of differing degrees of acute and chronic malnutrition to the intellectual development of Jamaican boys. The purpose of this paper is to determine whether differing degrees and types of malnutrition cause differing degrees of mental impairment. Subjects were 59 Jamaican boys hospitalized for malnutrition in infancy and whose intelligence was assessed at school age. The measure used for degree of chronic malnutrition was height for age and for acute malnutrition weight for height. The measure of intelligence was the I.Q. (WISC). Because the social environment in which a child lives influences his intellectual development, a measure of social background was used as an independent variable in addition to the nutrition measures. Social background showed a significant effect on I.Q. but neither measure of nutrition was significant. A further analysis using comparisons who had not been hospitalized for malnutrition suggests that malnutrition may contribute to mental impairment, through a threshold effect rather than acting as a continuous variable where increasing degrees of malnutrition cause increasing degrees of mental impairment.


Maternal blood pressure in pregnancy and newborn irritability. The neonatal period is being recognized as an important period for the development of patterns of interaction between mother and infant, and infant state has been shown to have a significant impact on mother--infant interactions. A major dimension of infant state, with implications for this interaction and for the development of later behaviour disorders, is the infant's irritability. Research with Navajo, Malay, Chinese and Tamil mothers and infants showed that normal variation in maternal blood pressure during pregnancy was related to newborn irritability as assessed with the Brazelton Scale. This relationship is discussed in terms of possible underlying mechanisms.


Is air trapping important in the maintenance of the functional residual capacity in the hours after birth? Serial measurements of thoracic gas volume revealed no evidence of air trapping in maintenance of functional residual capacity (FRC) in healthy term babies in the first days of life. Tidal pressue/volume and flow/volume analysis demonstrated intermittent air trapping in only 2 of 19 such babies. Artificial FRC reduction by continuous positive external pressure of 7 cm H20 induced grunting in 4 babies, but otherwise had no effect on spontaneous breathing pattern or on dynamic compliance. Group mean total pulmonary resistance rose by 52.9% but only one baby demonstrated evidence of air trapping. Our findings suggest that FRC is maintained in the immediate neonatal period by some means other than air trapping.


Nuclear glucocorticoid binding in chronic lymphatic leukemia lymphocytes. A reliable procedure is described for isolating 3H-triamcinolone acetonide (3H-TA) receptor complexes from purified chronic lymphatic leukemia (CLL) lymphocyte nuclei, based on the use of carbobenzoxy-L-phenylalanine (CBZ-L-phe) to prevent breakdown of hormone-receptor complexes during extraction of nuclei with 0.6M KCl. Using this method, specific nuclear glucocorticoid binding was demonstrated in 14/14 patients with untreated CLL. No correlation was found between levels of nuclear-associated 3H-TA and peripheral white blood cell count or rosetting ability of circulating lymphocytes.


Levels of lead and other metals in human blood: suggestive relationships, determining factors. Epidemiological studies on metal levels in blood were carried out. Evidence suggested the existence of a different trend in serum-iron levels in relation to blood lead levels in nonoccupationally exposed males (negative trend) and females (positive trend). There was a positive relation between blood lead levels and blood manganese levels in children and occupationally exposed male workers. Blood metal levels increased with age in young children. There was evidence for an influence of socioeconomic class on blood lead levels in children. A direct and an indirect effect of smoking was found on blood lead levels and on the activity of delta-aminolevulinic acid dehydratase activity in erythrocytes in adult nonoccupationally exposed females.


The role of hypersensitivity and the immune response in influencing susceptibility to metal toxicity. The immune status of the individual is an additional variable which has to be taken into account in any consideration of factors which influence the metabolism and toxicity of metals. The commonly occurring phenomena are described resulting from increased cellular reactivity to platinum, mercury, gold, nickel, chromium, and beryllium, and an attempt has attempt has been made to classify these into the four types of immune response. The clinical effects can be very varied, giving rise to conjunctivitis, rhinitis, asthma, urticaria, contact dermatitis, proteinuria, nephrotic syndrome or blood dyscrasia. Of these effects, cutaneous hypersensitivity is the most common, affecting both industrial and general population groups. Metal compounds used in therapeutics and metals used in prostheses have also been responsible for hypersensitive reactions.


Interrelationships among zinc, copper, lead, and cadmium in food, feces, and organs of humans. Concentrations of zinc, copper, lead, and cadmium were determined in 20 samples of food collected over a period of 20 days, 221 samples of feces collected over a period of 5 days from 19 males, 17 females, and 11 children and 85 samples each of renal cortex and liver from autopsied human cadavers in order to investigate the relationships among the four metals and among the various martices. In food the highest correlation was observed between copper and zinc (0.34). In feces the highest correlation was also between copper and zinc (0.45). In the highest correlation between cadmium and zinc (0.33), but that in the renal cortex was between copper and cadmium (0.52). These findings suggest that the relationships among the concentrations of the four metals in food and feces are almost equal to each other, but differ greatly from the concentrations in human organs due to the differing metabolic actions of the metals once they are absorbed into the body. In addition, it was observed that zinc and cadmium concentrations in the renal cortex increase with age, but copper and lead concentrations do not show much variation with age.


Cadmium and zinc relationships.

Cadmium and zinc relationships. Cadmium and zinc concentrations in kidney and liver have been measured under different exposure situations in different species including man. The results show that zinc increases almost equimolarly with cadmium in kidney after long-term low-level exposure to cadmium, e.g., in man, horse, pig, and  lamb. In contrast, the increase of zinc follows that of cadmium to only a limited extent, e.g., in guinea pig, rabbit, rat, mouse, and chicks. In liver, the cadmium--zinc relationship seems to be reversed in such a way that zinc increases with cadmium more markedly in laboratory animals than in higher mammals. These differences between cadmium and zinc relationships in humans and large farm animals and those in commonly used laboratory animals must be considered carefully before experimental data on cadmium and zinc relationships in laboratory animals can be extrapolated to humans.


Interaction between cadmium and selenium in rat plasma. The metabolism of (75)Se-labeled SeO(3) (2-) and its conversion by intact rat erythrocytes in vitro to a form which complexes with Cd and plasma proteins were studied. By utilizing both excess SeO(3) (2-) and N-ethylmaleimide to lower erythrocyte reduced glutathione (GSH) concentrations, it was shown that the uptake and metabolism of SeO(3) (2-) were GSH-dependent, the probable intermediate being glutathione selenotrisulfide (GSSeSG). Secondary release of selenium by rat erythrocytes had no relation to the erythrocyte transport of oxidized glutathione (GSSG). While fluoride depressed and chromate increased GSSG transport, chromate, a glutathione reductase inhibitor, decreased selenium release. This release appeared to be secondary to a reaction catalyzed by glutathione reductase. The similarity of I(50) values for chromate's inhibition of glutathione reductase and for the inhibition of selenium release further suggested a relationship between these two events. H(2)Se or a similar product of GSSeSG reduction is proposed to be the active product of SeO(3) (2-) metabolism by rat erythrocytes. By use of gel-filtration and ion-exchange methods it was noted that the incubation of H(2)Se with cadmium and plasma produced a Cd-Se complex indistinguishable from that produced by incubation of Cd, SeO(3) (2-), plasma, and erythrocytes in vitro, or that noted following the administration of Cd and SeO(3)in vivo. A mechanism whereby the tissue distribution and toxicity of cadmium are altered by selenium is suggested.


Nutritional considerations in designing animal models of metal toxicity in man. In recent years, exposure of man to increasing amounts of metals has occurred rather generally from industrial contamination and variably from intake of dietary mineral supplements. Adverse effects of individual metals can be markedly altered by dietary levels of other essential and nonessential inorganic elements, essential organic nutrients and other nonessential dietary components. Experimental diets for establishing baseline responses to excess elements should be formulated to meet the animal's requirements only. These reference diets can then be modified to mimic man's average dietary intake as well as meal patterns. Improved animal models should provide better data for assessing hazards of excess metal intake by man.


Biological interaction of selenium with other trace elements in chicks. Studies were conducted to determine whether or not elements whose valence shell of electrons was similar to that of selenium would reverse the toxicity of selenium to chicks. The elements studied were arsenic, tellurium, tin, and lead. Each of these elements, when added to the diet of chicks, reversed the toxicity of 25 ppm selenium as measured by weight gain. In spite of the protection afforded by these elements, there was no decrease in liver concentration of selenium except with levels of arsenic higher than that needed for reversal of toxicity.


Interactions between selenium compounds and those of mercury or cadmium. Two types of mechanisms are considered in this discussion of the interactions between compounds of selenium and those of cadmium or mercury: one based on a direct chemical reaction between compounds of these elements and the other based on metabolic changes induced by selenium administration and modifying the dose-effect relationship indirectly, without a reaction between selenium and the metallic compound. The second type of metabolic changes induced by selenium may explain why an increased selenium intake provides protection not only against methylmercury but also against the toxicity of methylated selenium compounds. A better understanding of the underlying mechanisms would help in assessing the importance of these interactions for man.


Interaction between selenium and inorganic mercury. Data on mercury and selenium interaction in the mammalian body are reviewed. Experimental data from studies on rats show that selenium interacts with mercury metabolism and toxicity after exposure to mercuric mercury. Autopsy data from workers exposed to mercury vapor indicate an association between mercury and selenium retention in the central nervous system, suggesting the formation of a mercury-selenium complex. In animal experiments, mercuric mercury interferes with selenium metabolism and toxicity. Available data do not, at present, permit deduction as to whether additional selenium intake in man, exposed to mercury vapor or mercuric mercury, will have any effect, beneficial or adverse.


Modification of methylmercury toxicity and metabolism by selenium and vitamin E: possible mechanisms. Selenium and vitamin E exert powerful effects in reducing acute or chronic methylmercury toxicity. Levels of selenium normally found in foods (below 1 ppm) delay the onset of toxic signs caused by much higher levels of methylmercury. Tissue levels of mercury in selenium-supplemented animals equal or exceed those found in animals given methylmercury alone. Selenium does not appear to act by simply modifying intake, absorption, excretion, or distribution of methylmercury, and direct effects of both selenium and vitamin E have been observed in vitro when methylmercury was added to cultured nervous tissue cells. The only established functions for selenium and vitamin E in animals are related to the prevention of oxidative damage in tissues. To encompass the protective effects of selenium and vitamin E and to explain other toxicological aspects of methylmercury and other alkylmetals, a new hypothesis is proposed: The toxicity of the alkylmetals is not caused soley by the intact molecule, but also involves free radicals formed by homolytic fission of the carbon-metal bond.


Metabolic interactions between metals and metalloids. The experimental evidence obtained with laboratory animals which shows that the toxicities of lead, cadmium, and mercury can be increased by deficiencies of certain essential nutrients such as calcium, iron, zinc, and selenium is briefly reviewed. An idealized theoretical model which indicates the possible influence of multiple nutritional deficiencies on the toxicity of a heavy metal is presented. It is suggested that multiple marginal nutritional deficiencies may be of importance in determining the response of humans to the toxic effects of various heavy metal pollutants.


Influence of age on metal metabolism and toxicity. The metabolism and toxicity of lead, cadmium, mercury, and manganese in the postnatal period was studied in rats. Absorption, whole body retention, and organ distribution of 203Pb, 115mCd, 203Hg, and 54Mn were determined after oral and parenteral administration of these radioisotopes. The acute oral toxicity (LD50) was determined after a single application of metal chlorides. The results obtained in sucklings show a very high intestinal absorption of all metals which is partly attributed to milk diet; a higher whole body retention, higher blood levels and a much higher accumulation in the brain; and a higher oral toxicity. These results indicate age specific differences in the pharmacokinetics of metals in sucklings. It seems reasonable to consider the early neonatal age as a critical period for metal accumulation and therefore for metal toxicity. The results are interpreted on the basis of current concepts of developmental physiology and pharmacology and suggestions for future research trends are made.


Interactions among lead, cadmium, and arsenic in relation to porphyrin excretion patterns. This paper reviews the effects of lead (Pb), cadmium (Cd), and arsenic (As) on the mitrochondrion with emphasis on alteration of mitochondrial heme biosynthetic pathway. The information was used to examine results of a Pb x Cd x As  interaction study which employed urinary porphyrin excretion patterns as one assessment criterion. Data from the study showed that dietary Pb produced increased urinary excretion of aminolevulinic acid (ALA) and coproporphyrin. Dietary exposure to organic or inorganic As caused increased excretion of uroporphyrin and to a lesser extent coproporphyrin, while dietary Cd caused no significant changes in urinary levels of any of the porphyrins measured. The combination of Pb plus As produced an additive effect on coproporphyrin excretion but not that of either ALA or uroporphyrin. These data are discussed in relation to utilization of urinary porphyrins for assessing toxicity and elemental interactions.


Investigations of factors influencing exposure and response to lead, mercury, and cadmium in man and in animals. The susceptibility of the heme biosynthetic pathway to lead, as reflected by increased free erythrocyte porphyrin (FEP) concentration, is in humans as well as in rats in the order of young greater than or equal to female greater than male. The difference between adult male and female rats can be explained at least partially by the interaction of estradiol and progesterone with the FEP response to lead; the hormonal influence on FEP does not seem to be mediated through changes in plasma iron. The classical "tubular type" proteinuria in workers chronically exposed to cadmium has two not necessarily concomitant components, namely, a tubular type and a glomerular type component characterized by increased excretion of low and high molecular weight proteins, respectivley. No synergistic effect of cadmium and lead on the proteinuria of workers simultaneously exposed to both metals was observed. Mercury (most likely methylmercury) is freely transferred from the mother to the fetus; there is only a slight placental barrier for lead and a rather strong one for cadmium. Compared to maternal blood, placenta does not accumulate lead or mercury but concentrates cadmium about 10-fold.


Hemoglobin, serum iron, and zinc protoporphyrin in lead-exposed workers. In a previous study of secondary lead smelter workers (males), a significant prevalence of low hemoglobin levels (less than 14 g/100 ml) was found; a statistically significant negative correlation between hemoglobin and zinc protoporphyrin was also detected. In the present study serum iron (Fe) levels and total iron binding capacity (TIBC) were included in the investigation of 111 secondary lead smelter workers and 37 nonexposed controls. The distribution and mean values of serum iron and TIBC were found to be in the normal range in the lead exposed workers; there was no significant difference when compared to the control population. There was no significant correlation between blood lead or zinc protoporphyrin and serum iron, TIBC and Fe/TIBC. A statistically significant negative correlation between hemoglobin and blood lead levels was found; the correlation between hemoglobin and zinc protoporphyrin reached a much higher level of significance. The results support the view that anemia (low hemoglobin levels) in lead exposed male workers is related to the heme synthesis inhibiting effects of lead, as reflected by elevated zinc protoporphyrin levels, and is not due to iron deficiency.


Neurochemistry and toxicology: overview. We have witnessed a tremendous increase in our knowledge of the molecular and biochemical mechanisms which underly the activities of the nervous system. Such knowledge is essential in order to determine the basic mechanisms involved in neurotoxic events. An overview of how neurotoxins could conceivably interfere with some basic neurochemical processes is presented, along with a specific example of how an understanding of such processes can contribute to the detection of neurotoxicity and to the development of predictive testing techniques.


Neuronal cell cultures as toxicologic test systems. Neuronal cell cultures now represent well-characterized systems with which acute and chronic toxicologic effects of a variety of agents can be evaluated. Extensive synapse formation occurs over a period of days and weeks in these cell cultures and can be assayed semiquantitatively by morphological and electrophysiological means. Detailed morphophysiologic correlations can be made using a technique for injecting an intracellular marker protein, horseradish peroxidase. A variety of neurochemical indices of development, such as transmitter-related enzyme levels, can also be conveniently determined. The developing neuron and its synaptic connections are important objects of investigation since they may be particularly vulnerable to pathogenic materials. Examples of the effects of acute (opiate) and chronic (inhibitory aminoacid) treatments on synaptic function are given.


Myocardial metabolism for the toxicologist. Drug effects on myocardial contractile function are obviously of considerable practical importance for the toxicologist. The basic mechanism of such actions must reside at some point in the metabolism of cardiac muscle. Interference in the liberation of energy from the fuels that the heart uses may be implicated. It is possible that drugs may interfere with the storage (conservation) of that energy as the high energy phosphates (ATP and CP). Finally, the utilization of that stored energy by the contractile proteins themselves may be altered. The latter process is highly dependent on intracellular calcium ion kinetics. Anesthetic drugs, which produce reversible depression of myocardial contractile function is a dose-dependent fashion, have been shown to interfere to some extent with all three processes. However, the most important mechanism probably involves utilization of energy and intracellular calcium ion movement. A basic knowledge of the biochemistry of cardiac muscle is necessary for the understanding of drug action and toxicity at the subcellular level.


Effects of fluorocarbons, chlorinated solvents, and inosine on the cardiopulmonary system. The effects of fluorocarbons and chlorinated solvents on the cardiopulmonary system are reviewed. The new information, not hitherto reported, relates to the antagonistic action of inosine, a naturally occurring nucleoside formed in the body by deamination of adenosine. The effect of inosine on methylene chloride toxicity was investigated in open chest dogs anesthetized with pentobarbital sodium. Methylene chloride (5% in air or 50,000 ppm) elicited a decrease of ventricular contractility represented by the diminished left ventricular (dp/dt)(max) and myocardial contractile force measured directly with a Walton-Brodie strain gauge arch. Coronary blood flow decreased slightly after exposure to methylene chloride. Arterial blood pressure and heart rate did not change. The negative inotropic effect of methylene chloride was reversed or prevented to a substantial extent by intravenous infusion of inosine (5 mg/kg-min). The effect of the latter compound was also characterized by significant coronary vasodilation. It was shown by the experiments that the cardiostimulatory action of inosine was associated with improved hypoxic adaptability of the coronary blood vessels. In contrast, the effect of catecholamines (epinephrine and isoproterenol) was not accompanied by such a beneficial coronary vascular effect. On the basis of these results, the conclusion has been arrived at that inosine might be recommended as a useful antidote in methylene chloride poisoning in particular, and of poisoning by chlorinated solvents and fluorocarbons in general.


Cardiac toxicities of antibiotics.

Cardiac toxicities of antibiotics. Isolated heart muscle preparations are useful in the study of cardiac toxicities of drugs and environmental chemicals: such tissues allow assessment of chemical effects on heart muscle that is free from indirect in vivo influences that can mask or even accentuate cardiac responses measured in the intact animal. In the present study, left atria of guinea pigs were used to demonstrate a direct cardiac depressant effect of greater-than-therapeutic concentrations of several aminoglycoside antibiotics. The toxic effect of these antibiotics seems to be a calcium-dependent event, and may prove useful to characterize contractile responses of the heart. Other antibiotic agents can also depress cardiovascular function, as summarized in this report, but mechanisms of action have not been clearly defined.


Pathophysiology of the atherosclerotic rabbit. The pathophysiology and histopathology caused by feeding rabbits a diet containing 2% cholesterol is described. Cholesterol deposition was seen in almost all organs after 15 weeks on the diet. Lesions were seen as early as 7 weeks in the aorta and pulmonary vessels and by 11 weeks in the small intramyocardial arteries and arterioles. Evidence of myocardial ischemia could be elicited by stressing the heart by electrical pacing at rapid rates or by administration of pharmacological agents which increased oxygen consumption (isoproterenol) or decreased oxygen supply (ergonovine). Susceptibility to such stress was increased by isovolumic hemodilution which decreased the oxygen-carrying capacity of the blood. Myocardial fibrosis and infarction were evident by 15 weeks on the diet and cardiac reserve was depleted by 25 weeks as evidenced by the presence of ascites in all animals examined. The preliminary results reported here suggest that further evaluation of the atherosclerotic rabbit as a cardiac toxicity model is warranted.


In vitro preparation of infarcted myocardium. An isolated ventricular endocardial preparation removed from canine hearts one to two days after coronary artery occlusion and superfused in vitro is described. The alteration in electrophysiological characteristics of subendocardial Purkinje fibers surviving in infarcted regions and the relationship of these changes to the generation of ventricular arrhythmias is discussed. The advantages of such preparations for assessing the mechanism of action of antiarrhythmic drugs in post-infarction ventricular arrhythmias is discussed.


Symposium on Target Organ Toxicity: cardiovascular system. The epidemiologic approach. Epidemiological studies rarely provide unequivocal data on the effects of toxic substances on human health. Unlike experimental studies, pertinent variables frequently cannot be controlled and some are often unknown. Nevertheless, these limitations can be dealt with by various facets of an epidemiological investigation. These include, the choice of a study design, selection of controls or comparison populations, evaluation of available data, statistical analysis, and the drawing of appropriate inferences from the data. Among the special problems that might be encountered in studies of the effects of cardiotoxic substances are, difficulties in establishing diagnoses, errors in death certificates, observer errors in electrocardiographic interpretations, and taking into account the effects of various risk factors known to be implicated in the etiology of cardiovascular diseases. In spite of various methodological problems and certain inherent limitations of epidemiological studies, they can, when properly conducted, make significant contributions to knowledge of disease etiology and provide the means of reducing the risk of a disease, even when its etiology is not completely known.


Strategy for the assessment of neurobehavioral consequences of environmental factors. One of the critical issues confronting the evolving discipline of behavioral and neurological toxicology is the general lack of test validation in animal models. This paper seeks to provide a strategy aimed at resolving this important problem. It is proposed that test validation be accomplished by evaluating known neurotoxins in a battery of tests chosen to assess in animal models a wide range of effects on the basis of reported human toxicosis symptomatology. We propose to measure ongoing home cage motor activity, food consumption, water consumption, clay consumption (and the diurnal cycling of these), neurological/physiological indices (reflexes, autonomic signs, equilibrium/gait, balance, tremor, reactivity, and muscular strength), and aspects of cognitive and associative behavior involving both endogenous and exogenous (sensory) control of responding. An integrated, time-efficient scheme, covering 90 days of chemical treatment and 30 days of post-dosing recovery will be used. Chemical substances to be evaluated were chosen with the view of representing classes of neurotoxic effects. For initial study, triethyltin was chosen as an agent producing demyelination of nerves, acrylamide as an agent producing "dying-back" neuropathy, and methylmercury as an agent producing mixed central and peripheral neuropathies. Agents which attack specific loci in the nervous system and those producing anoxia will not be assessed in the first stages of this research due to lack of species generality of known effects, present lack of appropriate exposure facilities, or other problems. In addition, two drugs (amphetamine and sodium salicylate) will be investigated to support the generality of the testing procedures. By comparing the observed results of the neurotoxins in the animal models with the predicted effects based on reported human symptomatology, some decision concerning the validity of each procedure will be made. It is expected that the validation of tests to be used in behavioral and neurological toxicology will permit the meaningful assessment of more complex issues, such as the mechanisms by which neurotoxins act.


Epistemology of screening for behavioral toxicity. A method is described for the assay of the behavioral effects of volatile solvents on mice and illustrated with pilot results on trichlorethylene. A dose-effect curve has been determined for the effects on schedule controlled responding and compared with the dose-lethality curve and the TLV for man. The OR50 for behavioral effects was 1/5 of the LD50 and 50 times the TLV for long-term exposure of man. An analysis of the errors involved in determination of effects on whole animals leads to the conclusion that subtle effects, representing a few per cent change, will not be detectable in routine screening. It is suggested nevertheless that information on the midrange, knowable, part of the dose-effect curve may prove useful in predicting safe levels for man.


Distal axonopathy: one common type of neurotoxic lesion. Neurotoxic chemicals commonly produce retrograde degeneration of the axons of long and large nerve fibers in the central and peripheral nervous system. This produces a clinical picture of polyneuropathy in man and animals in which sensory and motor disturbances develop in the feet and hands then progress with time to the legs and arms. Distal axonopathy, as the underlying pathologic process is termed, is one of four principal types of neurotoxic diseases, the others including degeneration of neurons (neuronopathy), myelin sheaths (myelinopathy) and damage to the neurovasculature (neurovasculopathy). In the experimental animal, these four types of neurotoxic diseases can be distinguished by examining selected areas of brain and nerve tissues prepared by contemporary methods of tissue fixation. These procedures may form the basis of a new and sensitive assay for neurotoxicity.


Activation of bee venom phospholipase A2 by oleoyl imidazolide. Imidazolide derivatives of long-chain fatty acids are shown to be potent irreversible activators of bee venom phospholipase A2. Activation corresponds to the addition of a single acyl residue to the protein molecule. The rate of activation increases with the acyl chain length of the activator, but the highest activation factors are given by the oleoyl and linoleoyl residues. Acyl group activation of the enzyme substitutes completely for activation by free fatty acids (but produces 3--4-fold higher activities) indicating that fatty acids are allosteric activators of the enzyme. The degree of activation is calcium dependent and exceeds 100-fold at low calcium concentration. Activation is extremely sensitive to substrate structure, but modification of the substrate surface by intercalated activator does not form the basis of this specificity.


Estrogen-binding sites of chicken liver. Preliminary characterization of nuclear components. 1. Liver nuclei from estrogenized chickens contain high-affinity low-capacity estrogen-binding sites, which are in part salt-extractable (60--70%) and in part tightly sticking to the nuclear residue (30--40%). During the preparation of chromatin with low salt buffers part of the salt-extractable nuclear-binding sites remains together with the non-extractable sites on the chromatin. Extractable and non-extractable sites can be separated by agarose as well as hydroxyapatite chromatography. 2. The extrogen-binding protein extracted from crude nuclei was characterized as follows: sedimentation coefficient of 3.9 S, Strokes' radius (a) of 3.3 nm, molecular weight (Mr) of 56,000 and frictional ratio (f/fo) of 1.20. Trypsination results in a globular receptor fragment (Mr = 41,000), which has lost a small asymmetric portion of the receptor molecule but still binds estradiol. 3. In contrast to the binding protein from crude nuclei the estrogen-binding protein extracted from purified nuclei at pH 7.4 is found mainly in an aggregated form. Dissociation of the aggregates is achieved in high salt/urea resulting in a receptor molecule with an apparent molecular weight of 130,000. Aggregation of the binding sites can be prevented to some extent by raising the pH of the extraction medium. At pH 8.7 the non-aggregated part of the binding protein from pure nuclei could be characterized as follows: 4.4 S, a = 4.3nm, Mr = 80,000 (apparent molecular weight of 150,000), f/fo = 1.40. 4. Mixing experiments indicate that an extranuclear protease present in a crude nuclear preparation converts the large receptor (the binding protein from pure nuclei) to the smaller one (the binding protein from crude nuclei) by digesting off an asymmetric portion of the molecule. This portion seems to be responsible for the strong tendency of the binding protein from pure nuclei to associate with other nuclear components.


Quantification and properties of tubulin polymerization in crude brain extracts and preparations of microtubular and purified tubulin. Removal of assembled tubulin by centrifugation, followed by measurement in the supernatant of the residual colchicine binding capacity of the non-polymerized, non-precipitable tubulin, is a sensitive and reliable method of measuring tubulin polymerization. This method can be used in both crude and purified preparations of brain tubulin and allows the molar quantification of the total, polymerized and non-polymerized tubulin species in each sample. Only 40--50% of the total tubulin present in crude adult brain extracts is capable of polymerizing when incubated with GTP. The percentage of tubulin polymerizing with GTP is slightly higher in crude foetal brain extracts than in the adult. Incubation of first polymerization supernatants, containing exclusively the GTP-insensitive tubulin, with guanosine 5'-[alpha, beta-methylene]triphosphate (GuoP[CH2]PP) but not with 2.4 M glycerol results in tubulin polymerization. High concentrations of glycerol (2.4 M) promote the polymerization of tubulin in adult but not in crude foetal brain extracts. Both ATP and adenosine 5'-[alpha, beta-methylene]triphosphate (AdoP[CH2]PP) are effective in promoting the polymerization of GDP-free (90%) microtubular protein. The microtubular protein assembled with GuoP[CH2]PP or AdoP[CH2]PP has the unique character of being resistant to calcium concentrations (2mM), which cause complete depolymerization of the tubulin assembled with GTP or ATP. Phosphocellulose-purified tubulin significantly assembles when incubated with GuoP[CH2]PP or AdoP[CH2]PP at protein concentrations at which GTP or ATP do not promote polymerization. 2 micrometer tubulin is the minimal concentration required for polymerization in both crude and purified preparations of adult rat brain tubulin.


Characterisation of mycobacteriophage ATCC 11759. Unusual physiocochemical properties of its DNA. Growth conditions and a purification procedure for mycobacteriophage ATCC 11759, a lytic phage for Mycobacterium smegmatis, are described. The phage is a large DNA phage with a very long tail (240 nm). A study of its DNA revealed three interesting features. 1. After denaturation the DNA molecule yields two strands of different buoyant densities. 2. The native DNA has unusual physical properties: its buoyant density in CsC1 is very low (1.654 g/cm3), its sedimentation rate is lower than expected for the molecular weight, its thermal stability at low ionic strength is high. 3. The DNA (in its native form or after reannealing) is resistant to various restriction endonucleases.


The localization of an intracellular membrane-bound proteinase from rat liver. To localize the membrane-bound, histone-degrading proteinase, which was previously isolated from the mitochondrial fraction, nuclei, mitochondria, lysosomes, peroxisomes, smooth and rough endoplasmic reticulum, ribosomes and plasma membranes were prepared from a rat liver homogenate according to established methods and characterized by marker enzyme activities. The isolated subcellular fractions were treated with digitonin, and subjected to a discontinuous sucrose gradient centrifugation. The material, which sedimented through 1.74 M surcrose was analyzed in respect to the various marker enzymes and for proteolytic activity. Proteinase activity was found in the material obtained after digitonin treatment and step gradient centrifugation of mitochondria. This finding shows the occurrence of a proteinase in mitochondria; After fractionation of mitochondria into outer and inner membrane, intermembrane fraction and matrix, the proteinase could be localized exclusively in the inner mitochondrial membrane. A possible physiological function of the enzyme during the biosynthesis of inner membrane constituents is discussed.


DNA-dependent RNA polymerase from Halobacterium halobium. DNA-dependent RNA polymerase core enzyme was isolated from Halobacterium halobium. The purification is based on the finding that the enzyme is stable in 40% (v/v) glycerol, in the presence of 0.05 M MgCl2 and involves adsorption of contaminants to DEAE-cellulose, precipitation of the complex of polymerase with DNA by streptomycin sulfate, chromatography over Biogel and affinity chromatography over heparin-Sepharose or heparin-cellulose. The enzyme consists of four or five different subunits. The composition formula was estimated as (150000) (86000)2 (72000)2 (49000)3 or 2; there may be one or two different 49000-Mr subunits. RNA synthesis requires a template. Denatured DNA is more efficient than native DNA. The transcription of native DNA is specifically stimulated by the addition of a possibly sigma-like factor eluted from DEAE-cellulose. The fidelity of transcription is indicated by the absolute requirement for UTP besides ATP with poly[d(A-T)] as the template.


Characterisation of a local structure in the synthetic parathyroid hormone fragment 1--34 by 1H nuclear-magnetic-resonance techniques. Previous studies had shown that the molecular conformation of the synthetic human parathyroid hormone fragment 1--34 in dilute aqueous solution contained a local non-random structure formed by the four consecutive residues--Val-21--GIn-22--Trp-23--Leu-24--. This paper gives a detailed description of this local spatial structure obtained from high resolution 1H NMR studies at 360 MHZ of several peptide analogs of the partial sequence 20--24. The most important spectral parameters were high-field shifts of the alpha and gamma protons of Val-21, the spin-spin coupling constants related to the rotamer populations of the side-chains of Val-21 and Trp-23, and pH titration shifts of the amide proton resonances. It was found that the backbone fragment 20--24 is so arranged that the side-chain of Val-21 is located next to the indole ring plane of Trp-23; evidence is presented that this non-random structure is mainly stabilized by hydrophobic interactions between the side-chains of Val-21 and Trp-23. The thermal population of the observed molecular structure at room temperature was estimated from the nuclear magnetic resonance data to be approximately 20%.


1H nuclear-magnetic-resonance studies of the molecular conformation of monomeric glucagon in aqueous solution. Dilute aqueous solutions of glucagon were investigated by high-resolution 1H nuclear magnetic resonance at 360 MHZ. Monomeric glucagon was found to adopt predominantly an extended flexible conformation which contains, however, a local non-random spatial structure involving the fragment--Phe-22--Val-23--Gln-24--Trp-25--. This local conformation is preserved in the partial sequence 22--26 and could thus be characterized in detail. Two interesting conclusions resulted from these experiments. One is that the local spatial structure in the fragment 22--25 of glucagon is identical to that observed in the fragment 20--23 of the human parathyroid hormone. Secondly, the backbone conformation in the C-terminal fragment of glucagon in solution must be different from the alpha-helical structure observed in single crystals of glucagon. These new structural data are analyzed with regard to relationships with glucagon binding to the target cells.


The interaction of caerulein with the rat pancreas. 1. Specific binding of [3H]caerulein on plasma membranes and evidence for negative cooperativity. 1. The binding of [3H]caerulein (a stable, biologically active labeled analog of cholecystokinin-pancreozymin) to semi-purified rat pancreatic plasma membranes was investigated. The binding was dependent on time and temperature, as well as saturable, specific and reversible. This process was pH-dependent and optimal at pH 7.0. Cysteine and serine residues in plasma membranes were of importance for binding. Mg2+ favored the binding. 2. The acceleration of the dissociation of [3H]caerulein in the presence of an excess of native caerulein suggests that binding was characterized by a negative cooperativity. The fast dissociation state evoked by a high degree of occupancy by caerulein was inhibited by lowering the temperature, by decreasing the pH, or by the presence of wheat germ agglutinin.


Isolation of organic anions by extraction with liquid anion exchangers and its application to micromethods for acetylcholinesterase and 4-aminobutyrate aminotransferase. Organic anions of particular importance to biochemistry such as Krebs cycle intermediates, glycolysis intermediates, simple fatty acids, adenine nucleotides and CoA derivatives can be quantitatively extracted from a buffered solution by high-molecular-weight ammonium salts in an organic solvent. Phosphate salts of tertiary amines in chloroform were the most efficient extractants. The isolation procedure was found to be an example of amine neutralization. The effect of pH, different inorganic anions, volume ratios between the two phases, concentration of the isolated anions and concentration of the ammonium salts have been investigated. The extraction technique has been applied to rapid and sensitive radiochemical methods for the determination of acetylcholinesterase and 4-aminobutyrate aminotransferase activities.


Microtubule formation by pure brain tubulin in vitro. The influence of dextran and poly(ethylene glycol). Homogeneous brain tubulin, free of microtubule associated proteins, forms microtubules in polymerization buffers containing 7.5--15% dextran T10 or 2--4.5% poly(ethylene glycol) type 6000. In both systems the resulting microtubules are sensitive to colchicine and low temperature. The critical tubulin concentration in both polymerization systems can be as low as 0.25 mg/ml.


Purification and properties of a protease from Lupinus angustifolius during germination. A protease, present in Lupinus angustifolius cotyledons on the fifth day after germination and assayable by following the release of amino groups from gliadin has been purified to the degree that the associated protein of the extract is undetectable. The enzyme is capable, under varying conditions, of releasing amino groups from lupin alpha, beta and gamma conglutins and possesses a mean molecular weight, by dodecylsulphate/polyacrylamide gel electrophoresis and Sephadex G-75 gel filtration of 27500 +/- 450. The isoelectric point is 9.0 +/- 0.848 with a pH optimum of pH 4.0 using gliadin as substrate.


Alfalfa mosaic virus RNA. Determination of the sequence homology between the four RNA species and a comparison with the four RNA species of cucumber mosaic virus. The method of Taylor et al. [Taylor, J. M., Illmensee, R & Summers, J. (1976) Biochim. Biophys. Acta, 442, 324--330 and Gould and Symons (1977) Nucleic Acids Res. 4, 3787--3802] has been used to transcribe complementary DNA probes from the four major RNAs of alfalfa mosaic virus (AMV). Analysis of the kinetics of hybridization of these probes in homologous and heterologous complementary DNA . RNA hybridization reactions has shown that the sequence of the smallest RNA (RNA 4), which contains the coat protein gene, is present within RNA 3 and located at the 3' end of this RNA species. RNAs 1 and 2 are unique RNA molecules with little or no sequence homology between them or RNAs 3 and 4. This latter observation contrasts with the situation that occurs in cucumber mosaic virus (CMV) as CMV RNAs 1--4 were shown to have a common nucleotide stretch of 200 bases at their 3' termini; the location of RNA 4 within RNA 3 of CMV was also shown to be at the 3' end of this RNA species.


Non-histone proteins in mononucleosomes and subnucleosomes. Nucleosomes and subnucleosomes separated either by sucrose gradient ultracentrifugation or by polyacrylamide gel electrophoresis contain proteins incorporating [3H]tryptophan, i.e. non-histone proteins. The fractions of mononucleosomes MN3 and MN2 are enriched in these proteins as compared to the MN1 fraction. Two-dimensional gel electrophoresis of chromatin digests reveals a number of non-histone proteins comigrating with deoxyribonucleoprotein particles in the first direction (in non-dissociating conditions). A significant fraction of these proteins corresponds to basic non-histone proteins, so-called HMG (high-mobility-group) proteins. Two HMG proteins are present in mononucleosomes MN3 exclusively and three others in mononucleosomes MN3 and MN2. One of them is recovered also in subnucleosomes SN2, and another in SN3 subnucleosome fraction, At least three HMG proteins are rapidly released from the oligonucleosome fractions as well as from the insoluble DNA . protein residue. Thus, they are located in chromatin readily available to DNAase action. Apart from HMG proteins, a number of other non-histone proteins are present in mononucleosomes but their relative content in the oligonucleosome fraction is much higher. The conclusion has been drawn that many non-histone proteins, in particular HMG proteins, interact with linker DNA in chromatin.


The interaction of caerulein with the rat pancreas. 2. Specific binding of [3H]caerulein on dispersed acinar cells. 1. [3H]Caerulein was bound to dispersed acinar cells from rat pancreas in a rapid, reversible, specific, saturable, and temperature-dependent manner. Binding decreased above pH 6.5. Treatment of intact cells with 2, 4-dinitrophenol and oligomycin, p-choloromercuribenzoate, diisopropylfluoro-phosphate and glutaraldehyde impaired [3H]caerulein binding whereas the addition of EGTA inhibited binding. The C-terminal octapeptide of pancreozymin, desulfated caerulein and pentagastrin inhibited binding of [3H]caerulein whereas vasoactive intestinal polypeptide, secretin, bombesin or carbamoylcholine were wothout effect. The good resistance of [3H]caerulein to inactivation by acinar cells at 37 degrees C was reflected in the high proportion of tracer remaining capable of binding to fresh acinar cells. 2. Scatchard plots of [3H]caerulein binding were curvilinear with an upward concavity. The addition of an excess of unlabeled caerulein resulted in the release of as much as 65% of bound [3H]caerulein within 1 min at 37 degrees C. The dissociation of remainder followed much slower kinetics. 3. The results suggested that intact rat pancreatic acinar cells have one class of caerulein binding sites existing in two states: one with high affinity and another with low affinity, the proportion of sites in each state depending on the degree of site occupancy (negative cooperativity), and on the intracellular concentration of nucleotides.


The interaction of caerulein with the rat pancreas. 3. Structural requirements for in vitro binding of caerulein-like peptides and its relationship to increased calcium outflux, adenylate cyclase activation, and secretion. 1. A comparison has been made of the ability of caerulein and caerulein analogs to compete with [3H]caerulein for binding to dispersed rat pancreatic acinar cells and to semi-purified rat pancreatic plasma membranes. A parallel study of the effect of such analogs on calcium outflux from isolated acinar cells, adenylate cyclase activity in pancreatic plasma membranes, and amylase secretion from pancreatic fragments was conducted. 2. In general, the biological potencies of caerulein analogs were proportional to their capacity to inhibit the binding of [3H]caerulein, which was interpreted as a reflection of the apparent affinity with which the various peptides interacted with hormone receptors. This comparison allows the conclusion that the C-terminal tetrapeptide of caerulein was sufficient for binding and for evoking the entire spectrum of biological activities. However, the presence of a tyrosyl sulfate residue in position 7 (from the C-terminal end) increased the affinity for the peptide substantially, and was also necessary for full efficiency for adenylate cyclase activation. 3. Dose-effect curves and previous data are compatible with the existence in pancreatic plasma membranes of spare receptors and of two-state receptors linked to two effector systems: a calcium ionophore and adenylate cyclase.


Biliprotein assemble in the disc-shaped phycobilisomes of Rhodella violacea. On the molecular composition of energy-transfering complexes (tripartite units) forming the periphery of the phycobilisome. Heterogeneous complexes with a molecular weight of about 790000 containing B-phycoerythrin (Bangiales phycoerythrin) and C-phycocyanin (Cyanophyceae phycocyanin) in a molar pigment ratio of 2:1 were isolated from purified, dissociated phycobilisomes. Electron microscopical investigations revealed structures of three discs aggregated face to face with an apparent distance of 1.5 nm between each disc. Two discs may represent phycoerythrin and one phycocyanin. The complexes are structurally identical with tripartite units of the phycobilisome periphery. Fluorescence data confirmed the integrity of isolated tripartite units. Excitation at 546 nm gives a fluorescence maximum at 644 nm, indicating intermolecular transfer of excitation energy from phycoerythrin to phycocyanin. Comparative subunit analyses and spectral data suggested that no allophycocyanin is present. Cross-linking experiments gave evidence for a polar arrangement of phycocyanin within the complex. This pigment itself is an aggregate of two smaller molecules each having a molecular weight of about 140000. Tripartite units contain all the phycoerythrin and phycocyanin of the phycobilisome. On this basis, a phycobilisome model is proposed which combines the aspects of biliprotein distribution, energy transfer and fine structure.


Clinical usefulness of computer controlled presentation in isocount levels of gamma camera liver scans. Results of investigations comparing computer displays in isocount levels with ordinary gamma camera scans are presented. The study on 109 patients with 12 month follow up shows that isocount level 25 is the best to see a smoothed out image of liver and is superior to conventional polaroid gamma camera scan in picking out more focal lesions (P less than 0.05).


A semiempirical model used to obtain values for scintiphoto contrast caused by spherical lesions arbitrarily located within the liver. This paper reports a simple model for calculation of maximal scintiphoto contrast caused by a spherical cold or hot lesion located in an arbitrary position inside an organ with uniformly distributed radioactivity. By applying this model, equidetection curves were constructed for cross sections through the liver. Comparison of equidetection curves obtained for different camera views enabled determination of the view to be selected for the best visualization of  a given lesion. The minimum size of a cold lesion that can be detected without regard to the location in the liver in 3.0 cm diameter using anterior, right oblique anterior, right lateral, and posterior views. 99mTc is found to be a more suitable radionuclide for liver scintigraphy than 113mIn.


A quantitative approach to the analysis of the normal thallium-201 myocardial image. The visual interpretation of Thallium-201 myocardial images is made more difficult by nonhomogeneity of myocardial tracer uptake in normal studies. To increase the objectivity of the study, the variation in count density in different myocardial areas has been calculated using a computer regions of interest technique in 14 healthy, young subjects following intravenous injection of the radionuclide at rest and in 10 after injection during maximal exercise. The "normal ranges" for regional Thallium-201 uptake so obtained are presented and discussed.


The interpretation of phlebograms using fibrinogen labeled with 99 mTc. A new method for the detection of deep-vein thrombosis is presented, consisting of a single antecubital injection of fibrinogen labeled with 99mTc. This atraumatic procedure allows one to visualize the large veins of the lower limbs, the venae iliacae and the distal part of the vena cava inferior. This paper discusses how to interpret these phlebograms.


Scintigraphy of hyperfunctioning adrenal tissue after total adrenalectomy. The significance of scintigraphic examination in four patients with hyperfunction of adrenal tissue after total adrenalectomy is described. The scintigraphic examination was done 7--8 days after the injection of 1 mCi of 131I-19-iodocholesterol using the Jumbo Thoshiba 202 scintillation camera and Informatek SIMIS 3 data processing system. Noticeable concentration of 131I-19-iodocholesterol occurred in all four patients of, in three cases in the region of the right adrenal gland and in one case in the region of the left one. Scintigraphic examination confirmed the clinical hypothesis that of cushing's syndrome recurred in these patients because of hyperfunctioning adrenal tissue left in the body after the operation. This diagnosis was given confirmed in two cases undergoing repeated operations. The scintigraphic examination allowed accurate localization of the adrenal tissue and facilitated finding it during the next operation. The authors believe that adrenal scintigraphy is at the present time one of the best methods of locating the hyperfunctioning adrenal tissue left in the body during total adrenalectomy.


Lung uptake to technetium-99m microaggregated human albumin in the rat after treatment with microaggregated human albumin or macroaggregated human albumin. Marked accumulation in lung and liver of intravenously--injected 99mTc-microaggregated human serum albumin (liver imaging agent) was observed in rats pretreated with the subcutaneous injection of microaggregated or macroaggregated human serum albumin, whereas accumulation of 99mTc-microaggregated human serum albumin was observed only in the liver of rats pretreated with plain human serum albumin or in non-treated control rats. The activity of the intravenously-administered 99mTc-sulfur colloid was concentrated in the liver and spleen only and not in the lung, of rats previously treated with human serum albumin, microaggregated human serum albumin, or macroaggregated human serum albumin. These observations suggest that the specific accumulation of microaggregated human serum albumin in the lung of rats pretreated  with aggregated albumin is due to rapid in vivo clumping of injected particles, possibly due to antigen-antibody reaction.


Kinetics of 131 I-o-iodohippurate in rats. The organ distribution of 131I-o-iodohippurate (OIH) was studied in rats in the time interval of 1--1440 min. The mean decrease of OIH  in plasma was fitted with a function composed of three exponential terms. A three-compartment model describing kinetics of OIH in rats was suggested and its parameters were computed. Comparison of organ and plasma concentrations of OIH showed that the liver, up to 30 min, and the heart and lungs, up to 15 min after administration, form with plasma a common central compartment.


Atopy as a minimal immunodeficiency?

Atopy as a minimal immunodeficiency? Despite impressive recent advances in the understanding of the chemical and cellular bases of the reaginic response, the pathogenesis of atopic diseases still remains a matter of speculation. The frequent finding of atopic diseases in some primary immunodeficiencies such as selective IgA deficiency and the Wiskott-Aldrich syndrome offers a unique opportunity for studying the immune mechanisms underlying the genesis of atopy. Recent studies in subjects with selective IgA deficiency have challenged the well known hypothesis that atopy is the result of defective "immune exclusion" by the secretory immune system. A number of immunological features found in the primary immunodeficiencies associated with atopic disorders suggest that defective homeostatic mechanisms regulating reaginic responses may play a major role in the pathogenesis of atopy. A thorough analysis of these disease combinations may help to generate new working hypotheses concerning the immune pathogenesis of atopic diseases.


3-methylglutaconic aciduria: report on a sibship with infantile progressive encephalopathy. Choreoathetosis, spastic parapareses, dementia and optic atrophy were the main clinical features in a sibship with progressive encephalopathy of late onset. The urine contained constantly elevated amounts of 3-methylglutaric and 3-methylglutaconic acids. The identity of these metabolites was confirmed by synthesis and mass spectrometry. On leucine loading, the excretion of the metabolites was elevated.


Analysis of left and right ventricular size and shape, as determined from human casts. Description of the method and its validation. A method is described to produce life-like left and right ventricular casts of 22 human hearts and to store their surface coordinates on magnetic tape for the analysis of ventricular shape and of angiocardiographic volume determination methods. According to their shape, experienced cardiologists divided these casts into diastolic, systolic and intermediate subgroups. On the basis of X-ray silhouettes and computer-simulated projections, single-plane as well as biplane model volumes were calculated with the multiple-slices and the area--length methods for various ventricular orientations. The mean correction factors (CF), relating actual and model volumes vary considerably with respect to cardiac phase and orientation. The systolic CFs are smaller than the diastolic ones, their averaged ratio being 0.74 for the left and 0.86 for the right ventricular casts. In general, the reported CFs are smaller than those published by other authors, which is attributed to different cast-production procedures. The described method uses selective, equql, and simultaneous filling of both ventricles, which prevents an unphysiologic shift of the interventricular septum.


Angiocardiographic left ventricular volume determination. Accuracy, as determined from human casts, and clinical application. On the basis of 21 life-like human casts (the method is described in the first paper of this series) the influence of (a) spatial orientation, (b) cardiac phase, and (c) biplane and single-plane methods of volume calculation on the accuracy of left ventricular (LV) angiocardiographic volume determination was quantitated. The best results are obtained, when a biplane approach is utilized and when position and cardiac phase appropriate correction factors (CF) are applied to the model volumes (area--length (AL) and multiple-slices (MS) methods). Thus the statistical error is decreased and a more important larger systematic error avoided. The AL and the MS methods perform equally well; on the average, however, the AL method is slightly favored. The application of this concept of differentiated CFs to 83 normal left ventricles of infants and children resulted in nonlinear relationships between LV volumes and their respective body surface areas (BSA) (EDV = 65.1 . BSA1.219, r = 0.961, SV = 46.7 . BSA1.219, r = 0.949). The ejection fraction (71.8%) does not correlate with the BSA (r = -0.036).


Angiocardiographic right ventricular volume determination. Accuracy, as determined from human casts, and clinical application. On the basis of 22 life-like human casts (the method is described in the first paper of this series) the influence of (a) spatial orientation, (b) cardiac-phase and (c) biplane (BP) and single-plane (SP) methods of volume calculation on the accuracy of right ventricular (RV) angiocardiographic volume determination was quantitated. The best results are obtained, when a BP approach is utilized and when position and cardiac-phase appropriate correction factors (CF) are applied to the model volumes (multiple-slices (MS) and area--length (AL) methods). Thus the statistical error is decreased and a more important larger systematic error (especially for SP) avoided. The MS and AL methods perform equally well; on the average, however, the MS method is slightly favored. The application of this concept of differentiated CFs to 100 normal right ventricles of infants and children  resulted in nonlinear relationships between RV volumes and their respective body surface areas (BSA) (EDV = 73.1 . BSA1.219, r = 0.961,SV = 46.2 . BSA1.219, r = 0.937). The ejection fraction (63.3%) does not correlate with the BSA (r = -0.292). The right ventricle accomplishes the same SV (with respect to BSA) as the left ventricle from a higher enddiastolic and endsystolic level.


Special problems in pulmonary atresia with ventricular septal defect: extreme hypoplasia of intrapericardial pulmonary arteries and autofocal collateral vessels. 4 patients with pulmonary atresia and ventricular septal defect are presented, who were selected from a group of 50 patients in whom intrapericardial pulmonary arteries were present. In 2 patients the pulmonary arteries were not only extremely hypoplastic but also displayed only minimal anastomoses with the arterial hilar vessels. They were considered not to be accessible for corrective surgery. In another patient about 50% of the pulmonary perfusion were supplied by collateral vessels not connected to the intrapericardial pulmonary arteries. The question is discussed, to what extent the systemic vessels are necessary for pulmonary perfusion and whether they may be all ligated at the time of corrective surgery. In the last patient anastomoses between 2 systemic vessels and the pulmonary arteries could be demonstrated, the right one of which was very hypoplastic. In this case a right-sided shunt operation combined with ligation of the collateral vessels seemed to be advisable to promote adaption of the pulmonary artery and to simplify the subsequent corrective procedure.


Myoglobin, creatine kinase and its isoenzyme MB in serum after acute myocardial infarction. Serum creatine kinase, creatine kinase MB and myoglobin were determined in patients suffering from acute myocardial infarction (AMI) with shorter duration of symptoms than 6 h. At admission 83% had increased concentrations of myoglobin while 28% had creatine-kinase value above the reference limit. After onset of symptoms peak levels were found after 9.4 h (myoglobin) and 23.0 h (creatine kinase). Maximal levels of myoglobin and creatine kinase divided by upper reference limits correlated and were approximately of the same sensitivity. Compared to myoglobin, there was no difference in behavior between creatine kinase and its isoenzyme. In conclusion the study demonstrates myoglobin to be an early and sensitive indication of AMI.


Aortic levopositions without ventricular inversion. A multi-center series of aortic levoposition (aorta anterior and to the left of the pulmonary artery) without ventricular inversion is presented and analyzed from an anatomical viewpoint. All the cases are exceptions to the 'loop rule' and amount to 0.9% of the total number or cases reviewed. A combined study of our own cases and those reported in the literature is presented. There is a high incidence of anomalies (malrotations, juxtaposition of the atrial appendages, atrioventricular valve anomalies, ventricular septal defects, pulmonary outflow tract obstructions and abnormal conal types) which may be related to the primary cause of the aortic levoposition, suggesting that they may form part of a new syndrome of diagnostic and surgical importance. In some cases, absence of coronary sinus was noted without asplenia or left superior vena cava draining into the left atrium. The major coronary artery pattern in cases of antomically corrected malposition with two well-developed ventricles was similar to that seen with ventricular inversion. Most of these cases can be helped surgically provided accurate and detailed preoperative evaluation and operative assessment and treatment is carried out.


Notes on ventricular tachycardia occurring during magnet waving and on the function of the Omni-Ectocor pacemaker. Magnet waving was performed in a patient with a normally functioning, program-mable, QRS-inhibited (VVI) pacemaker (Omni-Stanicor, Cordis Corporation), which was implanted for sick sinus syndrome. This procedure resulted in reversion to an asynchronous, nonsensing (irregular VOO) mode of operation with uneven stimulus-to-stimulus intervals. A short run of ventricular tachycardia occurred when a stimulus fell on the T wave of the preceding ectopic ventricular beat. This tachycardia was short-lived and was probably terminated by a single pacemaker stimulus. It is also suggested that magnet waving and external chest wall stimulation in patients with Omni-Ectocor and Starr--Edwards pacemakers require further study and that electrocardiograms recorded from patients in whom they have been implanted have to be analyzed taking into consideration that these pacemakers have features common to both, QRS-triggered (VVT), and QRS-inhibited (VVI) pacemakers.


Pure left anterior hemiblock: hemodynamic and arteriographic aspects in patients with coronary artery disease. The electrocardiographic pattern of pure (without bundle branch block) left anterior hemiblock was found in 20 (7.3%) out of 283 consecutive patients who showed significant coronary artery disease at coronary angiography. The clinical, hemodynamic and angiographic findings of these 20 patients are reported. 10 patients (50%) had the electrocardiographic features of old infarction. Pure left anterior hemiblock was associated with; (1) a significant lesion of the left anterior descending in all patients, (2) severe coronary artery disease (it affected 2.5 vessels per patient), (3) impairment of left ventricular contraction pattern in 14 patients (77%), 9 of whom had a ventricular aneurysm. Abnormal left axis deviation although with the features of left anterior hemiblock may be due to the conduction delay encountered by the impulse propagation through an ischemic or fibrotic anterosuperior wall.


Modern concepts of ventricular tachycardia. The value of electrocardiological investigations and delayed potentials in ventricular tachycardia of ischemic and nonischemic etiology (31 operated cases). Concepts on ventricular tachycardia (VT) have markedly changed in the last 10 yr, with the help of sophisticated electrophysiological methods of study. The importance of the reentry phenomenon in the mechanism of the arrhythmias has been pointed out by stimulation procedures. Epicardial mapping allowed the localization of the abnormal zone where delayed impulses could allow reentry. Surgical techniques have been developed from these observations, to prevent reentrant VT in some refractory cases.


Digoxin, whole body potassium and the electrocardiogram. Previous studies have shown a significant linear relationship between the PTQ-index (a combination function of the PR-interval, corrected QT-time and T-wave depression in the ECG) and serum digoxin level in chronically treated patients. The relationship was confirmed in the present study and it was shown that it could be changed by concomitant administration of potassium chloride or furosemide, and that there was marked interindividual variation in response. An inverse linear relationship between PTQ-index and whole body potassium was found during chronic administration of a constant daily dose of digoxin, but no such relationship was found for serum potassium.


A study of the calcium carbimide-ethanol interaction in man. In six male alcoholic volunteers, oral administration of calcium carbimide (0.7 mg/kg) before ingestion of ethanol (0.5 g/kg) produced an interaction consisting of increased blood acetaldehyde level, tachycardia and increased pulse pressure, which was due mainly to decreased diastolic blood pressure. For these experimental conditions, calcium carbimide had a duration of action of at least 24 h to produce an interaction with ethanol. The order of intensity of the interaction with regard to the calcium carbimide pretreatment time interval was 4 greater than 8 approximately 12 greater than 24 h. Using the criterion of heart rate above 100 as indicative of the calcium carbimide-ethanol interaction, the onset was 0.13, 0.25, 0.25 and 0.38 h for the 4-, 8-, 12- and 24-h pretreatment experiments and the duration of the interaction was 1.6, 1.0, 1.0 and 0.12 h, respectively. There were positive linear correlations between acetaldehyde level and heart rate and between acetaldehyde level and pulse pressure. There was appreciable interindividual variability in the heart rate and blood pressure responses. Increased blood acetaldehyde level seemed to be required for the physiological changes to occur. Calcium carbimide pretreatment at the 4-h interval produced increased blood ethanol level for the last hour of the interaction and reduced the rate of ethanol metabolism.


Pharmacokinetics of high-dose methotrexate treatment in children. The pharmacokinetics of intravenous high-dose methotrexate were studied in two groups of children being treated for malignant diseases, mostly acute lymphatic leukemia. The peak serum level of methotrexate of 2.32--10(-5) mol/1 was found in children given 500 mg methotrexate/m2 by a 24 h infusion, and another group given 2790 mg/m2 during a 6 h infusion had serum levels as high as 2.16--10(-4) mol/1. The decay of serum concentration of methotrexate after completion of the infusion followed a diphasic curve, with an initial serum half-life of 4.8 h, followed by a second half-life of 34.4 h at distribution equilibrium. The apparent volume of distribution was 56.8 litres/m2. Significant levels of methotrexate were found in cerebrospinal fluid, but penetration into cerebrospinal fluid was slow. Urinary excretion of methotrexate was considerable. Four to five days after commencement of the infusion, urinary concentrations of methotrexate still exceeded the serum levels.


Antipyrine disposition and liver size in the elderly. This study has examined the contribution of decrease in liver size to the decline in drug metabolising capacity which occurs with ageing. Liver volume and antipyrine kinetics were measured in two groups of healthy individuals aged 20 to 29 years and 75 to 86 years and in a group of hospitalised patients aged 70 to 89 years. Liver volume was reduced in both groups of elderly people compared to the young group. Antipyrine plasma half-life was prolonged and antipyrine clearance was reduced in the group of elderly normal individuals. In this group the index--antipyrine clearance per unit liver volume--was also reduced in comparison to that of the young group. Measurements of antipyrine elimination in the hospitalised elderly group did not differ significantly from those in the young group. It is concluded that both decreased liver mass and decreased hepatic enzyme activity contribute to the impairment of drug oxidation which occurs in the elderly and which may warrant a reduction in dosage of some drugs. However, differences have been demonstrated between groups of elderly people suggesting that under certain circumstances standard doses of such drugs may be normally tolerated.


Effects of propranolol and oxprenolol on the vasoconstrictor response to noradrenaline in the superficial hand vein in man. The effects of oxprenolol and propranolol on the venoconstrictor response to noradrenaline were studied in healthy volunteers by measuring superficial dorsal hand vein diameter at a standard congesting pressure. In 8 subjects dose response curves to noradrenaline (20-1280 ng/ml) were obtained with noradrenaline alone, with noradrenaline plus propranolol 10 microgram/ml, with noradrenaline plus propranolol 10 microgram/ml plus oxprenolol 3 microgram/ml and with noradrenaline plus propranolol 13 microgram/ml according to a double blind balanced randomised design. Propranolol 10 microgram/ml significantly (p less than 0.05) potentiated the vasoconstrictor response to noradrenaline and the addition of oxprenolol significantly (P less than 0.05) reversed the potentiation giving a response similar to that seen with noradrenaline alone. The higher concentration of propranolol did not produce further potentiation, the response being similar to that obtained with the lower concentration of propranolol. It is suggested that the effect of oxprenolol may be attributable to alpha blocking properties, to partial beta agonism or to its membrane stabilising properties.


Controlled study of the bronchoconstriction effect of pindolol administered intravenously or orally to patients with unstable asthma. Pindolol, a beta-blocking drug, was given intravenously (0.2 mg) to 4 patients and orally (15 mg) to 4 patients, all in remission after acute exacerbation of asthma. In all cases it induced chest tightness and marked decrease in specific airway conductance, FEV1 and FVC and maximum expiratory flow at low lung volumes. The increase in airway obstruction after pindolol was not reversed by inhalation of a beta-sympathomimetic aerosol. The results suggest that conventional doses of pindolol may cause significant worsening of asthma in patients with unstable disease.


Transplacental passage of atenolol in man. Maternal and umbilical serum concentrations of atenolol, a hydrophilic, cardioselective beta-adrenoceptor antagonist, were studied at delivery in seven cases of pregnancy hypertension. The drug had been administered to each patient for at least one week. Atenolol was detected in both maternal and umbilical serum in six cases, showing that there is transplacental passage of the drug. In the seventh case, who had stopped taking atenolol more than one day before delivery, neither maternal nor umbilical serum contained a measurable quantity of the drug. Atenolol concentration varied 3- to 6-fold between individuals, but there was no systematic difference between maternal and umbilical levels. It seems reasonable to assume that during steady state conditions the blood level of atenolol in mother and fetus is approximately equal, and that fetal accumulation of the drug does not occur.


Time and antigen dose-dependent variations of IgM antibody affinity. Affinity of IgM antibodies elicited in mice by a single injection of dinitrophenylated dextran was measured by equilibrium dialysis. Maturation of affinity was found to occur with time, the rate of increase being higher after larger antigen doses. Maturation was followed by a decrease of affinity with time, the fall being more pronounced after lower antigen doses. These findings are more in line with the theory of antigen-induced diversity rather than with the maturation theory.


The influence of some vasoactive drugs on bone circulation. We have studied the effect of various drugs on the intramedullary pressure in dog tibia after constant-flow autoperfusion of the nutrient artery by femoral arterial blood. The perfusion pressure and carotid arterial pressure were also recorded. Isoprenaline, acetylcholine, histamine, theophylline always lowered the perfusion pressure but had a variable effect on intramedullary pressure. This results from several factors e.g., perfusion pressure and intraosseous vasomotoricity. Adrenaline always caused a rise of the perfusion pressure and lowered the intramedullary pressure in most of the cases. Such effects were reduced or suppressed by alpha-blocking drugs. Isoprenaline caused a lowering of the perfusion pressure which was suppressed by propranolol. A rise of the intramedullary pressure through beta-induced vasodilatation was shown in some experiments. The effect of adrenaline on the perfusion pressure could be reversed after alpha-blockade. These results show the presence of intraosseous vascular alpha- and beta-adrenoceptors.


Effect of 1-(m-trifluoromethylphenyl)-piperazine on 3H-serotonin binding to membranes from rat brain in vitro and on serotonin turnover in rat brain in vivo. 1-(m-Trifluoromethylphenyl)-piperazine inhibited the specific binding of tritiated serotonin to membranes from rat brain in vitro at lower concentrations than did quipazine or MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine). In rats 1-(m-trifluoromethylphenyl)-piperazine decreased the concentration of 5-hydroxyindoleacetic acid (5-HIAA) without altering the concentration of serotonin in whole brain. The decrease in 5-HIAA was apparently due to a decrease in serotonin turnover, since 1-(m-trifluoromethylphenyl)-piperazine caused a slower decline in serotonin concentration after synthesis inhibition by alpha-propyldopacetamide and a slower accumulation of 5-HIAA after probenecid injection to block its efflux from brain. The decrease in serotonin turnover is an expected result of stimulating serotonin receptors in brain and has earlier been reported to occur with quipazine. Thus all of the results are compatible with the idea that 1-(m-trifluoromethylphenyl)-piperazine acts as a serotonin receptor agonist in rat brain.


Occurrence of H2-inhibitory histamine receptors in chicken ileum. Metiamide (H2-histamine receptor antagonist) blocked histamine-induced relaxations and significantly potentiated contractile responses to histamine on isolated spiral strips of chicken ileum. This investigation showed the presence of H2-inhibitory receptors in chicken ileum.


Influence of GABA receptor agonists and antagonists on the binding of 3H-diazepam to the benzodiazepine receptor. The GABA receptor agonists, GABA and muscimol, increased, while the GABA receptor antagonist, (+)-bicuculline, decreased the affinity of the benzodiazepine receptor for 3H-diazepam. The effect was seen at both 0 and 25 degrees C in spite of a large difference of affinity for 3H-diazepam at the two temperatures.


Inhibition of synaptosomal uptake of norepinephrine and dopamine by conformationally restricted sympathomimetic amines. The conformationally restricted cis and trans isomer of substituted cyclobutanes were examined for their ability to inhibit 3H-norepinephrine and 3H-dopamine accumulation by synaptosomes prepared from the cortex and corpus striatum, respectively. The drugs were more effective in preventing the accumulation of 3H-norepinephrine by cortical synaptosomes than 3H-dopamine by striatal synaptosomes. However, in the synaptosomes isolated from both regions, the trans isomers were more potent inhibitors of accumulation than the cis isomers. The greatest stereoselectivity was exhibited by the isomers of 2-amino-1-phenylcyclobutanol. The accumulation of 3H-norepinephrine by cortical synaptosomes and the accumulation of 3H-dopamine by striatal synaptosomes were inhibited 50% by concentrations of the trans isomer of 7.4 X 10(-6) M and 1.7 X 10(-4) M, respectively. The cis isomer was inactive. In separate experiments, the releasing capabilities of the restricted analogs were determined by superfusing cortical and striatal synaptosomes labelled in vitro with 3H-catecholamines. The trans and cis isomers elicited a trivial release of 3H-norepinephrine and 3H-dopamine from cortical and striatal synaptosomes, respectively. The results indicate that the decreased synaptosomal accumulation of 3H-catecholamines caused by the analogs was due mainly to inhibition of uptake. The influence of dihydral angle between phenyl--NH2 on the inhibition of uptake is discussed. It is concluded that the anti conformation of sympathomimetic amines is the preferred conformation at the noradrenergic amine pump.