The effects of ethanol and meperidine on auditory evoked potentials.

The effects of ethanol and meperidine on the auditory evoked potential (AEP) to stimuli of different intensities were investigated. Sixteen normal male volunteers received ethanol, 0.8 ml/kg, 100 mg meperidine, and a placebo on different days in a double-blind study. AEPs were recorded from Fz, Cz and Pz electrode placements. The stimuli were 500 msec 1000 Hz tones at 50, 60, 70 and 80 dB sound pressure level presented in a pseudo-random sequence. Meperidine had no significant effect on AEP variables. Ethanol reduced AEP activity between 24 and 250 msec but had no effect on the sustained potential measured between 300 and 450 msec.


Acute tolerance in inbred and selected lines of mice.

Mice of the C57Bl and C3H strains regained their righting reflex at higher brain ethanol levels than those at which they had lost their righting reflex, indicating that these animals developed acute tolerance. DBA mice did not develop acute tolerance. DBA mice "slept" significantly longer than C57Bl mice, but all mice lost their righting reflex at similar brain ethanol levels. Mice of SS and LS lines also showed no evidence for developing acute tolerance but differed significantly in brain ethanol levels upon loss of righting reflex. Both acute tolerance development and initial brain sensitivity to ethanol seem to determine duration of ethanol "sleep time" in mice.


The structure of synaptosomal plasma membrane.

Synaptosomal plasma membrane (SPM), like other plasma membranes, is composed of lipids and proteins and appears to conform to the "fluid mosaic" model proposed by Singer and Nicolson. SPM components show a marked asymmetry with respect to their inside-outside distribution, with the majority of proteins being external. The lateral distribution of proteins is also somewhat asymmetric; this asymmetry is maintained by the immobilization of species at the junction.


Differences in heroin addicts seeking inpatient detoxification, ambulatory detoxification, or methadone maintenance.

Fifteen psychosocial characteristics of 300 male and 90 female heroin addicts admitted for inpatient detoxification, ambulatory detoxification, and methadone maintenance within the same multiphasic drug-abuse program were compared to determine whether or not their characteristics differentiated those seeking each type of treatment approach; there were 100 men and 30 women randomly drawn to represent each of the three approaches. Only two variables differed among the three approaches for both men and women--length of daily heroin use and educational attainment. The ambulatory detoxification patients had started using heroin daily at a later age than the inpatients who, in turn, had started using heroin daily at a later age than the methadone maintenance patients, and the ambulatory detoxification patients were more educated than the inpatients. The other variables differentiating the three approaches for each sex were discussed, and the conclusion was drawn that addicts with higher socioeconomic levels preferred ambulatory detoxification over methadone maintenance.


Adaptive changes in membrane lipid composition and fluidity as the basis for ethanol tolerance.

This paper is intended as a brief commentary on the evidence for adaptation to ethanol at the level of the cell membrane with more detailed consideration of the possible mechanisms for such adaptation. Methodological and conceptual problems are raised and the current views of ethanol tolerance at the membrane level are criticised. The paper includes an abstract of work carried out by the author's group on changes in membrane phospholipid composition of mice during exposure to ethanol by inhalation.


Social background, attitudes and personality in a three-year follow-up study of alcohol consumers.

Eight hundred and forty-one men from the Canton of Zürich selected from a complete survey of males born in 1952 answered a questionnaire at age 19 and again three years later about their consumption of alcohol, drugs and cigarettes, social status, and social integration. The Freiburger Personality Inventory was used for personality assessment. Abuse of alcohol was connected with the following risk factors: lack of social integration, negative relations with parents, frequent relations with the peer group, heavy cigarette and cannabis consumption and lower social status of the father. Less important were: level of education, personality traits (emotional lability, extraversion), low fitness activities and the parental drinking pattern. Emotional lability was not increased in the heavy consumption group, but was rather a personality trait already existing before regular alcohol consumption began.


Methamphetamine-induced changes in brain catecholamines in rats and guinea pigs.

Repeated administration of methamphetamine was found to cause long-term changes in caudate dopamine levels in the rat and guinea pig. Methamphetamine was administered twice a day for thirty days. Two weeks following the last injection, the animals were killed and brains assayed for catecholamine content. These long-term depletions of dopamine, when combined with similar observations previously reported in rhesus monkeys, indicate a species generality of the effects of methamphetamine on caudate dopamine levels.


[Ultrasonically guided percutaneous fine-needle biopsy (author's transl)].

A new method is described of doing fine-needle biopsies, under continuous visual control with real-time ultrasonic guidance, of the neck, thoracic and abdominal regions. The method decreases the risk of needle puncture and improves the yield of material obtained. It is simple and hardly stresses the patient, pain being only slight and momentary. It can be easily repeated. It is particularly useful for amniocentesis in obstetrics because it employs the shortest possible pathway.


[Long-term results after operative treatment of acute haemorrhagic necrotising pancreatitis (author's transl)].

A follow-up investigation of 20 patients, surgically treated for acute haemorrhagic necrotising pancreatitis, was performed in an average of 2 3/4 years after the operation. Twelve patients showed manifest diabetes mellitus, four further cases had a suspicious oral glucose tolerance test. Only one patient was insulin dependent. A secretin-pancreozymin test performed in 15 patients showed a dissociated or global pancreatic insufficiency in 13 cases. The extent of the endocrine and exocrine functional disturbance did not correlate with the extent of surgery. Postoperative functional defects were readily improved therapeutically in most cases. Only in patients who continued to consume alcohol were there digestive disturbances. The results indicate that the functional state of the remaining pancreas does not only depend on the extent of surgery but also on the extent of already existing or persisting toxic inflammatory damage and on the regenerative capacity of the remaining parenchyma.


[Minimal effective dose of bacampicillin in urinary tract infections (author's transl)].

66 patients from a nephrological out-patient clinic in whom an ampicillin-sensitive pathogen had been demonstrated after suprapubic puncture, were divided into 3 randomised groups. The first group received 10, the second 20 and the third 30 tablets of 800 mg bacampicillin each. Tablets were given t.i.d. Due to randomising comparable groups were formed. When different criteria were used for assessment of success no advantages of long-term or disadvantages of short-term treatment were found. 10 tablets (possibly even less) are thus the minimal inhibitory dosage for the disease. Present experience suggests a short treatment with follow-up controls at short intervals and then a long-term reinfection prophylaxis.


[Adriamycin-combination chemotherapy with or without immune stimulation by corynebacterium parvum in metastasizing carcinoma of the breast (author's transl)].

In a randomised, multicentre study the effect of changing the combined cytostatic treatment with VAC (vincristin, adriamycin, cyclophosphamide) to FMC (fluorouracil, methotrexate, cyclophosphamide) was tested, as well as the effect of active non-specific immune stimulation with Corynebacterium parvum, and compared with a control group. In 59 of 120 patients (49%) in whom the results could be analysed there was a measurable significant regression of tumour size to less than 50% of its initial value. The course was stabilized in a further 43 (36%) women. Further tumour-growth progression or death in the early phase of treatment occurred in only 18 women (15%). Average remission was 16 months. Median survival time from start of the study in all analysable patients averaged 22 months. Patients with an ulcer at the site of application of Corynebacterium parvum had a clearly prolonged survival time. In all, immune stimulation with Corynebacterium parvum was no better, either with regard to the remission rate, remission duration or survival time.


[Effect of prazosin in therapy-resistant chronic cardiac failure (author's transl)].

In addition to standard treatment with digitalis and diuretics prazosin (20 mg/d) and placebo were given to 14 patients with chronic therapy-resistant cardiac failure mainly of stage III for periods of 6 weeks each. Cardiac frequency, blood pressure, cardiac volume, pulmonary artery pressures and cardiac minute volume were assessed at rest and during physical exercise. Body weight, congestive changes in the chest radiograph, oedema and complaints were evaluated. During the acute trial using 2 mg of prazosin a significant increase of cardiac minute volume was demonstrable at rest and during exercise (2 P less than 0.05). After administration for 6 weeks cardiac minute volume increased from 3.2 to 4.0 l/min at rest and from 6.9 to 8.0 l/min during exercise (2P less than 0.005; n=12). There was a noticeable decrease of cardiac size from 1440 to 1306 ml/1.73 m2 (2 P less than 0.02). Haemodynamic improvement paralleled the decrease of complaints which was equivalent to an improvement of half to one stage of the New York Heart Association. In severe cardiac failure prazosin has thus an additional therapeutic effect beyond digitalis and diuretics.


[Treatment of osteogenesis imperfecta with (+)-catechin (author's transl)].

4 girls aged 4--12 years with various forms of osteogenesis imperfecta were treated with (+)-catechin for several months. Bone punch biopsies from the iliac crest were investigated by electron microscopy before and during treatment. The frequency of fractures decreased clinically. There were no radiographic changes in the bones and there were no side effects. Electron microsopy showed a dilated coarse endoplasmatic reticulum with infrequent ribosomes, thin collagen fibrils and decreased predominantly disseminated mineralisation before treatment. Under the influence of treatment electron microscopical aspects of the bone improved. The cisternae of the endoplasmatic reticulum were arranged parallel with densely packed ribosomes, collagen fibrils were wider and in closely packed bundles and mineralisation was clearly improved. The electron microscopic findings are evidence for a possibly beneficial influence of (+)-catechin in some cases of osteogenesis imperfecta.


[Rapid radioimmunological test for HCG in normal and disturbed early pregnancy (author's transl)].

The clinical evaluation of a rapid radioimmunological test for HCG in serum showed that this method is as suitable as conventional radioimmunoassay or receptor methods in the diagnosis of normal and disturbed early pregnancy. Using a direct immunosorbent method total time requirements for the estimation could be reduced to half a working day. Sera of 314 women with normal pregnancies showed an exponential increase of HCG concentrations in serum during the first 8 weeks and thereafter steady levels for several weeks. As the anti-HCG serum used has only a slight cross reactivity with LH, false-positive results need hardly be expected in states of high LH levels in serum (menopause, polycystic ovaries, preovulatory LH peak). HCG concentrations in serum were clearly diminished in all pregnancies ending in abortion and in nearly all extrauterine pregnancies. Repeated estimations in early pregnancy enable a diagnosis of ectopic or disturbed intrauterine pregnancy to be made before symptoms of rupture, haemorrhage and similar complications occur.


Molecular conformation of thyroid hormones: structure and binding interactions of thyroxine.

In an accurately determined X-ray diffraction study of the thyroid hormone thyroxine (T4), the two independent conformations in the crystal lattice show significant differences in the outer phenyl ring geometry when compared with that of 3,5,3'-triiodothyronine (T3). The major differences between the T4 and T3 structures are a shortened C4'-O4' bond, contraction of the C3'-C4'-C5' angle and an increase in the C3' and C5' angles of T4. These changes can be correlated with the difference in acidity of the 4'-OH of T4 and T3 and help to explain binding affinity differences among thyroactive compounds. The hydrogen bond directionality observed in T4 and other thyroid structures offers an insight into the molecular details of the hormone-receptor site. The conformation of one T4 molecule is cisoid, that of the other transoid, the first such instance of different overall conformations to be found in the same crystal lattice. One T4 molecule has the side chain nearly coplanar with the inner ring, an unusual conformation among thyroid structures.


The follicular iodide pool as a two-compartment system: evidence from the unstimulated thyroid gland.

The isotopic equilibrium method was used for a 60-day period to follow iodine turnover in control and hypophysectomized rats. After the suppression of TSH by hypophysectomy, only the captured iodide is used for iodination of thyroglobulin, the iodide recycling being abolished. In unstimulated gland, two metabolically distinct iodide compartments do exist which differ either in their chemical form or in their morphological distribution, or both.


[Pituitary growth hormone content in swine].

The growth hormone content in the adenohypophysis in different lines of swine was determined by radioimmunoassay. The result indicates that animals of an obese type (Vietnamesisches Hángebauchschwein) show a significantly lower growth hormone content (154.9 +/- 34.3 microgram gh/mg protein) than animals of a lean type (Landrasse) (238.0 +/- 58.2 microgram GH/mg protein).


Ovarian steroidogenesis in rats following inhibition of DNA synthesis after administration of mitomycin C.

Suppression of delta 5-3 beta-hydroxysteroid dehydrogenase (delta 5-3 beta-OHD) and glucose-6-phosphate dehydrogenase (G-6-PD) activities were observed in the rat ovarian tissues following treatment with Mitomycin C (MC), an antibiotic which depresses DNA synthesis. The same treatment also resulted in accumulation of cholesterol and ascorbic acid in the ovaries and a decrease of uterine weight. The atretic changes in the treated ovaries were judged from the activity of the lysosomal enzyme leucine amino-peptidase (LAP). The results suggest a diminution in ovarian steroid biogenesis following an alteration of DNA synthesis.


Urinary pregnanetriol and delta 5-pregnentriol in women with idiopathic hirsutism.

Urinary pregnanetriol and delta 5-pregnenetriol were determined in 90 normal women and in 90 women with idiopathic hirsutism of comparable age group. When group Student's "t"-test was carried out, the mean steroid excretion values in hirsute women were found to be significant with delta 5-pregnenetriol more significant than pregnanetriol. Of the 90 women with hirsutism, 8 patients had pregnanetriol and delta 5-pregnenetriol values higher than normal. When, on the basis of these elevated values, the women were sent for a thorough gynaecological investigation, they were found to have the polycystic ovary syndrome. After wedge resection, the diagnosis was confirmed and the urinary excretion of pregnanetriol and delta 5-pregnenetriol came down to a normal level. This study shows that, in the case of women with idiopathic hirsutism suspected of any ovarian disorder, the measurement of these two steroids could be of diagnostic importance.


Psychic and intellectual development in girls with precocious puberty.

Examinations of psychic and intellectual development were made in 9 girls with idiopathic precocious puberty. The question was, whether precocious somatic maturation corresponds with an accelerated development of intellectual efficiency and psycho-social behaviour. Whereas psychodiagnostic investigations and questionnaires to parents and teachers suggested age-related, normal results, there was found a remarkable tendency to elevated IQ values, averaging 123. Complex influences as increased general vitality, elevated pression towards psycho-social achievement and accelerated maturation of certain brain areas are discussed as conditional factors.


Glucocorticoid receptors in cytosol and nuclear extract of human leukocytes.

Cortisol binding by cytosol and 0.4 M KCl extract of the nuclear fraction of human leukocytes were studied by gel chromatography and ion exchange filtration on DEAE cellulose. The cytoplasmic cortisol binding protein has a molecular weight 95 000 and the soluble nuclear binding protein 50 000. The absence of the uptake of radioactive cortisol by isolated nuclei and the apparent requirement of the cytosol for glucocorticoid specific binding in nuclear receptor sites was observed. The association constant characterising the binding of cortisol to cytosol was KA = 3.5 . 10(9) l/mol.


The effect of adrenal and gonadal hormones on vascular permeability in rat skin.

The effect of adrenal and gonadal hormones on vascular permeability induced by intradermal injection of prostaglandins (PGs) E1, F2alfa, arachidonic acid and compound 48/80 have been examined in the rate. PGE1, arachidonic acid and compound 48/80 produced an increase in local vascular permeability. PGF2alfa decreased the action of these vasoactive agents, when it was injected in a mixture intradermally with PGE1, arachidonic acid and compound 48/80. Vasoactive response induced by PGE1, arachidonic acid and compound 48/80 was inhibited by the removal of adrenals and testes, and it was restored to normal by injection either of cortisol, deoxycorticosterone (DOC) or testosterone. In adrenalectomized rats, no change was observed in the inhibition of vascular permeability elicited by PGF2alfa response to compound 48/80. The blocking effect of PGF2alfa on vascular permeability evoked by PGE1 and arachidonic acid showed a considerable decrease. After orchidectomy the inhibitory effect of PGF2alfa on the vascular permeability induced by arachidonic acid and compound 48/80 was completely blocked, while in the case of PGE1 the inhibition was partial. Testosterone treatment restored the anti-inflammatory effect of PGF2alfa against compound 48/80. Ovariectomy was without any effect on vascular response.


Effects of cadmium chloride on testicular steroidogenesis and fertility of male rats.

Effects of a single subcutaneous injection of 1 or 5 mg/rat of cadmium chloride (CdCl2) on circulating steroids and fertility were studied over a period of 120 days in fertile male rats. Androgens and fertility returned to normal 120 days after 1 mg CdCl2 but males treated with 5 mg showed none to poor restoration of some of these parameters. The in vitro release of testosterone (T), 5 alpha-dihydrotestosterone (5 alpha-DHT) and androstenedione (delta 4A) by the decapsulated tests from CdCl2 treated males was significantly reduced whereas progesterone (delta 4P) was accumulated in significantly higher amounts into the incubation medium. When testes from CdCl2 treated males were incubated in vitro with hCG, a dose and time dependent stimulation of steroidogenesis was evident. Since the testes regained the steroidogenic capacity but the males remained sterile 120 days after 5 mg CdCl2 treatment, it appeared that CdCl2 induced a permanent damage to the germinal components of the testes.


Relationship between adipocyte hypertrophy and metabolic disturbances.

Enlargement of fat cells is known to be a factor stimulating metabolic rates in adipose tissue and thus playing a role in the pathogenesis of certain metabolic disorders. Excessive adipose-cell hypertrophy of the same degree was observed in disturbances of carbohydrate (e.g. in subclinical or maturity onset diabetes) as well as of triglyceride metabolism, despite the fact that body weight in these patient groups was lower than in control subjects (with the exception of subclinical diabetics). Significant correlations between adipocyte volumes and serum triglyceride levels are in agreement with this conception. Similar characteristics of insulin concentrations measured during an oral glucose tolerance test and adipose-cell hypertrophy of the same degree may suggest a comparable influence on the development of carbohydrate intolerance and hypertriglyceridemia. Moreover, our investigations show an increasing of the prevalence of diabetes mellitus, hypertriglyceridemia and hypercholesterolemia up to a Broca Index of 1.2. This points to an extremely high metabolic risk even in people with slight overweight provided the adipocytes are significantly enlarged. Thus, adipocyte size appears to be a good parameter to characterize metabolic impairments.


Estrogen biosynthesis and its inhibition--a review.

A short review is given about extragonadal sources of estrogens via androgen aromatization; the possible importance of this aromatization; the mechanism of aromatization, the inhibition of androgen aromatization by steroidal compounds; the importance and possible usefulness of such an inhibition.


Nutritional needs in environmental intoxication: vitamin E and air pollution, an example.

Dietary vitamin E affects the susceptibility of mice and rats to ozone and nitrogen dioxide, suggesting a free radical mechanism of toxicity. Conventional peroxidation does not completely explain the effects of alterations of lung fatty acid composition on both nitrogen dioxide and ozone toxicity. A new scheme is proposed based on the cyclization of beta, gamma-allylic peroxyl free radicals to monocyclic and bicyclic peroxides to explain the relationship between diet and toxicity. Similar results are likely with other toxicants producing peroxidation as a mechanism of toxicity. Such cyclic peroxides may mimic or interfere with the prostaglandin system. Several chronic diseases may be exacerbated through such a subtle toxic mechanism. The level of vitamin E needed for protection against peroxidation toxicity may be much greater than the present U. S. dietary intake.


Lead toxicity and nutritional deficiencies.

Under appropriate conditions, deficiencies of certain minerals and vitamins as well as high intakes of dietary fat increase the toxicity of a given dose of lead in experimental animals. The severity of lead poisoning can also be increased by the consumption of either deficient or excessive levels of protein. Mineral deficiencies appear to have some of the most profound effects on lead toxicity, since the consequences of plumbism can be exaggerated by feeding diets low in calcium, phosphorus, iron, zinc, and in some cases, copper. Evidence for an antagonism between lead and nutritional levels of selenium is inconclusive. Vitamin E deficiency and lead poisoning interact to produce an anemia in rats that is more severe than that caused by either treatment alone. Lead apparently exerts a pro-oxidant stress on the red cell, thereby causing its accelerated destruction. One of the biochemical mechanisms of lead poisoning may be the disruption of normal membrane architecture, thereby leading to peroxidative damage. Epidemiological surveys have suggested a negative correlation between the poor nutritional status of children with regard to calcium and the concentration of lead in blood. Other examples of potential interactions of mineral status and lead poisoning in humans include the hypothesized hazards of soft water to public health in areas with lead plumbing and the possible role of mineral deficiencies in the etiology of pica. Experimental studies have shown that in some situations combined nutritional deficiencies can have an additive effect in potentiating lead toxicity.


Asthma and respiratory irritants (ozone).

Asthmatics appear to be more susceptible to the effects of air pollutants than nonasthmatics. The present studies were undertaken to examine the effects of exposing asthmatics to ozone concentrations that occur in the environment. Seventeen well-documented male and female asthmatics have been exposed for 2 hr in an environmental chamber to 0.25 ppm of ozone on one occasion (ozone) and to air on another occasion (air). Effects were assessed by measurements of pulmonary function obtained prior to (0 hr), every half-hour during and at the end of all exposures (2 hr). Paired t-test analysis of lung volumes, forced expiratory volume in 1 sec (FEV1.0), and maximum expiratory flow rates at 50% of vital capacity (V50%VC) showed no significant changes (p greater than 0.05) when the following comparisons were made: 0 hr air vs 0 hr ozone, 0 hr air vs. 2 hr air, 0 hr ozone vs. 2 hr ozone, 2 hr air vs. 2 hr ozone. There was variability in severity of asthma and pulmonary function status; most subjects were taking some form of medication at the time of study. Some asthmatics showed no change or improvement with both air and ozone and others developed greater reductions in pulmonary function with ozone than with air. Approximately one-third of the asthmatics demonstrated greater changes in V50%VC with exposure to 0.25 ppm of ozone relative to air exposure. These studies indicate that acute exposures to ozone at realistic concentrations in the environment can produce adverse responses in some asthmatics.


Effects of NO2 on chronic bronchitics.

The acute influence of NO2 on mechanics of breathing and respiratory gas exchange was investigated in a total of 111 subjects, aged 25 to 74 years, with chronic nonspecific lung disease (CNSLD). They breathed NO2-air mixtures containing 0.5 to 8.0 ppm NO2 for up to 15 to 60 min. Additionally in nine subjects the protective action of atropine, meclastine, and orciprenaline was investigated. While the alveolar PO2 remained constant during inhalation of 5 and 4 ppm NO2, a significant decrease of the arterial PO2 and a corresponding increase of the arterial to alveolar PO2 gradients occurred. Inhalation of 2 ppm NO2 had not such an effect. Inhalation of NO2 at concentrations down to 1.5 ppm resulted in a significant increase of airway resistance. Lower concentrations had no significant effect. Prolongation of the exposure period from 15 to 60 min at a NO2 concentration of 5 ppm did not result in a more pronounced disturbance of the respiratory gas exchange for oxygen beyond the extent observed after exposure to 5 ppm NO2 for 15 min. Meclastine, in comparison with orciprenaline and atropine, showed a pronounced protective effect on the negative impact of NO2 on respiratory gas exchange and airway resistance. It is concluded that NO2 may act by release of histamine, causing a bronchiolar, alveolar, and interstitial edema, thus differing from irritant air pollutants like SO2, where reflex bronchoconstriction causes in some bronchitics dramatic increases of airway resistance at similar low concentrations.


Effect of age on immune function in terms of chemically induced cancers.

Neonatal, fetal, and very old animals are particularly sensitive to chemical carcinogenesis. Reasons for this increased sensitivity could be due to increased susceptibility of "target" organs or cells, peculiar hormonal levels at these age groups, relatively deficient immune functions, or combinations of these and/or other factors. During the late fetal and first three weeks of neonatal life, the immune system is rapidly maturing, is relatively incompetent, and its diverse components are developing at different rates. For example, thymus-dependent (T) alloreactive cells capable of proliferating in mixed lymphocyte reactions (T helper cells) develop by 7 days of age, but precursors of T killer cells are not competent until approximately 14 days of age. Bursa equivalent-dependent (B) cells capable of generating antibody responses are present in fetal liver but are extremely sensitive to tolerance induction until 10-14 days of age when IgD cell surface receptors are detectable. Marrow-dependent (M) cells responsible for regulation of suppressor cells and for natural cytotoxicity to transformed tumor cells do not mature until 3 weeks of age. In very old animals, the thymus is atrophic and cell-mediated immunity is moderately suppressed. Natural cytotoxicity against tumor cells is less than normal but antibody formation (B cell function) is adequate. Gonadotrophic hormones of the pituitary or placenta are high during pregnancy, the early neonatal period, after the menopause, and in a large fraction of men over 60 years of age. These and other hormones are immunosuppressive and could theoretically facilitate carcinogenesis. The particular immune cell type, if any, responsible for resistance to chemically induced tumors has not been determined. One can only state that susceptibility to chemical carcinogenesis is associated with a relative dysfunction of the immune system and that age is an important factor.


Household surface lead dust: its accumulation in vacant homes.

House dust has been suspected as a source of lead in the exposure of children, particularly those whose blood lead levels are in the moderately elevated range. The means by which household surface lead accumulates is at present not clear. By towel wipe sampling, 24 vacant houses in urban Rochester and Buffalo, New York, were examined for lead content on windowsills, floors, and other surfaces. High yields of lead were obtained from windowsills and floor areas adjacent windows. When washed and resampled, these areas yielded greatly reduced lead values. It is suggested that surface lead may represent a deposit phenomenon. The entry of exterior airborne particulate lead around the loose-fitting windows of older homes appears possible.


Age and sensitivity to lead toxicity: a review.

During the past 20 years considerable attention has been focused on the epidemiologic features of childhood lead poisoning in the United States. Large numbers of children with symptomatic intoxication, as well as those with incipient symptoms, were commonplace a decade ago for physicians working in inner-city hospitals. With the recent availability of improved screening techniques, as well as a variety of environmental control measures, the incidence of symptomatic lead poisoning in children has diminished significantly in recent years. With the focus shifting from children with dangerously elevated body lead burdens to those with less significant exposures, increased attention has been directed to the various inherent metabolic and physical characteristics of the young that may influence the toxic effects of lead exposure. A number of differences with respect to lead exposure, absorption and retention, and varying nutritional conditions between children and older individuals are discussed. Experimental studies dealing with age differences of lead-treated animals are examined, and relevant human studies are reviewed.


Age as a function in the development of sodium-related hypertension.

The populations of the developed nations of the world exhibit an increase in blood pressure with age, while in primitive societies blood pressure remains relatively constant throughout adult life. Hypertension may be a complex of diseases all having the same clinical manifestations but not being caused necessarily by the same factors. A possible common denominator in the development of any chronic elevation of blood pressure is the need for the kidney to increase urine volume to promote sodium excretion and, thereby, prevent a chronically expanded extracellular fluid (ECF). Hypertension may be viewed as a maladaptation of the body in its attempt to maintain homeostasis of the ECF. Man evolved under conditions of relative scarcity of salt and even now can maintain normal body function with an intake of less than 2 g/day. The high risk person appears to have a hereditary predisposition to a rise in blood pressure in the presence of a high sodium (NaCl) intake. Actually, the degree of rise in blood pressure may be an interaction between the amount of genetic predisposition and the level of sodium and its relation to potassium intake. Recent work in two Massachusetts communities supports this interpretation and suggests that differences in blood pressure distribution may increase with age between a higher and lower sodium community.


Effects of environmental oxidant stressors on individuals with a G-6-PD deficiency with particular reference to an animal model.

Individuals with a G-6-PD deficiency have long been known to be at increased risk to experience acute hemolysis following exposure to elevated levels of certain oxidant drugs and industrial chemicals. However, the recognition of enhanced susceptibility to environmental (or ambient) pollutants has generally not been considered. Recent theoretical studies have suggested that elevated levels of ambient ozone may be an etiologic factor in the onset of acute hemolysis in the G-6-PD deficient individual. Furthermore, the proposed usage of either chloramines or chlorine dioxide as replacements for chlorine for the disinfection of drinking water should be investigated with respect to their potential adverse effects of individuals at increased risk to oxidant stressors. In order to test these theoretical associations, two mouse strains, one with low and the other with high levels of G-6-PD activity in their red blood cells are being investigated to determine if they simulate human G-6-PD deficient and normal individuals, respectively. Preliminary results indicate that the mouse strain with low G-6-PD activity is markedly more susceptible to sodium chlorite than mice of the high G-6-PD strain. This differential susceptibility to sodium chlorite toxicity between the high and low G-6-PD mouse strains suggests that further research designed to validate the efficacy of this mouse model as a predictor of the human situation is warranted.


Biological activity of tobacco smoke and tobacco smoke-related chemicals.

Exposure to whole cigarette smoke from reference cigarettes results in the prompt (peak activity is 6 hrs), but fairly weak (similar to 2 fold), induction of murine pulmonary microsomal monooxygenase activity. This activity can be detected by using as substrates either benzo(a)pyrene or ethoxyresorufin, and can be inhibited by treatment with cycloheximide or actinomycin D. Unlike the induction of pulmonary monooxygenases following intratracheal administration of 3-methylcholanthrene, these cigarette smoke-induced increases were not unequivocally linked to the Ah locus. Whole smoke condensate and fractions derived from these condensates can; a) induce pulmonary monooxygenase activity, b) inhibit benzo(a)pyrene metabolism in vitro, c) be metabolized to forms mutagenic to Salmonella typhimurium tester strains TA153, or TA98, d) transform C3H 10T1/2 cells in vitro, and e) enhance the carcinogenicity of benzo(a)pyrene in murine pulmonary tissue. A potentially important observation is that whereas hepatic tissue is capable of activating whole cigarette smoke condensate to mutagenic forms in vitro, murine pulmonary tissue does not seem capable of such activation. Although these pulmonary-derived tissue homogenates have significant AHH activity and can metabolize Aflatoxin B1, 2-aminofluorene and 7, 8-dihydro-7,8-dihydroxybenzo(a)pyrene to mutagenic forms, these homogenates fail to activate both cigarette smoke condensate and the pro-mutagen, 6-aminochrysene. These results are discussed with reference to the concept that whole cigarette smoke may be both a potential "initiator" and "promotor" of lung cancer in mice, and that this latter property may be the most important in determining cancer risk.


Metabolic activation/deactivation reactions during perinatal development.

The role of metabolic activation/deactivation reactions during development is evaluated in relation to developmental pharmacology and toxicology. Enzyme systems evaluated include the mixed-function oxidases (aryl hydrocarbon hydroxylase and oxidative demethylation), epoxide hydration and conjugation (glutathione conjugation, sulfation, and glucuronidation). Placental transfer and milk secretion of chemicals are discussed in relation to maternal, placental, and fetal metabolism. Normal patterns of enzyme development can be modified in two ways: (1) enzyme induction and (2) enzyme imprinting. Postnatal induction of the mixed-function oxidases and glucuronyl-transferase following treatment of pregnant rats with TCDD is shown to be caused primarily by newborn exposure to TCDD in milk. Structure-activity relationship are defined for the perinatal induction of hepatic enzymes by the pure PCBs. PCBs are divided into two classes: P-450 inducers and P-448 inducers. Imprinting or programming of hepatic metabolism is a function of the sexual differentiation of enzyme activity; male and female activities are similar in prepubertal animals, whereas pronounced sex differences are evident in adults. Treatment of newborn rats (days 2--6) with diethystilbestrol or testosterone resulted in a feminization (decrease) of mixed-function oxidation and glucuronidation in adult males. No changes were seen in immature males or females or adult females. This effect appears to be irreversible and is under pituitary-hypothalamic-gonadal control. In addition to the feminization of enzyme activity, neonatal exposure to hormonally active chemicals also feminizes the hepatic response to cadmium in resultant adult animals.


N-acetyltransferase phenotype and risk in urinary bladder cancer: approaches in molecular epidemiology. Preliminary results in Sweden and Denmark.

A variable but often significant proportion of urinary bladder cancer in urban areas can be attributed to occupational and cultural (cigarette smoking) situations associated with exposures to various arylamines. The variable N-acetylation of carcinogenic arylamines by human hepatic enzyme systems, the known genetic regulation and polymorphic distribution of this enzyme activity in humans, and the known enhanced susceptibility of individuals with the genetically-distinct "slow acetylator" phenotype to various arylamine toxicities, has prompted examination of possible correlations between N-acetyltransferase phenotype and urinary bladder cancer risk in rural and urban populations. In this context, N-acetylation is viewed as a component of detoxication pathways with respect to arylamine bladder carcinogenesis. In preliminary utilizations of this approach, a population of urban urinary bladder cancer patients from Copenhagen, Denmark displayed a 13% excess (p = 0.065) of individuals with the slow acetylator phenotype (46/71 = 64.8%) when compared to a Danish control population (38/74 = 51.4%). These data are consistent with the possibility that arylamines may play an etiological role in bladder cancer in this locale and that slow acetylator individuals may be at higher relative risk (1.74) than rapid acetylator individuals. As 95% of patients reported histories of smoking, it was not possible to isolate and examine smoking factors. In contrast, a population of rural urinary bladder cancer patients from Lund, Sweden, where bladder cancer incidence (20/100,000) (1971) is lower than in Copenhagen (43.8/100,000) (1968-72), no difference in slow acetylator distribution was observed between bladder cancer (80/115 = 69.6%) and Swedish control (79/118 = 66.9%) populations, indicating a relative lack of involvement of arylamines in the etiology of rural bladder cancer. Populations of "spontaneous" bladder cancer patients would be expected to contain variable portions of disease related to arylamine exposure and would be less likely to display a detectable correlation than would an industrial population with documentable arylamine exposure. Consequently, confirmation of this hypothesis is being pursued by examination of industrial populations in an effort to obtain an empirical estimate of relative risk for slow and rapid acetylator phenotypes. These studies involve exposure-matched workmen both with and without bladder cancer.


Nutrient-toxicant interactions: susceptible populations.

Nutritional status can substantially modify the toxicity of environmental pollutants. Investigations with experimental animals and epidemiological observations on humans have established the role of nutrition in altering susceptibility to a variety of pollutants including pesticides and heavy metals. The degree of nutritional deficiency that alters susceptibility need not be severe. Frequently only biochemical indications of nutritional deficiency can be associated with changes in the dose-response of an animal or person to a toxic compound.


Vitamin A and the susceptibility of respiratory tract tissues to carcinogenic insult.

The influence of vitamin A on the development of chemically induced lung carcinomas in rats was investigated. Rats were maintained on low, "normal" and excess levels of retinyl acetate (RA). Respiratory tract-squamous carcinomas were induced by intratracheal injections of 3-methylcholanthrene (3-MCA). The carcinogen doses used ranged from 1.25 to 10.0 mg of 3-MCA. Serial sacrifices conducted during the first 20 weeks following carcinogen exposure showed that metaplastic lung nodules, presumed to be precursors of later appearing carcinomas, occurred earlier and at higher incidence in rats maintained on low levels of RA than in rats maintained on moderate or high levels of RA. The development of invasive pulmonary carcinomas was enhanced at all four carcinogen doses in rats receiving low levels of RA as compared to rats receiving moderate or high levels of RA. No consistent difference in lung cancer incidence existed between the groups receiving normal and high levels of RA. The data clearly show an increased susceptibility of vitamin A-deficient rats to develop chemically induced lung cancers. Possible mechanisms underlying this effect are discussed.


Nutritional influences on metal toxicity: cadmium as a model toxic element.

The nutrient quality of the diet has been shown repeatedly to be a significant factor in modifying the response of man and animals to toxic element exposure. Deficiencies of several essential nutrients have been shown to exacerbate the effects of cadmium and supplements of such nutrients have been shown to ameliorate the toxicity. Thus the effects of exposure to a toxic element, such as cadmium, may vary, depending on interactions with other elements which are present in the diet in different concentrations.


Characterization of ribonucleotide reductase activity from mouse L cells.

We describe some fundamental properties of the cytidine 5'-diphosphate (CDP) and guanosine 5'-diphosphate (GDP) reductase activity from mouse L cells. Both activities increased in a nonlinear fashion at low protein concentrations; this may be due to dissociation of two protein subunits of the enzyme at very low concentrations. CDP reductase activity was greatly stimulated in the presence of ATP and required magnesium and iron for maximum activity. GDP reductase required 2'-deoxythymidine 5'-triphosphate for maximum activity. Also apparent Km values of 0.14 mmol/l for CDP and 0.05 mmol/l for GDP were determined from double reciprocal plots of velocity against substrate concentrations. Activity in extracts of logarithmically growing mouse L cells was very high indicating that attempts to purify the enzyme from this source should be rewarding.


Essential arginine residues in the active sites of propionyl CoA carboxylase and beta-methylcrotonyl CoA carboxylase.

At least one arginine residue is essential for substrate binding in or near the active sites of propionyl CoA carboxylase (PCC) and beta-methylcrotonyl CoA carboxylase (beta MCC) in cultured human fibroblasts. This conclusion is based on studies of enzyme inhibition by phenylglyoxal, a reagent which specifically modifies arginine residues. Human fibroblast PCC both in extracts and in a 20-fold purified preparation was nearly completely protected from phenylglyoxal inhibition following incubation with propionyl CoA or ATP. It appears that a phosphate group from either ATP or the CoA moiety of propionyl CoA reacts with the essential arginine residue(s). beta MCC which was similarly inhibited by phenylglyoxal was protected by beta-methylcrotonyl CoA and ATP. Thus phenylglyoxal may be used to label specific arginine residues within the active sites of previously sequenced carboxylases.


Enzymatic methylation of alkane thiols.

A membrane-bound enzymatic activity has been found in rabbit liver microsomes, which catalyses the transmethylation from S-adenosylmethionine to a series of C1-C3 alkane thiols. Methane and ethane thiols are known to be endogenous toxins, which may play an important role in the pathogenesis of hepatic coma, and methylation could provide an important pathway for the metabolic 'detoxification' of this class of compounds through neutralisation of the highly reactive sulph-hydryl group.


Influence of Mg2+ ions on the activity measurement of isoenzymes of alkaline phosphatase.

The activity of alkaline phosphatase isoenzymes from liver, bone and small intestine is differently influenced by Mg2+. The stimulation of isoenzymes from liver and bone is higher by Mg2+ ions than in the case of isoenzymes from small intestine. An obligatory preincubation of the serum sample in a buffer-Mg2+ mixture is necessary to avoid difficulties which may arise in the kinetic determination of alkaline phosphatase activity under extreme conditions, i.e. low Mg2+ concentration in serum, the necessity of dilution of the sample or the high isoenzyme content from liver or bone in the serum.


The energy metabolism of the leucocyte. X. Kinetics of oxygen consumption during phagocytosis by polymorphonuclear leucocytes. A photometric method.

A simple micromethod for quantitative assay of the oxygen consumption by phagocytosing human neutrophils had been described. The continuous assay shows a lag time between the addition of zymosan and the maximal rate of oxygen uptake, which is a measure of the serum opsonic activity. Several factors can alter the oxygen uptake and also the delay of response.


Effects of metal ions and selenoamino acids on induction of glutathione peroxidase in mouse neuroblastoma.

The induction of glutathione peroxidase in mouse neuroblastoma cells by selenite is enhanced by equimolar amounts of arsenate, arsenite, molybdate, chromic or dichromate ions. At equimolar selenium concentration, selenite, selenocystine and selenomethionine induced glutathione peroxidase activities having the ratios 4:4:1. Protein synthesis inhibitors prevented the induction of glutathione peroxidase by selenite indicating that de novo protein synthesis is required.


Cholesterol ester:lysolecithin transacylation in the aorta.

Acyl transfer from cholesteryl oleate on lysolecithin to release cholesterol and form lecithin has been demonstrated in the aortic wall. Mechanism of the enzyme-catalyzed transacylation is considered in relation to the arterial cholesterol ester hydrolase.


Modes of inhibition of activities of trypsin and chymotrypsin by potassium thiocyanate.

Potassium thiocyanate inhibited the activities of trypsin and chymotrypsin. The inhibition was mixed type on both enzymes with casein as substrate and on trypsin with tosyl-L-arginine methyl ester as substrate, but was uncompetitive on chymotrypsin with benzoyl-L-tyrosine p-nitroanilide as substrate.


[Approaches to reduce the retroaction of long-term monitoring of bioelectric events in ergonomic field studies (author's transl)].

When monitoring bioelectric signals the surface electrodes can cause a retroaction on the subject thereby introducing an error of measurement. There are two types of retroaction: physical and psycho-physiological. A physical retroaction due to the hydration process of the skin occurs if 'wet' electrodes are used for the recording of the skin conductance level (SCL) causing a continuous drift of the SCL and a decrease in sensitivity to SCL changes. Therefore a dry electrode was developed with improved performance: It exhibits less sensitivity to motion, is not subject to polarization, and features better SCL long-term stability. When recording the electrocardiogram or the electromyogram a psychophysiological retroaction occurs due to the annoyance caused by the skin-irritating abrading techniques in order to decrease the skin impedance and reduce the motion artifact. In an attempt to abandon the skin preparation whenever permissible without sacrificing the measurement accuracy a performance estimation procedure was developed. Basing on the information on the signal frequency content, the electrode contact area, the required accuracy of measurement and the amplifier input impedance a decision on the necessity of skin preparation is made. Moreover, the results of a study are reported investigating the reduction of motion artifacts by means of electrode design and appropriate electrode jelly formulation.


Effects and post-effects of two-hour exhausting exercise on composition and gas transport functions of blood.

Eleven male sport students (age 23.3 +/- 1.7 years) exercised for 2 h on a bicycle ergometer (60 rpm), the braking force of which was regulated to yield a constant pulse rate (156 +/- 3 min-1). Before, at end of, and 3 and 6 h after exercise blood was sampled from a cubital vein and an earlobe for measurement of hemoglobin (Hb) concentration, hematocrit (Hct) value, osmolality (Osm), plasma protein (Prot), sodium (Na+), potassium (K+), inorganic phosphate (Pi), and lactate (Lac) concentrations, red cell 2,3-diphosphoglycerate (DPG) and adenosin triphosphate (ATP) concentrations, acid base status and half saturation pressure (P50) of the oxygen dissociation curve. At end of exercise [Hb], Hct, [Prot], Osm, [K+], [Pi] and [Lac] were significantly elevated, pH in ear lobe (+ 0.04) and venous blood (+ 0.08) was also increased by both respiratory and nonrespiratory effects (BE + 1.4 mmol/l). The oxygen dissociation curve showed an unexplained slight right shift (standard P50 + 0.19 kPa). During the post-exercise period most parameters approximated to control values after only 3 h. [Prot] and especially [Pi], however, remained elevated while [DPG] slightly rose during the post-exercise period. It is suggested that these changes are first signs of adaptation to exercise, perhaps caused by endocrine stimulation.


The physiological cost of carrying light and heavy loads.

Nine subjects walked on a treadmill with load weights equal to 10% and 40% of body weight carried on the back. Although the speed of the treadmill was selected so that the measured oxygen consumption (VO2) was the same for both load conditions, the heavier load placed an extra strain on the cardiopulmonary system and was perceived by all subjects as harder work than the lighter load. When the subjects worked at their own pace, walking on a level road or climbing stairs with load weights equal to 10% and 40% of body weight, they compensated for the heavier load by decreasing walking speed or climbing rate. Although the energy costs calculated from walking speed, body and load weight for self-paced walking and the external work of stair climbing were the same for both load conditions, the heavier load was again perceived as harder work. These findings are discussed as they relate to the definition of acceptable load weights.


Seasonal variation in work performance and heart rate response to exercise. A study of 1,835 middle-aged men.

A near maximal bicycle exercise test in 1,835 presumably healthy Norwegian men indicated a seasonal variation in physical fitness. Thus, the total amount of work performed was significantly higher, and the work pulse on equivalent loads significantly lower during the summer than during the autumn. Although the differences were small, they may invalidate comparisons made between exercise tests in populations tested at different seasons of the year. In particular, there was a considerable and sudden change in the above mentioned parameters from June--August to September--October.


Thermoregulation during exercise in relation to sex and age.

The thermoregulatory responses to 1 h exercise of 14 male (age range 18--65 year) and 7 female (age range 18--46 year) athletes and 4 (3 male and 1 female) non-athletic subjects have been investigated in a moderate environment (Tdb = 21 degrees C, Twb = 15 degrees C and rh less than 50%) and analysed in relation to age, sex, and maximum aerobic power output (VO2max). The maximal sweat loss (Msw max) under the given conditions was closely related (r = + 0.90) to VO2max and for a given relative work load (%VO2max), rectal (Tre) and mean skin (Tsk) temperatures was the same in all subjects. Sweat loss (Msw) was linearly related to total heat production (H) and to peripheral tissue heat conductance (K) and if expressed in relative terms (%Mswmax) was linearly related to Tre. For a given Tre relative sweat rate was identical in the groups studied. From these results it would seem that during exercise Tre rises to meet the requirements of heat dissipation by establishing a thermal gradient from core to skin and stimulating sweating in proportion to maximal capacity of the system. Thus provided the thermal responses to work were standardised using the appropriate physiological variables, there was no evidence to be found for differences in thermoregulatory function which could be ascribed to sex or age.


[Ergonomical studies about the superposition of control activity and mechanical vibration (author's transl)].

The effects of combined stresses due to control activity and vertical mechanical vibration on man are analysed. In the first part, the processes in the human being at those superposed stresses are shown in a deterministic way, starting from morphological and physiological facts, which leads to a division of the organismic data processing in the fields of information reception, central information processing and information output. Hypothesis of the effects of vibration in the parts of information reception and information output as well as indications to measurable variables at laboratory experiments can be deduced from the model formulation. In the experimental part about factorized laboratory experiments with combined stresses consisting of an ideal-typical compensatory-tracking-task and mechanical vibration is reported, which can be divided into short-time experiments with measurement of the statistical control-factor and perseverance experiments with additional measurements of physiological variables. As established in the first part, influences of vibration in the regions of information reception and information output were found as well as thresholds for the performance-reducing effects of mechanical vibrations. The magnitudes of the thresholds are dependent on the task difficulty.


Urinary excretion of oligosaccharides induced by galactose given orally or intravenously.

The effect of oral administration of galactose, lactose, and sucrose and intravenous injection of galactose on the urinary excretion of blood-group-active oligosaccharides has been studied. Galactose given either as the free sugar, a glycoside (lactose) or a constituent of normal diet was an absolute requirement for the formation and excretion of A-trisaccharide, B-trisaccharide and 2'-fucosylgalactose in blood group A, B and O(H) secretors, respectively. Great individual variation was seen in the amounts of galactose-dependent oligosaccharides excreted. Injection of galactose resulted in excretion of 3-59% of the amount of oligosaccharide formed after oral administration to the same individual. The mean ratio A-trisaccharide/B-trisaccharide was 2.7 in four blood-group-A1B secretors and 0.22 in three A2B secretors and can thus serve as a parameter for chemical differentiation between the two blood groups. The excretion of larger blood-group-active oligosaccharides, including the A-pentasaccharide, the B-pentasaccharide and lactodifucotetraose, that are normal components in urine from, respectively, starved A, B, and H secretors, was about the same after oral administration of galactose or lactose. The B-trisaccharide was the only oligosaccharide detected in plasma after oral galactose administration to a blood-group-B secretor individual. The concentration was 0.38 mg/l of plasma.


Amino acid sequence of the 'b5-like' heme-binding domain from chicken sulfite oxidase.

We present in this paper the sequence of the heme-binding domain of chicken sulfite oxidase which can be obtained by chymotryptic digestion of the native enzyme. The results of an automatic degradation have been reported previously. In the present work peptides were obtained from the heme-binding domain by digestion with trypsin, chymotrypsin and Staphylococcus aureus V8 protease; they were manually sequenced by the dansyl/Edman procedure. The evidence thus obtained is sufficient to completely establish the order of the 97 residues. In addition, two rounds of Edman degradation on sulfite oxidase itself allowed us to identify the same two residues, H-Ala-Pro, present at the N-terminus of the heme-binding domain; this result suggests that the latter constitutes the amino-terminal end of the sulfite oxidase peptide chain. The data presented here confirm the strong similarity between sulfite oxidase and microsomal cytochrome b5 already suggested by our first results. A sequence alignment is proposed for the two proteins. Inspection of the calf liver cytochrome b5 three-dimensional model together with the alignment suggests a similar overall structure for sulfite oxidase core with a limited number of backbone modifications. Our results point to a common evolutionary origin for sulfite oxidase core and microsomal cytochrome b5.


Reaction of liver alcohol dehydrogenase with halogenoacids. Fate of the iodide anion released by carboxymethylation and enzymic catalysis of iodide solvolysis.

The fate of the iodide liberated during carboxymethylation of Cys-46 in horse liver alcohol dehydrogenase has been determined with 125I-labeled iodoacetate. The [125I]iodoacetic acid was prepared from mesyloxyacetic acid and sodium [125I]iodide. When carboxymethylation of the enzyme is carried out in solution or in the crystalline state, no iodide is bound to the protein. The rate of iodide during the reaction of iodoacetate, determined with an iodide-specific electrode, has been found to be biphasic: the fast phase corresponds to the carboxymethylation and the slow phase to iodide liberation due to the presence of protein. With 3-iodopropionate (2.5 mM), no inactivation was detected, but in the presence of the enzyme, 10 equivalents of iodide were liberated per subunit in 1 hr. NADH does not inhibit this reaction. The electron density attributed to an iodide bound to the zinc atom of the crystalline enzyme is reinterpreted in view of these results as due to an imidazole bound to the active-site zinc. In the carboxymethylation, the reactivity of bromoacetate is higher than that of iodoacetate.


Thyroid hormones and the precocious induction of hepatic glucokinase in the neonatal rat.

1. Oral intubation of glucose is more effective than intraperitoneal injection in inducing the premature appearance of hepatic glucokinase in suckling rats. 2. The inducing effect of glucose is enhanced by treatment of the animals 12 h or more earlier with 1 microgram triiodothyronine/g body weight. 3. Low but significant activities of glucokinase appear at the normal time of development in hypothyroid neonatal rats. Intubation of glucose into 13-day-old and 24-day-old hypothyroid results in the rapid appearance of glucokinase similar to that in normal animals treated likewise. 4. The enhancing effect of thyroid hormones on glucokinase induction by glucose does not necessarily mean that the normal postnatal increase in plasma thyroid hormones is essential for the normal appearance of glucokinase activity at the time of weaning. Other possible explanations are discussed.


Estrogen action in rooster liver. Modification of a tRNASer-inactivating activity.

The hepatic synthesis of the yolk protein, phosvitin, can be induced in rooster by the administration of estrogen and this provides a model for studying the regulatory mechanisms involved. Since phosvitin is unusually rich in serine the effect of estrogen on the metabolism of serine transfer RNA (tRNASer) was examined. Rooster liver contains an activity capable of inactivating rooster liver tRNASer. This activity has specificity in that it inactivates only part of the tRNASer in the unaminoacylated form. Upon estrogen administration this activity is modified with a change in specificity and the modified activity is able to inactivate only a significantly smaller amount of tRNASer than the unmodified activity. This novel mechanism may be involved in the regulation of some species of tRNASer and thus may be part of the translational control involved in estrogen-induced phosvitin synthesis.


Interaction of diphtheria toxin fragments A, B and protein crm 45 with liposomes.

Diphtheria toxin, its fragments A, B and the protein serologically related to toxin, crm 45, have been studied for their hydrophobicity using the method of charge shift electrophoresis. These molecules were then assayed for liposome interaction. The results have shown that the diphtheria toxin B fragment behaves as an amphiphatic protein because it contains a hydrophobic domain located in that portion of the B chain which remains in protein crm 45. Toxin fragment A is hydrophilic. Incubation of protein crm 45 or toxin fragment B with preformed liposomes leads to association of these proteins with lipid vesicles. Fragment A does not interact with liposomes. Binding of protein crm 45 with lipid vesicles is dependent on time and temperature. Protein crm 45 is unidirectionally associated with liposomes, its enzymic fragment A directed outside the liposome. Fragment B or protein crm 45, upon binding with liposomes, does not affect the permeability of the vesicles.


Distribution of lymphocyte messenger RNA during stimulation by phytohaemagglutinin.

Additional of phytohaemagglutinin to cultured lymphocytes results in a progressive increase in the rate of protein synthesis of up to 7-10 times the initial rate after 20 h. Between 2 h and 12 h after the addition of mitogen, the increase in the rate of protein synthesis can be accounted for by the transfer of mRNA from messenger ribonucleoprotein complexes to polysomes. Between 12 h and 20 h the increase also reflects the accumulation of mRNA and ribosomes. However, the proportion of mRNA associated with ribosomes in unstimulated lymphocytes is unexpectedly high and paradoxically decreases during the first 2 h after mitogen addition, although the rate of protein synthesis increases. A mechanism involving mRNA selection is suggested.


The mechanism of ageing of phosphonylated acetylcholinesterase.

1. The extent of potential reactivation of organophosphate-inhibited acetylcholinesterase decreases with time, a phenomenon called ageing. Ageing is due to dealkylation of the alkoxyl group of the residue bound to the enzyme. The rate of ageing is proportional to the electron-donating capacity of the alkyl group. 2. The ageing of phosphophonylated cholinesterase cal also be demonstrated using a phrenic nerve-diaphragm preparation. The same relationship between the rate of ageing and the structure of the alkyl group was observed. 3. Ageing occurs much faster in electrically stimulated preparations than in resting preparations. This may be due to production of a more acidic environment for the enzyme at the active centre by the products of hydrolysis of the acetylcholine released by stimulation.


Relaxation of chromatin structure induced by ethidium binding. Involvement of the intercalation process.

In this paper we study the effects of the binding of ethidium on the structure of chromatin, using micrococcal nuclease as a structural probe. This binding induces two structural changes of chromatin either isolated or in the nuclei. (a) An unfolding of the overall structure which results in an activation of the rate of degradation by the nuclease. (b) A disorganisation of the core particle structure which has the effect of unwrapping the DNA from the histone core, this disruption can go on so far as to leave only 90 base pairs. By comparing the bindings of ethidium and tetramethylethidium, we conclude that the first type of structural change is due to an electrostatic effect and does not depend upon intercalation. On the other hand, the second one is due to the intercalation process and to the change of topological constraints on the DNA that such a process involves.


Effects of low concentrations of guanidine . HCl on the reconstitution of lactic dehydrogenase from pig muscle in vitro. Evidence for guanidine binding to the native enzyme.

The presence of low concentrations of guanidine . HCl has a pronounced effect on the overall rate of reactivation of lactic dehydrogenase from pig muscles after preceding dissociation and deactivation in various denaturants. The obseverd attenuation is a function of the amount of guanidine . HCl present during reconstitution. At a given guanidine concentration in the reactivation buffer the yield, but not the rate of reactivation, is influenced by the extent of denaturation caused initially in the process of deactivation and dissociation. As a possible explanation for the influence of guanidine . HCl on the kinetics of reconstitution, binding of the ligand to intermediates of folding and association is considered. This hypothesis is corroborated by the observation that guanidine . HCl in the relevant concentration range does bind to native lactic dehydrogenase without inactivating the enzyme or disrupting its quaternary structure. A kinetic model comprising guanidine binding to both the native enzyme and structured intermediates is proposed to describe the observed effects of guanidine . HCl on the rate of reactivation. In addition, the dissociation constants for guanidine binding to intermediates of reconstitution and to native lactic dehydrogenase are estimated.


Fluorescence properties of reduced flavins and flavoproteins.

Fluorescence lifetimes and polarized emission properties of reduced flavin were measured using several model compounds and flavoproteins. Depending on the conditions of solvent and temperature or reduction method the lifetimes vary between 1 and 15 ns. The longer lifetime values are found in several forms of reduced lactate oxidase, in which a good correlation exists between fluorescence intensity and lifetime. In practically all flavoproteins the fluorescence is heterogeneous. Several mechanisms are proposed to explain the observed heterogeneity in lifetimes. The reduced models in glycerol at subzero temperature exhibit high degrees of polarization of the fluorescence, whereas distinct depolarization is encountered in several reduced flavoproteins suggesting a certain mobility of the flavin chromophor.


Isolation of synaptosomal plasma membranes from cholinergic nerve terminals and a comparison of their proteins with those of synaptic vesicles.

Plasma membranes were purified from purely cholinergic nerve endings (synaptosomes) isolated from the electric organ of Torpedo marmorata. Synaptosomes were lysed, membranes recovered and further separated by density gradient centrifugation. A fraction was obtained enriched in 5'-nucleotidase, Na+, K+-activated ATPase and acetylcholine esterase. Morphological examination showed abundant membrane fragments of the size range of synaptosomes and few of vesicle size. The fraction has a characteristic protein composition upon gel electrophoresis. Five reproducible major bands with apparent Mr of 100000, 75000, 52000, 42000 and 35000--33000 are found. A gel-electrophoretic comparison with proteins from synaptic vesicles from the same source (major bands Mr 160000, 147000, 34000 and 25000) was made. Comigration of major bands was detected in one-dimensional gel electrophoresis with the 42000-Mr, 35000--33000-Mr and 34000-Mr components. Upon two-dimensional gel electrophoresis the 42000-Mr component comigrates with a similar component in vesicles, recently characterized as actin; the other components are different. The presence of tubulin-like polypeptides is unlikely. Beside actin, all major vesicle proteins are often detected in small amounts in the plasma membrane preparation. It cannot be decided if they result from fused or contaminating vesicle membranes, but since they are essentially absent in some preparations, it seems that the plasma membrane does not contain vesicle proteins.


Purification and properties of strictosidine synthase, the key enzyme in indole alkaloid formation.

A new enzyme, strictosidine synthase, which catalyzes the synthesis of 3-alpha(S)-strictosidine from tryptamine and secologanin was isolated from the soluble protein extract of Catharanthus roseus cell suspension cultures and was purified approximately 50-fold by ammonium sulfate fractionation, column chromatography on DEAE-cellulose. Ultrogel AcA34 and isoelectric focusing. The apparent molecular weight of the enzyme was 34000. The pH optimum was 6.8, apparent Km values for tryptamine and secologanin were 2.3 mM and 3.4 mM respectively for the enzyme to synthesize strictosidine. Strictosidine synthase shows high substrate specificity. No apparent cofactor requirement could be demonstrated. Of several enzyme inhibitors tested, only p-chloromercuribenzoate inhibited the enzyme. The enzyme was relatively stable and could be stored at -20 degrees C for periods of up to 1 year without appreciable loss of catalytic activity. The enzyme was demonstrated to occur in suspension cultures of 15 different species belonging to 9 different genera of the indole-alkaloid-producing subfamily Plumerioideae of the Apocynaceae family. This enzyme is responsible for the synthesis of strictosidine the key intermediate in the formation of the majority of monoterpenoid indole alkaloids occurring in the plant kingdom.


Increased urinary excretion of free N-acetylneuraminic acid in thirteen patients with Salla disease.

Thirteen severely retarded patients with Salla disease, a new type of lysosomal storage disorder, have been studied biochemically. All patients excreted approximately ten times more free sialic acid than normal individuals. The isolated sialic acid was characterized by paper chromatography, thin-layer chromatography, optical rotation, 13C and 1H nuclear magnetic resonance spectroscopy, and mass spectrometry of its permethylated derivative. The results clearly indicated that the excreted sialic acid was identical to N-acetylneuraminic acid. The main sialylated trisaccharide present in the urine of the patients was identified as 3'-sialyllactose by sugar and methylation analysis. The excreted amounts were found to be within normal range.


Improvements in immunoprecipitation of specific messenger RNA. Isolation of highly purified conalbumin mRNA in high yield.

We have described previously procedures for the isolation of specific mRNA employing immunoprecipitation of polysomes. In spite of our success with ovalbumin mRNA in the chicken oviduct, we have had considerable difficulties in applying these same published techniques to the immunopurification of conalbumin mRNA, despite the fact that the chicken oviduct synthesizes up to 10% of protein as conalbumin. Here we describe a number of modifications and refinements which have proved essential in obtaining intact conalbumin mRNA in high purity and high yields. These refinements include: (a) improved purification of conalbumin in order to remove contaminating proteins that result in impure antibodies; (b) improved isolation of specific conalbumin antibody in high yields; (c) improved methods for reducing contamination by non-specific polysomes; (d) improved techniques for isolation of RNA from immunoprecipitates resulting in less degradation and higher recovery of conalbumin mRNA; (E) improved techniques for efficient translation of conalbumin mRNA involving treatment of the RNA with methylmercury prior to translation. We conclude that problems involved in the immunoprecipitation of different mRNAs may differ, and that various refinements in techniques may be required for obtaining highly purified preparations of intact mRNA in high yields.


Mechanism of O-specific polysaccharide biosynthesis in Salmonella serogroups C2 and C3.

Cell envelope and soluble glycosyl transferase preparations from Salmonella newport (serogroup C2) and Salmonella kentucky (serogroup C3) were found to catalyze formation of polyprenyl pyrophosphate tetrasaccharides corresponding to the structure of the repeating unit of the main chain of O-specific polysaccharides. Plant polyprenyl phosphate may serve as an exogenous sugar acceptor. Galactose residue is an initiator of a chain growth: transfer of galactosyl phosphate from uridine diphosphate galactose onto the acceptor is followed by two consecutive mannosyl transfers from guanosine diphosphate mannose and rhamnosyl transfer thymidine diphosphate rhamnose. Uridine diphosphate glucose and polyprenyl phosphate are converted by the enzyme preparations into polyprenyl monophosphate glucose which may transfer a glucosyl residue onto the polyprenyl pyrophosphate oligosaccharides. The resulting pentasaccharide derivatives may be polymerised by enzymes present in cell envelope preparations. The significance of these results for the understanding of the mechanism of O-specific polysaccharide biosynthesis is discussed.


Routes of thrombin action in the production of proteolytically modified, secondary forms of antithrombin-thrombin complex.

The reaction between thrombin and antithrombin results in the formation of an inactive, stable, equimolar complex between the two proteins. However, under most reaction conditions several secondary complex forms, which have lower apparent molecular weights in dodecyl sulfate/polyacrylamide gel electrophoresis, appear concomitantly with or immediately following the production of the primary form of the complex. Purification of nascent, intact complex and treatment of this complex form with thrombin demonstrated that these subsidiary forms of antithrombin-thrombin complex may arise by proteolysis of the nascent complex by excess thrombin. Dissociation of such proteolytically modified complex preparations by hydroxylamine, and examination of the dissociation products by dodecyl sulfate/polyacrylamide gel electrophoresis suggested that degradation occurs primarily in the thrombin part of the complex, and only after prolonged proteolysis in its antithrombin moiety also. Incubation of antithrombin with several autolytically modified thrombin preparations showed that formation of subsidiary complex forms can also occur by an alternative route, i.e. between premodified thrombin forms and the inhibitor. In contrast, complex formation between thrombin and active forms of antithrombin, which have been modified by thrombin before complex formation, is unlikely, since no such active forms of antithrombin could be demonstrated.


Bacteriophages of Streptococcus pneumoniae. Physicochemical properties of bacteriophage Dp-4 and its transfecting DNA.

The properties of Dp-4 phage and its DNA have been studied. The phage has a polyhedral head of 60 nm diameter, a tail 155 nm long and a buoyant density in CsCl of 1.48 g/cm3. Analysis by acrylamide gel electrophoresis indicates the presence of five polypeptides. Dp-4 DNA has a molecular weight of 37 x 10(6), a melting point of 83.5 degrees C (when dissolved in 0.15 M NaCl/0.015 M sodium citrate, pH 7.0) and a G + C content of about 33%. Denaturation of DNA yields two strands of different buoyant density in a neutral CsCl gradient. The interaction of poly(U, G) with the heavy strand strongly enhances its density and allows the preparative separation of both strands. Native Dp-4 DNA has unusual physical properties: abnormally low buoyant densities both in CsCl (1.666 g/cm3) and in Cs2SO4 (1.410 g/cm3) (which do not correspond to the value predictable from the G + C content of the DNA), and a high thermal stability at low ionic strength.


Central nervous system involvement in severe arterial hypertension of childhood.

The case histories of 125 children with hypertension and no apparent primary CNS disease were analyzed for neurological symptoms or complications. Eleven children had neurological symptoms of high blood pressure. In only one of these patients was the diagnosis of arterial hypertension made before the observation of the neurological findings. The symptoms were severe headache in eight children, convulsions and coma in four, hemiplegia in two, and impaired vision and apraxia in one child. Symptomatology was rapidly reversed by antihypertensive treatment in four children, while six had long-term stigmata and one child died in hypertensive crisis. Because elevated arterial pressure can cause severe neurological disease, routine blood pressure measurement in children--especially those with neurological symptomatology--is stressed.


The radiological evaluation of children with hypertension.

The value of radiological examinations in hypertension was analyzed in a series of 44 children. An i.v. urography had been performed in 43 cases with a pathological finding in 19 (44%). Renal angiography, employed in 19 cases, revealed abnormal findings in 12 (63%) patients. Micturating urethrocystography performed in 16 children gave no additional important information. The only complication noted was thrombosis of the femoral artery subsequent to renal angiography in one child less than one year of age. The diagnosis of hypertension based mainly on the i.v. urography in 12 cases but the renal angiography gave additional important information in 6 children. One child with obstructive hydronephrosis was also found to have a renal artery stenosis at renal arteriography. Based on these results, and particularly because secondary hypertension may frequently be treated surgically, we consider extensive radiological investigation with renal angiography is mandatory before receiving a final diagnosis of essential hypertension, and before starting long-term treatment.


Elucidation on sudden death in children with the mucocutaneous lymph node syndrome.

Atrial pacing was carried out in six children aged one year to eleven years with the mucocutaneous lymph node syndrome (MCLS) during cardiac catheterization. The cardiac index (CI) was measured before pacing and at pacing rates of 150 and 180/min. The CI increased in cases which did not show any pathological findings on the coronary artery angiograms. Conversely, CI decreased at a pacing rate of 150/min, in the case which showed arterial stenosis. Atrial pacing with measurement of CI may be a good method for detecting and evaluating coronary artery lesions in children with MCLS.


Investigation of accelerated metabolic function in small for gestational age infants.

Small for gestational age (SGA) infants are known to develop relatively mild transient hyperbilirubinaemia, especially in comparison with premature infants. This may be interpreted as an index of accelerated maturation of particular vital functions. In the present study 12 SGA infants, 12 appropriate for gestational age (AGA) infants, and 12 premature infants had 24 h urine collections under standardized conditions on the third day of life. Urinary excretion of D-glucaric acid and creatinine, which can be increased by drugs (e.g. phenobarbital), were estimated. Haematocrit and bilirubin were determined at the age of 72h. In the 3 groups, the SGA infants had the highest mean haematocrit (SGA = 0.58, AGA = 0.5, Prem = 0.561/1) and the lowest mean bilirubin (SGA = 6.3, AGA = 8.6, Prem = 11.1 mg/dl). Despite a comparatively small urine volume (SGA = 19.6, AGA = 28.3, Prem = 37.3 ml/kg), excretion of D-glucaric acid (SGA = 0.18, AGA = 0.11, Prem = 0.06 mumol/kg) and creatinine (SGA = 101.6, AGA = 79.6, Prem = 80.2 mumol/kg) was significantly higher in the SGA infants. While the results do not provide conclusive evidence, the increased excretion of glucaric acid and creatinine associated with mild transient hyperbilirubinaemia can be considered an indicator of metabolic differences in SGA infants.


Clinical, morphological, and biochemical investigations on a patient with an unusual form of neuronal ceroid-lipofuscinosis.

A patient with a progressive neurological disorder beginning at the age of three years is described. Mental and visual disturbances were the first signs, soon followed by ataxia and myoclonic jerks. Fundoscopy revealed a decreased pigmentation of the retina. Ultramicroscopic investigations of muscle and skin disclosed the typical changes seen in the late infantile and juvenile forms of neuronal ceroid-lipofuscinosis. In contrast to the clinical and ultrastructural findings, the fatty acid pattern of the serum lecithin showed a significant increase of arachidonic acid and a corresponding decrease of linoleic acid which is characteristic of the so-called infantile form of neuronal ceroid-lipofuscinosis (Hagberg-Santavuori variant; polyunsaturated fatty acid lipidosis). The obvious heterogeneity of the clinical, histological and laboratory findings within the subgroups of neuronal ceroid-lipofuscinosis is briefly discussed.


Reduced mucosal blood flow and acid secretion related to accelerated healing of gastric ulcer in rats after omentectomy including partial gastric devascularization.

Gastric ulcers were produced in rats by local application of acetic acid to the serosal surface of the stomach. In half of the animals the greater omentum was excised just before the application of acid. Gastric mucosal blood flow was estimated by means of the (14C)-aniline clearance technique. Gastric acid secretion was determined under basal conditions and under pentagastrin stimulation. Removal of the greater omentum resulted in accelerated healing of the gastric ulcers. Maximal acid output and mucosal blood flow were found to be decreased in omentectomized animals 24 h after ulcer induction. 3 weeks later the secretion and blood flow in omentectomized animals did not differ significantly from the values of the control animals. The accelerated ulcer healing in omentectomized animals is assumed to be due to decreased acid secretion resulting from decreased mucosal blood flow following partial devascularization of the stomach.


Tissue PO2 during reanimation with hemoglobin solutions.

Solutions of conventional stoma-free hemoglobin (SFH) and of pyridoxylated stoma-free hemoglobin (SFH-PLP) were compared in a dog model of reanimation from severe arterial blood loss. SFH and SFH-PLP restored central hemodynamics after infusion without yielding significant differences between the experimental groups. To cope with the developing hypovolemia, Ringer's lactate load amounted to about 120 ml/kg, edema formation was not encountered. Skeletal muscle oxygenation was studied by means of a multiwire platin electrode. The infusion of SFH-PLP was associated with a shift to the right of the cumulative PO2-distribution curve, indicating better tissue oxygenation. Oxygen was not unloaded from SFH in plasma unless the oxygen extraction from red cell hemoglobin exceeded 40%. Oxygen unloading was, however, improved when SFH-PLP with low oxygen affinity was used. Thus, SFH-PLP merits further consideration as a short-term oxygen-carrying blood substitute.


Phospholipase A2 in serum and ascitic exudate in experimental acute haemorrhagic pancreatitis in pigs.

We have developed a model of experimental haemorrhagic pancreatitis in pigs with a 100% mortality within 24 h without treatment. In this model we have studied the production of peritioneal exudate and compared the concentrations of amylase, lipase and phospholipase A2 in the ascitic exudate and serum. The results suggest that the determination of phospholipase A2 might be important in the diagnosis and follow-up of acute pancreatitis.


Prognostic value of urinary fibrinogen degradation products in bladder carcinoma.

In this study, the value of urinary fibrinogen degradation products as a biological marker of bladder carcinoma has been studied. An increase in fibrinogen degradation products was found in 86% of bladder cancer patients independent of the fact that they had active tumors or that they were disease free. A highly significant correlation between the amount of the increase, the grade, local invasiveness, and the risk of recurrence of the tumor has been established. One can conclude that urinary fibrinogen degradation products are of great prognostic value in patients with bladder carcinoma.


Reconstructing of the right ventricular outflow tract using an inlayed aortic root homograft.

Our experience with the use of a fresh antibiotic sterilized aortic root homograft inlayed into the right ventricular outflow tract is described. With this technique, compression of the graft between the sternum and heart has been avoided and residual right ventricle to distal pulmonary artery pressure gradients have been small. The functional status of the survivors is good over a follow-up period of up to 3 yr. The advantages of this approach compared with a conventionally placed heterograft conduit or an outflow tract gusset are discussed.


Short-term prognostic index in acute myocardial infarction. Multivariate analysis by Cox model.

A new multivariate stepwise linear regression analysis (Cox's model) with survival time as prognostic endpoint was utilized in 281 patients with acute myocardial infarction. From 18 prognostic factors occurring during the first 5 days in the Coronary Care Unit a new prognostic index was calculated for the chance of survival in the first 36 days after admission. The significant prognostic variables were heart failure, cardiogenic shock, atrioventricular block and age. The total group of patients was classified in 6 subgroups with different mean indices and prognosis. There were 2 large groups of patients with relative bad and good prognosis (with and without heart failure). Over half of the patients had no prognostic variables. There was a trend of overestimating the expected deaths. A definite cardiac cause of death was shown by 23 patients (82%). This prognostic index based on the 4 variables can for the individual patient predict the chance of survival, which can be the basis of an individualized duration of hospital stay.


Echocardiographic aortic root motion in ventricular volume overload and the effect of mitral incompetence.

Echocardiographic aortic root motion in systole was studied in 57 patients: 13 normal subjects, 4 patients with left ventricular (LV) volume overload due to anaemia, 16 patients with mitral incompetence, 13 with aortic incompetence and 11 with mitral stenosis. In normal subjects, patients with mitral stenosis and in patients with LV volume overload, in whom the increased stroke volume was ejected forwards into the ascending aorta (anaemia, aortic incompetence) the amplitude of motion of the posterior aortic wall (vp), the aortic widening fraction (AWF) and total aortic motion (TAM) were increased. In mitral incompetence, however, despite the large increase in total LV stroke index, there was a decrease in vp (P less than 0.01), AWF (P less than 0.001) and TAM (P less than 0.001), and the decrease in aortic motion for a given stroke index was related to the mitral regurgitant fraction, indicating that aortic wall movement in systole depended predominantly on forward ejection of the LV stroke volume. Reduced echocardiographic aortic root motion and widening during systole are useful echocardiographic signs of mitral regurgitation.


Failure of pacemaker electrode leads.

With the application of new power sources to pacemakers, considerable improvement has been achieved in the theoretical implant lifetime of current pulse generators, and equally reliable electrode leads will be necessary to ensure long-term pacing. The durability of the electrodes implanted in the past ten years in this centre has been carefully studied. The findings suggest that the use of a more durable conductor material and development of the concept of a 'fail safe' lead (using multi-filament conductors or a secondary conductive pathway along the electrode) will be necessary to match with the implant lifetime of the newer pulse generators. The diagnosis and management of broken conductors is discussed.


An anatomical orthogonal four-electrode X-Y-Z lead system for universal ECG recording.

Features of the P, QRS and T waves in the normal 12-lead ECG have been measured and the information displayed is estimated to be 75% redundant. The high level of redundancy results in an excessive volume of superfluous data. A simple 4-electrode 3-lead X-Y-Z system has been developed and is proposed for wide use in electrocardiology. The electrodes are anatomically orthogonal rather than electrically orthogonal. In a clinical test using only 3 of the standard leads, 95 of 100 records could be adequately interpreted. This high level of satisfactory interpretation with 3 leads has been experienced by other investigators. The 4-electrode system is currently being used for studies in high fidelity electrocardiology. It is suggested that a more appropriate name for vectorcardiogram (VCG) would be correlocardiogram (CCG). The 4-electrode system would simplify and be useful for this application. A simple 4-electrode 3-lead X-Y-Z system would facilitate the teaching recording and interpretation of ECG information by eliminating excessive redundant data. Evaluation of this lead system by other investogators is invited.


Patterns of activation in ventricular arrhythmias of late myocardial infarction in dogs.

Ventricular arrhythmias were produced in 12 dogs 4 to 6 days after coronary artery ligation by programmed ventricular stimulation. The electrocardiogram and 7 composite electrograms from endocardial and epicardial surfaces of the ischemic, border and normal zones, as well as from the right ventricle, were recorded during and after programmed ventricular stimulation. The ventricular arrhythmias were preceded and sustained by delayed, fragmented activity in the ischemic epicardial zone bridging diastole. Efferent pathways from the ischemic epicardium led to direct epicardial spread to adjacent normal epicardium in most instances. Efferent pathways into the endocardial regions were also observed, but to a lesser extent. The efferent reentry pathways led to both ventricles, and produced right and left ventricular arrhythmias in 8 of the 12 dogs; they were exclusively of left ventricular origin in the remaining 5. Classification of right and left ventricular arrhythmias may only be related to the exit points and not necessarily to their origin.


Cardiac responses to impulse exercise and recovery: systolic time intervals.

Exercise responses depend on work load and its pattern of delivery. Administering a very brief ("impulse") load aims to elicit significant responses through biologic sensitivity to rate - rather than degree - of change. Electrocardiograms, systolic time intervals (STI) and heart rate (HR) were recorded continuously in 10 normal subjects during  and after brief (20-sec) bicycle exercise at 50, 100 and 150 W. The purpose of this protocol was to identify a low load impulse-type exercise challenge which would be optimal in terms of (a) reproduction of the time course of exercise changes produced by longer duration (steady-state) exercise, (b) rapid achievement of quantitative responses reaching some or all of the steady-state changes at comparable work load, and (c) absence of ST changes in normal subjects. The onset of exercise produced the greatest rates of change. Directional changes and time course of all measurements paralleled those of steady-state exercise and recovery at the same loads: HR, ejection time index (ETI) and corrected ejection time (ETc) increased sharply; preejection period (PEP) and PEP/LVET fell sharply. Ejection time (LVET), stable through most of exercise, "paradoxically" decreased for up to 15 sec of recovery despite decreasing heart rates. For all measurements, restitution to control levels was complete by one minute of recovery.


Left ventricular pump function in effort angina.

The successive deterioration of left ventricular pump function during exercise-induced angina pectoris was studied in 20 candidates for aortocoronary bypass surgery. Left ventricular stroke work and power were calculated from continuous left ventricular pressure recordings and repeated measurements of cardiac output every 30 sec using the thermodilution technique. The average left ventricular enddiastolic pressure (LVEDP) increased continuously during exercise whereas stroke work index (SWI) did so only in the beginning of the exercise period up to a maximum value and then fell towards the end of exercise. The onset of angina occurred at an average LVEDP of 34 mm Hg when SWI had already started to fall in most patients. During exercise all patients had markedly lower SWI than normals. Patients with high coronary arteriographic score and patients with a previous myocardial infarction had significantly lower SWI during exercise than those with low score or those without a previous infarct. At rest there were no differences between these groups which emphasises the importance of haemodynamic measurements under stress conditions in patients with ischaemic heart disease.


Restoration by serum thymic factor of colony-forming unit (CFU-S) entry into DNA synthesis in thymectomized mice after T-dependent antigen treatment.

Adult thymectomy prevents stimulation of hematopoietic stem cells as measured by colony-forming units (CFU-S) if T-dependent antigens are injected, but not when T-independent antigens are used. This can be observed as soon as 10 to 15 days after thymectomy. The serum thymic factor can restore CFU-S response to T-dependent antigens in thymectomized mice.


Dopamine modulation of acetylcholine release from the guinea-pig brain.

The effect of dopamine (DA) and apomorphine (Apo) on acetylcholine (ACh) release from guinea-pig brain was investigated (i) in superfused slices of cerebral cortex, caudate nucleus, tuberculum olfactorium, brain stem and (ii) in unrestrained, unanaesthetized animals, provided with epidural parietal cups. DA reduced the ACh release only from slices of caudate nucleus, whereas Apo was also effective in the cerebral cortex. DA and Apo inhibition in caudate nucleus was antagonized by spiroperidol. The injection of DA (1.5 and 5 micromoles) into the cerebral ventricles (i.c.v.) caused a late, moderate behavioural stimulation and enhanced ACh outflow from the parietal cortex. The injection of Apo, either i.c.v. or i.p., promptly elicited similar effects. Spiroperidol 0.5--2 mg/kg i.p. counteracted the behavioural stimulation by Apo and amphetamine, but unexpectedly enhanced the cortical ACh outflow, leaving unaffected the cholinergic responses to Apo and Amphetamine. These results show that DA directly hinders ACh release from the striatal cholinergic structures surviving in vitro, via classical neuroleptic-sensitive receptors. On the other hand, the enhanced cortical ACh outflow caused by DA and DA-mimetic drugs in the unanaesthetized animals is suggestive of a disinhibition of the corticopetal cholinergic neurones, via neuroleptic-insensitive mechanisms. Hence, the 'paradoxical' effect of spiroperidol might represent the consequence of the increased activity of nigral DA cells with collaterals possibly involved in the control of the ascending cholinergic pathways.


Effects of the beta-adrenergic blocking agents propranolol and timolol on canine cardiac refractory periods.

The effects of d,1-propranolol and 1-timolol on cardiac refractory periods (RP) were compared in 14 phentobarbital-anesthetized dogs using endocavitary His bundle electrograms and programmable electrical stimulation. Beta-blocking agents were injected at cumulative doses in each dog at 3 day intervals. A control group (6 dogs) received 4 successive saline injections at the same time intervals. RP measurements at a constant drive rate were done before and 10 minutes after each dose of either drug or saline. Propranolol and timolol produced a dose-dependent increase of atrial and atrioventricular nodal refractory periods; dose-response curves were parallel. Depending on the parameter chosen timolol exerted an 8--36 times more potent effect than propranolol. The effects of propanolol and timolol on ventricular effective (VERP) and functional (VFRP) RP were measured in 6 dogs. Both drugs increased VFRP significantly, but saline had the same effect. Only the higher doses of timolol increased VERP significantly. These data confirm that blockade of myocardial beta-adrenergic receptors exerts predominant effects on supraventricular refractoriness and that in anesthetized dogs timolol has more potent beta-blocking properties than does propranolol.


Mechanisms of bronchoconstriction and of thrombocytopenia induced by collagen in the guinea pig.

Collagen injected to guinea pigs i.v. increased the pulmonary resistance to inflation (bronchoconstriction) and induced thrombocytopenia. Immune platelet depletion protected against the effects of collagen, and has been shown not to prevent bronchoconstriction induced by the prostaglandin/thromboxane A2 precursor arachidonic acid. Use of inhibitors demonstrated that histamine, serotonin, acetylcholine and bradykinin were not involved with the effects of collagen in the guinea pig. Aspirin and indomethacin inhibited collagen-induced bronchoconstriction completely and thrombocytopenia partly, supporting the hypothesis that the former is prostaglandin cyclo-oxygenase dependent, whereas the latter has a thromboxane A2-independent mechanism as well. Carrageenan, heparin and reserpine inhibited the in vivo effects of collagen to various extents, but their precise mechanism of action could not be discovered. Collagen-induced bronchoconstriction is strictly platelet and thromboxane A2-dependent.