Seasonsal variations in the reported incidence of sexually transmitted diseases in Scotland (1972-76). The seasonal variation in the quarterly incidence of some sexually transmitted diseases and other conditions in Scotland is compared with that of gonorrhoea and of conceptions leading to live births or abortions. The seasonal incidence for non-specific genital infections and for other conditions not requiring treatment in both men and women was similar to that of gonorrhoea, thus indicating an association with promiscuity, whereas the seasonal variation for candidosis in men and women-an infection not usually associated with promiscuity-was similar to that of conceptions. Differences between the sexes occurred, however, in the seasonal incidences of scabies, pubic lice, genital herpes, trichomoniasis, and other conditions requiring treatment; thus men with these conditions appeared to be more promiscuous than women. The seasonal variations in incidence of genital scabies and pubic lice indicate that these infestations are more easily transmitted by close bodily contact indoors during cold weather than in the open air.


Changes in amino acid metabolism caused by 6-azauridine triacetate: relevance to cancer treatment. 6-Azauridine triacetate (6-AzUrd-TA) administration causes changes in amino acid metabolism both in experimental animals and in man. This effect is dose-related. Amino acid changes caused by 6-AzUrd-TA resemble those in inborn homocystinuria, beta-alaninemia, and hyperhistidinemia. Inhibition of certain enzymes using pyridoxal phosphate as a coenzyme appears to be the common denominator for these changes. There is supportive evidence suggesting that homocystinemia and thrombotic episodes, both caused by 6-AzUrd-TA, are related. These results also reveal that anticancer drugs other than amino acid analogs and amino acid-depleting enzymes may cause significant changes in amino acid metabolism. Their detection and correlation with the therapeutic or adverse effects can be used as an alternative method for studying the relevance of amino acid changes to the treatment of cancer.


Radionuclide imaging and echography of thyroid nodules. The usefulness of grey scale ultrasonography in association with radionuclide imaging in the evaluation of thyroid nodules is discussed. Nodules were classified in five categories, according to the magnitude of the internal echoes (echogenicity). The assessment of neoplasms in each of these categories is reported in 143 cases in which radionuclide imaging disclosed nonfunctioning or cold nodules. In this study, echography is used principally to clarify the nature of nonfunctioning or cold nodules found on radionuclide imaging.


Computerized tomographic diagnosis of aneurysms of the thoracic aorta. Accurate diagnosis of aneurysms of the thoracic aorta and its major branches can easily be performed by CT scanning of the mediastinum. The use of contrast enhancement aids in the diagnosis and allows distinction between flowing and clotted blood within the aneurysm. CT scanning of these lesions seen on chest radiographs may obviate the need for arteriography for diagnosis.


Effect of the venereal diseases epidemic on the incidence of ectopic pregnancy -- implications for the evaluation of contraceptives. This paper identifies a basis for quantifying the risk of ectopic pregnancy in pregnancy seekers and in users of the major means of contraception, with and without prior tubal infection. The doubling, in U.S. in recent years, of both numbers of ectopic pregnancies and the prevalence of nonsurgical sterility is correlated with the epidemic of gonorrhea and other sexually transmitted, salpingitis-producing diseases. The risk of ectopic pregnancy in women who have once had salpingitis is shown, on the basis of Weström's landmark prospective study and many retrospective studies, to be approximately 10-fold that of normal women. Fertilization-preventing contraceptives reduce uterine and ectopic pregnancies in the same proportion and in both categories of users--that is, in normal-risk and high-risk (post-salpingitis) women. Intrauterine contraceptives, however, markedly reduce uterine pregnancies, but have little effect on the incidence of ectopic pregnancy. Among IUD users, therefore, the incidence of ectopic pregnancy will be disproportionately great in relation to the fraction of high-risk women in the population of users. This disproportionate influence of prior salpingitis may confuse the comparative evaluation of contraceptive safety because the proportions of normal-risk and high-risk women probably vary widely, since public health data show extremely wide geographic differences in the incidence of gonorrhea -- the best known but not the only sexually transmitted, salpingitis-producing disease.


[Chondrocalcinosis (pseudogout) of the meniscus]. Among 1060 histologically examined meniscus cartilages from patients aged 11--74 years 20 (2%) had chondrocalcinosis. Age at onset of symptoms was 28--67 years, duration of symptoms until surgical removal of the meniscus six weeks to 20 years. All patients had pain, 12 had pain-independent limitations of knee movement. Effusions of the knee were present in ten. Independent of the radiological findings, in the majority of patients the symptoms were markedly improved or completely absent one-two years after meniscus removal. All meniscus specimens revealed severe changes both macroscopically and histologically. The clinical diagnosis confirmed by demonstrating calcium pyrophosphate crystals in haemalauneosin stained sections, examined by polarisation microscopy. The X-ray films demonstrated arthrosis in at least 50% of cases. There appeared to be a close mutual relationship between chondrocalcinosis and arthrosis of the knee-joint.


Successful outcome of ergocryptine-induced pregnancies in twenty-one women with prolactin-secreting pituitary adenomas. The natural history of prolactin-secreting adenomas is not known. For this reason, optimal therapy for women harboring these adenomas who desire to conceive is also unknown. Argument can be found to favor surgical excision, radiation therapy, prolactin-suppressing chemotherapy, and clinical observation. In a large series of women with prolactin-secreting pituitary adenomas, 21 have conceived and delivered healthy infants, all of whom had ergocryptine-induced prolactin suppression as the sole form of therapy. Endocrinologic, neurologic, biochemical, and radiologic assessment failed to demonstrate any obvious growth of the pituitary adenoma, except for slight enlargement of the sella turcica in one patient who delivered twins. The failure to demonstrate any worsening of the clinical state may reflect the fact that no large tumors were included in this series, only small but definite microadenomas found on sellar tomography. All of the various modalities of therapy must be considered with each patient, but this series suggests that ergocryptine treatment with careful clinical follow-up is relatively safe in patients with small pituitary tumors.


A simple lectin-mediated cell-adhesion method for investigating the cell surface. A very simple, rapid and reproducible method has been developed for studying the interaction of lectins with the cell surface. This involves determining the number of adherent cells after shaking cell suspensions in Petri dishes which have had a lectin coupled to their surface using 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluene sulfonate. Using concanavalin A coupled to 60 mm diameter dishes and between 1.5 and 2 x 10(6) tumour cells, this adhesion reached a maximum after 10 min shaking. Maximum cell adhesion also varied according to the particular lectin used. Adhesion was absent or was very low if cells were shaken in untreated dishes, or in dishes coupled to bovine serum albumin, or in the presence of the lectin-specific sugar-competitor. Under conditions of maximum cell adhesion, the binding of two different lymphosarcoma lines to four different lectins was very similar, whereas the binding of a carcinoma line to these lectins was completely different from that observed for the lymphosarcomas.


HSA fosters hospitals' voluntary cooperation in areawide planning. An HSA convinced the 31 hospitals in its health service area to participate in a voluntary moratorium on expansion and a voluntary planning process through which their long-range institutional plans are reviewed for incorporation into the HSA's areawide plans.


Pulmonary epithelial-mesenchymal interactions: beyond organogenesis. Epithelial-mesenchymal interactions are important regulators of lung growth and organogenesis, but later functional maturation of the fetal lung is though to be primarily under hormonal control. Recent evidence, however, suggests that hormonal effects on pulmonary cellular and biochemical maturation continue to involve intercellular interactions. Communication between cells may have wider importance than has hitherto been appreciated. It should be noted that in addition to organogenesis and biochemical development, mature lung requires an extensive capillary network in close proximity to areas of gas exchange. Recent attempts to isolate and culture pumonary endothelium may be expected to provide new insights into this neglected aspect of lung maturation. The possibility of hormonal or intercellular mediation of the differentiation of airway epithelium might also merit investigation.


[Prevention of paralytic ileus after colonic surgery by continuous peridural sympathetic block. Preliminary report]. Gastrointestinal atony must be considered as a reflex response to surgical intervention, due to activation of sympathetic nerves. Following colonic surgery, the duration of this response may be notably extended and the ensuing intestinal distension becomes the paramount factor of a persisting ileus. Blocking the sympathetic fibers prevents intestinal distension. Introducing appropriate catheter into the peridural space up to the level of the 10th--11th thoracic vertebra makes it possible to realize a segmental continuous block between T6--L2, where gastrointestinal sympathetic innervation actually originates. Using bupivacaine at low concentration (0.125% with epinephrine 1/400,000) reduces untoward effect on circulation and may even prove beneficial if volaemia is effective. In addition, it produces a selective block on the visceromotor fibers which allows a differential diagnosis of the ileus, without risking to pass over a perforation of the gut whenever a coexisting mechanical factor is suspected.


In-vitro maturation and penetration of mouse primary oocytes after removal of the zona pellucida. The spontaneous maturation of intact, cumulus-free and zona-free oocytes of the mouse was studied in complex and in simple media. The rates and frequencies of maturation from the germinal vesicle to the metaphase II stage were similar for all oocytes, indicating that these investments are not critical to maturation. The penetration characteristics of zona-free oocytes were examined; before germinal vesicle breakdown (GVB), evidence for penetration was obtained only when the ionophor, A23187, was included in the medium. After GVB, oocytes readily incorporated spermatozoa and were usually polyspermic when inseminated with 10(5) capacitated epididymal spermatozoa/ml. The kinetics of sperm incorporation indicated that primary oocytes were capable of a plasmalemma block to penetration similar to that seen with tubal eggs.


Mycotic aneurysm of the ulnar artery.

Mycotic aneurysm of the ulnar artery. A mycotic aneurysm is an uncommon, but serious, complication of infective endocarditis, occurring as a result of an infected embolus being lodged in the vasa vasorum or lumen of an artery. Involvement of the ulnar artery is rare, but its peripheral location renders its diagnosis more simple. A case of mycotic aneurysm of the ulnar artery complicating infective endocarditis is reported, with successful management by ligation and excision.


Changes in blood flow of growing experimental tumor determined by the clearance of 133Xe. 133Xe clearance method has been employed for measurement of the blood flow in 6C3HED lymphosarcoma implanted in flank of C3H mice. In small tumors (9-day old) the mean rate of blood flow was 9.4 +/- 5.0 ml/100g/min. but with progressing growth of tumors the rate of blood flow significantly decreased. In large tumors (14-day old) the mean rate of the blood flow was only 5.4 +/- 2.8. Our results demonstrate that this type of tumor, similarly as most of transplanted tumors are not well perfused and, that there is an inverse relationhip between the blood flow and the tumor size.


Phosphoenolpyruvate carboxykinase in experimental intrauterine growth retardation in rats. This study examines the role of impaired gluconeogenesis in the pathogenesis of neonatal hypoglycemia in intrauterine growth retardation (IUGR). IUGR was produced experimentally in eight pregnant rats by ligation of uterine arteries at the 17th day of gestation. Delivery occurred spontaneously at term. Sham operations were performed in five pregnant rats at the same gestational age and the fetuses delivered at term served as controls. The body weights of newborn rats with IUGR were significantly lower than the controls (5.32 +/- 0.12 vs. 6.22 +/- 0.06 g, mean +/- SE, P less than 0.001). The fetal liver weights were also significantly smaller in IUGR than in the control animals (0.224 +/- 0.14 vs. 0.340 +/- 0.12 g, P less than 0.001). The activity of phosphoenolpyruvate carboxykinase (PEPCK) (the rate-limiting enzyme of gluconeogenesis) in liver cytosols was significantly lower in rats with IUGR (0.06 +/- 0.01 vs. 0.11 +/- 0.02 microM phosphoenolpyruvate/g liver/min when compared with controls (P less than 0.05). A direct relationship between this enzyme and the birth weight was observed, suggesting a close relationship between intrauterine nutrition and the status of gluconeogenesis. The blood glucose level was also lower in growth-retarted fetuses (36.6 +/- 4.7 vs. 69.6 +/- 4.3 mg/dl, p less than 0.001) when compared with controls. The data suggest that gluconeogenesis is impaired in IUGR and is partly responsible for the increase in the incidence of neonatal hypoglycemia in this group of subjects.


Augmentation of pulmonary surfactant secretion by lung expansion at birth. To study the effect of lung expansion at birth on surfactant secretion, we delivered by hysterotomy 11 litters of rabbit pups at 30 days of gestation and divided them into three groups that were killed: 1) after 30 min air-breathing, 2) after 30 min nitrogen-breathing, and 3) after 30 min tracheal occlusion. Each group was compared to a littermate group killed at birth. Groups 2) and 3) continued respiratory efforts for 30 min despite progressive asphyxia. Six additional litters were pretreated with atropine; at delivery one-half of each litter was killed, the remaining pups were subjected to 30 min of hypoxic gas breathing. After sacrifice, alveolar surfactant was recovered by saline lavage and estimated quantitatively on a surface-tension balance. Surfactant concentration at birth was 1.40 +/- 0.22 mg/g dry lung and increased to 1.86 +/- 0.19 (+/- SEM) after 30 min air-breathing (P less than 0.01). Also, surfactant was increased in the nitrogen-breathing pups (from 1.61 +/- 0.35 in littermate controls to 2.41 +/- 0.58; P less than 0.03), but not to a significant degree in the occluded group (1.34 +/- 0.33 vs. 1.41 +/- 0.28), or the atropine pretreated breathing pups (1.77 +/- 0.29 vs. 1.89 +/- 0.25).


Biochemical modifications of pulmonary surfactant after bromhexine derivate injection. The authors study the influence of bromhexine metabolite VIII on phospholipid and fatty acid composition comparatively to controls. The subcutaneous injection of NA 872 produces on pulmonary surfactant an increase of 43% of total phospholipids. This change in the distribution of phospholipids is shown by the increase of 53% of phosphatidylcholines. A rise of 61.9--74.4% of palmitic acid appears in the phosphatidylcholines of the pulmonary surfactant. It can be noticed that the specific activity of the phosphatidylcholines rises by 31%.


Effects of metabolite VIII of bromexine (Na 872) on type II epithelium of the lung: an experimental and morphological study with reference to surfactant secretion. 50 Wistar rats were divided into 5 groups: 4 experimental and 1 control group. The experimental groups A and B received, per os, a daily dose of 100 mg of Na 872 (metabolite VIII of Bromexine) for 3 or 6 days and were killed 1 day later. The experimental groups C and D received 200 mg of the same substance according to the same experimental procedure and for the same periods. The lungs were fixed in situ by perfusion, examined by light and electron microscopy using morphometric methods. No manifest lesions occurred in alveolar tissue. Morphometric analysis showed an increase in the volume ratio of type II epithelial cells and of lamellated body volume in respect to total alveolar tissue volume. Furthermore, our findings suggested an increase in lamellated bodies in respect to type II cell volume, particularly in group C (200 mg/3 days); they showed the existence of a hypertrophy of type II cells, particularly at 6 days.


Bladder involvement with lymphoma.

Bladder involvement with lymphoma. Two case reports of different ways lymphoma involves the bladder are presented, with a brief updating of diagnosis and management. Symptoms and cystoscopic and roentgenographic findings are discussed. While primary lymphoma of the bladder has been reported in a few instances, the disorder is generally considered a widespread lymphatic disease.


Fertility of norgestomet treated suckler cows. Four studies are described involving 3050 single suckled mainly Hereford-Friesian cross beef cows treated with norgestomet and oestradiol valerate to control the ovarian cycle. In study 1 the effect of insemination timing on pregnancy rate was studied. A greater proportion of cows inseminated 48 and 72 hours after treatment became pregnant than after a single insemination at 48 hours. In study 2 large variations in fertility among farms were recorded in field trials of norgestomet and oestradiol valerate. In study 3 the effect on fertility of nutrition, weight and body condition was examined. In study 4 57.9 per cent of 1113 treated cows became pregnant to insemination at 48 and 72 hours. Cows were fed a balanced ration designed to provide for a predicted daily milk yield of 9.0 kg for a 12-week period starting six weeks before insemination. The range of fertility was from 36.7 per cent to 94.9 per cent.


Effect of hermaphroditic gland homogenate on the regulation of the gametogenesis in Helix pomatia (Gastropoda, Pulmonata). On the effect of ovotestis (glandula hermaphroditica) homogenate the number of ovocytes of 1st and 2nd order and of the eggs increased very significantly, while spermiocytes of 1st order sperms significantly decreased in number. When snails with extirpated tentacles were injected with ovotestis homogenate the ovogenesis was activated which was proved by a significant increase in the number of ova.


Effect of taste and temperature on neonatal sucking behaviour. The sucking behaviour of 10 healthy newborns was studied while feeding them with milk of different types (V formula and EBM) and temperature (23.5 degrees C and 37.5 degrees C) on the 4th, 5th, and 6th days of life. Total feeding time, duration and number of intervals, frequency and pressure were analysed from 120 sucking patterns. The babies did not alter their sucking behaviour on feeding with different milks, but they reacted to the different temperature in one of three trials.


Dietary risk factors in human bladder cancer. Retrospective data on dietary habits, employment history and tobacco use were obtained from 569 bladder cancer patients and 1025 age-matched controls admitted to Roswell Park Memorial Institute. Sex-adjusted relative risks revealed increases in risk for lower levels of an index of vitamin A intake. A similar pattern of risk elevation was associated with infrequent milk and carrot intake. Some elevation of risk was found for heavy coffee drinking but the apparent protective effect for milk consumption was not found to be a spurious result of lower coffee intake. Neither was the role of vitamin A explained by its relationship with smoking or employment in high risk occupations. Some association of bladder cancer with infrequent consumption of cruciferous vegetables was also observed. The findings of this investigation are consistent with tumor inhibition by retinoids in animal studies and the low risk associated with vitamin A in epidemiologic studies of lung cancer.


Antepartum aminophylline treatment for prevention of the respiratory distress syndrome in premature infants. The frequency of idiopathic respiratory distress (IRD) among premature offspring born of women who were given aminophylline before the thirty-fourth week of pregnancy was evaluated. Sixty-seven premature deliveries were included in the aminophylline group and 75 in the control group. The perinatal death rate was 7.1% in the aminophylline group and 17.9% in the control group (p less than 0.05). A statistically significant difference was noted between the aminophylline and control groups in the frequency of IRD which was three times lower (10%) in the aminophylline group than in the control group (29.5%) for the total of premature infants. If the time of rupture of membranes is taken into consideration, a significant decrease in the frequency of IRD following aminophylline administration is noted in the infants, whose mothers had ruptured membranes for more than 24 hours. No complications or side effects of aminophylline administration were noted in the mothers or their infants.


Mycotic aneurysm of the inferior mesenteric artery. This is the first reported case of successful management of a mycotic aneurysm of the inferior mesenteric artery. The only helpful clinical manifestations were episodes of previous abdominal pain and a history of bacterial endocarditis. The surgical management involved simple excision without revascularization of the inferior mesenteric artery.


Diagnosis of food allergy through bronchial challenge. Bronchial provocation tests were performed in 48 children whose skin tests were positive to food extracts or in cases in which anamnestic data suggested food allergy. In 20 cases a marked change of dynamic compliance, vital capacity or FEV1 could be demonstrated within 1--5 minutes after the inhalation of food extracts. Ten of them had bronchoconstriction after milk or egg; 5 among them had negative skin tests. Twenty patients were examined before and after 1--3 hours after the ingestion of 300 ml. of milk. Five of them showed definite decrease of FEV1, whereas the vital capacity did not change. It is concluded that food allergy can be established as the cause of bronchoconstriction in 5--10% of asthmatic children.


[Echocardiographic study of hyperthyroidism based on 9 cases of Basedow's disease (author's transl)]. An echocardiographic study of nine patients with graves' disease before and after treatment demonstrates changes in myocardial contractility predominantly in the posterior wall and, to a lesser extent, in the intraventricular septum. The parameters most significantly changed were: velocity of posterior wall thickening and posterior left ventricular wall relaxation rate. There was not in any of the cases neither evidence of cardiac insufficiency nor a diminution of VCF. All of the modifications regressed rapidly with the euthyroid state. These results affirm the functional character of this disease dismissing the existence of an autonome cardiomyopathy of thyroid etiology.


[The surgical treatment of thyrotoxic exophthalmos using Ogura's operation (author's transl)]. Ogura's operation consists of resection via De Lima's approach of the bony floor of the orbit and the lateral wall of the ethmoid. The orbital periosteum is then incised in order to allow the orbital fat to enter the sinuses and thus decompress the orbit. In most cases the operation is performed on both sides at the same time. It is used in cases of malignant or severe thyrotoxic exophthalmos, or in the presence of optic neuritis. The results obtained were good in 9 cases with a marked reduction in exophthalmos and rapid cure of optic neuritis. An additional ophthalmological procedure is sometimes necessary in order to perfect the anesthetic result.


Gynecomastia after chemotherapy for lymphoma. Although development of gynecomastia in a patient with cancer may indicate persistence or regrowth of a tumor, we studied three patients with lymphoma in whom development of gynecomastia during or after chemotherapy did not portend a poor outcome. In all patients, serum testosterone levels were normal, serum luteinizing hormone (LH) levels were high-normal or elevated, and serum follicle-stimulating hormone (FSH) levels were clearly elevated. The serum estradiol level of one patient was elevated at the onset of gynecomastia, but it fell to normal as the gynecomastia resolved spontaneously over a three-month period during which the patient received no chemotherapy. In a second patient, gynecomastia resolved over a period of eight months while the patient continued on maintenance chemotherapy, and he remains clinically well in remission 21/2 years after onset of gynecomastia. In the third patient, gynecomastia developed while the patient was in complete remission and off of all therapy, and it remained unchanged for the duration of a 21/2-year remission without therapy. Gynecomastia after chemotherapy for lymphoma is not an ominous prognostic sign and does not necessarily indicate the need for alteration of the treatment regimen.


Myasthenia gravis, pernicious anemia, and Hashimoto's thyroiditis. A 68-year-old woman with clinical, electromyographic, and pharmacologic evidence of myasthenia gravis experienced increasing proximal and bulbar muscular weakness. The diagnosis of pernicious anemia was established by typical abnormalities in the peripheral blood and bone marrow aspirate, the serum B12 level, by results of the Schilling test, and by the presence of serum parietal cell antibody. The diagnosis of Hashimoto's thyroiditis was established by the presence of diffuse thyroid enlargement, microsomal thyroid antibodies, an increased thyroid stimulating hormone level, and depressed T2 and T4 levels.


[Evolution of the circadian organization (author's transl)]. The evolution of cicadian rhythmicity was possible by selection and mutation. Rhythms which strongly deviate from the circadian rhythms are still existent in case no selective pressure has occurred. An evoluution regressive to those strongly deviating rhythmus can be observed in case the selective pressure has disappeared. The circadian rhythmicity in the various cells and organs of multicellular organisms has not got lost during the evolution. But certain organs have grown important for maintaining the circadian organization within the body and for allowing the synchronization with the light-dark cycles. In addition, contrary to lower organisms, certain processes, e. e. photoreception, are coupled to the circadian rhythm only in specially differentiated organs. The high precision in the clock's running within higher organisms becomes possible by mutual synchronization within the multioscillator system.


Circulating antibodies to cow's milk proteins in children with acute diarrhoea. Circulating antibodies to cow's milk protein were investigated in 35 normally nourished infants aged 2 to 11 months. Nine were healthy (control group), and the remaining 26 were convalescents from acute diarrhoea. At the time of assay they were normally hidrated and being fed diluted cow's milk. The results showed elevated hemagglutinating antibody titers in the group of children with diarrhoea, statistically different to the control (p less than 0.001). The existence of an enhanced absorption of non degraded milk protein during the disease is assumed. This observation constitutes one more element in favour of the risk of exposing the digestive tract to antigenic loads in pathological situations as those considered.


[Circadian rhythms in man (author's transl)]. The circadian system of man consists of a multiplicity of self-sustaining oscillators which are coupled to each other and which can be entrained by periodic factors in the environment, the zeitebers. From the interaction of these two forces results a high degree of temporal order within the organism. Freerunning circadian rhythms to be observed in isolated subjects living in constant conditions, usually have periods close to 25 h. The circadian system can split into components that freerun with different frequencies (internal desynchronization) and that partially can be entrained by zeitgeber. Analysis of the circadian organization has become of increasing importance for theory and practive in medicine.


[Tidal and lunar rhythms (author's transl)]. Behavioral and developmental rhythms of some species inhabiting the intertidal zone of sea-coasts as well as some species of tropical lakes and forests have adapted to environmental cycles which are determined by the moon (the semi-diurnal tides, the semi-monthly cycle of springs and neaps, and the changes in moon-light during the night). The underlying timing mechanisms of these tidal and lunar rhythmus are of different kinds. Some of them belong to the oscillating types of physiological clocks (circa-tidal oscillator, circa-semilunar and circa-lunar oscillator), others may represent an hour-glass type (resulting in a single programming), or they are based on a stochastically influenced control of the duration of activity and rest. The combination of a circa-semilunar oscillator with a circadian oscillator enables an intertidal organism to synchronize its rhythms with an environmental situation which reoccurs only every 15 days at the same time of day (1.3., low-water phase of spring tides). The speculations on true lunar rhythms in humans are discussed.


[Annual rhythms in frequency of electroencephalographic patterns (author's transl)]. A series of electroencephalographic features were measured for about 11,500 patients from a clinical population, over a period of five years (1972 to 1976) and were documented using a standarized procedure. It could be shown that for males a definite yearly rhythm was present for the relative frequencies of alpha-type, partial beta-type, and low voltage EEGs, as well as for continuous and grouped dysrhythmias, the amplitudes of which were in the main 20--30% of the average. For females on the other hand, apart from grouped dysrhythmias, no such yearly rhythms could be proven, at the most such with a periodicity of between 14 and 16 months. The data often display trends that are more distinct than the rhythmicity and as such these should be taken into consideration when deciding upon the model used for statistical regression.


[Shift work and biological rhythms (author's transl)]. In highly industrialised countries shift work has become inevitable for technological, economic and social reasons. At the present time approximately 20% of the workforce are engaged in shift work, which partly includes night and weekend work. As a result of this form of work, diseases and disorders manifest themselves in shift workers which--combined with an individual predisposition or with certain situational factors--arise partly from disturbance of sleep on the day after night work, partly from difficulties in adapting biological function to the phase-shift of work and sleep. The resulting biological and organisational problems with respect to the practicabilities of shift work are discussed in the light of studies on experimental shift work.


Special experiments on central nervous effects of amitriptylinoxide considering pharmacokinetic aspects. A few conclusive experimental models (barbiturate sleep, tetrabenazine reversion, maximum electroshock) were chosen to collect comprehensive data on the pharmacodynamic characteristics of amitriptylinoxide. The following results appear to be of particular importance: 1. The drive-promoting effect of amitriptylinxide increases with repeated application of the substance. Its maximum level is reached after approx. 5 to 10 days. A simultaneous decrease of the sedative component is observed during the same interval. These processes can be explained neither by accumulation nor by developing of drug tolerance but have to be attributed to a change in metabolic processes. 2. Comparative investigations of oral and i.v. application led to the conclusion that amitriptylinoxide is absorbed rapidly and almost completely from the intestine when administered orally. Maximum action is demonstrable at about 1 h after oral administration. 3. As had been expected, diazepam intensified the sedative effect of amitriptylinoxide. The findings obtained suggest an additive action of the two substances.


Comparative single-dose kinetics of amitriptyline and its N-oxide in a volunteer. Plasma drug levels and urinary metabolites were measured in a volunteer for 28 h after ingestion of amitriptyline hydrochloride or amitriptyline N-oxide (amitriptylinoxide) equivalent to 100 mg of amitriptyline base. The N-oxide initially produced high plasma levels and 15% of the dose was excreted unchanged within 14 h. From comparison of the metabolite excretions, it can be concluded that about 70% of the dose was reduced at the N-oxide group, while comparison of the areas under the plasma group, while comparison of the areas under the plasma level-time curves for amitriptyline pointed to a 55% reduction to the amine. Less drowsiness was experienced after ingesting the N-oxide, and there was no depressive mood.


[Radioimmuno assay of drugs (author's transl)]. Radioimmuno assays for routine analyses of hormones were developed in clinical laboratories in the early sixties. The importance of this procedure has increased permanently. The method bases upon the reaction of an antigen with an antibody to an antigen-antibody complex. A labelled antigen is used to quantify the formation of the complex. To demonstrate the development of a drug radioimmuno assay nomifensine was used, that has a complex pattern of metabolism. High sensitivity, high specificity, low interference in samples of patients with multiple therapy, simple handling of a great number of samples per person, good interlaboratory reproducibility, and low costs are the advantages of this procedure justifying the relatively high expense for introducing a control area for isotopes.


[Column extraction analysis in pharmacology and toxicology (author's transl)]. The extraction of lipophilic compounds from body fluids is preferably performed with a new procedure, the Extrelut-column extraction. The aqueous solution is applied onto the column and remains as the stationary phase on the porous support material. On elution with organic solvents lipophilic substances are extracted from the aqueous phase into the eluent. The method offers several advantages: No formation of emulsions, saving of solvents, high recovery rates and purer extracts than are obtained using conventional extraction. Three examples of application are described: A barbiturate determination from blood and serum, which is highly simplified compared with the conventional extraction. The isolation of basic compounds from blood using extraction and simultaneous purification by means of coupled extraction and absorption columns. A thin-layer chromatographic screening procedure for drugs in urine including column extraction.


[Quantitative determination of drugs by means of gaschromatography. Further development of detectors (author's transl)]. Gaschromatography is an excellent and well established method for the separation of volatile compounds. Up to now the flame ionization detector was used almost exclusively for the quantitative determination of organic compounds separated by gaschromatography. This detector is an unspecific detector and responds to all organic compounds containing at least one C-H bond. Due to that this detector can be used for the determination of almost any drug, however, the chromatographic column must have a very high resolution, especially when small amounts of drugs are to be determined in the presence of large amounts of interfering compounds. As a consequence "substrate specific" detectors were developed, among them the electron capture detector, the nitrogen-phosphor-sensitive detector and the mass spectrometer are the most important ones. The function of these detectors and their advantages for the quantitative determination of drugs are discussed in this paper.


[Metabolite isolation for mass spectrometrical determination of new drugs (author's transl)]. Only very minute concentrations of metabolites of highly effective and consequently low dosed drugs can be detected in urine. In order to identify the structure of these compounds they must be concentrated by a factor up to 1:10(6). Isolation of metabolites, especially when present as conjugates, becomes more complicated the greater the polarity. In this paper some methods for isolation are presented using column- and thin-layer chromatography as well as extraction and dialysis, finally their practical application and their most effective combination are described. Priority must be given to solving two problems: firstly, a rough pre-purification is necessary to eliminate physiological components from the urine such as salts, urea, etc., and secondly, the mixture of metabolites has to be separated into single metabolites. Examples are given to demonstrate the practicability of these methods for the isolation and structural identification of metabolites belonging to varying structural classes.


[Modern analytical methods and drug safety (author's transl)]. With the N-nitroso compounds for an example this paper tries to show the problems we are confronted with by the commonly admired perfection of modern analytical techniques. By the very same example, however, it can be illustrated how we retreat to decisions ut aliquid fieri videatur if we cannot really master those problems. This seems particularly so when problems of drug safety are at issue.


[Quantitative thin-layer chromatography and its use in clinical pharmacology (author's transl)]. Different methods of in situ determination of drugs on TLC-plates are described and discussed. Suitable examples are given demonstrating the value for pharmacokinetics.


[The use of high-performance liquid chromatography in biochemical and medical analyses (author's transl)]. The HPLC (high-performance liquid chromatography) is applicable for all biochemical analyses, because of the wide variety of separation principles (adsorption-, partition-, ion-exchange- and steric exclusion-chromatography). Of exceptional importance is the reversed phase technique, a special case of partition chromatography. The sensitivity of detectors depends upon the structure of the respective substance, but is ordinarily lower -- apart from fluorescence detection -- than GLC-detectors. The development of new systems is going on. The HPLC is used in the quantitative determination of plasma levels of drugs and their metabolites. This is of special importance during the development of new drugs and for monitoring therapy. The measurement of concentrations of certain biogenic substances helps in diagnosis. An important field of application of HPLC is the use in sample clean-up for other analytical methods. In this application HPLC surpasses all other chromatographic techniques by fastness, reproducibility and suitability for automation.


[The predictive value for man of toxicological findings in experimental animals (author's transl)]. The extrapolation of toxicological findings in experimental animals to man is an important and difficult problem. However, experiments on several animal species form the basis for deciding whether or not a new substance should be given to or tested on humans. Compounds which even in low doses lead to dose-dependent organic damage should obviously not be developed any further. There are, however, cases in which no firm conclusion can be reached by the toxicologist on the grounds of the results of animal experiments alone, as to whether or not the substance should be used in man. In such cases close collaboration is necessitated between the pharmacologist, toxicologist, biochemist and physician. Their aim is to decide if preliminary trials may or may not be carried out in human subjects. If the answer is in the affirmative, early administration to man should follow, as there is no clear-cup solution to the question of extrapolating findings in animal experiments to test subjects. Medical progress relies on research which, in the end, has to be supported by experiments on humans.


[Histopathological diagnosis in the animal experiment (author's transl)]. Spontaneous and experimentally induced organ alterations in laboratory animals do not always coincide with comparable lesions in human pathology. In addition, the discrimination between experimental tissue alterations and non-pathological structural variations may be difficult. In such cases a clear-cut separation can only be achieved by a proven dose-response relation, which, however, requires a quantitative or semiquantitative registration of histological findings.


[Studies of drugs without randomization (author's transl)]. Post marketing studies of drugs are frequently performed without randomization. In this paper the most important differences between controlled clinical trials and epidemiologic studies are discussed from a cognitive theoretical point of view. It is shown that on the transition of informations from the basic population to the document many biases may arise so that the feasibility of interpreting epidemiologic studies is doubtful. Hence, epidemiologic studies only allow us to make statements on differences between populations but not on the reasons causing them; they merely contribute to the generation of certain hypothesis on the action of drugs. These hypothesis can only be tested in experiments.


Antimotility and antisecretory activity of some aryl substituted amidinoureas. A number of aryl substituted amidinoureas have been prepared and examined for their gastrointestinal spasmolytic, antimotility, antidiarrheal and antisecretory effects. In general, antisecretory and antimotility effects have been found to be associated with each other in these compounds. The structure-activity relationships found show that substitution of the aromatic ring in positions other than 2 and 6 correlates poorly with potency, and potency of such compounds is low. In contrast to this, 2,6-disubstitution confers high potency. The potency of 2,6-disubstituted compounds declines sharply with increasing weight of substitution of the amidinourea chain, with the important exception of the N-alkoxyamidinoureas. Increasing the molecular weight of an N-alkoxy substituent has a much less profound effect than the corresponding increase has in an N-alkyl substituent. High potency in an amidinourea may well be related to low basicity (or a high pKa value for its conjugate salt) but there is insufficient data to support this hypothesis fully. The actual tautomeric structure of an amidinourea probably affects its potency and this is discussed briefly.


Analytical-physical profile of lidamidine hydrochloride (WHR-1142A), a novel antidiarrheal agent. The structure elucidation, physical and chemical parameters and hydrolysis kinetics of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride (WHR-1142 A, lidamidine hydrochloride), a novel antidiarrheal agent, were determined. The stability of the substance in aqueous solution (pH 1-13) was studied at 50 degrees, 65 degrees and 80 degrees C.


In vivo antimotility and antidiarrheal activity of lidamidine hydrochloride (WHR-1142A), a novel antidiarrheal agent. Comparison with diphenoxylate and loperamide. 1-(2,6-Dimethylphenyl)-3-methyl-amidinourea hydrochloride (WHR-1142A, lidamidine hydrochloride) was shown to have potent antimotility, antidiarrheal and intestinal antisecretory activity in mice, rats and dogs. Antimotility activity was demonstrated in charcoal intestinal motility, gastric emptying and gastric and intestinal intraluminal pressure studies. Antidiarrheal activity was evaluated in castor oil-, prostaglandin E2-, carbachol-, and serotonin-induced diarrhea. Intestinal secretion induced by cholera toxin was inhibited by WHR-1142A. In general, WHR-1142A was more potent than diphenoxylate and loperamide although species differences were noted. The ED50 for inhibition of castor oil-induced diarrhea was 1.8 mg/kg p.o. and the duration of action at 16 mg/kg p.o. was at least 6 h. Unlike diphenoxylate, WHR-1142A showed no tolerance.


Effects of lidamidine hydrochloride (WHR-1142A), a novel antidiarrheal agent on the cardiovascular and central nervous systems. 1-(2,6-Dimethylphenyl)-3-methylamidinourea hydrochloride (WHR-1142A, lidamidine hydrochloride) has been reported to be a potent antidiarrheal agent in laboratory animals. This study defines its effects on the cardiovascular and central nervous systems. At doses greater than 1 mg/kg i.v., WHR-1142A reduced cardiac output in the anesthetized dog primarily by depressing heart rate; the blood pressure was slightly elevated due to an increase in peripheral resistance. WHR-1142A was effective in reverting ouabain-induced ventricular arrhythmias to a sinus rhythm. Unlike diphenoxylate, WHR-1142A did not potentiate the CNS depressant effects of hexobarbital or ethanol. WHR-1142A did not block pentetrazole-induced convulsions, electroshock seizures or amphetamine aggregate toxicity. At high doses WHR-1142A caused a general CNS depressant effect was not related to a neuroleptic- or barbiturate-like action.


Pharmacological properties of lidamidine hydrochloride (WHR-1142A), a novel antidiarrheal agent. 1-(2',6'-Dimethylphenyl)-3-amidinourea hydrochloride (WHR-1142A, lidamidine hydrochloride), a potent, unique antidiarrheal agent, was tested for other pharmacological properties. It inhibited gastric acid secretion in both 4-h and 22-h pylorus-ligated rats and reduced mortality and gastric ulcer severity in the latter test. WHR-1142A also exhibited local anesthetic activity in the rabbit corneal reflex and guinea pig intradermal wheal tests and reverisbly blocked conduction in isolated frog nerves. Low doses of WHR-1142A increased plasma glucose concentration in fasted mice and rats and prolonged the hyperglycemia in response to a glucose meal. WHR-1142A showed mild diuretic activity but had no anti-inflammatory or antibacterial activity. The acute oral LD50 of WHR-1142A was 260 (208,328) mg/kg in male mice, 267 (212,336) mg/kg in male rats and 160 130,197) mg/kg in female rats.


[Studies on psychophysiology in Schizophrenia (author's transl)]. The psychophysiological and psychopathological implications are discussed for the finding that absence of electrodermal orienting response to acoustic stimuli was observed among 40% of the schizophrenic patients in two samples. It was found that withdrawal symptomatology and thought disturbance frequently appear among those patients without orienting response. Examples from previous studies are presented which verify deficient or excessive responses of schizophrenics in other physiological variables. It is suggested that extreme psychobiological primary characteristics of schizophrencis be taken into account in psychopharmacological therapy.


[Dose-effect relations. Doubleblind study on two different doses of pimozide (author's transl)]. Two identical groups of schizophrenic patients were treated for 28 days randomized with 3 and 8 mg of pimozide. In the antipsychotic efficacy no difference could be seen. Difference was in side effects: The 8-mg group had three times more extrapyramidal signs, mostly akathisia and agitation, and needed seven times more minor tranquilizer than the 3-mg group. Severe agitation as a psychotic symptom was equal in both groups. Preference therefore is given to the smaller dosage.


[ECG changes in psychiatric patients under long-term therapy with psychopharmacological drugs (author's transl)]. 1726 psychiatric patients, aged 40-69, under permanent hospitalization were examined electrocardiographically. There were few pronounced indications of a relationship between pathological ECG findings and drugs. ECG changes, mainly T-flattening, were rarest among patients treated exclusively with non-tricyclic drugs, and most often among those patients who received tricyclic and non-tricyclic compounds simultaneously. These disturbances appeared more often among women.


[Methods for detecting "cataleptic states" in the rat]. For the detection of drug-induced cataleptic states four new methods of "dynamic" character are described. They are based on passive extension of the muscles, changes in spatial position or force to motoric activity. Together with the well-known methods of "static" character, they are compiled to a "Test Battery" in which eight neuroleptics as well as bulbocapnine, metoclopramide, two cholinergic and two opioid drugs were investigated. Due to the pattern of reaction in the "Test Battery" it is possible to differentiate between various classes of cataleptiogenic drugs.


[Quipazine antagonizing baclofen activity. Influence of baclofen and gamma-hydroxybutyric acid on serotonin metabolism in rat brain (author's transl)]. Baclofen increases the concentration of serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) in the rat c. striatum without causing concomitant increase in 5-HT biosynthesis. The effect of baclofen on 5-HIAA, but not that on 5-HT, was antagonized dose-dependently by quipazine. It is assumed that quipazine acts by stimulating 5-HT autoreceptors.


Influence of baclofen and GABA-minetic agents on spontaneous and olfactory-bulb-ablation-induced muricidal behaviour in the rat. Effects of baclofen, 5-aminomethyl-3-hydroxyisoxazol (muscimol) and GABA-cetylester on spontaneous and olfactory bulb-ablation-induced muricidal behaviour in rats was investigated. At doses of 3--10 mg/kg i.p. baclofen inhibited the killer reaction in spontaneous and lesioned rats to the same extent. In contrast, muscimol (0.75--1.5 mg/kg i.p.) and GABA-cetylester (10--50mg/kg i.p.) depressed markedly only the spontaneous muricidal response. These findings suggest a possibility that muscimol and GABA-cetylester exert their inhibitory action through an activation of GABA-neurons localized in the bulbus olfactorius, whereas baclofen appears to affect also neuronal systems outside this nervous structure.


[A method for describing monotonic dose-effect curves and areas in yes/no reactions (author's transl)]. A method combining a polynomial statistical model and multiple probit regression, is useful in describing nonmonotonic dose-effects in yes/no-reaction variables. An example shows the application of this method to the combination of two substances. The effects can be described with a minimum of polynomial coefficients. The application of a simple X2-test allows to test for additivity of substance effects by testing whether interaction coefficients improve the fit of the model significantly or not.


[Development of tolerance of phenobarbital after administration over several days (author's transl)]. In mice daily testing by maximal electroshock (MES) and pentylenetetrazole infusion (PTZ) 2 h after an i.p. injection of 25 mg/kg penobarbital (PB) was performed on days 1, 2, 4 through 8. The first twitch was delayed as compared to NaCl controls (50.4 +/- 4.8 s; 36.6 +/- 3.6 s; n = 53) on day 2, 4, 6 through 8. There was no tolerance of the PTZ induced tonic extension with Pb-treatment. In contrast, MES-tested mice developed tolerance, at day 5 the number of protected animals fell to about 50%. In view of the constant phenobarbital levels in plasma, a functional tolerance was assumed. The development of tolerance seemed to be connected with the spread  of the discharge but not with discharge of the neurones themselves since it was observed only with MES but not wih PTZ-testing.


[On improved prophylaxis of endogenous-phasic psychoses. Influence of L-aspartate on lithium transport (author's transl)]. The influence of aspartate on lithium transport was studied with humna red blood cells (rbc) in vitro and after i.p. injection of Li-DL-asp or LiCl in different tissues of the rat. After administration of Li-asp the lithium concentrations in brain and rbc of the rats increased more slowly compared to rat treated 3 to 6 days with Li-asp were more than two times higher than those of rats treated with LiCl. After daily injection of the two salts, lithium levels in the brains of rats teated with LiCl. Results of in vitro experiments with human rbc indicate that the effect of aspartate on lithium transport is specific for L-aspartate. In addition a similar but smaller effect has been observed with l-glutamate.


[Effects of lithium on learning, memory, and mood (author's transl)]. In a double-blind study the effects of a 14-day lithium medication (dosage: 24 mval/d to 36 mval/d) were investigated. The subjects were 24 healthy male volunteers. The effect of lithium on their mood, ability to learn nouns, and memory of the words learnt was measured after 2 h and 14 days. In spite of a relatively low mean plasma lithium level on the 14th day (0.54 +/- 0.15 mmol/l), the lithium volunteers assessed themselves after 2 weeks of treatment as significantly less relaxed, less active, less socially involved, more bored, and more tired than the placebo group. As to learning, the lithium group showed only a slight impairment of performance compared to the placebo group. As to memory, there was only a significant difference in free recall over two weeks: the lithium group remembered fewer words than the placebo group. Additional motivation of free recall over 2 h was uneffective. It is discussed whether lithium changes spontaneous initial action and thereby the will to act. This could be interpreted as a change in the production of the characteristics of experience and behaviour.


[Lithium: EEG, performance and mood under subchronic therapy (author's transl)]. In a controlled double-blind trial 2X12 healthy male volunteers were tested during treatment with lithium sulphate (24--36 mval/d) or placebo. Volunteers were tested after one and two weeks' drug intake using the following tests: Quantitative pharmaco EEG, psychological performance and mood scales. In comparison to pacebo, lithium shows increased mistake duration of the pursuit rotor (MLS), decreased flicker fusion threshold and an impairment of mood. The EEG effects (decrease 7--9 cps, increase 20--50 cps) require further clarification.


[Biochemical studies in delirium tremens (author's transl)]. During the delirium and a drug-free control period concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in CSF, activity of dopamine-beta-hydroxylase (DBH), and urinary excretion of norepinephrine, epinephrine, and dopamine (DA) were measured in eight male patients. There were some indications for an increase of noradrenergic activity in the central nervous system.


[Changes in the oxidative glucose brain metabolism under long-term xantinol-nicotinate medication (author's transl)]. 8 patients suffering from dementia were treated with xantinol-nicotinate for 4 weeks. At the beginning and at the end of the treatment cerebral blood flow and cerebral metabolic rates of oxygen, glucose and lactate were measured with the N2O-method. With regard to the initial level of each parameter CBF, CMR glucose and CMR oxygen increased significantly, if it had been decreased at the first measurement, while primarily normal or even increased parameters did not change. Seming contradictions to other authors are discussed.


[The effect of the morphine antagonist naloxone on the effect of fentanyl]. 1. In healthy volunteers fentanyl (0.15 mg i.v.) induces a reduction of awareness and vigilance and in some persons a transition to sleepiness or sleep stages. The course of these changes with time can be shown in narcograms, consisting of vigilance indices which correspond to the different EEG-stages. 2. Naloxon (0.4--1.6 mg i.v.) reduces the hypnotic effect of fentanyl or antagonizes it completely. 3. Index values of rapid eye movements in wakefulness measured oculographically indicate a reduction of motor activity after administration of fentanyl, when stages of reduced vigilance appear. Injections of naloxone following later on diminish this effect of fentanyl or antagonize it completely, not so does levallorphan.


Synthesis and molluscicidal activity evaluation of some nitrosalicylanilides. The hitherto unknown 5,6-dinitrosalicylic acid has been obtained as a by-product during nitration of salicylic acid. Synthesis of some 3-nitro-, 5-nitro- and 5,6-dinitrosalicylanilides with different substituents on the amine moiety was carried out. Evaluation of the molluscicidal activity of the synthesised salicylanilides is discussed.


1,2-Diphenylethylamines as potential non-stimulant anorectics. A series of 1,2-diphenylethylamines has been synthesized in which the phenyl rings were substituted with Cl, OCH3 or CF3 at various positions and in various combinations. Four N-ethylpiperazino and N-ethylmorpholino compounds were also prepared. When tested in rats, some of the compounds were found to be potent anorectics and none of them stimulated motor activity.


[No increase in chemotherapeutic effectiveness of cyclophosphamide (CPA) in rat leukemia L 5222 by 5-ethyl-2'-deoxyuridine (EDU) (author's transl)]. Monotherapy of early rat leukemia L 5222 with 5 X 100 mg/kg EDU over 48 h yielded no increase in lifespan as compared to untreated controls. Combination therapy of advanced L 5222 with EDU and CPA in four different schedules results in no increase in life-span as compared to treatment with CPA only. DNA histogrms of preterminal L 5222 revealed no synchronizing effect of EDU.


[Studies on possible interactions of thalidomide and genetic material from chicken embryos (author's transl)]. Tritium labelled thalidomide was applied to chicken embryos of various stages and the distribution of the readioactive label was investigated. No specific binding tendency to components of the cell could be found, especially no affinity to nucleic acids and to the chromosomal proteins (histones and non-histones) could be observed, which had been discussed hypothetically. An influence on DNA replication and transcription rate could also not be detected.


[Studies on the pharmacodynamic activity of several drug solvents. 1st communication: Diethyleneglycol monoethylether, N,N-diethylacetamide, dimethylsufoxide (author's transl)]. The drug solvents diethyleneglycol monoethylether (Transcutol), N,N-diethylacetamide, and dimethylsulfoxide were examined for their pharmacodynamic properties in the following tests: i.p. toxicity, "sign pattern", inclined screen test, balance rod test, and potentiation of hexobarbitone sleeping time in mice, spasmolytic activity in the guinea pig isolated ileum, and cardiovascular studies in anaesthetized rats, cats and dogs including the i.v. toxicity. Except for the cat, N,N-diethylacetamide exhibited the highest toxicity; this solvent, too, was particularly potent in inducing behavioural changes and in potentiating hexobarbitone sleeping time. In the isolated ileum the solvents showed unspecific spasmolytic activities with histamine, carbachol, or BaCl2 as spasmogens. After i.v. administration in rats, cats, and dogs the solvents caused cardiovascular effects even in very low doses. Based on the pharmacodynamic properties doses are recommended for each solvent which should not be exceeded without control experiments in the laboratory routine. These tolerable doses do not only depend on the species but also on the test concerned.


[Studies on the pharmacodynamic activity of several drug solvents. 2. Glycerin, N-(beta-hydroxyethyl)-lactamide, polyethylene glycol 400]. The drug solvents glycerin, N-(beta-hydroxyethyl)-lactamide, and polyethylene glycol 400 (Lutrol 9) were examined for their pharmacodynamic properties in the following tests: i.p. toxicity, "sign pattern", inclined screen test, balance rod test, and potentiation of hexobarbitone sleeping time in mice, spasmolytic activity in the guinea pig isolated ileum, and cardiovascular studies in anaesthetized rats, cats, and dogs including the i.v. toxicity. In mice and rats glycerin exhibited the highest tocicity as well as the greatest activity in potentiating hexobarbitone sleeping time. In the isolated ileum the solvents showed unspecific spasmolytic activities with histamine, carbachol, and BaCl2 as spasmogens. After i.v. administration in rats, cats, and dogs the solvents caused cardiovascular effects even in very low doses. Based on the pharmacodynamic properties, doses are recommended for each solvent which should not be exceeded without control experiments in the laboratory routine. These tolerable doses do not only depend on the species but also on the test concerned.


[Studies on the parmacodynamic activity of several drug solvents. 3. 1,2-Propanediol, tetrahydrofurfuryl alcohol-polyethylene glycol ether (THFP), olyoxyethylene sorbitan monooleate (PSM)]. The drug solvents 1,2-propanediol, tetrahydrofurfuryl alcohol polyethylene glycolether (THFP, Tetraglycol), and polyoxyethylene sorbitan monooleate (PSM, Tween 80) were examined for their pharmacodynamic properties in the following tests: i.p. toxicity, "sign pattern", inclined screen test, balance rod test, and potentiation of hexobarbitone sleeping time in mice, spasmolytic activity in the guinea pig isolated ileum, and cardiovascular studies in anaesthetized rats, cats, and dogs including the i.v. toxicity. The solvents showed only small differences in their toxicity in the mouse and rat; PSM, however, was more toxic than 1,2-propanediol and THFP in the cat and dogs. The latter solvent, on the other hand, was the most potent in inducing behavioural changes and in potentiating hexobarbitone sleeping time. In the isolated ileum the solvents showed different spasmolytic potencies, depending on whether histamine, carbachol or BaCl2 was used as a spasmogen. The spasmolytic activity of 1,2-propanediol and THFP is classified as unspecific, whereas PSM seemed to have a specific anticholinergic pattern in the isolated ileum. After i.v. administration in rats, cats, and dogs the solvents caused cardiovascular effects even in very low doses. Based on the pharmacodynamic properties, doses are recommended for each solvent which should not be exceeded without control experiments in the laboratory routine. These tolerable doses do not only depend on the species but also on the test concerned.


Biological properties and clinical application of propolis. XI. Histophathological analysis after intravenous application of ethanol extract of poprolis (EEP). Mice were given i.v. injections of water solutions of ethanol extract of propolis (EEP) over a varying period of time. Some of the animals were sacrificed immediately following the last injection and some within 2--4 weeks after the last injections. Internal organ samples were taken and underwent a microscopic examination. Insignificant pathological changes in the liver were observed. These changes were transient and regressed within 2--4 weeks after the application of EEP.


Cefoxitin, a semi-synthetic cephamycin antibiotic. Metabolism in rats with renal insufficiency. The metabolism of cefoxitin, a new semi-synthetic cephamycin antibiotic, in rats with renal insufficiency was examined in comparison with that in control. Ascending urinary tract infection was produced in rats by intra-cystic inoculation with a virulent strain of Escherichia coli. In rats with severe infection progressed into purulent inflammation in the pelvis and medullar and cortical abscess formation, the urinary excretion of the antibiotic was reduced till the first 2 h after an i.v. dose of 40 mg/kg, while its serum levels and biliary excretion during this period were contrarily higher than those in rats with mild infection limited to pelvic inflammation and in control. On the other hand, in rats with renal arteriarctia produced by constriction of the renal artery with silver clip, blood levels of the antibiotic were higher than those in control. In the former animals, the urinary excretion was reduced to about a half, while the biliary excretion was increased up to twofold of that in control through the whole experimental period. In animals either with severe infection or with renal arteriarctia, the total recovery in the urine and the bile during 6 h of the experimental period was almost equal to those in mild infection or control groups.


Chemotherapeutic effect of cefoxitin on experimental pyelonephritis in rats. Comparative study with cefazilin. Ascending pyelonephritis was successfully produced in rats by means of direct inoculation with a virulent strain of Escherichia coli into the bladder enclosing a glass ball. 3-Carbamoyloxymethyl-7-alpha-methoxy-7-[2(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid (cefoxitin) or cefazolin as a control drug was applied to the affected rats characterized by purulent inflammation in pelvis and medulla sometimes accompanied with abscess formation in medulla and/or coretex 3 days after challenge. The treatments were performed at an i.v. dose of 40 mg/kg 3 times a day for 5 consecutive days. The improvement of the disease, that is disappearance of the bacilli in the kidney, improvement of BUN value and of histopathological findings in cefoxitin-treated animals was approximately equal to that in cefazolin-treated ones. Both antibiotics exhibited great effectiveness against purulent pyelonephritis, however, not sufficiently effective against medullar and cortical abscesses. Chemotherapeutic effect of cefoxitin on experimental pyelonephritis was discussed with special reference to its distribution into the affected tissues.


[Experimental studies on topic application of amikacin to the eye (author's transl)]. The compatibility of amikacin as well as its penetration into the different tissues of the eye were studied experimentally in rabbits. Amikacin is well tolerated, both when applying drops and subonjunctival injections. When 1% solution of amikacin is dropped into the eye, antibacterially effective concentrations are achieved in the cornea and in the aqueous humour. There was only minimum penetration in the cornea found after subconjunctival injection. No amikacin was found in the vitreous body, neither when applying drops nor subconjuctival injections.


Haemodynamic effects of molsidomine.

Haemodynamic effects of molsidomine. The haemodynamic effects of N-carboxy-3-morpholino-sydronimine-ethylester (molsidomine, SIN 10, Corvaton) were studied in anaesthetized mongrel dogs. The effects of molsidomine were identical when given i.v. or i.d. Because of the lack of difference in activity with similar doses i.v. or i.d. complete absorption of the drug can be assumed. There was a sustained decrease in arterial blood pressure accompanied by a long lasting decrease in left ventricular enddiastolic and mean pulmonary artery blood pressure. Heart rate was only moderately affected. Left ventricular endsystolic and enddiastolic volumes, as estimated from measurements of left ventricular outer dimension with ultrasonic techniques, decreased. Even in nearly toxic doses molsidomine did not influence left ventricular contractility as judge from measurements of dp/dt max., (dp/dt)/(LVP-LVEDP + c) max., ejection time and duration of systole. All the observed effects of molsidomine can be explained by an extracardiac action: increase in systemic venous capacity. Consequently venous return, mean pulmonary artery pressure and left ventricular filling pressure are reduced leading to a decrease in left ventricular volumes. This should cause a reduction of cardiac output, of peripheral blood pressure and of external cardiac work. In connection with reduced left ventricular wall tension a fall in myocardial oxygen consumption can be expected.


[Effect of molsidomine on the regional distribution of cardiac output in the anaesthetized dog (author's transl)]. In anaesthetized dogs blood pressures were measured in the following parts of the circulation: A. femoralis, aorta, left ventricle and A. pulmonalis. By means of particle distribution technique blood flow was measured in 25 different organs. By additional determination of arterio-venous O2 difference (AVDO2) between heart and brain oxygen consumption could be calculated. All data were measured before, 15, 30, 45 and 60 min after injection of 0.05 or 0.1 mg/kg, respectively, N-carboxy-3-morpholino-sydnonimine ethylester (molsidomine, Corvaton) i.v. 1. Molsidomine reduces blood pressures in all parts of the circulation measured. The duration of effects exceeds the experimental period. 2. The compound is no coronary vasodilator in the dose range selected, no dilation of cerebral occurs. Blood flow in kidneys remains constant. Blood flow values of all other organs do not give any indication of an essential peripheral dilatory effect of the drug. 3. Oxygen consumption of left ventricle is significiantly reduced by 25% with molsidomine (0.05 mg/kg i.v.). Oxygen consumption of brain remains constant. 4. All data are in accordance with the hypothesis that molsidomine exerts its effect predominantly by acting on capacitance vessels (venous pooling) of the circulation.


The central actions of nicotine on blood pressure and heart rate after administration via the left vertebral artery of anaesthetized cats. Distribution of nicotine into the brain after central application. After injection into the vertebral artery of anaesthetized cats, low does of nicotine (10(-9)--10(-8) mol = 0.5--5 micrograms . kg-1) induce potent cardiovascular effects. The hypotensive action is always accompanied by a severe bradycardia. Dose-response curves for these pharmacological actions have been established. It is concluced that nicotinic receptors in the medulla oblongata and pons are involved. Administration of 10(-8) mol = 5 micrograms (radioactive) nicotine/kg into the left vertebral artery gives rise to a specific distribution pattern. Nicotine mainly accumulates into the ponto-medullary area, whereas higher brain regions (hypothalamus) contain only insignificant amounts. The experimental results suggest that the nicotine-like effect of endogenous acetylcholine might play an important physiological part in the central regulation of blood pressure and cardiac frequency.


[Caffeine and bile secretion. Experimental studies in the unanaesthetized piglet (author's transl)]. We investigated the distribution and excretion of 8-14C-caffeine as well as the effects of caffeine on bile secretion in the unanaesthetized piglet after intravenous and intraduodenal application. The findings confirm a) data known from other species concerning the intestinal absorption, distribution and excretion of 8-14C-caffeine, b) the delayed plasma disappearance of 8-14C-caffeine known in the pig following an initial rapid disappearance rate and c) a hydrocholeresis, so far only known from rats. However, the increase in bile flow accompanied by an increase of urine flow was noticed not before 3--4 h after caffeine application. Therefore the question arises whether this increase is caused by caffeine itself or by its metabolites. On the basis of our results and those of the literature it is attempted to answer this question.


Pharmacological studies on 3-[gamma-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino(1,2-a)quinoline hydrochloride (compound 69/183). Part IV: other CNS effects and acute toxicity. 3-[gamma-(p-Fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino(1,2-a)quinoline hydrochloride (centpyraquin), a potent antihypertensive and tranquillising agent, was tested for anticonvulsant, analgesic and anti-inflammatory activities in mice and for anti-emetic activity in dogs. It did not modify supramaximal electroshock seizures and failed to protect the animals against pentylenetetrazole and strychnine induced convulsions. It, however, produced some elevation in the threshold dose of strychnine. Tremorine induced tremors and salivation were not antagonised. The compound had weak analgesic activity as detected by antagonism to phenylquinone writhing and the hot plate test. It had no anti-inflammatory activity. Centpyraquin had strong anti-emetic activity against apomorphine as well as morphine. At high doses it produced fall out in the rota-rod test. The LD50 of centpyraquin in mice was 296 mg/kg i.p. and more than 1000 mg/kg p.o. and in rats it was 161 mg/kg i.p. and more than 800 mg/kg p.o. The observed CNS effects resemble those of other neuroleptics.


Comparative analgetic testing of various compounds in mice using writhing techniques. Anti-writhing assays to detect analgesia or specific activity against selected agonists were performed on albino mice. Acetylcholine Cl, bradykinin triacetate, phenylquinone, and serotonin creatinine sulfate were used as agonists. 10 compounds, including 5 standard analgetics, were tested against each agonist. Attempts to study histamine phosphate as an agonist were not successful. Results of these investigations showed satisfactory analgetic acitivity for codeine phosphate and acteyl salicylic acid (ASA) in all assays. weaker analgetics displayed varying degrees of activity depending on the agonist tested. Acute oral toxicities  were determined for the 10 test compounds and the analgetic ED50 vs the LD50 of each compound was compared. The data confirmed the nonspecificity for writhing assays as well as a variability in activity of the test compounds against the various agonist.


[Human-pharmacokinetic Studies on Penetration Kinetics of a 6 alpha-Fluoro-9 alpha-chloro-16 alpha-methyl-delta 1,4-pregnadiene-11 beta-dihydroxy-3,20-dione-21-trimethyl-acetic acid (Clocortolone Trimethyl-acetic acid) after e picutaneous application]. Investigation on 6 alpha-fluoro-9 alpha-chloro-16 alpha-methyl-delta 1,4-pregnadiene-11 beta-dihydroxy-3,20-dione-21-trimethylacetic acid (clocortolone trimethylacetic acid) are reported. The aim of the trial was to prove the penetration kinetics of the steriod into the skin. Three healthy female subjects took part in the investigations. They were treated with an oil-water emulsion of the substance on two spots on the back, after having observed alcohol abstinence. One of the treated spots was stripped after 30 min, the second after 60 min using the "Tesafilm" stripping method. The strips were then analysed gaschromatographically on the presence of clocortolone-trimethylacetic acid. It could be shown that the steroid penetrates into the skin up to the 12th-14th strips, building up a certain congestion of the substance at this time because of reaching the stratum corneum, as we suppose. At this place a depot is built of which probably only a very small or no permeation into the system occurs, as clocortolone could not be detected either in the subjects' serum nor in the urine.


Cutaneous lupus erythematosus and autoimmune thyroiditis. A 19-year-old girl presented with cutaneous lupus erythematosus and hypothyroidism, and developed a thyrotoxic crisis when chloroquine therapy was discontinued.


Differential diagnosis of malignant and benign cutaneous lymphoid infiltrates: a study of 57 cases in which malignant lymphoma had been diagnosed or suspected in the skin. Clinical and histopathologic findings were reviewed in 57 cases in which there had been a diagnosis or suspicion of malignant lymphoma in the skin other than mycosis fungoides. Patients were included only if 1) extracutaneous tissue satisfactory for lymphoma classification was available, or 2) there was no evidence of extracutaneous involvement after a minimum of five years. Thirty-five patients had systemic lymphoma; in eight of these that disease first became manifest in the skin. There were two patients with typical lymphomatoid papulosis and one with a somewhat similar but solitary lesion which did not recur after excision; we have termed the latter a "solitary lymphomatoid papule." The remaining 19 cases without extracutaneous involvement were regarded as benign lymphoid hyperplasia. Clinically, the cutaneous lesions of malignant lymphoma were difficult to distinguish from those of lymphoid hyperplasia; only lymphomatoid papulosis was distinctive. Histologically, it was found that a definite diagnosis of malignant lymphoma (other than mycosis fungoides) could be made in the skin when three criteria were fulfilled: 1) exclusive presence or marked preponderance of medium-sized or larger lymphocytes, 2) absence of preferential involvement of the upper dermis, and 3) absence of extensive epidermal infiltration. These criteria were met in 21 cases of lymphoma. In both cases of lymphomatoid papulosis, the infiltrate was predominantly composed of large lymphocytes but was primarily limited to the upper dermis. The "solitary lymphomatoid papule" contained a similar cell population and involved the full thickness of the dermis; however, it displayed a prominent intraepidermal component. Fourteen cases of malignant lymphoma and all cases of lymphoid hyperplasia were characterized by a mixture of lymphocytes of varying size or a predominance of small lymphocytes. Nine cases of lymphoid hyperplasia exhibited at least one of three findings not observed in lymphoma; these findings were 1) germinal centers, 2) marked paucity of medium-sized lymphocytes in comparison to both small and large lymphocytes, and 3) sharp margination between adjacent groups of small and large lymphocytes. Aside from one case of small lymphocytic lymphoma which showed deep subcutaneous extension, the remaining cases (13 malignant and 10 benign) could not be reliably differentiated from each other by skin biopsy findings alone and were thus considered histologically indeterminate. The 13 lymphoma cases in this group were all of the small lymphocytic or follicular types; the failure of follicular lymphoma to exhibit a follicular pattern in the skin was a major impediment to its recognition in that location. The cutaneous infiltrates in all cases of large lymphocytic, Burkitt's, and lymphoblastic lymphoma were diagnostic of malignancy.


Atypical hyperplasia of lymph nodes: a follow-up study. Atypical hyperplasia of lymph nodes (AH) is neither a clinical nor a pathologic entity but represents cases in which the pathologist expresses concern about neoplasia and is unable to diagnose lymphoma. We reviewed 70 cases of AH diagnosed over the years 1961-1972. Thirty-seven percent developed a malignant lymphoproliferative disease during a follow-up that varied from 2-13 years. When the cases were histologically reexamined without knowledge of their clinical outcome or initial clinical features, 19 were diagnosed as benign, 10 as malignant, 37 as AH, and 4 as angioimmunoblastic lymphadenopathy. None of the patients of the first group developed a malignant lymphoma, but lymphoma occurred in 30% of the AH group. This latter group was divided into two subgroups according to the expectation of the course of disease; those with a probably malignant course and those with a probably benign course. Malignant lymphoma developed in 8 (73%) of the 11 patients in the first group but in only 14% of the 26 patients in the second group. It appears that although the pathologist can rather well appreciate the probable development of malignant lymphoma in AH cases, he is wrong too often--in this series 16%. Therefore, the common practice of designating a suspicious lymph node biopsy as atypical hyperplasia with a request for a later repeat biopsy is recommended.


Tumors in male rats fed ethyl chlorophenoxyisobutyrate, a hypolipidemic drug. Clofibrate (ethyl chlorophenoxyisobutyrate, Atromid-S), because it contains a chlorinated phenoxy moiety and is the most commonly used hypolipidemic drug in the United States and Europe, was fed at a concentration of 0.5% in the diet of 25 male F344 rats for 72 to 97 weeks, and the animals were inspected for tumors up to a maximum of 129 weeks. Between 72 and 129 weeks, there were 10 rats with a total of 16 tumors. These included 4 hepatocellular carcinomas, an adenocarcinoma of the glandular stomach, papillary carcinoma of the urinary bladder, acinar cell carcinoma of the pancreas, lymphosarcoma involving pancreas, acinar cell adenomas of the pancreas, renal carcinoma, and sarcomas of the lung and parotid gland. Although the number of experimental animals was small, none of these tumors were present in 25 controls, and systematic examination of available literature dealing with spontaneous tumors in several thousand rats indicated that the tumors in clofibrate-fed rats were not spontaneous. A number of the tumors were transplanted through several generations. Clofibrate, like two other hypolipidemic drugs that are carcinogenic, causes peroxisome proliferation. It is speculated that some drugs that cause peroxisome proliferation may represent a new class of chemical carcinogens and that there may be a relationship between peroxisome proliferation and malignant transformation.


Breast cancer mortality and diet in the United States. Internationally, breast cancer mortality is correlated with intestinal lactase sufficiency and dairy product consumption beyond childhood. Within the United States, age-adjusted breast cancer mortality is positively associated with consumption of milk, butter, and total milk fat in regional analyses, and it is associated with milk demand in state-based analyses. Breast cancer mortality is also positively associated with demand for total calories, protein, fat, beef, and table fats (butter and margarine), and it is negatively associated with egg demand. Only the associations with milk and egg demand, however, survive when the Southern states are eliminated from the analyses or when either age of first marriage or income is controlled. The associations with milk and egg demand persist despite multiple controls for other dietary and demographic variables, although the association with milk demand loses statistical significance in some second- and third-order partial correlations. The inverse correlation with egg demand is strong but in the opposite direction from what might have been expected from previous studies. The correlation between milk demand and breast cancer mortality, although weaker, is consistent with results from previous studies, and it suggests a possible special role for dairy products in the etiology of breast cancer.


Ophthalmopathy after neck irradiation therapy for Hodgkin's disease. Ophthalmopathy associated with autoimmune thyroid disease (Graves' ophthalmopathy) may occur years after irradiation of the neck for nonthyroid malignant disease. Two patients developed this complication 2 and 18 years after irradiation treatment of Hodgkin's disease: one with hypothyroidism associated with Hashimoto's thyroiditis and the other with hyperthyroidism. Careful long-term observation of thyroid function following neck irradiation is recommended in view of this unusual complication and the frequent occurrence of hypothyroidism.


Evaluation of two assays of functional surfactant in amniotic fluid: surface-tension lowering ability and the foam stability index test. We characterize two assays of total amniotic fluid surfactant that are based on function: the surface-tension lowering ability of extracts of amniotic fluid lipid (I) and the foam stability index test (II). I is determined on chloroform extracts of amniotic fluid. II is defined as the highest ethanol volume fraction of an amniotic fluid-ethanol mixture that will permit a stable foam to form after 30 s of vigorous shaking. The relationship of I to disaturated phosphatidylcholine concentrations (after osmium tetroxide treatment of the amniotic fluid lipid extract) is in the expected theoretical form of a hyperbolic function. The relation between values for II and disaturated phosphatidylcholine concentrations showed a consistent bias, suggesting that components other than disaturated phosphatidylcholine contribute to stable foam formation. Phosphatidylclycerol concentrations did not appear to account for this bias. The relation between I to II values suggest that both assays measure total surfactant. I, II, and concentration of disaturated phosphatidyl choline are all excellent indicators of fetal pulmonary maturity. From a practical standpoint, the foam stability index test is the most efficient approach to routine assessment of fetal pulmonary status.


Thyroid stimulating antibodies and metastatic thyroid carcinoma. A patient with previously treated follicular carcinoma of the thyroid developed Graves' disease with a high titre of thyroid-stimulating antibodies (TSAb). He developed functioning pulmonary metastases leading to hyperthyroidism. Levels of TSAb paralleled the functional status of the metastases suggesting that hyperfunction of the neoplastic tissues was caused by TSAb.


Mode of action of carbimazole in Graves' disease. In a series of hyperthyroid subjects treated with a high dose 'block-replace' regime, mean thyroidal technetium uptake was shown to fall progressively over an 18 month period. Furthermore, sub-total inhibition of hormone biosynthesis could be demonstrated, without evidence of proportionate inhibition of organification, the regression of radio-iodine on technetium thyroid uptake showing similar slopes in euthyroid, treated and untreated hyperthyroid subjects. Together with the reported differential in remission rates between propranolol and anti-thyroid drugs, it is concluded that carbimazole does not act solely by inhibiting intrathyroid hormono-genesis, but more definitively by affecting thyroid hyperstimulation at a pre-biosynthetic level. The inability to demonstrate normal suppressibility of trapping in any subject in the present series despite extended therapy with a 'block-replace' regime, further suggests that current concepts of 'suppressibility' are invalid, the progressive fall in technetium uptake being unlikely to represent spontaneous restoration of a normal pituitary-thyroid axis, but rather a direct influence or prolonged therapy with anti-thyroid drugs on the natural history of the disease.


A quantitative analysis of orbital soft tissue in Graves' disease based on B-mode ultrasonography. Using B-mode ultrasonography, an attempt was made to measure the volume of extraocular muscles and retrobulbar fat in 31 patients (62 orbits) with Graves' disease. None of the patients had exophthalmometric measurements greater than 21 mm or had eye symptoms. The mean value of muscle volume of Graves' patients was significantly larger than that of normal controls (6.48 +/- 2.70 cm3 and 3.25 +/- 1.30 cm3, respectively, p less than 0.001). All of the patients had extraocular muscle swelling, although 2 of them had no extraocular muscle change for their unilateral eye. The extraocular muscle volume increased as the degree of the proptosis increased. The fat volume tended to increase in parallel with the degree of the proptosis. In the Graves' group with obvious proptosis (Hertel reading: 19--21 mm), the fat volume increased more significantly than in any other group. The ratio of extraocular muscle volume to retrobulbar fat volume was significantly higher in Graves' disease, but it did not increase as the degree of the proptosis increased. A significant correlation between proptosis and muscle volume plus fat volume was observed. No significant difference of the extraocular muscle volume was observed between the patients untreated and treated with antithyroid drugs. The data show a uniform enlargement of the extraocular muscles in Graves' disease and also suggest an involvement of increased retrobulbar fat volume in a group of obvious exophthalmos. The degree of the proptosis is in aclose proportion ot the quantitative change of the orbital soft tissue.


Comparison of the analgesic effects of various opioid peptides by a newly devised intracisternal injection technique in conscious mice. To determine accurately the central analgesic effects of opioid peptides, we devised a special technique for intracisternal administration of drugs to conscious mice. When this method was utilized we found that a series of endogenous opioid peptides and enkephalin analogues, (D-Ala2,Met5)-enkephalinamide and (D-Met2,Pro5)-enkephalinamide produced dose-related analgesic effects, as determined by the tail pinch test. These effects were antagonized by pretreatment with naloxone 0.5 mg/kg s.c. This technique should be a most accurate one for the determination of central analgesic effects of various drugs in conscious mice.


Investigations towards an artificial cochlea. Two versions of multichannel cochlear stimulators have been implanted, one allowing stimulation against a common distributed ground within the cochlea and the other allowing bipolar stimulation. The results obtained indicate that with both versions sufficiently discrete stimulation of the auditory nerve is possible in order to be able to make use of tonotopy for the processing of speech. The bipolar stimulation, however, besides of being characterized by higher thresholds than unipolar stimulation, also leads to a very narrow range of stimulus frequency within which perceived pitch is influenced by stimulus frequency. Surprisingly different psychophysical behaviours are exhibited by the two subjects considered, one being a case of prelingual, the other of acquired deafness. This indicates the marked influence which etiology of deafness might have on design considerations for auditory prostheses.


[Incidence of venereal infections in soldiers of the German Federal Armed Forces]. The incidence of venereal diseases in the German Armed Forces is presented with reference to statistics covering a 20-year period. The chief interest is in gonorrhoea and syphilis. The most new admissions were registered in 1960 and 1971 with 605 and 601 per 100,000 men actual strength. On the other hand, in 1926 the numbers in the German Imperial Forces and in the British and American Armies were about 4,000-5,000. Armies of occupation are particularly at risk. Thus, in 1922 25,400 of 100,000 British soldiers in Germany were infected in comparison with only 7,890 in the German army. The number of venereal infections in the German Forces is lower than ever before in the German Forces. Syphilis infections have decreased steadily for years. In 1977 only 80 cases were reported for the entire Federal Forces, among these latent syphilis was predominant. The epidemiological situation in the civil population ought to be similarly favourable.


On splitting plasters. A useful analogy. An inner tube was inflated and then surrounded with plaster wool and plaster-of-Paris bandages. The plaster and the wool were next progressively divided. There was no significant reduction of the pressure inside the tube until both the plaster and the wool had been divided and separated from the inner tube along the entire circumference. These findings demonstrated that wool and plaster applied to limbs likely to swell should be split right down to skin and widely separated immediately after their application. A plaster slab is safer still, but the wool must be cut before the crepe bandage is applied.


Comparative cranial CT enhancement in the normal primate. The application of intravenous, intrathecal, and inhalation enhancement techniques to the CT evaluation of the nonhuman primate (Papio cynocephalus/anubis) is described. The falx cerebri cortical vasculature, vein of Galen, straight sinus and tentorium cerebelli were defined with intravenous enhancement. Intrathecal CT enhancement with air was limited by distortion in cerebrospinal fluid spaces. Intrathecal CT enhancement using a low dose of metrizamide accurately delineated the subarachnoid spaces and the brain substance they surrounded with minimal morbidity. Symmetrical brain enhancement (perfusion) was prominent following inhalation CT enhancement; the degree of enhancement correlated with the estimated xenon concentration in the bloodstream. In addition, by performing repeated CT scans during the clearance of xenon from the brain, an approximate analysis of regional cerebral blood flow was obtained.


Membrane events in the acrosomal reaction of Limulus sperm. Membrane fusion, filament-membrane particle attachment, and the source and formation of new membrane surface. The membranes of Limulus (horseshoe crab) sperm were examined before and during the acrosomal reaction by using the technique of freeze-fracturing and thin sectioning. We focused on three areas. First, we examined stages in the fusion of the acrosomal vacuole with the cell surface. Fusion takes place in a particle-free zone which is surrounded by a circlet of particles on the P face of the plasma membrane and an underlying circlet of particles on the P face of the acrosomal vauole membrane. These circlets of particles are present before induction. Up to nine focal points of fusion occur within the particle-free zone. Second, we describe a system of fine filaments, each 30 A in diameter, which lies between the acrosomal vacuole and the plasma membrane. These filaments change their orientation as the vacuole opens, a process that takes place in less than 50 ms. Membrane particles seen on the P face of the acrosomal vacuole membrane change their orientation at the same time and in the same way as do the filaments, thus indicating that the membrane particles and filaments are probably connected. Third, we examined the source and the point of fusion of new membrane needed to cover the acrosomal process. This new membrane is almost certainly derived from the outer nuclear envelope and appears to insert into the plasma membrane in a particle-free area adjacent to an area rich in particles. The latter is the region where the particles are probably connected to the cytoplasmic filaments. The relevance of these observations in relation to the process of fertilization of this fantastic sperm is discussed.


Changes in circulating iodothyronines in euthyroid and hyperthyroid subjects given ipodate (Oragrafin), an agent for oral cholecystography. A dose (3 g) of sodium ipodate used routinely in oral cholecystography caused a fall in serum 3,5,3'-triiodothyronine and a rise in serum 3,3',5'-triiodothyronine in three patients taking thyroxine (T4), four euthyroid subjects,and four hyperthyroid patients. Serum T4 fell in patients with hperthyroidism, whereas it rose in the other two groups. Sodium ipodate appears to alter peripheral T4 metabolism and, in addition, produces thyroid-inhibiting effects in hyperthyroidism.


Intrathecal metrizamide enhancement of the optic nerve sheath. The subarachnoid space continues into the orbit as part of the optic nerve sheath. This space varies in size but is usually tiny. Occasionally, prominent (one case in our experience) enhancement of the optic nerve as part of metrizamide computed tomography (CT) cisternography is seen on transverse and coronal scans presumably because of a patulous optic subarachnoid space. In five cases, we have appreciated minimal enhancement of optic nerves with metrizamide only by close comparison of CT numbers with base-line scans. One of these patients had a tiny meningioma removed successfully from the optic sheath, with return to normal vision of a previously blind eye.


Spontaneous mycotic aneurysm of the abdominal aorta. Aneurysms of the abdominal aorta may dissect, become infected, and rupture spontaneously. Since the mortality of infected mycotic aneurysm is high, a rapid diagnosis is a must. We describe a patient with a spontaneous mycotic aneurysm accurately diagnosed by computed tomography.


Graves' disease manifesting after maintenance lithium. A 36-year-old woman with no prior history of thyroid dysfunction developed Graves' disease (hyperthyroidism with exophthalmos) 4 months after her maintenance lithium therapy was stopped. Although a causal relationship between these events cannot be established, several hypotheses are presented. The possibility that lithium may mask the hyperthyroidism of Graves' disease but allow the exophthalmos to develop cryptically is discussed. Hyperthyroidism and mania have similar symptoms, but in the case presented two psychiatrists were able to distinguish between these two conditions by careful examination.


Multiple, prolonged actions of neuroendocrine bag cells on neurons in Aplysia. II. Effects on beating pacemaker and silent neurons. 1. A survey of identified cells of the abdominal ganglion of Aplysia was undertaken to determine the extent of bag cell influence in the ganglion. Bursts of bag cell spike activity lasting 5--40 min were elicited by brief, 0.6- to 2 s local stimulation while recording simultaneously from bag cells and other ganglion cells with intracellular electrodes. 2. Slow inhibition occurs in giant cell R2, neurosecretory cells R3-R14, and ink-gland motoneurons, L14A, B, C. The cells remain hyperpolarized for from 15 to 60 min. 3. Transient excitation occurs in mechanoreceptor cells L1 and R1. The cells are strongly depolarized by a slow excitatory potential that lasts for about 10 min and produces spike activity for 3--7 min. 4. Prolonged excitation occurs in some cells of the LB and LC identified cell clusters. The cells are depolarized and spike activity is increased for 3 h or more. 5. A biphasic response occasionally occurs in the command interneuron L10. Inhibition of this cell lasts 10--15 min and is followed by excitation for several hours. Excitation is accompanied by facilitation of synaptic potentials for 40--60 min in cells innervated by L10; the facilitation apparently results from the increase in L10 firing rate. 6. The results indicate that the bag cells have multiple types of actions and affect large numbers of ganglion neurons. All effects have the slowly graded onsets and prolonged durations to be expected of hormonally mediated interactions. 7. Previous studies have indicated that in intact animals the bag cell burst discharge initates a stereotyped egg-laying behavioral pattern that persists for several hours (3, 27). The present data support the hypothesis that certain elements of egg-laying behavior and homeostasis are regulated by a direct action of the bag cells on the central nervous system.