Initiation of protein synthesis in eukaryotes. Binding to Sepharose-heparin and partial purification of initiation factors from Krebs II ascites cells. By means of affinity chromatography of lysates from Krebs II ascites cells and rabbit reticulocytes on Sepharose-heparin an active fraction of initiation factors has been obtained. The fraction is eluted from the column at 350 mM KCl using a linear gradient and displays a number of activities, i.e. binding of Met-tRNAfMet to form a ternary complex with GTP; transferring this complex to 40-S subunits in an A-U-G-independent step and finally coupling of the 40-S initiation complex to the 60-S subunit, a reaction which is completely A-U-G-dependent. Moreover, MettRNA is bound into the P-site as is indicated by its puromycin sensitivity. The method is very suitable for large-scale preparation. Further purification and characterization of the factors have been carried out on DEAE-cellulose and phosphocellulose columns. Evidence is presented that the polysomes present in a lysate that has been passed through the Sepharose-heparin column can only complete their nascent chains, initiation of new polypeptides is completely dependent on addition of initiation factors.


Tissue limited mosaicism for unbalanced autosomal translocation in a child with congenital anomalies and mental retardation. We studied a patient with a sporadic mental retardation/multiple congenital anomalies syndrome. Chromosome analysis showed a 46,XX, inv(9)(p 11;q13) karyotype in all lymphocytes. Fibroblasts from two separate skin biopsies revealed a mosaic karyotype. Some 22.5% of fibroblasts had a karyotype like that of the lymphocytes, while 77.5% of fibroblasts had a karyotype 46,XX,inv(9)(p11;q13),der(12),t(12;?)(P13;?). The data in this case emphasize the drawbacks of confining cytogenetic analysis to lymphocytes.


The characteristics of amylase activity and the isoamylase pattern in serum and urine of infants and children. Determination of amylase activity and isoamylase patterns were performed in serum and urine of normal newborns, infants and children of different ages. In the serum of newborn infants measurable amounts of amylase were present. The activity increased with the age and reached the normal adult level by approximately 8 months of age. Isoamylase analysis revealed that the low level of serum amylase in infants was mainly due to deficiency of the pancreatic-type isoamylase. The absence of the pancreatic isoamylase in newborns and young infants is a physiological and developmental phenomenon. Great caution is therefore necessary when amylase isoenzymes are used in the diagnosis of abnormal pancreatic function and such results have always to be interpreted in relation to the age of the child.


Studies on the kinetics and renal excretion of low and high molecular weight dextrans in preterm babies, newborns and young infants. Administration of low and high molecular weight dextrans in the initial phase of shock is no longer controversial. The special conditions in newborns, however, have been insufficiently considered in planning therapy. This investigation aimed at determining the biological half-lives of dextran 40 (Rheomacrodex) and dextran 60 (Macrodex) in this age group. The half-life of dextran 40 was found to be 60 min and that of dextran 60 3 h. Preterm babies and newborns excrete up to 25% less dextran 40 and 60 in 24 h than infants and adults. Normal adult values for excretion are only reached towards the end of the first year of life.


The effects of oral alanine administration on blood glucose, pyruvate, lactate, serum glucagon and insulin in human newborns. Alanine (500 mg/kg body weight) was given orally to 27 healthy full term newborn infants, and the changes in blood glucose, pyruvate, lactate, alanine, glucagon and insulin were determined. Significant increments in blood glucose were found in 15 infants with blood glucose levels below 60 mg/100 ml, 4 of whom showed significant elevation of serum glucagon levels on day 1. This observation suggests that hepatic gluconeogenesis is possible immediately after birth.


Mechanism of diet-induced uraemia and acidosis in infants. Five patients aged between 40 and 70 days were admitted to our Clinic with an initial diagnosis of "renal failure", but the high levels of urea nitrogen, metabolic acidosis and oliguria were found to be related to a high renal solute load and to the very high protein and electrolyte content of the diet. By calculating urinary output (V/m'), clearance of osmotically-active substances (COsm), clearance of free water (CH2O), maximum tubular reabsorption of water (TcH2O) and the change in metabolic H+ production, it has been possible to demonstrate that dietary protein and electrolytes were both responsible for the high blood urea nitrogen levels and metabolic acidosis.


3,3',5'-Triiodothyronine (Reverse T3) in amniotic fluid and cord serum. 3,3',5'-triiodothyronine (reverse T3, rT3) was measured in 122 samples of amniotic fluid obtained between the 29th--40th weeks of gestation, and in the blood of 37 newborn and their mothers. The mean rT3 concentration in amniotic fluid was 0.769 +/- 0.47 ng/ml, with a slight decrease from the 29th--40th weeks of gestation which was not statistically significant. Because of the great scatter of rT3 concentrations in amniotic fluid, its estimation does not seem to be useful in prenatal diagnosis of hypothyroidism. The mean rT3 concentration in cord blood (2.62 ng/ml; range 1.4--4.9 ng/ml) was greatly elevated in comparison to the mean maternal level at delivery (0.34 ng/ml; range 0.08--0.69 ng/ml). The possible use of rT3 measurements in cord blood as a screening test for congenital hypothyroidism is discussed.


Congenital sinus bradycardia combined with congenital total atrioventricular block. Sinus bradycardia and total atrioventricular block were found at the age of seven months in a boy who is now 16 1/2 years old. According to Yaters (1929) criteria, these are likely to be congenital disorders. While the frequency of the ventricular impulse generator in the upper bundle of His only slowed in accordance with age during the period of observation, the sinus node activity deteriorated considerably. Finally potentials could only be sporadically demonstrated. Under heavy stress and with a simultaneous slight increase in ventricular frequency, a re-occurence of regular but slow sinus node activity came about. The cause of this binodal disorder of rhythm is unknown. There is no indication of family affliction or of myocarditis in early childhood. Congenital heart disease could also be excluded.


The effect of aging on synaptosomal Ca2+ transport in the brain. The effect of aging on Ca2+ -transport in synaptosomal preparations from rat brains was assessed by measuring the accumulation of radioactive 45Ca within these particles. Four groups of rats at 6, 12 24 and 30 months of age were used for this study. Synaptosomal particles were isolated from the cerebral cortex of each animal and the radioactive 45Ca inside the particles were measured after incubating the particles with media containing an energy source and 45Ca Cl2. Results indicated that the transport of 45Ca was lower in the younger rats than the older groups. A 20% increase was consistent with the old rats (30 mo) as compared with the young ones (6 mo). The increase in Ca2+ -transport across synaptic plasma membranes may be related to the transmitter release and behavioral activity after senescence.


Age-related decline in receptivity in normal, neonatally androgenized female and male hamsters. The pattern of female sexual behavior shown by aging male and female hamsters was related to exposure to perinatal androgen. Twenty-five female and 37 male hamsters in Experiment 1 was gonadectomized on the day of birth or at 43 days of age. The received 11 tests for receptivity between the ages of 28 and 66 wk. In Experiment 2, 83 females were implanted with a Silastic pellet containing 3, 1, 3 or 9% testosterone (T) or testosterone propionate (TP) by weight from the second to the tenth day of life, and tested approximately every 2 wk from 22 to 58 wk of age. Receptivity was induced by estradiol benzoate and progesterone injected before each 600 sec mating test. Normal females exhibited the highest lordosis scores, followed by minimally androgenized females and males castrated at birth. High doses of exogenous or endogenous perinatal T suppressed receptivity throughout the animal's lifespan, but did not accelerate the rate of decline in female behavior over time. Non-androgenized animals showed the greatest decrease in receptivity with advanced age.


Behavior of immature and middle-aged mice as a function of dietary protein. The differential effects of continued maintenance on a 12% vs. 24% protein diet were examined in immature and middle-aged male and female C57BL/6J mice. Exploratory behavior, body weight and fluid consumption of water, saccharin and quinine were monitored over 9 weeks of presentation of the special diets. No rehabilitation datawere obtained. The dietary manipulations differentially effected the various groups, but the pattern of change in behavior was a function of the age and sex of the subject and the specific measure employed.


Determinants of anagram problem solution in adulthood. An evaluation of the indices proposed in the literature regarding measures of anagram difficulty was made by asking three groups (ages 17-26, 39-51, 59-76) of adults (n = 54) to solve a list of 30 anagrams. Results indicated that only two of these indices (Thorndike-Lorge and Bigram Rank measures) significantly predicted frequency of solution in samples beyong college age. It was also found that the cognitive variable mediating the effects of these indices in middle aged and elderly subjects was crystallized ability, suggesting an experiential basis for the effects of both task and organismic variables as determinants of anagram problem solving in adulthood. The role of fluid ability as a mediator of problem solution in the young received limited support.


Sex differences in serial learning for aged persons with high verbal ability. Serial rote learning was examined in men and women with high verbal ability aged 60-74 years. No sex differences were found in total errors, commission errors, or omissions errors. The results are in accord with the findings reported in a study by Wilkie and Eisdorfer (1977) and suggest that high verval ability may, in part, mediate sex differences in serial learning.


Aging, and crosslinking in mammlian collagen. The amount and type of borohydride-reducible crosslinks in collagen have been examined as a function of animal age. In a variety of bovine, canine and human tissues the level of redicible crosslinks decreases with time and the ratios of individual compounds change. There is both tissue and species specificity in the extent of these changes. A decrease in the level of reducible crosslinks correlates with the cessation of growth. Loss of reducible crosslinks does not imply a small total number of crosslinks since physical changes with age imply the opposite. We conclude that reducible crosslinks are converted to a stable nonreducible state and the persistence of low levels of reducible crosslinks may be indicative of a low level of turnover in the tissue. Changes in ratios of reducible crosslinks are of doubtful functioal significance and may simply reflect variation in post-translational modification of lysine residues.


The effect of metiamide in in vitro and in vivo canine models of type I hypersensitivity reactions. The histamine H2-receptor antagonist metiamide was evaluated in in vitro and in vivo canine models of immediate-type hypersensitivity reactions. At concentrations of 2 and 4 X 10(-4) M, the antagonist significantly increased the amount of histamine present in the medium surrounding passively sensitized canine lung fragments which had been challenged with ascaris antigen. In contrast, the compound was without effect on the release of a slow reacting substance of anaphylaxis. On the basis of these observations metiamide was investigated in an in vivo canine model of allergic asthma. At doses of 10, 30 and 50 mu moles/kg, the antagonist did not enhance the ascaris antigen-induced pulmonary pathophysiology. Similarly, at 10 and 50 mu moles/kg metiamide did not alter histamine-induced increases in pulmonary resistance or decreases in dynamic lung compliance. Insofar as the canine model of allergic asthma may be predictive of the human disease, it could be anticipated that the use of histamine H2-receptor antagonists may not be deleterious to allergic asthmatics.


Interactions of substance P with putative mediators of inflammation and ATP. Substance P has recently been localized in sensory nerves and has been suggested to be the mediator of antidromic vasodilatation. Interactions of substance P with putative mediators of inflammation and adenosine 5'-triphosphate were studied in rats using a quantitative Evans blue dye-leakage technique. Rats anaesthetized with either were given Evans blue. i.v. and intracutaneous injections of inflammatory agents were given into the shaved abdominal skin. Doses of substance P, 1-5 X 10(-10) mol, produced graded dye leakage. A low dose of substance P (5 X 10(-11) mol) potentiated responses to 5-hydroxytryptamine (2.5 X 10(-10) mol), bradykinin (5 X 10(-10) mol), prostaglandin E1 (5 X 10(-10) mol) and adenosine 5'-triphosphate (2.5 X 10(-7) mol) but no histamine (2 X 10(-8) mol). A higher dose of substance P (5 X 10(-10) mol) was potentiated by prostaglandin E1 (5 X 10(-11) mol) and adenosine 5'triphosphate (5 X 10(-9) mol) but but not by histamine (5 X 10(-10) mol) or bradykinin (5 X 10(-11 mol) and was inhibited by 5-hydroxytryptamine (5 X 10(-12) mol). If substance P is released from sensory nerves in some inflammatory states these interactions might be of importance in determining the response observed.


Amphetamine discrimination as a test for anti-parkinsonism drugs. Rats were trained and tested on a two-lever discrimination task based upon the presence or absence of 0.8 mg/kg d-amphetamine. After 80% criterion performance was attained, dopaminergic drugs reported to be effective in the treatment of Parkinson's disease were tested to investigate their ability to produce d-amphetamine-like responding. Amantidine (50 mg/kg), apomorphine (2.5 mg/kg), n-propylnoraporphine (0.1, 0.2 and 1.0 mg/kg), and piribedil (25 mg/kg) were all observed to produce d-amphetamine-appropriate responding. These results indicate that discriminative behavior controlled by d-amphetamine is mediated by central dopaminergic systems and the use of this technique in the evaluation of potential anti-Parkinsonism drugs is discussed.


Central serotonin-like activity of 6-chloro-2-[1-piperazinyl]-pyrazine (CPP; MK-212). CPP, administered systemically, elicited four distinct responses characteristic of serotonin-receptor activation in the central nervous system. The crossed extensor reflex in the acutely spinalized rat was enhanced by treatment with CPP, 1-16 mg/kg. CPP, 1.11-10 mg/kg, elicited a dose-related increase in head twitches in mice. A complex motor syndrome in rats similar to that produced by pargyline plus tryptophan (or other treatments effecting increased activation of central serotonin receptors) was produced by 1.25-5 mg/kg of CPP. An increase in twitch frequency of the mylohyoideus muscle in the urethane anesthetized rat occured after CPP at 0.1 mg/kg or less. Complete abolition of all four effects of CPP was achieved by pretreatment with the centrally acting indoleamine antagonist methergoline. The peripherally acting serotonin antagonist xylamidine was ineffective or only weakly active, depending upon the test procedure, in preventing the serotonin-like actions of CPP. These findings indicate that CPP has a serotoninmimetic action in the central nervous system.


Delayed appearance of propranolol sensitivity in cultured heart cells. Examination of the appearance of adrenaline responsiveness and propranolol sensitivity with culture age in myoblasts cultured from neonatal rat hearts shows that propranolol sensitivity lags behind adrenergic responsiveness. Such a finding may illustrate subtle differences in sites for agonist and antagonist at the beta-receptor of these cells.


Radioimmunological determination of thromboxane release in cardiac anaphylaxis. A sensitive and specific radioimmunoassay for thromboxane B2 were detected in perfusates of anaphylactic guinea pig hearts. Indomethacin decreased thromboxane B2 levels in the perfusates to below the detection limit of the radioimmunoassay and concomitantly delayed the onset of coronary vasoconstriction after antigenic challenge.


Influence of several anesthetic agents on the effect of delta9-tetrahydrocannabinol on the heart rate and blood pressure of the mongrel dog. delta9-Tetrahydrocannabinol (delta9-THC) 1 mg/kg, i.v. produced a slight but significant reduction in the heart rate of conscious mongrel dogs, and these effects were greatly potentiated by pentobarbital and/or urethane anesthesia. However, significant increase in the heart rate was noted following delta9-THC administration in the dogs anesthetized with a combination of morphine plus chloralose; further, neither morphine nor chloralose alone could reverse the bradycardic effects of delt9-THC. Tachycardia induced by delta9-THC in these dogs could be reversed by bilateral vagotomy or by pretreatment of the animals with methylatropine, or propranolol and/or practolol. The data indicated a complex interaction between delta9-THC and morphine-chloralose combination and the tachycardia induced by delta9-THC under this anesthesia may be due to release of epinephrine by a reflexogenic mechanism involving afferent vagi. Further, while the bradycardic effects of delta9-THC were essentially identical under pentobarbital or urethane anesthesia, the hypotensive effects were similar in urethane or chloralose anesthetized dogs. The study emphasizes that anesthetic interaction should be taken into consideration while investigating mechanisms of actions of pharmacological agents.


Renin-angiotensin mediation of adrenal catecholamine secretion induced by haemorrhage. The mechanism involved in catecholamine (CA) release from cat adrenal gland, in response to haemorrhage was studied. In intact cats, in cats with bilateral cervical vagotomy or following bilateral ureteral ligation, haemorrhage induced an increased catecholamine release from the adrenal (with increased percentage of noradrenaline). Acute bilateral nephrectomy, chronic sodium loading with repeated administration of desoxycorticosterone acetate (DOCA), or acute denervation of the adrenal gland, completely abolished the increased CA release from the adrenal gland following haemorrhage. Haemorrhage induced an increase of plasma renin concentration in intact cats and after ureteral ligation but there was no increase in plasma renin after haemorrhage in cats with bilateral nephrectomy or following pretreatment with DOCA and salt load. Following haemorrhage in intact cats, blood pressure showed an immediate fall followed by rapid recovery. The recovery of blood pressure after haemorrhage was abolished in cats with bilateral nephrectomy. It is concluded that the adreno-medullary response to haemorrhage in the cat, depends primarily on the intact renal renin angiotensin system. Angiotensin, generated peripherally, probably affects the CNS and activates the sympathetic nerves.


Distribution of metaraminol and its relation to norepinephrine. A modified fluorometric procedure of high specificity and sensitivity id described for the analysis of metaraminol (MET) in biological material. With this method the distribution of MET was studied in the rat. Except for brain, peripherally administered MET was well distributed. Organs with a large population of norepinephrine (NE) storage vesicles such as the heart, spleen and adrenal, took up relatively large amounts of MET and retained it longer than those tissues with few vesicles such as the liver, lung and kidney. MET had a longer blood half-life than described for NE in other species. In part, this can be attributed to the lack of metabolism of MET as well as our finding that MET, unlike NE, was concentrated in the cellular fraction of blood. Under the conditions of these experiments there was no close correlation on a concentration or time basis with respect to the appearance and disappearance of MET and NE in various organs. This was particularly evident in the adrenal gland where MET resembled reserpine in that one unit of drug displaced many units of catecholamines. In this case, however, we did not rule out a possible contributing effect via the CNS.


Effects of bovine SRS-A (SRS-Abov) on bovine respiratory tract and lung vasculature in vitro. Evidence from isolated bovine pulmonary vessels and respiratory smooth muscles suggests that bovine slow-reacting substance of anaphylaxis (SRS-Abov) may contribute to bronchoconstriction and pulmonary oedema during anaphylaxis in cattle. Bovine bronchus is sensitive to low concentrations of SRS-Abov and is considerably more sensitive than trachea. Contraction of the calf bronchus to SRS-Abov can be antagonized by sodium meclofenamate, suggesting prostaglandins may be involved in the contraction. Bovine pulmonary artery did not contract to SRS-A at any of the concentrations examined. None of the proposed SRS-A receptor antagonists, FPL 55712, PR-D-92-EA, or sodium meclofenamate, inhibit the effects of bovine SRS-A in bovine pulmonary vein.


Failure of cycloheximide to alter rate of recovery of temperature following acute DFP treatment. Cycloheximide, 400 microgram intraventricularly 4 h after a 1 mg/kg i.m. injection of the irreversible anticholinesterase DFP, failed to alter the rate of recovery of temperature to normal. Tolerance to the hypothermic effects of DFP developed at the same rate in cycloheximide-treated rats. These findings suggest that neither recovery from the acute effects of DFP nor tolerance to its chronic effects depends on protein synthesis.


The prevention of alloxan-induced diabetes in mice by dimethyl sulfoxide. Dimethyl sulfoxide (DMSO, 7.3 g/kg) administered to mice prior to alloxan completely protected against the diabetogenic actions of 50 mg/kg alloxan. The same dose of DMSO provided a partial protection against 75 mg/kg alloxan. This protection against alloxan-induced diabetes is consistent with the scavenging of the hydroxyl radical by DMSO.


The effect of 5-hydroxytryptamine on the chick biventer cervicis muscle. The actions of 5-hydroxytryptamine have been studied in the chick biventer cervicis nerve--muscle preparation. At concentrations between 2.5 X 10(-3) and 3.7 X 10(-3) M, 5HT produced a transient increase in responses to indirect stimulation, but not to direct stimulation. At higher concentrations, 5HT produced a reversible depression of twitches, which was much more marked in indirectly than in directly stimulated preparations. In a concentration range of 2.5-3.7 X 10(-3) M, 5HT increased the response to exogenous acetylcholine but reduced the response to carbachol. After pretreatment with neostigmine, 5HT inhibited responses to both acetylcholine and carbachol. It is suggested that the facilitatory effects of 5HT are due to its anticholinesterase activity. The blocking actions of 5HT are thought to be curare-like. In addition, irreversible toxic effects on the muscle preparations were found after repeated exposures to high concentrations of 5HT.


The jamming avoidance response in Rhamphichthys rostratus: an alternative principle of time domain analysis in electric fish. A Jamming Avoidance Response was found in the weakly electric fish Rhamphichthys rostratus, a South American pulse-Gymnotid. The analysis of the response suggests that it requires a key stimulus which is fundamentally different from that in previously described harmonic Gymnotids. It relies on a sensitivity for the direction of phase shifts of stimulus pulses relative to the fish's own electric organ discharge rather than on a sensitivity for beating frequencies.


Compensation of postural effects of hemilabyrinthectomy in the cat. A sensory substitution process? A photographic technique was used to study the evolution of lateral head-tilt following hemilabyrinthectomy in adult cats. Animals were maintained post-operatively in normally lit conditions (LM cats), in total darkness (DM cats), or in stroboscopic light. In LM casts, the head tilt peaked at 45 degrees (with the lesionned side down) on the second post-operative day, and decreased to about 0 degree within about 10 days. This evolution was followed by rebounds of head-tilt to large angles before a stable compensated head postion could be maintained (approximately at the end of the third post-operative month). In DM cats the head remained tilted by a large angle throughout the duration of the dark period. Re-exposure to light was followed by a rapid decrease of head-tilt. In stroboscopic light, the evolution of head-tilt was found to be closely similar to that in the normally lit condition. Finally, when put back in the dark at a late post-operative stage, already compensated animals were found to loose their symmetrical head position, and to re-acquire a strong head tilt. This effect resumed on re-exposure to light. It is inferred that static visual input is a necessary condition for compensation of the postural deficits of hemi-labyrinthctomy in the cat. Maintenance of a stable head posture also depends upon continuous availability of visual input.


Evidence that GABA is not the afferent transmitter in the cochlea. The GABA antagonists picrotoxin, bicuculline and bicuculline-methochloride, when applied intracochlearly, do not affect the compound action potential of the cochlear nerve. It is therefore concluded that these drugs do not interfere with afferent synaptic transmission, and therefore that GABA is not the afferent transmitter. With very high doses, picrotoxin as well as bicuculline-methochloride partially block the efferent synapses. This effect is most likely to be unspecific, but shows that with the technique used the agents can reach the synaptic site.


Temporal aspects of spatial vision in the cat. Using behavioral techniques, contrast sensitivity for flickering and stationary gratings was measured in ordinary cats. Gratings of low spatial frequency were more easily detected by the cat when temporal modulation was present, but at high spatial frequencies temporal modulation reduced grating visibility. These psychophysical results are consistent with neurophysiological evidence for the existence of two classes of visual cells in the cat, which are distinguishable in terms of their spatio-temporal response properties.


Lamellar organisation in the rat hippocampus. A series of experiments was conducted in the urethane anaesthetised rat to determine the organisation of some hippocampal pathways in this species, using stimulating and recording microelectrodes to elicit and record pupulation spikes. It was found that the mossy fibres, alvear fibres and perforant path were clearly arranged in a lamellar fashion. Lamellar organisation could not be demonstrated for the afferents in the stratum radiatum which include the Schaffer collaterals. It was concluded that hippocampal organisation in this species essentially resembles that in the rabbit and cat.


Degeneration of two of nine types of synapses in the putamen after center median coagulation in the cat. The cat putamen contains the identical nine types of synapses and the same proportion of axo-dendritic (or axo-somatic) synapses as described for the fundus striati. However, type III (cortico-striatal) (31:16%) and type V Caxon-callateral) (13:1%) occur much more frequently and type I (nigro-striatal) much less frequently (14:34%) in the putamen than in the fundus striati. Of the axo-spinous synapses only type IV, with densely arranged small round vesicles and interrrupted, asymmetric contact, shows a dark degeneration after center median lesions, mainly in the parvocellular part. Of the six axo-dendritic (or axo-somatic) synapses, only type VII, with densely packed small round vesicles and asymmmetric contact, is degenerated after the same lesion in the center median nucleus. However, after such lesions type VII synapses are much more frequently degenerated in the putamen than those of type IV.


Extraocular proprioceptive projections to the visual cortex. Electrical stimulation of the intraorbital part of the motor branches of extraocular muscles, where proprioceptive fibers run, evokes responses in 25% of the units of the striate cortex of the cat. The latency ranges between 25 and 40 msec. Mechanical stretch of extraocular muscles evokes multiunit responses in the striate cortex. The response is abolished by injection of xylocaine into the stretched muscle. The suppression of the response is reversible.


Pharmacokinetics of digoxin.

Pharmacokinetics of digoxin. The pharmacokinetics of digoxin, the most frequently used digitalis preparation, are reviewed. The dominate serum turnover time is about 34 hours, and is not affected by the route of administration. Excretion is largely as unchanged digoxin in the urine and this excretion is compromised in renal failure. Serum levels of digoxin (determined by radioimmunoassay) are generally available and are useful clinically in assessment of both toxicity and the state of underdigitalization, even though significant overlap exists. Special problems are presented in patients with myocardial infarction, pulmonary heart disease, and thyroid disease.


Are hormonal contraceptives teratogenic? The widespread use of hormonal contraceptives for a prolonged time in women during the child-bearing period necessitates that appropriate precautions be taken to ensure safety for the patient as well as for her progeny. Hormonal administration during or prior to pregnancy may be potentially teratogenic. Although there have been many reports during the last decade, it has been very difficult to document conclusively such a relationship. Over-all, it seems that hormonal use prior to pregnancy does not lead to an increase in the frequency of chromosomal aberrations or of congenital malformations. The use of certain hormones during pregnancy, on the other hand, may lead to an increase in the incidence of congenital malformations, probably in the genetically predisposed fetus. In view of this concept hormonal contraceptives should not be used to treat threatened abortion, and their use as a pregnancy test should be abandoned. Since the question of the safety of the inadvertent administration of pills during early pregnancy has not been resolved, the mother should be informed of the potential risks.


Oxyphenbutazone--an adjuvant to be used in prevention of adhesions in operations for fertility. A laparotomy was performed in 40 rats and the cecum was subjected to a standardized trauma. Half the rats were treated with oxyphenbutazone in a dose of 40 mg/kg body weight daily for 14 days. The remaining 20 rats served as controls. All of the rats were killed 2 weeks after the laparotomy, and the number of intraperitoneal adhesions was recorded. There were significantly (P less than 0.001) fewer rats with adhesions in the group treated with oxyphenbutazone than in the control group.


Danazol inhibits steroidogenesis.

Danazol inhibits steroidogenesis. Danazol was found to inhibit multiple enzymes of steroidogenesis directly in the pregnant mare serum (PMS)-treated hamster ovary and the rat testis and adrenal in vitro. In the PMS-treated hamster ovary, danazol inhibited 17alpha-hydroxylase, 17,20-lyase, and 3beta-hydroxysteroid dehydrogenase. In the rat testis, danazol inhibited 17alpha-hydroxylase, 17,20-lyase, 3beta-hydroxysteroid dehydrogenase, and 17beta-hydroxysteroid dehydrogenase. In the rat adrenal, danazol inhibited 3beta-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11beta-hydroxylase. Two hours after a subcutaneous injection of 5 mg/kg of danazol to adult male rats, serum luteinizing hormone levels were significantly increased and serum testosterone levels were significantly suppressed. These findings suggest that in the rodent one of danazol's major pharmacologic effects is the direct inhibition of steroidogenesis.


Immunoglobulin e-mediated severe allergy to human seminal plasma. Two women with allergy to human seminal plasma are described. Both patients had generalized and local allergic symptoms, i.e., hypotension, asthmatic dyspnea, urticaria, and vaginal swelling, beginning within a few minutes of intercourse. The antigen causing the reaction in these patients was common to all seminal plasmas examined. Most of the antigenic activity was shown to be present in one protein band detected by acrylamide gel electrophoresis. The seminal plasma reaction was mediated through an immunoglobulin E (IgE) antibody. Passive transfer of the hypersensitivity with the serum of both patients was successful, and the radioallergosorbent test showed that the serum of the first patient contained IgE specific to seminal plasma.


Immunoreactive insulin in serum and seminal plasma of diabetic and nondiabetic men and its role in the regulation of spermatozoal activity. Concentrations of immunoreactive insulin (IRI) and, in some cases, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured in serum and seminal plasma (SP). IRI levels were usually higher in SP. They were unaffected by masturbation; circulating testosterone, LH, and FSH levels were also unaffected. The IRI concentration was higher in the second (vesicular) fraction of split ejaculates. Semen quality was unrelated to IRI in SP in normal and diabetic (chlorpropamide-maintained) men. The addition of insulin in vitro to washed spermatozoa from diabetic and nondiabetic men had no effect on oxygen and glucose uptake or on lactate production and spermatozoal motility. Furthermore, administration of L-arginine to infertile men for 3 months (4 gm/day) was followed in four of seven men by significant increases in IRI concentrations in blood and SP. However, neither semen quality nor fertility was improved.


Morphology of postcoital spermatozoa in the cervical secretion and its clinical significance. Morphologic analysis of spermatozoa recovered 10 hours postcoitally from the human female genital tract and its correlation to the clinical situation have shown that (1) spermatozoa in the vagina are equivalent to those in the semen sample; (2) spermatozoa within the cervical secretion exhibit significantly better morphology than do those of the semen sample, indicating the presence of a barrier against abnormal spermatozoa at the level of the external os; (3) this barrier is significantly more effective in cases where conceptions later occur than in cases of persistent, unexplained infertility; and (4) the barrier is particularly active against spermatozoa with abnormal heads.


Molecular forms of human chorionic gonadotropin in serum, urine, and placental extracts. The molecular forms of human chorionic gonadotropin (hCG) were assessed in serum, urine, and placental extracts by gel filtration chromatography using radioimmunoassays for hCG, hCGalpha, and hCGbeta and a radioreceptor assay for hCG. The predominant form in all three biologic specimens was native-sized hCG. An excess of free alpha-subunit was also found in all three specimens. A small molecular weight fragment, reactive in the hCGbeta assay, was noted in urine and placental extracts. A large molecular form, reactive in all three radioimmunoassays and in the radioreceptor assay, was found in placental extracts. This large molecular species could not be dissociated by conditions that totally dissociate hCG.


The ultrastructure of preimplantation hamster blastocysts developed in vivo and in vitro. Scanning electron microscopy of zona-free blastocysts showed bulging trophoblast cells possessing slender microvilli and many small projections of various lengths. The trophoblast cells contained mitochondria in two shapes. One type consisted of spheroids with a few mitochondrial inner membranes. The other type had a more conventional appearance. Fibrous material varied in amount. The trophoblast cells from blastocysts cultured for 1 day had an appearance similar to that of trophoblast tissue fixed in vivo. However, the large, dense mitochondria with few cristae had diminished in number, and globular mitochondria occurred more frequently. Furthermore, the fibrous material was more sparsely distributed after culture. The experiments demonstrated that cultured hamster blastocysts have ultrastructural characteristics similar to those of in vivo blastocysts. Experiments are in progress to test whether the in vitro technique can determine the growth requirements of the hamster blastocyst.


Pregnancy following thyroid hormone treatment in a patient with amenorrhea-galactorrhea due to primary hypothyroidism. A 32-year-old female with amenorrhea-galactorrhea due to primary hypothyroidism was treated with thyroid hormones, and serum levels of thyrotropin (TSH), prolactin (PRL), triiodothyronine (T3), thyroxin (T4), and T3 resin sponge uptake (RT3U) were measured throughout the course of treatment. The elevated serum levels of TSH and PRL fell into the normal range following T3 treatment. Subsequently, the menstrual cycle was restored within 1 month, and galactorrhea completely ceased and conception was achieved within 3 months. Desiccated thyroid was administered during pregnancy, and the patient gave birth to a female infant. Impaired secretion of PRL during pregnancy and poor milk secretion with blunted response of PRL to the suckling stimulus during the puerperium were noted.


Correlation of some in vitro and in vivo investigations in rats sensitized with complete Freund's adjuvant. The survival of peripheral blood lymphocytes following 24 hours of incubation with PPD, migration of peritoneal exudate cells from capillary tubes in the presence or absence of specific antigen in culture medium were investigated at different time intervals after sensitization with complete Freund's adjuvant. Relative regional lymph node weights and enlargement indices were evaluated in all animals. Furthermore, total leucocyte counts and differential counts of different cell types were determined. A correlation between the parameters studied was found, especially between the migration of peritoneal exudate cells and the survival of blood lymphocytes. The kinetic changes in the regional lymph node weights in sensitized animals in relation to those of IFA injected animals can be considered specifically affected. Increasing numbers of peripheral blood leucocytes after sensitization with complete Freud's adjuvant and the finding of increased numbers of monocytes and eosinophils in the initial stages of the observations have been reported in the literature. The results are discussed in relation to problems of tuberculin skin hypersensitivity in ratswhich has long been contradictory in the literature.


Cell cycle in heteronuclear cell line VUP-1. I. Locomotion behaviour analysis. Time-lapse cinemicrography was used to study the locomotory activity of sperical cells of a heteronuclear cell line VUP-1 originating from a malignant melanoma of chorioidea. Migration of cells was followed during the entire cell cycle and locomotion was analyzed in relation to the population density and to the morphological and functional characteristics of the leading undulating membrane. The variations in cellular motility were related to the morphology of the membranes and their possible functional regulation.


Cell cycle in heteronuclear cell line VUP-1. II. Analysis of mitosis. Mitosis in spherical cells of heteronuclear cell line VUP-1 was analyzed by means of time-lapse cinemicrography. A comparison with another permanent cell line (hamster) revealed some differences in the duration of individual mitotic stages. Metaphase was the longest stage in VUP-1 line cells (about 3-4 hours). Various irregularities in mitotic cycle kinetics were also found, such as absence of anaphase or separation of chromosomes from the aster in metaphase. Attention was further focussed on cytokinesis.


Circadian rhythm of RNA and DNA in some organs of fed rats. Circadian changes in RNA and DNA contents in the thymus, spleen, liver and myocardium were studied in rats fed ad libitum (maintained in a room illuminated from 07.00 to 19.00 and darkened from 19.00 to 07.00 hours). The values for the thymus, liver and heart muscle fluctuated broadly over the 24-hour period: between 25% and 42% for RNA, and between 46% and 58% for DNA. However, no significant changes in RNA and DNA contents were detected in the spleen. In general the lowest values of nucleic acid content in the thymus, spleen and myocardium were recorded aroung 23.00-02.00 hours, and were replaced by a quick increase in the following hours (mainly till 05.00) up to a maximum reached around 11.00 in the thymus and liver, and around 17.00 in myocardium. The changes in the amount of RNA and DNA did not always run in parallel; consequently the ratio RNA/DNA varied, with the widest fluctuations found in the thymus.


Chromosomal characteristic of Chinese hamster cells and their HGPRT-deficient mutant line. Chinese hamster cell line (line K 431, HGPRT+) and its mutant (line K II, HGPRT-) are similar in the numberical composition of the karyotype (modal number 22 chromosomes), but differ in its structureal constitution (occurrence of trisomy, breaks in the centromeric region, chromosome losses and others). Deletion and rearrangement of some heterochromatic segments of the X chromosome appeared with a higher frequency in HGPRT- line and can constitute one of the conceivable causes of the HGPRT activity loss in the mutant line.


Thyrotropin-induced plasma membrane protein modifications in porcine thyroid cells. Highly purified plasma membranes were obtained from isolated porcine thyroid cells maintained in conditions of culture in the presence of thyrotropin (stimulated cells) or in their absence (non-stimulated cells). Analyses of both types of membranes by high-resolution sodium dodecylsulfate-polyacrylamide slab gel electrophoresis showed reproducible quantitative differences in protein bands of apparent molecular weight 38,000, 36,000 and inconstantly 96,000. Phosphorylation of membranes by [gamma-32P]ATP was 2-3 times higher in membranes from thyrotropin-stimulated than in membranes from non-stimulated cells. About 20 32P-labeled bands were detected by slab gel electrophoresis in denaturing conditions, among which the catalytic subunit of Na+, K+ ATPase was characterized. In addition, plasma membranes from thyrotropin-stimulated cells contained a firmly bound [14C]glucosamine-containing glycoprotein probably related to an aggregation-promoting factor. 125I-labeled thyroglobulin and components of unknown nature were associated with plasma membranes from thyrotropin-stimulated cells. Whether they participate in the structure and function(s) of the plasma membrane or represent contaminants of the preparation is not clear at the present time.


Hydrocortisone enhancement of insulin's action on macromolecular synthesis in MCF-7 cells. In MCF-7 human breast cancer cells, insulin stimulated the rate of [3H]uridine incorporation into RNA, [3H]thymidine incorporation into DNA, and [3H]leucine incorporation into protein. In addition, hydrocortisone appeared to augment the effect of insulin, by further increasing the rate of [3H]uridine incorporation into RNA and [3H]thymidine incorporation into DNA. A significant increase in the total amount of DNA and protein was present in cultures treated with insulin compared to untreated controls. Hydrocortisone was shown to augment the insulin effect on total protein accumulation and total RNA accumulation in MCF-7 cells.


HLA antigens in Japanese patients with diabetes mellitus. Lymphocytes of 84 Japanese patients with diabetes mellitus and 150 normal controls were tested for HLA antigens by the microcytotoxicity test. HLA-B12 was found in 37.5 per cent of 32 patients with juvenile-onset diabetes mellitus, 13.5 per cent of 52 patients with late-onset diabetes, and 9.3 per cent of 150 normal controls. In the insulin-dependent juvenile form, HLA-B12 was associated with the disease more frequently and at a significant level (p less than 0.0005). In Japanese patients with juvenile-onset insulin-dependent diabetes mellitus the association is with HLA-B12, not with HLA-B8 and BW15, as in Caucasian patients. There was no significant increase of HLA-B12 in patients with insulin-indpendent diabetes mellitus.


Topical corticosteroid response and retinopathy in juvenile-onset diabetes mellitus. In a prospective study, 64 patients with insulin-dependent juvenile-onset diabetes mellitus were followed for eight to 12 years to determine if those with higher spontaneous intraocular pressures (IOPs) would be protected from the development of retinopathy. The patients were also classified initially as high (GG), intermediate (NG), or low (NN), responders on the basis of their IOP response to corticosteroid eyedrops. High responders were found to be considerably in excess (25 per cent) of the proportion found in the general population (6 per cent). Retinopathy developed significantly less often and was less severe in the high (GG) corticosteroid responders. Although the GG diabetics had significantly higher mean baseline IOPs than the less responsive NN and NG groups in each corticosteroid response category, the mean IOP of the group with retinopathy was not significantly different from that without retinopathy. This suggested that factors associated with the GG response other than increased IOP might be important in the relative resistance to diabetic retinopathy.


Relationship of microvascular disease in diabetes to metabolic control. Dogs were made alloxan-diabetic and randomly distributed into either of two prospective treatment groups. In one group it was intended that the metabolic signs of diabetes be controlled poorly, and commercial insulin was administered in doses inadequate to prevent chronic, severe hyperglycemia and glucosuria. In the other group it was intended that the metabolic disorder be well controlled, and the animals received food and commercial insulin twice daily such that the hyperglycemia and glucosuria became mild or infrequent. Experimental improvement of the carbohydrate disorder was accompanied by amelioration of hyperlipemia and other clinical signs of deficient insulin activity. By 60 months of diabetes, retinal capillary aneurysms, pericyte ghosts, obliterated vessels, and other microvascular abnormalities typical of diabetes were apparent in each animal of the poor-control group. Better control was found to reduce significantly the incidence and severity of microvascular lesions. The data suggest that the mechanism responsible for diabetic retinopathy is initiated as a result of deficient insulin activity and that the development of the microvascular complications of diabetes are preventable and may be inhibited by careful control of the metabolic disorder.


Serum glucose levels and alcohol-consumption habits in a large population. Using information from approximately 100,000 multiphasic check-ups performed in these facilities, we have found an association between alcohol-drinking habits and serum glucose values one hour after an oral challenge with 75 gm. of glucose. There was a positive dose-response relation between reported alcohol intake and serum glucose level over the most common range of alcohol intake. Serum glucose levels were highest in the group who consumed six to eight alcoholic drinks per day. However, among those who said they took nine or more drinks per day, mean serum glucose levels were significantly lower than in the six-to-eight-drink group. These relations persisted when the analysis was controlled for the effects of age, sex, race, adiposity, time since last food intake, time of day, previously known diabetes, and previously known liver disease. A search of the literature failed to uncover a complete explanation for these phenomena.


Growth hormone antiserum suppresses the growth effect of diabetic serum. Studies on rabbit aortic medical cell cultures. Growth medium containing serum from young diabetic subjects caused a significant stimulation both of cell proliferation and of the outgrowth in cultures of rabbit aortic medial cells above that noted with normal human sera. The addition to the sera of guinea-pig human growth hormones antibody caused a marked inhibition of these stimulatory effects. The growth effect of rabbit serum was not affected by the human growth hormone antiserum. Reinvestigation of the effect of human growth hormone disclosed that the same increase as observed in growth with the diabetic sera could be obtained with a growth hormone concentration of 0.2 ng. per milliliter medium. The present results strongly suggest that the increased stimulatory effect of normolipemic human diabetic serum on growth and cell proliferation of aortic medial cell cultures is due to increased serum growth hormone concentration.


[Pregnancies in spite of intrauterine pessaries in situ]. Reviewing literature the fate of 3027 pregnancies with intrauterine devices in situ, included 43 own cases, is reported. The data strongly suggest to remove the intrauterine devices as early as possible in pregnancy, because otherwise the rate of spontaneous abortion, premature birth and stillbirth is negatively affected. The known elevated risk of extrauterine pregnancies is corroberated. The ratio of 1:4 with the progesterone-T is higher than with other IUDs (1:31 to 1:24,5). The observations do not support the view that intrauterine devices cause malformations. From the results instructions for the management of pregnancies associated with intrauterine devices are set up.


[Treatment of delayed labour with prostaglandin E2 (author's transl)]. 26 patients suffering from delayed labour at term were treated with Prostaglandine E2 (PGE2). The compound was administered i.v. in a dosage of 0,5-1,0 microgram/min. Delivery was completed in 20 patients approximately 5 hours after starting the PGE2-infusion. In 6 patients delivery had to be performed by caesarean section, 4 times because of maternal and 2 times of fetal indications. In none of the cases uterine hypertension was recorded. The rate of side effects was negligible.


[Diagnosis and monitoring of endangered early pregnancies with determination of oestrone, oestradiol 17beta, oestriol, progesterone and HPL in plasma and the pregnancy test in graduated dilutions of urine (author's transl)]. Unconjugated oestrone (Oe1), oestradiol-17beta (Oe2), oestriol (Oe3), progesterone (P) and HPL in plasma were determined by radioimmunoassay and the immunological pregnancy-test in urine was carried out in 70 patients with normal pregnancy or imminent abortion from 4th-20th week of gestation. Oe2 and HPL showed the most pronounced rises, Oe3 increased especially after the first trimester. In cases with abortion symptoms and poor prognosis Oe2 and HPL gave the most reliable results concerning the endocrin function of early normal pregnancy. Oe1- and P-values in normal pregnancy did not differ so clearly from concentrations observed during normal menstrual cycles and were thus of  less value. The pregnancy-test was positive (greater than 1000 IU/1) even in most cases of dead pregnancy and therefore not reliable. With increasing production of oestrogen precursors in the fetal adrenal cortex after the first trimester determination of Oe3 becomes more important. In cases with abortion symptoms in early pregnancy and subsequent normal development, plasma Oe2- and Oe3- values represented best criteria for a prognosis. -- For the diagnosis and control of the endangered early pregnancy we recommend, as a consequence of this study, determination of Oe2 up to the 13th week of pregnancy and thereafter Oe3 in maternal plasma.


[Experience with the Marshall-Marchetti operation for stress incontinence (author's transl)]. From 1962 to 1975 severe stress incontinence or recurrent stress incontinence was operated according to Marshall-Marchetti In 64 cases. Sixty patients were followed up. More than 2/3 of the patients were satisified with the result. Objective follow-up with urethrocystotonometry showed that only slightly more than 50% of the patients were cured. It was possible to divide the cases in 4 groups to elucidate the discrepancy between subjective and objective cure. The operative and postoperative complications were minor. The recurrence rate was the same with follow-up from 3 to 14 years. The results can probably be improved by precise pre-operative diagnosis regarding intrinsic urinary tract disease and by an extension of the indication for this operation or risk cases. The patients must be warned that the result also depends on their cooperation.


[Cytologic follow-up examination of patients with a suspicious Papanicoaou type 3D smear (author's transl)]. The cytological differential diagnosis "dysplasia" was made in 176 cases between January 1968 and June 1975. An immediate microscopic diagnosis was possible in 18 cases (10.22%). 14 cases eluded further follow-up. In 144 cases, long term observation was carried out. In some cases up to 6 years. Cytological regression to a permanently negative smear occurred in 57 patients (39.58%). A microscopic confirmation of the diagnosis was not obtained in these patients. In cytologically persistent cases microscopic confirmation was obtained after varying times of observation. The cytological differential diagnosis was correct in comparison to the histologic findings in 82.6% of the cases. 62 cases of the total (43.05%) showed cytological persistence of the suspicious smear. A cytological progression became apparent in 25 cases (17.36%) and was always subjected to microscopic confirmation by cone biopsy or primary hysterectomy. In 71 cases with microscopic confirmation persistent dysplasia was found in 64.78% of the cases and a progression occurred in 30.98% of the cases. 21.12% showed carcinoma in situ, 7.04% (5) cases showed a microinvasive carcinoma and 2 cases (2.82%) showed an invasive carcinoma. Cervical dysplasias are apparently capable of regression in a large number of cases. However about 10% of the cases will show progression to a micro-invasive or invasive carcinoma after varying lengths of time. In order to avoid unnecessary operations and to improve our knowledge on the biology of dysplasias, observation with cytological diagnosis dysplasia (Papanicolaou 3D) is justified.


[Comparative clinical studies on clomiphen, cyclofenil and epimestrol (author's transl)]. Report on the treatment of 310 anovulatory woment in 1173 treatment cycles with Clomiphen, Cyclofenil and Epimestrol. 63% of the patients had a biphasic basal body temperature record after treatment in 718 cycles. Patients with secondary amenorrhea of the first or the second degree had a satisfactory ovulation rate in 71% of the cases only by treatment with Clomiphen. In women with anovulatory cycles an overall ovulation rate of 75% was observed with all three medications. In 73 patients 78 pregnancies occurred. Of these, 38 pregnancies followed Cyclofenil, 25 pregnancies followed Clomiphen and 15 pregnancies followed Epimestrol corresponding to a 15%, 17% and 13% rate in the treated patients. 22 of these pregnancies ended in incomplete abortion. The side effects of Clomiphen especially visual and cystic ovarian and vasomotor side effects are more pronounced than the side effects of Cyclofenil and Epimestrol. The statistical analysis of the clinical results showed that Clomiphen and Cyclofenil had a higher rate of ovulation in secondary amenorrhea of the first or second degree than Epimestrol.


[Follow-up of patients who underwent reduction mammoplasty according to Strombeck between 1972 and 1975. Postoperative complications and results. Modification of the technique. Postoperative mammographic results (author's transl)]. Follow-up examinations were carried out in 60 women who underwent a reduction mammoplasty. Their review concentrated on the questions of the frequency of postoperative complications, the possibility to avoid complications by a modification of the technique and the question of mammographic evaluation of the breast in the face of scars from the mammoplasty. There were 12 severe complications. There were 6 necroses of the nipples, there were 3 abscesses, there were 2 suture fistulas and there was one case of massive hematoma. The complications depend on the amount of tissue resected. Especially necroses of the nipples depend upon the amount of tissue resected. With increasing experience of the surgeon, the nipple is moved without tension by lateral division of tissues and omission of resection of tissue above the nipple. This reduces the risk of necrosis of the nipple. Ugly scars are avoided by additional subcutaneous dexon double O sutures and additional subcuticular structures. Prolonged immobilization and later removal of the sutures help to obtain fine scars. A comparison of the preoperative and postoperative mammographies showed that 78% of the X-rays could be evaluated for carcinoma more readily postoperatively than before. For the differential diagnosis to scars from the operative, a preoperative and postoperative mammogram is necessary for comparison.


[Intraoperative sphincterotonometrie during plastic repair of the urogenital diaphragm (author's transl)]. The method of using sphincterotonometry during the operation, which is described in this paper, adds further importance to this means of examination besides the pre-operative classifying of urinary incontinence and the postoperative control of the surgical success. By drawing up a urethral profile and by performing simultaneous impact palpation the functional effect of the operation can be checked during the same, so that a possibly necessary correction can follow at once.--Up-til now this test has been carried out during 16 operations on urinary incontinence (diaphragma plastic by Kelly with at least one years of postoperative control).--According to our hitherto existing examinations a positive closing pressure of more than 10 mmHg is necessary for achieving a functionally satisfying operation result.


[Unusual fetal heart pattern during pregnancy (author's transl)]. A rare case of severe fetal heart bradycardia at 29 weeks gestation by dates followed by prolonged extreme tachycardia is reported and the literature on antepartum fetal bradycardia and fetal tachycardia is reviewed. Fetal bradycardia at the beginning of the third trimester with good fetal movements is not necessarily due to fetal distress. A prolonged fetal tachycardia does not have to be due to hypoxia but is probably due to unknown changes in the exitability of the myocardium. A prolonged fetal tachycardia antepartum and during delivery is in itself no indication for a Caesarean Section.


[The influence of anemia on the weight of child and placenta]. To determine the influence of anemia on the weight of child and placenta, a group of people suffering from anemia was compared with a non-anemic group (Hb median 8.6 g%). It was found that: 1. The median weight of the newborn child in the anemic group is 83,5 g less than in the non-anemic group. This insignificant difference is dependent solely upon the lesser weight of the mother in the anemic group (difference 6.2 kg). 2. The distribution curve of child weight which is displaced by 83,5 g on the side of lesser weight of the children explains an increase of birth rate from 5,5% to 7,5% among children under the 2500 g limit. 3. In contrast to the anticipated parallel behaviour to child weight, the placenta shows an increase in weight which can be considered as a compensatory achievement.


[Duffy-blood-factor incompatibility during pregnancy (author's transl)]. Routine screening of maternal antibodies showed presence of anti-Fya (from the antigen Fya of Duffy Blood Group System) in a 25 years old second time pregnant woman. The spectroscopic examination of amniotic fluid has been carried out and gave values which decrease within Zone II. In the beginning of 39. week of gestation a mature newborn has been delivered, who survived without need of exchange transfusion immediately after birth.


[The development of coagulopathy in missed abortion (author's transl)]. A case of fetal death is demonstrated, where a primary hyperfibrinolysis induced a bleeding tendency after curettage. Writings on the subject give differing opinions on the pathogenesis of coagulopathy in the case of fetal demise (= dead fetus syndrome). It is shown that the coagulopathy is caused most frequently by a combination of disseminated intravascular coagulation (DIC) and subsequent hyperfibrinolysis. In sporadic cases, however, one of both pathogenetic mechanisms can occur isolated.


[Carcino-embryogenic antigen (CEA) in patients with genital tumors (author's transl)]. The concentration of carcino-embryogenic antigen in the serum of healthy women and of patients with different benign and malignant genital tumors was determined before and after treatment. The carcino-embryogenic antigen was elevated to more than 2.5 ng/ml in 11% of the healthy control patients. Patients with carcinoma of the breast had positive CEA tests in 60%. Patients with ovarian cancer had positive CEA tests in 57%, women with carcinoma of the uterine cervix had positive tests in 50% and women with endometrial carcinoma had increased CEA levels in the serum in 38% of the cases. Following treatment the CEA values decreased.


[Results of needle aspiration cytology in proliferative fibrocystic disease of the breast (author's transl)]. The accuracy of needle aspiration cytology in fibrocystic disease of the breast was evaluated in 101 cases with microscopically proved proliferative fibrocystic disease. The morphology of the obtained cytosmears was described. In about 50% of the cases a cytological diagnosis of proliferating fibrocystic disease is possible with accuracy. The needle aspiration is therefore a new method for intensive follow-up of patients with a high risk of develop carcinoma of the breast. The accuracy is increased in cases with well developed proliferation of the glandular cells. In cases with intraductal and intracystic proliferations, the results were better than in cases with adenosis.


[Contraception with the Lippes Loop D with or without contraceptive foam (author's transl)]. Contraception with Lippes Loop D was compared in 1 group of women (N 172) who used a spermicidal preparation with intercourse and a second group (N 190) who used no spermicidal preparation. In the group with a Lippes Loop and a spermicidal preparation, there were 1.2% unplanned pregnancies compared to 6.4% unplanned pregnancies without spermicidal preparation. This combined method approaches the reliability of oral contraception. The third group of women who used a spermicidal preparation erratically is not comparable in the statistical sense to the other two groups. However in this third group there were less unwanted pregnancies than in the group without the use of spermicidal preparation.


[The primary isolated ovarian abscess. Clinical and bacteriological observations and a new pathogenetic hypothesis (author's transl)]. 42 of 86 patients with suppurated ovaries had primary isolated ovarian abscesses (PIOA), 44 secondary tubo-ovarian abscesses (STOA). Parts of ectopic endometrium in the abscess wall could be identified by serial sections in 23 PIOA. With Berlin-blue-staining was a special phenomenon in 28 of 42 PIOA demonstrated: a basal layer of hemosiderophages underlying the abscess membrane. Thus in 36 of 42 PIOA the histogenesis out of cystic ovarian endometriosis or other pathologic ovarian hematomas is assured. The PIOA is a typical major complication of ovarian hematomas, especially in cases of ovarian endometriosis caused by vaginal aplasia (gynatresia). Concomitant salpingitis in PIOA is therefore often better explained as secondary descending infection from pelveoperitonitis. Before laparotomy it is extremely difficult to diagnose PIOA on a clinical basis only. More than laboratory data helps this special consideration if an inflammatory adnexal mass could be or not the result of an ascending infection and if an ovarian endometriosis could exist. Besides the abscesses out of cystic ovarian endometriosis PIOA were observed after hysterectomies and complicated appendectomies possible due to the infection of traumatic ovarian hematomas. The only curative therapy for PIOA is surgery--as soon as possible. Antibiotics are poorly helpful. However the inefficacy of antibiotics usually gives the final indication for laparotomy. Knowing the usual etiology of PIOA out of pathologic (endometriotic) ovarian hematomas we have new guidelines in other clinical problems also: Thus every ovarian endometriosis has to be cured--hormonally or surgically; evacuation of endometriotic cysts during pelvic endoscopy is not a sufficient therapy, for the endometrium would be left in the ovary. During operations provocation of traumatic hematomas of the adnexa should be avoided.


Traumatic induction of early maturity in tetrahymena. Exposure of conjugating pairs of Tetrahymena thermophila to high temperature (37 degrees) during macronuclear development causes an abortion of many macronuclei, but it also often induces an early appearance of sexual maturity in clones completing macronuclear development. Lines become mature after about 15 cell divisions rather than after 50 or more cell divisions in untreated pairs. The phenotype resembles that associated with Em (early maturity) mutants but, because it is not transmitted to the progeny in the next generation, it must be considered a phenocopy. The hypothesis is developed that an early genotype-environment incompatibiltiy, whether associated with an abnormal genotype or an unusual environment, activates a shunt mechanism permitting the organisms to undertake quickly an ordinarily forbidden sexual lottery.


Genetic analyses of "paranoiac" mutants of Paramecium tetraurelia. Six mutants of Paramecium tetraurelia with curious "Paranoiac" phenotypes have been isolated and examined. Instead of the normal transient avoiding reactions in Na+ solution, these mutants show "violent avoidances"--backing continuously for 10 to over 60 sec. This behavior corresponds to prolonged membrane excitation excitation.--Genetic analyses establish five genic loci at which mutations give the "Paranoiac" phenotype. Close linkage between two of these genes occurs. Allelic variants are found for two of the genes. In one case, the two alleles determine very different behavioral phenotypes ("Paranoiac" and "fast-2"). These results show that the mechanism(s) which shuts off excitation in the wild-type membrane is (are) complex, but in the future may be fruitfully pursued in mutants which are defective.


Sites of the 5S ribosomal genes in Drosophila. I. The multiple clusters in the virilis group. Drosophila melanogaster 125I-5S RNA was annealed to salivary gland preparations of 6 species in the virilis group of Drosophila. Two patterns of annealing were found. D. virilis, D. montana and D. borealis showed three 5S gene clusters on chromosome 5; Sd-f and Wc-j were strongly labeled, but Xa-e was weakly labeled. D. montana and D. borealis have a greater percentage of their total 5S cistroms at S d-f than does D. virilis. D. americana americana, D. americana texana and D. novamexicana showed 2 sites labeled; no label was seen at Sd-f while Wc-j was weakly labeled and Xa-e was strongly labeled, the reciprocal of the previous pattern in the W-X region. Hybrids between D. a americana and D. virilis showed no difference in chromosome banding at the sites of the 5S clusters despite their pattern difference. D. a texana X D. virilis, on the other hand, did show a difference in staining the Xa-e region. These patterns fall squarely into the biosystematic groupings deduced by many previous workers.


Genetic and developmental analysis of some new color mutants in the goldfish, Carassius auratus. The genotypes of three color mutants in goldfish: a depigmentation character of larval melanophores, albinism and a recessive-transparent character, were analyzed by crossing experiments. The depigmentation character in the common goldfish is controlled by two dominant multiple genes, Dp1 and Dp2, and only fish with double recessive alleles dp1dp1 dp2dp2 can retain larval melanophores throughout life. Albinism is also controlled by double autosomal genes, p and c. The genotype of an albino fish is represented by PP CC; the non-albino fish is PP CC. Fish with either a pp CC or pp Cc genotype are albino when scored at the time of melanosome differentiation in the pigment retina, but after the time of skin melanophore diffrentiation, they change to the nonalbino type under the control of the C gene. The recessive-transparent character is controlled by a single autosomal gene, g. The mechanisms of gene expression of these characters were proposed as a result of observation and/or experimental data on the differentiation processes of their phenotypes, and the genotypes of these color mutant goldfish were considered in relation to the "gene duplication hypothesis in the Cyprinidae."


Genetic variation in Hawaiian Drosophila. IV. Allozymic similarity between D. silvestris and D. heteroneura from the island of Hawaii. The species are endemic to the newest island in the archipelago and are broadly sympatric. They are easily distinguished morphologically in both sexes. Using standard electrophoretic procedures, we have examined 25 loci encoding for structural proteins from 539 silvestris and 325 heteroneura collected at three widely-separated localities where the two species are sympatric. Pairwise comparisons within and between the species show the following coefficients of genetic identity (NEI'S I): within silvestris, 0.961 +/- 0.01; within heteroneura, 0.949 +/- 0.02; between silvestris and heteroneura, 0.939 +/- 0.01. Neither the differences within nor between the species are significant. There are no fixed allelic diffrences either within or between the species. At the three areas of sympatry, the species show gene frequency differences (P less than 0.05) at 9,11 and 13 loci respectively. This is not much different from the variation within either one of the species across the three localities. The two species have similar heterozygosity (H) levels (silvestris, 0.083; heteroneura, 0.089) and percent of polymorphic loci (both 0.37). It is suggested that despite their morphological divergence, these species are much more newly formed than classical sibling species. Significant allozymic differences may not have had time to accumulate.


The effects of overdominance of linkage in a multilocus system. Computer simulations were performed with overdominant muliple alleles among tightly linked multiple loci under a multiplicative fitness model. The quantity chi2/N (n--1) was introduced as a new measure of linkage disequilibrium which, unlike previously available measures, can be applied to multiple allele models, where N is the sample size, and n is the number of alleles at the locus possessing fewest alleles. Simulations showed that (1) With multiple (three or four) alleles, the approach to stable disequilibrium is slower and the amount of disequilibrium established is weaker than in a two allele system. (2) The number of complementary chromosomes is a function of number of alleles and of population size. (3) As population size increases, the rate of the approach to stable disequilibrium is slower. (4) There is an optimum selection coefficient which minimizes the transient fixation probability of alleles when linkage is present. (5) The absence of linkage disequilibrium is in most cases not a practical method of testing the hypothesis of balancing selection of genetic polymorphisms because it depends strongly on population size in determining linkage disequilibria.


Multiple interactions of a DNA-binding protein in vivo. III. Phage T4 gene-32 mutations differentially affect insertion-type recombination and membrane properties. We have investigated in in vivo roles of T4 gene-32 protein in recombination. We have studied the effects of gene-32 mutations under conditions that allow normal DNA replication and are permissive for progeny production. Under these conditions, certain gene-32 mutations specifically reduce insertion-type (short-interval) recombination but none affect crossover-type (long-interval) recombination (see Figure 5). Heterozygote frequencies in all gene-32 mutants are similar to or higher than in a gene-32+ background and are not correlated with recombination deficiencies. "Recombination-deficient" alleles are dominant or codominant over the "recombination-proficient" gene 32 mutation tsL171. This explains apparent discrepancies between a gene-32 map deduced from two-factor crosses and the map derived from three-factor crosses. We have also found that the "recombination proficient" mutation tsL171 and it homdoalleles suppress the characteristic plaque morphology of rII mutants. Under restrictive conditions, tsL171 is partially suppressed by rII mutations, which allow the use of host ligase in recombination. Our present and previous results are discussed in terms of current recombination models. We conclude that gene-32 protein functions in recombination by forming a complex with DNA, with recombination enzymes and with membrane components. Since gene-32 protein interacts with many components of this recombination complex, gene-32 mutations may differentially affect various recombination steps.


Differentiating causes of headache.

Differentiating causes of headache. Headache may be the presenting symptom of many diseases in the elderly. Some headaches are caused by significant intracranial disease, and the patient's age and general cardiologic and respiratory status may not allow investigation or neurosurgical management. Conditions that demand urgent neurosurgical attention are subarachnoid hemorrhage, pituitary apoplexy, subdural hematoma, and meningioma. Cranial arteritis, too, should be remembered as a possible medical cause of headache in the elderly.


Factor VIII deficient plasma for laboratory tests prepared from normal plasma and a human antibody. Plasma from a patient factor VIII inhibitor was mixed at several low concentrations with fresh normal plasma. The factor VIII deficient plasmas obtained after a short incubation period were used as substrate plasmas in the normal one-stage factor VIII assay method. Results obtained using 0.5-1% of the inhibitor plasma in normal plasma compared favourably with those obtained using normal haemophilia A factor VIII deficient plasma provided that tests were carried out without delay. A single plasma exchange of this patient provided enough antibody to prepare more than 500 litres of factor VIII deficient plasma by simple mixing with fresh normal plasma.


The effect of heparin on the interaction of factor VIII and human platelets in vitro. Heparin was found to inhibit the interaction between human factor VIII and platelets. This was noted in two different systems, namely, platelet aggregation induced by neuraminidase-treated human cryoprecipitate and platelet aggregation induced by ristocetin-human factor VIII complex. Heparin appeared to have an inhibitory effect on the above systems similar to that reported on bovine factor VIII-induced platelet aggregation.


Human blood platelet elastase and proelastase. Activation of proelastase and release of elastase after ahesion of platelets to collagen. After an in vitro incubation of platelets with fibrillar collagen, their elastase activity is markedly and rapidly increased while proelastase decrease: proelastase is activated in situ into elastase which is released in its active form from the platelet. The activation of proelastase is likely due to the action of a trypsin-like enzyme present in the platelet. This protease has the same type of localization as proelastase and elastase: their highest activity is associated with light granules but part of these enzymes (or precursor) is also associated with the membranes. The mechanism of the arterial elastolysis induced by the platelets probably involves their adhesion to intimal thrombogenic surfaces (collagen) followed by a reaction during which proelastase would become available to the trypsin-like enzyme and would be activated into elastase directly released in the vessel wall.


Plasma and platelet phospholipids in normal subjects and in patients with chronic arterial obliterations. Normally a substantially higher percentage of phosphoethanolamine is found in thrombocytes (24%) than in plasma (2.7%). The thrombocytes of patients with chronic arterial occlusions contain significantly less phosphoethanolamine (16.1%) than thrombocytes of normal subjects (24.0%; p less than 0.01). On the contrary, the plasma phosphoethanolamine levels of these patients are significantly elevated (4.8%) in comparison to normal subjects (2.7; p less than 0.05), possibly as the result of some 'leakage' of phosphoethanolamine from platelets. An anti-aggregating treatment did not change the phospholipid pattern of the plasma and of the thrombocytes.


The role of histones in the restriction of chromatin activity in successive stages of development of the antheridial filaments of Chara vulgaris L. The binding of 3H actinomycin D(3H AMD) was studied autoradiographically and the extinction following Feulgen's reaction at short (5 minutes) hydrolysis in 1N HCl was investigated cytophotometrically in 4 successive (4-, 8-, 16-, and 32-cell) generations of synchronously dividing antheridial filaments of Chara vulgaris L. Four stages of interphase, i.e. early and late S and early and late G2 were taken into consideration in each generation. The intensity of 3H AMD binding, except for early S, declines gradually in successive generations, i.e. in the developmental stages of antheridial filaments. Each generation reveals the highest radioactivity in the cells of early G2. Removal of lysine-rich histones in late G2 is the more effective for enhancing 3H AMD binding the more advanced is the stage of development of antheridial filaments. In early phase S extraction of arginine- or lysine-rich histones stimulates the binding of 3H AMD in the same degree. When all histones are removed, differences in the intensity of 3H AMD binding between particular generations of antheridial filaments disappear altogether. After a 5 minutes hydrolysis Feulgen's reaction reveales mainly loose chromatin, whereas after 16 minutes compact chromatin predominates. Removal of lysin-rich histones brings about an increased extinction after a 5 minutes hydrolysis in all phases of the cell cycle and in all developmental stages of antheridial filaments. After 5 minutes of hydrolysis, the extinction value per nuclear area in all experimental series, despite identical DNA content, undergoes a gradual reduction with the diminishing nuclear volume in the successive generations of antheridial filaments. This reduction is correlated with a decreased intensity of 3H AMD binding. The obtained data indicate that a decline in chromatin cativity in successive developmental stages of antheridial filaments of Chara vulgaris L. is caused by the progressing condensation of chromatin for which lysin-rich histones are responsible.


The effect of 5,5-diethylbarbituric acid on the biosynthesis of anthracyclines in Streptomyces galilaeus. 5,5-Diethylbarbituric acid (barbital) stimulates the production of anthracycline antibiotics called galirubins in Streptomyces galilaeus in dependence on the strain, concentration and cultivation conditions. The stimulation is more pronounced (up to 300%) in the low-producing strain than in the production mutant. Under conditions of limited aeration the effect of barbital is increased in both strains. In the production strain barbital narrows the spectrum of metabolites produced. Higher barbital concentrations inhibit growth of the mycelium of both strains and decrease the formation of free anthracyclinones.


Dependence of cell yield and specific growth rate of Candida boidinii on temperature during continuous cultivation. Investigation of the dependence of cell yield of Candida boidinii in a chemostat and specific growth rate in a turbidostat on temperature was carried out using methanol as substrate. Each of the curves obtained had only one maximum, the optimum temperature for yield (Ys) and for specific growth rate (micron) being somewhat different. With deviation of temperature from the corresponding optimum the micron value decreases more sharply than that of Ys. The shape of two-factor dependences Ys(micron, T) and micron(S, T) is analyzed on the basis of these data and the known dependences of Ys on micron and micron on the limiting substrate concentration S. It is shown that the decelerating action of methanol on the growth rate increases at elevated and lower temperatures.


[Central hemodynamics and left ventricle contractility in experimental septicemia]. A well-defined septicaemia in dogs was induced using different initiating causes, such as abscess of thigh and peritonitis. The determination of the septicaemia was based upon both quantitative (number of bacteria) and qualitative criteria (staphylococcus aureus, pseudomonas aeruginosa). The hemodynamic changes lead to the classification of three time intervals, which occur constantly. There are correlations between the general infection and the reaction of blood circulation. There is no evidence of specific types of shock corresponding to the type of bacteria. Correlations exist between the moment when endotoxin is present and the occurrence of low-cardiac-output shock-syndrome. A disturbance of myocardial contractility develops in all types of shock in septicaemia. The decrease of contractility correlates in time with the first duration of the presence of the endotoxin. Several causes of the negative inotropic effects are discussed. Some of these are possible cardiotoxic effects of endotoxin shock mediators, lactate acidosis, and the decrease of coronary perfusion pressure.


[Extracorporeal liver perfusion in the treatment of liver failure]. An evaluation of therapeutic approaches in acute liver failure needs essentially experimental studies. Devascularization of the liver seems to be the superior form of liver damage induced by a variety of toxins. A perfusion circuit for extracorporeal pig liver perfusion was investigated. Oxygen utilization of the livers under experimental conditions proved to be the fastest and most reliable test of organ viability. In therapeutic use in devascularized pigs the survival time could be prolonged. Biochemical parameters were normalized or improved during a 2 hour perfusion. The method was of value in a 59 year old patient perfused for 9 1/2 hours with an isolated baboon liver. Controlled trials, however, seem to be necessary to evaluate each therapeutic method in acute liver failure in man.


[Internal complications following jejunoileostomy in the treatment of extreme obesity]. More than 250 patients with extreme obesity were treated at the Chir. Univ.-Klinik Erlangen by 30 + 20 cm jejunoileostomy. The patients lose overweight and reach nearly normal weight after 9-12 months. Carbohydrate intolerance and hypertriglyceridema disappear. Ensuing malabsorption and also the surgical procedure are responsible for complications like wound infection or intussuception. The resulting chronic vomitting causes hypoproteinemia, hypokaliemia and liver dysfunction. Continuous therapeutical substitution is necessary, especially of potassium, to avoid deficiency. The diarrhea is treated by drug administration, i.e Reasec. The long time results are not yet sufficiently known. Calcium deficiency may occur many years later. The rate of cholelithiasis and nephrolithiasis ranges from 2 to 10%. The over-all lethality over 5 years is 2,8% as seen in the patients of our clinic during the past 6 years.


Practical and experimental studies on the use of prostaglandins F2alpha in pigs. The possible practical uses of F2alpha prostaglandins (two different experimental preparations) in pigs are discussed. It was shown that the intramuscular injection of 1-2 mg PGF2alpha (in the region behind the ear) could result in oestrus, ovulation and subsequent conception in a considerable number (78.3%) of virgin pigs with persistent clinical anoestrus (15-16 months old), the start of normal oestrous cycles in pigs 10-11 months old and also the early appearance of oestrous symptoms in pigs of prepuberal age (6-7 months). As the PGF2alpha treatment did not have any adverse effects on the composition and the normal growth of the piglets (except for a smaller litter size in the prepuberal gilts, probably due to age of the animals), while transitory side-effects only occurred exceptionally after treatment (slight excitement), the use of PGF2alpha is suggested for production of functional recovery in virgin gilts with apparent persistent clinical anoestrus, for the synchronization of oestrus in primiparous gilts on farms with no apparent reproductive disorders, and for the concentration of births also in pluriparous pigs past the 12th day of the normal oestrous cycle before injection, and for the induction of precocious oestrus and subsequent early conception in gilts of prepuberal age.


Observation on chemotherapy in cows chronically infected with Coxiella burnetii (Q fever). Pregnant dairy cows chronically infected with Coxiella burnetii were treated orally with 8 mg of chlortetracycline per kilo of body weight each day for 30 days during their dry period. With the exception of a sample of mammary fluid collected at 28 days, rickettsiae were not recovered from the mammary fluids after the second week of treatment. In addition, the organism was not recovered by mouse inoculation from placental tissues, colostrum or calf tissues that were examined after parturition. Results of oral chemotherapy studies in cows and guinea-pigs suggest that in some cases chlortetracycline may suppress rather than eradicate the Q fever agent.


[Indications for percutaneous fracture fixation in bone surgery]. Because of its technical improvement percutaneous pinfixation of bones is now a successful procedure of osteosynthesis. The indications of this method are: Open fractures of second and third degree, emergency treatment of polytraumatized persons with debris fractures, fractures in combination with vascular injuries or burns, elongating osteotomy, pseudarthrosis, osteomyelitis and arthrodesis. External pin-fixation offers the following advantages: High range of stability with the possibility of early exercises. In case of resorption of the bone fragments it is possible, to correct the axial compression. No lesion of the fragments periosteum or endosteum. The operative damage to cortical vascular supply is minimized. The danger of bone infection is reduced. Subsequent correction of the bone axis can be performed. Altogether the pin-fixation is a safe and satisfactory method of osteosynthesis without physical strain for the patient.


[Caries prophylaxis].

[Caries prophylaxis]. The extent of dental caries incidence has reached such proportions that it may no longer be kept under control by restorative methods alone. Parodontopathy is besides tooth caried the most wide spread ailment. Bacterial plaque can be considered as main cause and key-factor for caries incidence and parodontopathy. All other causes are co-factors. It follows that decrease of dental plaque must be the most urgent goal in prophylactic dentistry. The combination of all caries and parodontal prophylactic remedies and methods determines as a complex the fate of hard and soft tissues exposed to bacterial plaque.


[The effect of nutrition on aging].

[The effect of nutrition on aging]. It is possible to prevent some degenerative processes of old age. Special prescriptions should respect: 1. A reasonable diet in order to slow up ageing should be started before the age of 60 years; 2. diet for common metabolic diseases of old age:obesity, diabetes, hypertension; 3. diets adapted to gastric achlorhydria and to digestive diseases frequent in old age; 4. knowledge about the relationship between diet and cancer.


[The effect of low dose gestagens on the hypothalamic-pituitary-ovarian axis]. The contraceptive effect of continuous treatment with low dose progestogens (minipill) has been attributed mainly to alterations of the cervical mucus and the endometrium. This study was undertaken to investigate the effect of low dose progestogens on hypothalamic-pituitary-ovarian function. Plasma concentrations of follicle stimulating hormone (FSH), luteininzing hormone (LH), estradiol-17 beta (E-2) and Progesterone were measured daily during apparently ovulatory menstrual cycles and during treatment cycles with different low dose progestogens. From the results obtained it was concluded that the minipill has a clear-cut effect on the LH/FSH peak at midcycle and on corpus luteum function. A cyclic secretion of E-2 is maintained in the majority of cases. In a few treatment cycles however, follicular maturation was suppressed as indicated by low E-2 concentrations. It was concluded that the minipill exerts a profound effect at the central and ovarian level which contributes to its satisfactory contraceptive efficacy.


[The effect of fludilat on carbohydrate metabolism]. Fludilat (bencyclane-hydrogen-fumarate) increases the O2 consumption and CO2 production of a 10% bovine lens homogenate. An increase of the glucose substrate supply of the homogenate from 25 mM to 37 mM enlarges the above mentioned effects. Investigations on the content of ATP, ADP and AMP show that bencyclane is able to stabilize the physiologic distribution pattern of the three free adenine nucleotides. Changes of the distribution pattern pointing to disturbances of the energy metabolism could in part be normalized by incubation  with the addition of bencyclane. This is not only true for lens homogenates but also for whole bovine lenses. Investigations with the enzymes fumarase and malatedehydrogenase indicate that the fumaric acid rest of bencyclane may serve as a substrate for these enzymes in the same way as fumarate. The Km-values found are identical.


Tolbutamide-induced insulin release in pregnant diabetics. A study was undertaken to determine whether the abnormal insulin release pattern in insulin-independent pregnant diabetics (IID) was due to a lack of stored insulin and whether their clinical response to treatment with tolbutamide was correlated with enhanced plasma insulin values. Ten pregnant diabetics in the third trimester of pregnancy were subjected to both an oral glucose tolerance test and an intravenous tolbutamide tolerance test. The results indicated that an enhanced early release of insulin could be evoked by intravenous tolbutamide. The biochemical inertia of the beta cell noted in pregnant IID is therefore more likely to be associated with a relative insensitivity of the beta cell to glucose or to a defect in the enteroinsular axis. Although the individual hypoglycaemic effect of intravenous insulin was similar, the plasma insulin response varied greatly. The clinical improvement in tolbutamide-treated diabetics cannot be explained solely on the basis of enhanced insulin release.


Influence of indomethacin on glucose-induced insulin response in normal man--role of prostaglandins in the rapid insulin release? The possibility of a role of endogenous prostaglandins in glucose-induced insulin release was investigated in normal human subjects with short-term indomethacin treatment. This treatment was found profoundly to inhibit the early insulin response to a 1 h glucose infusion test. In contrast, the later insulin response was enhanced, probably mainly as a result of the higher degree of hyperglycemia induced in experiments with the drug. Together with in vitro data on the relationship between prostaglandins and cyclic AMP in the pancreatic islets, the present finding is considered to point at the possibility of an involvement of prostaglandins in the normal regulation of the rapid glucose-induced insulin release.


Insulin release in response to vagal stimulation in anaesthetized cats. Peripheral and portal plasma insulin concentrations were determined in eviscerated cats before, during and after vagal stimulation. Basal peripheral insulin levels averaged 2.4 ng/ml and portal levels 18 ng/ml. The portal blood flow was recorded continuously, thus enabling the insulin output/min to be calculated. In addition, the total insulin content of the pancreas was determined, which permitted quantitative comparisons of insulin release and pancreatic insulin content to be made. About 2% of the insulin store was released during one hour under basal conditions. Unilateral vagal stimulation with frequencies ranging between 1 and 20 Hz induced an almost immediate release of insulin into the portal vein. Following stimulation with frequencies of 3-4 Hz, the release mechanism was fatigued by a total of 2000-3000 impulses. The insulin output produced by such a supramaximal stimulation averaged 1.5 microgram and constituted about 2% of the total pancreatic insulin content. 15-20 min was needed for the release mechanism to recover.


Degradation, receptor binding affinity and biological potency of monoiodoinsulin in isolated rat fat cells. The degradation, binding affinity and biological potency of monoiodoinsulin was studied in isolated rat fat cells. The rate of inactivation by a concentrated cell suspension was indistinguishable from that of native insulin, whereas the relative biological potency (increase in lipid synthesis from glucose) and binding affinity (inhibition of receptor binding of 125 I-labelled insulin) was 60-80%. Assuming that the insulin receptor binding is a simple, reversible, bimolecular reaction, the following are the consequences for the interpretation of experiments at equilibrium in which an unlabelled species of insulin competes with (125I) monoiodoinsulin present in a concentration much below the dissociation constant for the insulin: 1. The dissociation constant is estimated without bias. 2. The total number of receptors is slightly underestimated.


Insulin-glucose dynamics during flow-through perfusion of the isolated rat hindlimb. The dose-response relationship between glucose and insulin concentration and utilization in skeletal muscle was examined in hindlimbs of overnight fasted normal male rats. The perfusion was by flow-through technique utilizing an artificial perfusate containing beef erythrocytes. Glucose disappearance correlated significantly with insulin concentration. Insulin effect was detected within 5 minutes. When arterial glucose was 10 mM, glucose disappearance during maximal insulin stimulation was fivefold greater than glucose disappearance in the absence of insulin. A half-maximal effect occurred at an insulin concentration of 411 U per ml. Arteriovenous difference of immunoreactive insulin during a single passage thorugh the hindlimb averaged 16.7% over the range of 50 to 10,000 U per ml. In the presence or absence of insulin, glucose disappearance was positively correlated with glucose concentration up to a glucose concentration range of 30 to 45 mM. In this range and above glucose uptake averaged twelvefold above that observed for 5 mM glucose. When insulin (500 muU/ml) was added at any glucose concentration, glucose disappearance was augmented. The data thus indicate that rat skeletal muscle is a major site of insulin metabolism. In addition to the effect of insulin on glucose uptake by the muscle cell, glucose mass action appears to be quantitatively equipotent.


Pancreatic glucagon-like immunoreactivity in a pancreatectomized patient. True or 'pancreatic' glucagon-like immunoreactivity (GLI) was found in the plasma of a pancreatectomized patient. In contrast with the regulation of pancreatic GLI in normal controls, there was paradoxical release after oral glucose, no response to arginine or insulin-hypoglycaemia and somatostatin did not suppress its release, but tolbutamide did. Similar to controls, this pancreatic GLI appeared to be under adrenergic beta-receptor control. There was no apparent effect on blood glucose regulation despite marked changes in pancreatic GLI levels during the various manipulations. On polyacrylamide gel electrophoresis, pancreatic GLI from our patient's plasma eluted as two equivalent peaks: one with the glucagon marker and the other in a more cathodal position. We therefore suggest that, although the extra-pancreatic 'pancreatic' GLI in our patient's plasma has immunologic similarities with pancreatic glucagon, the responses to stimulation and suppression are quite different from those in controls and the biologic activity does not appear to be that of pancreatic glucagon.


Effect of pregnancy on the glucagon response to protein ingestion. Plasma glucose, insulin and glucagon concentrations were measured before and after the ingestion of a protein-rich meal in 11 healthy pregnant women in the last trimester of pregnancy, and again in the same subjects postpartum. Compared to postpartum, basal levels of plasma glucose were lower in late pregnancy whereas basal insulin and glucagon concentrations were both enhanced. After the meal, insulin and glucagon concentrations in plasma increased in gestation as well as postpartum. Plasma glucose increased slightly in pregnancy but remained unchanged postpartum. The mean insulin response to the meal was unaffected by pregnancy whereas that of glucagon was reduced. Thus following protein ingestion, plasma glucose rose in pregnancy in spite of unchanged levels of insulin and depressed levels of glucagon. Favouring analbolism, the reduced glucagon response to protein ingestion in pregnancy fits in the concept of 'facilitated anabolism' in late pregnancy and, moreover, it lend further support to the idea that changes in glucagon secretion per se are not involved in the pathogenesis of the diabetogenicity of pregnancy.