Diabetogenic effect of triamcinolone in man with impaired thyroid function: serum free fatty acids, inorganic phosphorus, calcium and total protein pattern after an oral glucose load. In a group of 35 subjects (12 hypothyroid, 11 euthyroid and 12 hyperthyroid) the changes of FFA, inorganic phosphorus, calcium and total proteins were investigated during glucose tolerance test with (TGTT) or without (OGTT) triamcinolone pretreatment. In hypothyroidism the decrease of FFA during TGTT was blunted, whereas the pattern of phosphatemia was unaltered and total proteins were increased. In euthyroidism triamcinolone exerts the opposite effect on the behaviour of FFA (decline was smaller and shorter) and phosphatemia (decline was pronounced and persists for longer period). In hyperthyroidism the fasting level of FFA decreased in TGTT but during the test no significant differences in FFA and phosphatemia patterns were observed. The calcemia was not influenced by triamcinolone in any subgroup. Our results suggest the importance of thyroid function as modifying factor in some metabolic effects of triamcinolone in man. Changes in hypothyroidism are in good agreement with changes of blood glucose and insulinemia, as described previously. Opposite effect of triamcinolone on FFA and phosphatemia pattern in euthyroidism may suggest the changes of sensitivity of some peripheral tissues to insulin action. The decline of fasting level of FFA after triamcinolone in hyperthyroidism is surprising and might be of importance in maintaining unaltered glucose tolerance after triamcinolone in this subgroup.


Computer interviewing of patients with epilepsy. Epilepsy histories obtained by the computer interview were similar in substance and detail to histories recorded by house staff and attending physicians. In general, more information was obtained by the computer, and negative findings were consistently recorded by the computer. For potentially embarrassing questions, the computer may obtain more accurate information (Slack and Van Cura, 1968b). This might explain the contradictions concerning incontinence and medication. This preliminary study suggests that computer interviewing can provide a reliable method for obtaining epilepsy histories. The study also pointed out where changes in question wording and branching logic would improve the computer interview. These changes are being incorporated into the second version of the epilepsy interview. We hope computer-based interviewing will prove useful to patients and physicians in the diagnosis, treatment, and study of epilepsy.


Left and right temporal lobe epileptics: a controlled investigation of some psychological differences. Twenty-two young adults with clinically and electroencephalographically diagnosed temporal lobe epilepsy were selected from an outpatient neurology source; 11 with focal epileptic activity in the right temporal lobe and 11 with left temporal lobe involvement were included. All patients had normal intelligence and comparable educational and socioeconomic backgrounds. Matched nonepileptic controls were also tested. Subjects were given psychological tests assessing differences in cognitive style and affect communication. Greater reliance on the ear ipsilateral to discharge focus in a dichotic listening paradigm was discovered, confirming appropriate lateralization assignment. Left lateralized patients exhibited a more reflective cognitive style than controls; right lateralized patients were more impulsive. Previously confirmed associations between impulsivity and externalized aggressive responses suggest the hypothesis that externalization of aggressive responses may occur more often among right lateralized patients. Left lateralized patients exhibited a more reflective cognitive style than controls; right lateralized patients were more impulsive. Previously confirmed associations between impulsivity and externalized aggressive responses suggest the hypothesis that externalization of aggressive responses may occur more often among right lateralized patients. Left lateralized patients made more atypical assignments of affect labels to emotionally evocative descriptions. Right laterlized patients tended to assign affect labels as controls. A greater potential for disturbance in the verbal communication of affect among left laterlized patients is suggested.


Seizure admissions to a city hospital: the role of alcohol. Among 472 adult seizure admissions to a municipal hospital, 41% had a history of alcohol abuse. Those were predominantly men aged 40 to 50 years. The primary underlying conditions were the alcohol withdrawal state (59%) and posttraumatic seizures. The nonalcohol groups included men and women equally, commonly between 20 and 40 years old, and frequent causes were vascular disease and posttraumatic seizures. However, many patients (24% in the alcohol and 39% in the nonalcohol groups) had no demonstrable cause. Focal sizures comprised 24% of the alcohol and 20% of the nonalcohol groups. Nonalcoholic focal seizures had a tumor or vascular lesion in 47%; above age 50 the association was 60%. Alcohol-related focal seizures had such a lesion in 15%, and only 19% above age 50. Conditions associated with alcoholic focal seizures were alcohol withdrawal and posttrauma sequelae.


Mephenytoin: a reappraisal.

Mephenytoin: a reappraisal. Serum levels of mephenytoin (Mesantoin) and its metabolite nirvanol were correlated with effectiveness and side effects in 93 patients. Mean mephenytoin level was 8% of the combined mephenytoin plus nirvanol levels. "Total mephenytoin" level should be used clinically, as neither individual component is as well correlated with clinical phenomena. Serum levels of 25 to 40 mug/ml usually yield improvement in seizure control without discomfort, and three-quarters of patients had fewer seizures. Side effects frequently associated with phenytoin were absent, but drowsiness, an occasional rash, and a single, fatal case of aplastic anemia were found. Performance on psychological tests of cognitive-attentional skills showed a modest improvement during mephenytoin administration. The drug merits wider employment in refractory seizure problems, but vigilant follow-up is required.


Interaction of epileptic activities of bilateral deep temporal origin. An experimental study. The interaction of epileptic activities obtained with electrical or chemical (penicillin) stimulation of the amygdaloid nuclear complexes of the two sides was studied in acute experiments on the rabbit. Several findings indicate that reciprocal influences between the two epileptogenic amygdalae can occur. Inhibitory as well as facilitatory interactive phenomena were observed. The occurrence of interaction and its sign seem related to the level of epileptic activity.


Experimental bilateral deep temporal epilepsy. Effects of ablation of one focus and of different brain lesions. In acute experiments in the rabbit, the amygdaloid nuclear complexes of the two sides were made epileptogenic through electrical stimulation or local injection of penicillin in gel. The effects on the epileptic pattern produced by surgical removal of one of the two epileptogenic amygdalae and the effects of sterotactic lesioning of the region of anterior commissure, head of caudate nucleus, and occipital cortex were analyzed. The occurrence of phenomena of both inhibitory and facilitatory interaction between the two epileptogenic amydalae was confirmed. In some experimental conditions, the restraining influence of an amygdaloid penicillin focus on the contralateral one was quite relevant, and its effect could persist even after surgical removal of the focus from which it originated. The mediation of the interamygdadoid epileptic interaction could not be ascribed to a single cerebral structure or anatomofunctionally homogenous group of structures. The phenomenon appears to involve several structures at different encephalic levels.


Acute renal failure caused by nephrotoxins. Renal micropuncture studies have greatly changed our views on the pathophysiology of acute renal failure caused by nephrotoxins. Formerly, this type of renal insufficiency was attributed to a direct effect of the nephrotoxins on tubule epithelial permeability. According to that theory, glomerular filtration was not greatly diminished, the filtrate formed being absorbed almost quantitatively and nonselectively across damaged tubule epithelium. Studies in a wide variety of rat models have now shown glomerular filtration to be reduced to a level which will inevitably cause renal failure in and of itself. Passive backflow of filtrate across tubular epithelium is either of minor degree or nonexistent even in models where frank tubular necrosis has occurred. This failure of filtration cannot be attributed to tubular obstruction since proximal tubule pressure is distinctly subnormal in most models studied. Instead, filtration failure appears best attributed to intrarenal hemodynamic alterations. While certain facts tend to incriminate the renin-angiotensin system as the cause of the hemodynamic aberrations, others argue to the contrary. The issue is underactive investigation.


Methoxyflurane nephropathy.

Methoxyflurane nephropathy. Investigations of methoxyflurane-induced nephrotoxicity in man have been extensively aided by the use of an animal model. To be of value the animal model must share similar metabolic pathways with man and have the same clinical manifestations of the diseases process. The Fischer 344 rat appears to meet these criteria. The predominant factors in the production of methoxyflurane nephrotoxicity appear to be high methoxyflurane dosage and serum inorganic fluoride concentration. It is likely that secondary factors include: (1) a high rate of methoxyflurane metabolism and sepsitivity of the kidney to inorganic fluoride toxicity: (2) concurrent treatment with other nephrotoxic drugs; (3) preexisting renal disease; (4) surgery of the urogenital tract, aorta, or renal vasculative; (5) repeat administration of methoxyflurane due to accumulation of inorganic fluoride and, perhaps, methoxyflurane induction of its own metabolism: and (6) concurrent treatment with enzyme-inducing drugs such as phenobarbital.


Perinatal nephropathies.

Perinatal nephropathies. The purpose of this paper is to review the development of the mammalian kidney and to assess the influence that various perinatal manipulations may have on the developmental process either morphologically or functionally. Immature kidneys in general have less functional capacity than adult kidneys and a low rate of glomerular filtration, perhaps related to renal blood flow, which appears to limit the disposition of a fluid or solute load. Tubular reabsorption is also limited leading to the urinary loss of glucose, amino acids, bicarbonate and phosphate. Although the relatively low function of the immature kidney is a normal part of development, its capacity to respond under conditions of stress may be less adequate than in adults. An additional concern is that a variety of perinatal manipulations, such as the incidental or accidental ingestion of a chemical, may lead to varying degrees of altered morphogenesis or functional development of the kidney. Chemical induced renal anomalies may be of several types, but in typical teratology experiments hydronephrosis may be the most frequent observation. The functional consequences of these renal malformations may be lethal or inconsequential or while an animal may be able to survive and develop normally in the presence of a renal malformation, it is possible that a stressful situation would unmask a functional malformation which could compromise survival. Thus, some renal abnormalities may be subtle enough to go unnoticed without experimental tests. Without such tests it is impossible to evaluate the effect of functional alterations on successful adaptation.


Structural and functional changes in acute liver injury. Carbon tetrachloride produces liver cell injury in a variety of animal species. The first structurally recognizable changes occur in the endoplasmic reticulum, with alteration in ribosome-membrane interactions. Later there is an increase in intracellular fat, and the formation of tangled nets of the ergastoplasm. At no time are there changes in mitochondria or single membrane limited bodies in cells with intact plasmalemma, although a relative increase in cell sap may appear. In dead cells (those with plasmalemma discontinuties) crystalline deposits of calcium phosphatase may be noted. Functional changes are related to the endoplasmic reticulum and the plasma membrane. An early decrease in protein synthesis takes place; an accumulation of neutral lipid is related to this change. Later alterations in the ergastoplasmic functions (e.g., mixed function oxidation) occurs. Carbon tetrachloride is not the active agent; rather, a product of its metabolism, probably the CC1, free radical, is. The mechanisms of injury include macromolecular adduction and peroxide propagation. A third possibility includes a cascade effect with the production of secondary and tertiary products, also toxic in nature, with the ability to produce more widespread damage to intracellular structures.


Determination of human body burden baseline date of platinum through autopsy tissue analysis. Results of analysis for platinum in 97 autopsy sets are presented. Analysis was performed by a specially developed emission spectrochemical method. Almost half of the individuals studied were found to have detectable platinum in one or more tissue samples. Platinum was found to be deposited in 13 of 21 tissue types investigated. Surprisingly high values were observed in subcutaneous fat, previously not considered to be a target site for platinum deposition. These data will serve as a human tissue platinum burden baseline in EPA's Catalyst Research Program.


Assaying potential carcinogens with Drosophila. Drosophila offers many advantages for the detection of mutagenic activity of carcinogenic agents. It provides the quickest assay system for detecting mutations in animals today. Its generation time is short, and Drosophila is cheap and easy to breed in large numbers. The simple genetic testing methods give unequivocal answers about the whole spectrum of relevant genetic damage. A comparison of the detection capacity of assays sampling different kinds of genetic damage revealed that various substances are highly effective in inducing mutations but do not produce chromosome breakage effects at all, or only at much higher concentrations than those required for mutation induction. Of the different assay systems available, the classical sex-linked recessive lethal test deserves priority, in view of its superior capacity to detect mutagens. Of practical importance is also its high sensitivity, because a large number of loci in one fifth of the genome is tested for newly induced forward mutations, including small deletions. The recent findings that Drosophila is capable of carrying out the same metabolic activation reactions as the mammalian liver makes the organism eminently suitable for verifying results obtained in prescreening with fast microbial assay systems. An additional advantage in this respect is the capacity of Drosophila for detecting short-lived activation products, because intracellular metabolic activation appears to occur within the spermatids and spermatocytes.


Factors influencing the deposition of inhaled particles. Because the initial deposition pattern of inhaled particles of various toxic agents determines their future clearance and insult to tissue, respiratory tract deposition is important in assessing the potential toxicity of inhaled aerosols. Factors influencing the deposition of inhaled particles can be classified into three main areas: (1) the physics of aerosols, (2) the anatomy of the respiratory tract and (3) the airflow patterns in the lung airways. In the physics of aerosols, the forces acting on a particle and its physical and chemical properties, such as particle size or size distribution, density, shape, hygroscopic or hydrophobic character, and chemical reactions of the particle will affect the deposition. With respect to the anatomy of the respiratory tract, important parameters are the diameters, the lengths, and the branching angles of airway segments, which determine the deposition. Physiological factors include airflow and breathing patterns, which influence particle deposition. Various lung models used in predicting particle deposition are reviewed and discussed. The air-way structures of various animal species are compared, showing the unique structure of the human lung compared to the animal species under study. Regional deposition data in man and dog are reviewed. Recent deposition data for small rodents are presented, showing regional difference in deposition with the right apical lobe having the highest relative deposition.


Various forms of chemically induced liver injury and their detection by diagnostic procedures. A large number of chemical agents, administered for therapeutic or diagnostic purposes, can produce various types of hepatic injury by several mechanisms. Some agents are intrinsically hepatotoxic, and others produce hepatic injury only in the rare, uniquely susceptible individual. Idiosyncrasy of the host is the mechanism for most types of drug-induced hepatic injury. It may reflect allergy to the drug or a metabolic aberation of the host permitting the accumulation of hepatotoxic metabolites. The syndromes of hepatic disease produced by drugs have been classified hepatocellular, hepatocanalicular, mixed and canalicular. Measurement of serum enzyme activities has provided a powerful tool for studies of hepatotoxicity. Their measurement requires awareness of relative specificity, knowledge of the mechanisms involved, and knowledge of the relationship between known hepatotoxic states and elevated enzyme activities.


Quantitative aspects in the assessment of liver injury. Liver function data are usually difficult to use in their original form when one wishes to compare the hepatotoxic properties of several chemical substances. However, procedures are available for the conversion of liver function data into quantal responses. These permit the elaboration of dose-response lines for the substances in question, the calculation of median effective doses and the statistical analysis of differences in liver-damaging potency. These same procedures can be utilized for estimating the relative hazard involved if one compares the liver-damaging potency to the median effective dose for some other pharmacologie parameter. Alterations in hepatic triglycerides, lipid peroxidation, and the activities of various hepatic enzymes can also be quantitiated in a dose-related manner. This permits the selection of equitoxic doses required for certain comparative studies and the selection of doses in chemical interaction studies. The quantitative problems involved in low-frequency adverse reactions and the difficulty these present in the detection of liver injury in laboratory animals are discussed.


Assessment of hepatotoxic potential.

Assessment of hepatotoxic potential. Philosophic concepts and pragmatic approaches toward improved understanding of the effect of drugs in the hepatocyte are reviewed. No set pattern of studies is advocated but rather observations are encouraged within the framework of studies that provide for varied exposure of the hepatocyte. Clinical usage should be imitated to provide earliest possible indications of toxicity in man. The need for definitive characterization through utilization of appropriate methodology derived from cross-fertilization of related disciplines is stressed. Both minimal and maximal dose effects should be established. Selected use of electron microscopy has become essential for characterizing responses of the liver to injury. The advantages of the toluidine blue-stained Epon "thick" sections are emphasized. Such observations are used to implement the utility of serial biopsies from the beagle dog prior to and during long-term study of potential hepatic injury. Examples of the critical effects of drug concentration within the hepatocyte are presented.


Renal function tests: what do they mean? A review of renal anatomy, biochemistry, and physiology. Renal physiology, biochemistry, and anatomy are reviewed. For the most part, those aspects of these disciplines will be discussed which relate directly to the question of the evaluation of nephrotoxicity. In addition, emphasis is placed on those procedures and techniques which are useful in the evaluation of nephrotoxicity. A detailed discussion of histological and anatomical considerations is not given, since this is probably the least useful criterion for evaluation of renal damage. This information is intended as background for the remainder of the symposium which will be directed toward an understanding of specific nephrotoxicity phenomena.


Urinary epinephrine and norepinephrine levels in women athletes during training and competition. Training and competitive epinephrine and norepinephrine levels and proportions were compared in two groups of women athletes to determine whether changes in catecholamine excretion reflect the added mental stress of athletic competition on physical effort. An intercollegiate basketball team and a group of track and field athletes volunteered as subjects. Competitive epinephrine urinary levels were significantly (P less than 0.01) higher than training levels. A concomitant rise in the norepinephrine with an increase in physical effort was observed in both groups of athletes following training sessions as well as after athletic competition. Track and field athletes trying to qualify for an international team exhibited significantly ( less than 0.01) higher epinephrine levels than the team members; thus suggesting that anticipation of competition imposes a mental stress on an athlete. Constant changes in the catecholamine pattern as against a normal work load have yet to be established.


[Adaptive modifications of cold pain (author's transl)]. 38 healthy subjects 22-28 years of age underwent the cold-pressor-test seven times on each of 21 consecutive days always at the same time of day. The subjective sensations of cold pain and the objective circulatory reactions were registered. There was observed only a very distinct subjective cold pain habituation from one exposition to the other. The habituation effect on blood pressure reaction however was of expected extent. The long term adaptation showed to have effect on the predominance of the two components of pain perception the epicritic and protopathic pain experience. Initially the cold stimulus produced an overwhelmingly protopathic sufferenig whilst at the end of the three weeks of adaptation there remained only a reduced and localized epicritic pain sensation. Typological differences of pain reactions and pain adaptation are discussed.


Influence of growth and athletic training on heart and lung functions. Studies were performed at rest and during exercise of varied intensity on 52 boys of pre- and post-pubescent age. Each age group consisted of boys who were engaged in a strenuous prolonged hockey training program; this group was compared with a matched control group who did not participate in a regular training program. Any differences observed in the measured lung functions could be explained on the basis of physical size. Relationship of pulmonary capillary blood flow (Qc) and pulmonary diffusing capacity (DLco) to oxygen consumption were similar to those reported for adults and no difference between the trained and control groups was found in either the pre- or post-pubertal aged boys. Similarily, the trained pre-pubertal boys did not differ significantly from their matched control group in respect to the relationships of heart rate (HR) and stroke volume (SV) for any level of oxygen consumption. In contrast, the post-pubertal trained boys had significantly lower HR and higher SV (P less than 0.01) at each level of work than the control group. These differences between the trained and control post-pubertal boys are consistent with training effects observed in adults. The lack of differences between the trained and control pre-pubertal groups was surprising. Whether the differences in the post-pubertal groups due to a detraining effect in the post-pubertal control boys (as compared to the pre-pubertal control group) or to a continued high level of physical activity during and after the on-set of puberty in trained boys cannot be answered by this study. The findings suggest the importance of high intensity exercise programs during the growth period of adolescence if the efficiency of the oxygen delivery system, and possibly its ultimate dimensions, are to be enhanced.


Serum urea and amino nitrogen changes with exercise duration. In eight groups of healthy male athlets, aged 19-44 years, serum urea, alpha-amino nitrogen and free tyrosine were determined before and after physical exercise of different duration. Exercise was competitional running, skiing, march or bicycle ergometer work, its duration between 15 and 765 min. The results were compared with previous data from this laboratory and those of other authors. After about 60-70 min of exertion, there is a significant fall in serum amino nitrogen and a rise in urea and free tyrosine; the magnitude of these changes correlated well to the duration of exercise. Likewise, there is a significant correlation between increase in serum urea and decrease in amino nitrogen. The observed changes strongly suggest an increased breakdown of nitrogen-containing compounds during prolonged exercise.


Effects of beta blockade and atropinisation on plasma catecholamine concentration during exercise. The changes in plasma catecholamine concentration (deltaC) following beta-blockade (practolol, 15 mg) and atropinisation (Atropine, 1.8 mg) have been studied on 5 healthy male subjects during exercise on a motor driven treadmill. The results showed that for a given V-2 and % VO2 max, beta blockade was without effect on delta C (except in one athletic subject, but atropine produced a rise in deltaC. In relation to Q, both drugs produced an increase in deltaC, but for a given cardiac frequency (fH) deltaC was higher with beta blockade, and lower with atropinisation than found in control experiments. The intra- and inter-subject variability of delta C in relation of fH was resolved by considering the change in cardiac frequency calculated from baseline value obtained during walking at 6.44 km/h on the level, and expressed as a percentage of the maximal fH attainable for given individuals under the different drug and control conditions (%deltafH). It was concluded that during short term exercise, the rise of deltaC in relation to %deltafH reflects both the myocardial sensitivity to vagal and beta blockade, and the circulatory vasoconstrictor control of blood vessels which is required to sustain increases in systemic and muscle blood flow.


Plasma volume, albumin and globulin concentrations and their intravascular masses. A comparative study in endurance athletes and sedentary subjects. Plasma volume, hematocrit, intravascular protein concentration, colloid osmotic pressure and the intravascular mass of proteins were measured in 49 sedentary subjects and 40 endurance athletes (long-, middle distance runners, cyclists). The plasma volume in sedentary subjects was 42.7(35.8-51.7) ml/kg body weight (BW) as compared to 54.6(46.7-65.9) ml/kg BW in athletes. The protein concentrations were 71.0 (66.5-77.1) g/l in sedentary subjects and 69.0 (64.8-75.2) g/l in athletes. The respective numbers for the hematocrit were 44.6 (40.1-49.25)% and 42.8 (38.2-49.6)%, for the colloid osmotic pressure 38.0 (36.0-40.5) cm H2O (n=35) and 30.0 (25.0-34.4) cm H2O (n=31), for the intravascular mass of proteins 3.09 (2.45-4.01) g/kg BW and 3.75 (3.31-4.67) g/kg BW. All differences were statistically significant at least on the 5% level. The physiological consequences for athletes of having a lower hematocrit and lower protein concentration but a higher intravascular mass of proteins (+22%) for their waterbalance as well as for their dietary protein intake are discussed. Endurance exercise stimulates mainly the synthesis of albumin and globulins produced by the liver resulting in an expansion of the PV. The protein synthesis of the RES does not seem to respond to exercise stimulus.


Circulatory effects of isometric muscle contractions, performed separately and in combination with dynamic exercise. Studies on central circulation and regional blood flow were performed in healthy male volunteers at rest, during sustained isometric forearm contraction at 20% of MVC, during dynamic leg exercise (100 W) and during combined isometric and dynamic exercise. In 10 subjects pulmonary oxygen uptake, arterio-venous oxygen difference, heart rate, leg blood flow and blood pressures in the pulmonary and subclavian arteries and in the right atrium were measured. In 4 of these subjects the temperature was measured in mixed venous blood and in subcutaneous tissue in an attempt to further analyse the blood flow distribution through central versus peripheral parts of the circulatory system. In 5 other subjects the splanchnic blood flow was estimated by hepatic vein catheterization and dye dilution technique at rest and during isometric forearm contraction. It was found that cardiac output, oxygen uptake, heart rate and arterial blood pressure all increased in response to isometric contraction. Quantitatively the changes in heart rate and cardiac output induced by a sustained contraction were more marked when the contraction was performed separately than when it was added to dynamic exercise. In spite of the increased arterial pressure, the leg blood flow did not increase significantly. Neither did the splanchnic blood flow increase in response to hand-grip contrmic exercise. Isometric exercise, however, caused a blood temperature fall and a rise in subcutaneous temperature indicating an increased blood flow through the skin. It is concluded that during sustained isometric muscle contraction 1. the blood flow increase is mainly distributed to peripheral circulatory areas, 2. a concomitant dynamic exercixe interferes with the circulatory adaptation only to a small extent.


Management of bleeding disorders in traumatic-haemorrhagic shock states with deep frozen fresh plasma. Coagulation disorders in traumatic-haemorrhagic shock need not represent a simple coagulation problem. They may also occur as a complex of local and disseminated intravascular consumption, dilution, extravascular loss and depressed synthesis of coagulation factors. In the severely bleeding patient with a haemorrhagic diathesis heparin is contrainedicated because it does not normalize coagulability immediately. Therefore, it fails to stop haemorrhage and the shock becomes untreatable. Fresh frozen plasma, however, has proved to be suitable as a simultaneous substitution therapy for the coagulation disorder and the hypovolaemic shock. 25 patients suffering from severe traumatic-hemorrhagic shock associated with coagulation disorders and haemorrhagic diathesis were successfully treated with fresh frozen plasma, after conventional shock therapy had failed over a period of 2 hours. The success was documented clinically and by numerous laboratory tests. Thrombocytopenia has only a secondary responsibility for the haemorrhagic state.


The occurence and significance of microaggregates in stored blood. During storage whole blood progressively forms microaggregates by adhesion of platelets and leucocytes. This occurs from the second day of storage and the presence of such potential microemboli can be demonstrated by light microscopy of smears of blood samples. They cause an increase in the viscosity of the blood as measurable by the screen filtration pressure method. If infused into a patient they, by causing microvascular occlusion, result in multiple organ dysfunction, primarily of the lung. It is recommended that, if whole blood greater than 4 days in storage is to be infused, an in-line microfilter be used to remove the microaggregates from the transfusion. Alternatively, early separation, or the use of fresh blood is recommended.


Organic acidaemia in intensive care unit patients. Forty ICU patients were studied as to the prevalence and importance of organic acidaemia. It was observed that organic acidaemia was extremely common, secondly that a persistence of such an acidaemia heralded a poor prognosis and finally that the acidaemia rarely needed treatment in its own right.


Ethylene imine poisoning. A case report. A case is described of accidental inhalation of ethylene imine vapour in a chemical worker. This resulted in glottic oedema which required tracheostomy. Artificial respiration was needed because of failure to maintain adequate arterial oxygen levels. The patient developed profuse salivation and sputum production. Endoscopy showed that the mucosal surfaces of the pharynx, trachea and major bronchi were destroyed. The patient was treated with steroids and antibiotics for pulmonary infection. Recovery was slow but he was eventually able to leave hospital. He was later readmitted with recurrent infection and developed acute airway obstruction from which he died. Post-mortem examination shoed extensive destruction of the mucosal lining with erosion and collapse of the cartilages. This was the cause of death. Previous reports of ethylene imine poisoning are reviewed. This appears to be the third fatal case.


Immunologic defense in bacterial and viral meningitis in children. The investigation of a number of parameters of nonspecific and specific defense in 13 purulent and 18 mumps meningitides gave no indication of underlying primary immunodeficiencies. Only in the acute phase of mumps meningitis did we find a temporary suppression of cellular immune reactions measured as diminished rate of incorporation of thymidine by phytohemagglutinin-stimulated peripheral blood lymphocytes.


Bodyplethysmography in healthy children. Measurement of intrathoracic gas volume and airway resistance. In 94 healthy children, 6-15 years of age, the intrathoracic gas volume at resting expiratory level (TVG) was measured by means of a pressure corrected flow body plethysmograph and compared to functional residual capacity (FRC), measured simultaneously to TGV by means of the Helium dilution technique. TGV is 1.9% (+/- 11.7% SD) smaller than FRC, this difference being not significant (P greater than 0.05). A predicted equation for TGV (in ml) in correlation to standing height (in cm) is published in boys and girls. In 82 healthy children, 6-15 years of age, airway resistance (Raw) was measured plethysmographically. Raw(in cmH2O/1/s) is smaller, the larger is the child (r = -0.57; P less than 0.01), the residual standard deviation around the regression line is considerable (29%) and corresponding to the value, published previously for total pulmonary flow resistance. Difficulties in the evaluation of recorded resistance curves as well as calculation and lung volume correction of the Raw-value are discussed.


Solitary hepatic hemangioma in a newborn infant complicated by cardiac failure, consumption coagulopathy, microangiopathic hemolytic anemia, and obstructive jaundice. Case report and review of the literature. A newborn infant with a large hepatic hemangioma developed congestive heart failure, consumption coagulopathy, microangiopathic hemolytic anemia, and obstructive jaundice. The patient was mildly heparinized (250 units per kg and day) and underwent successful resection of the tumor without lobectomy at the age of 3 days. Blood volume increased from 93.9 ml/kg at the age of 5 h to 124.2 ml/kg prior to surgery. Red-cell mass simultaneously decreased from 53.8 to 39.4 ml/kg. The increase of blood volume is explained by congestive heart failure, the decrease of red-cell mass by intravascular coagulation within the tumor resulting in formation of thrombi and microangiopathic hemolytic anemia. A review of the literature on infants with symptoms caused by an intrahepatic hemangioma during the first month of life confirms that surgical intervention is the treatment of choice for infants with giant solitary hemangioma of the liver.


Mild variant of maple syrup urine disease. Amino acids analysis were made on serum and cerebrospinal fluid samples of a Japanese 5-month-old infant suffering from irritability and mental retardation noticed at 2 months of age. Excessive amounts of branched-chain amino acids and of keto acids were detected in those samples and the large quantity of keto acids was found in urine with a qualitative 2,4-dinitro-phenyl-hydrazin test and with quantitative estimation. When thiamine hydrochloride (100 mg/day) was administered orally for 7 days to the patient fed with the cow's milk formula containing 2.1 gm/dl milk protein, there was no improvement of the branched-chain amino acidemia. Urinary keto acids, however, showed a marked decrease 7 days after the administration of thiamine hydrochloride. An overnight fast for 13 h resulted in normoglycemia. There was found no difference of blood L-lencine level between both parents and normal infants to whom L-leucine was loaded. The relation between decarboxylase activity for keto acids of branched-chain amino acids and thiamine hydrochloride was studied clinically, in the present communication.


Primary perireticulin amyloidosis in a 14-year-old girl. A primary perireticulin amyloidosis is reported in a 14-year-old girl, which showed the symptoms of a steroid-resistant nephrotic syndrome. The diagnosis was established by biopsies of kidney and rectum. Occurrence of amyloidosis in childhood and the clinical picture are discussed and references to clinical trials carried out are given.


Immunologic function of patients with chronic benign lymphadenopathy. Three children with chronic lymphoid hyperplasia and hypergamma-globulinemia are presented. They had normal numbers of circulating T-cells and normal in vitro lymphocyte responses to phytohemagglutinin and specific mitogens. The number of cells staining for surface immunoglobulins was decreased in two patients but increased in one patient with chronic lymphocytosis which is still present 5 years after his initial hospitalization. Lymphocytes without detectable markers ("Null cells") were increased in all three patients. Levels of antibody titers to common antigens were normal. Lymph node biopsies showed nonspecific hyperplasia of the B-cell areas. The combination of normal immune responses with lymphoid hyperplasia and with a chronic lymphocytosis in one of the children suggests that this syndrome may be due to a defect in the regulation rather than the initiation of immune responses.


Xylose absorption before and after surgical correction of atrial septal defect (asd) and ventricular septal defect (vsd). The aim of the study was to ascertain whether the acceleration of physical development in children after surgery for ASD or VSD is due to improved intestinal absorption. There were 17 patients with ASD and 9 patients with VSD (aged 5-15 years) examined. Significantly increased values of the xylose test after surgery were found in both groups. The authors suggest that the improvement in intestinal absorption is due to an increase of systemic blood flow after operation. Simultaneously, the stldy confirms, on natural human model, the known dependence between blood flow and the intestinal absorption rate.


Bone marrow hypoplasia in anorexia nervosa. Within a 2-year period, from March 1974 until May 1976 10 patients with anorexia nervosa were seen at the children's university hospitals of München (2 patients) and Giessen (8 patients). The patients were 10-16 years old, with one exception all girls, and had the typical cachexia, hypothermia, bradycardia, gray, hairy skin, and amenorrhea in those who had reached menarche. The blood counts at diagnosis revealed a leukopenia (below 5000/mm3) in 6 patients and a thrombocytopenia (below 150000/mm3) in 4 patients. The bone marrow was examined in 7 patients and showed marked hypocellularity with only few megakaryocytes present and abundant vacuolated hyaline material. Bone marrow erythroblasts were decreased (below 20%) in 5 patients, although peripheral blood hemoglobin and hematocrit were normal or even elevated in all 10 patients. In 7 patients blood urea nitrogen was elevated above 30 mg%, the highest value being 145 mg%. Blood and bone marrow alterations as well as the renal abnormalities disappeared within days to a few weeks after a regimen of strict fluid and caloric intake was initiated and a gain in body weight of up to 10 kg was achieved.


Circulating quantities of sodium, potassium, calcium, inorganic phosphorus, and magnesium in serum of healthy newborn infants. The main serum ions were determined in healthy, full-term newborn infants having different plasma volumes. The serum sodium, potassium, and calcium concentrations were found to be constant, thus their circulating quantities were dependent on the actual plasma expansion. The serum inorganic phosphorus and magnesium concentrations were found to be inversely related to the plasma volume and therefore the circulating total quantities of these ions remained constant in different expansion of the plasma volume.


Right ventricular involvement in acute myocardial infarction. Involvement of the RV in AMI is not as rare as previously thought and may lead to a particular clinical and hemodynamic syndrome with raised RV filling pressures, hypotension and oliguria. Major extension to the RV from inferior LV infarctions can be recognized by ST segment elevations iead CR4R or V4R. The significance of anterior RV extension and of RV papillary muscle infarction is still largerly unknown. It has been suggested from autopsy studies that the prognosis of patients with RV involvement might be poor healed extensive RV infarction is rarely seen. Indeed, ST segment elevation in lead CR4R indicating RV involvement has been found to carry a poor short-term prognosis. An increased awareness of the possibility of impaired RV function and of the special therapeutic considerations in some of these patients may increase survival.


A study of the verapamil-induced changes in conductivity and refractoriness and monophasic action potentials of the dog heart in situ. In the dog heart in situ, verapamil 0.30 mg/kg injected intravenously did not impair intraatrial, His--Purkinje and intraventricular conduction. The monophasic action potential (MAP) derived from the right atrium and ventricle was not altered by the drug. The functional refractory period (FRP) and the effective refractory period (ERP) of the atrium was not changed by verapamil. However, the drug caused a small but statistically significant decrease in the ratio between 50 and 90% repolarization, respectively, and the ERP of the right atrium, i.e. the ERP of the atrium increased in relation to the MAP duration. Verapamil used a marked reduction of the conduction velocity within and a pronounced increase of the AV nodal FRP and ERP. These changes were reversed by a rapid injection of calcium gluconate 40 mg/kg. The sinus node automaticity was not influenced by verapamil.


Problems in assessing infarction size by epicardial mapping: preliminary studies with quinidine. Some of the laboratory difficulties in assessing infarction size produced by intermittent coronary artery occlusion were demonstrated by using an epicardial mapping technique in anesthetized open-chest dogs. Intermittent occlusion of a left anterior descending coronary artery branch resulted in a marked elevation of the ST segment above the baseline in the areas of the myocardium supplied by this vessel. Repeated occlusions after administration of normal saline as a control produced less ST-segment elevation thn that noted during control occlusions; however, repeated occlusions after infusion of quinidine produced a further lessening in ST-segment elevation. The problems encountered in interpreting these results are emphasized. Long-term coronary occlusion studies were performed in order to correlate epicardial electrograms with histological findings of ischemia or myocardial necrosis. Our investigations show that epicardial mapping tended to underestimate the area of injury, and this limits the interpretation of drug intervention studies such as those in which quinidine is administered. Therefore, caution should be exerted when using epicardial mapping techniques to assess the effect of various pharmacological interventions on infarction size in open-chest dogs.


Enzyme release after myocardial infarction: comparison of serial serum alpha-hydroxybutyrate dehydrogenase with creatine phosphokinase levels. Serial measurements on serum creatine phosphokinase (CPK) and alpha-hydroxybutyrate dehydrogenase (HBD) activity were made in 17 patients with acute myocardial infarction. Activities of both enzymes were measured 4-hourly from less than 12 h after the onset of chest pain until CPK activity had returned to near-normal levels. Blood was then sampled twice daily for a further 4--6 days in order to follow the decline in HBD activity. Degradation rates (KD) were calculated for both enzymes, and individual figures for KD were used in order to estimate the total cumulative release of each enzyme. We found a significant correlation between the duration (r = 0.66, P less than 0.01) and magnitude (r = 0.67, P less than 0.01) of release of the 2 enzymes, comparing different patients with one another. Duration od HBD release was 11 h greater than the duration of CPK release in 9 of the 17 patients who were suffering from cardiac failure (t = 0.01, P less than 0.02). Degradation rate (KD) for HBD was on average about one quarter of that for CPK, but there was no significant correlation between KD for the 2 enzymes. KD did not appear to be reduced in patients with cardiac failure. We conclude that the release patterns of CPK and HBD after myocardial infarction are similar, and this strengthens the case for acceptance of total enzyme release as a valid index of myocardial infarct size.


Regression of coronary artery obstructions demonstrated by coronary arteriography. To determine the incidence and clinical features of regression of coronary artery obstructions we reviewed the angiograms of 93 nonoperated and 201 operated patients who had repeated coronary arteriographic studies. Regression of obstructions was found in 4 nonoperated cases (4.3%), all involving the left anterior descending artery. This was associated with improvement of the patient's clinical condition in only 1 case. No regressions were found in the surgical cases. Our data demonstrate that regression of coronary artery obstructions is rare and unrelated to clinical parameters.


Intra-His bundle blocks (102 cases).

Intra-His bundle blocks (102 cases). Some intra-His bundle (intra-HB) blocks escape the routine exploration of the His bundle and are confused with supra- or infrahisian blocks. We believe that a more accurate exploration (recording of His bundle activity successively at the proximal end and the distal end of the His bundle, dynamic tests and drug injection) is needed to detect some concealed cases, mostly paroxysmal intra-HB blocks. In this series of 102 cases of intra-HB blocks, 20% had no criteria of AV block on the surface electrocardiogram, and only 4% had an intact conduction pattern (normal PR interval and normal QRS complexes.) A first degree intra-HB block was found in 35% (15 cases with a normal PR interval), a second degree intra-HB block in 23% and a thired degree intra-HB block in 42% of the cases (unidirectional in 4 cases). Of the 43% having an isolated intra-HB block, most were elderly women with a chronic third degree AV block.


Right juxtaposition of the auricular appendages. 3 cases are described exhibiting the rare malformation of right juxtaposition of the auricular appendages. 1 case was encountered unexpectedly during surgical repair of an atrial septal defect and the patient survived. In this instance the segmental arrangement was solitus-concordant-normally connected arteries and the only associated defects in the heart were the atrial septal defect and a persistent left superior vena cava. In contrast, the other cases were discovered at autopsy and in both the juxtaposition accompanied severe additional anomalies. Common atrioventricular canal deformities were present in ambiguus 1-loop hearts and the ventriculo-arterial connections were double outlet right ventricle with d-malposition and normal connections with d-malposition respectively. Histological study in one of the hearts confirmed the presence of 1-bulboventricular looping, and showed an unusual arrangement of conducting tissues. Two atrioventricular nodes were present, and each communicated via separate atrioventricular bundles with the ventricular conducting tissues. The cases are compared with other reported examples of right juxtaposition, and it is indicated that whereas right juxtaposition is frequently an isolated finding this is rarely the case in the more common left juxtaposition.


Kidney and plasma renin in human renovascular hypertension. Renin activities were determined in plasma and in single, microdissected juxtaglomerular apparatus in 19 patients with unilateral renal artery stenosis. The mean juxtaglomerular apparatus renin concentration in the stenosed kidneys was 5.5 +/- 1.2 (SEM) mug.l-1.h-1 which is about ten times that of the suppressed renin concentration in the contralateral kidneys (0.6 +/- 0.05 mug.l-1.h-1). On the affected side a positive correlation was found between intrarenal and renal venous renin concentration (r = 0.93; p less than 0.001). Both intrarenal and renal venous renin concentrations of the stenosed kindeys were positively correlated to renin secretion rates, as calculated from renin analysis in plasma from the vena cava and renal veins. No relationship could be demonstrated between intrarenal or renal venous renin concentration and the degree of blood pressure elevation or transstenotic pressure gradient. However, a positive correlation was evident between peripheral plasma renin activity and diastolic blood pressure (r = 0.88; p less than 0.001). Comparative enzyme kinetic analyses of renin from the juxtaglomerular apparatus and renal venous plasma were performed using sheep substrate. The lowest apparent Km-values of renin were found in renal venous plasma from the stenosed kidneys (198 +/- 13 mug/l) compared with the contralateral side (301 +/- 20 mug/l; p less than 0.001). Mean apparent Km-values of juxtaglomerular apparatus renin in the stenosed (270 +/- 36 mug/l) and contralateral (292 +/- 37 mug/l) kidneys did not differ. No significant differences were found between mean apparent Km-values for renin in peripheral plasma of renovascular hypertensive patients and control subjects using either homologous human or heterologous sheep renin substrate. The results suggest that, in addition to the renin concentration other factors are relevant to chronic high blood pressure in renovascular hypertension.


Enzyme activities in skeletal muscles from patients with peripheral arterial insufficiency. The enzyme pattern in gastrocnemius muscle tissue was studied in 39 patients with peripheral arterial insufficiency. Phosphofructokinase and glucose-6-phosphate-dehydrogenase were significantly increased in the skeletal muscles from these patients. The most pronounced changes were found in 3-OH-acyl-CoA-dehydrogenase, citrate synthase, and in cytochrome-c-oxidase. These enzyme activities were increased by 60, 40 and 25 per cent respectively. In patients with claudication as the only symptom, the metabolic capacity was generally increased in  skeletal muscles affected by the low blood flow. With increasing severity of arterial insufficiency, all enzyme activities decreased and glycolytic enzymes were affected first. 3-OH-acyl-CoA-dehydrogenase, citrate synthase and cytochrome-c-oxidase activities were still comparatively high in patients with gangrenous foot ulcers, indicating some maintenance of the muscle viability even in situations with very low blood flow.


Hepatic storage and biliary transport maximum of taurocholate and taurochenodeoxycholate in the dog. The purpose of this work was to validate for taurocholate and taurochenodeoxycholate the multiple infusion method of Wheeler et al. previously used for the study of hepatic sulphobromophthalein transport and to obtain numerical estimates of the relative storage capacity and secretory transport maximum of both bile acids. Experiments were performed in anaesthetized dogs after depletion of the endogenous bile acid pool. Bile was collected continuously to prevent recirculation of bile acids and to measure their secretion rates. Taurocholate or taurochenodeoxycholate were infused intravenously at 3 different rates and blood samples were collected every ten min to measure serum bile acid concentrations. Extrahepatic distribution spaces of taurocholate and taurochenodeoxycholate were measured by an isotope dilution method. Serum bile acid concentrations varied linearly with time during the last 30 min of each infusion period. A linear relationship was found between the calculated hepatic removal rate and the rate of change of serum bile acid concentration. The mean values of relative storage capacity were (in mumol.mumol-1.l-1.kg body weight-1) 0.16 +/- SD 0.07 for taurocholate and 0.08 +/- SD 0.03 for taurochenodeoxycholate. The mean values for secretory transport maximum were (in mumol.min-1.kg body weight-1) 4.81 +/- SD 1.24 for taurocholate and 3.56 +/- SD 0.60 for taurochenodeoxycholate. The values of secretory transport maximum with the multiple infusion method were only slightly higher than those obtained by direct measurement of biliary secretion. The values of relative storage capacity obtained during infusions resulting in decreasing plasma concentrations were usually lower than those obtained when the plasma concentration increased. This suggests that the limitations of the method previously noted for sulphobromophthalein may apply to bile acids.


Defective renal handling of water in the rat with a portacaval shunt. Male rats with a portacaval anastomosis, placed in metabolic cages excreted twice as much urine as unoperated control rats. After subcutaneous injection of one unit of pitressin tannate in oil, the rats on average exhibited a 27% reduction in fluid intake and a 37% reduction in urine volume. Nevertheless the rats still excreted 60% more urine than control rats. Fluid restriction resulted in a reduction in urine volume and an increase in urine osmolality in both groups of rats. Shunted rats, however, continued to excrete 49 ml.kg.(-1)24h-1, while drinking only 43 ml.kg.(-1)24h-1. Owing to the negative water balance plasma osmolality rose by 22 mosm/kg H2O. Two weeks after portacaval anastomosis arterial prostaglandin-E concentrations were 412 ng/1, compared to 158 ng/1 in control rats. The results are consistent with the idea, that the shunt induced diuresis may be due to the renal effects of prostaglandin-E.


Natriuresis and renin release by the denervated dog kidney during furosemide administration. Renal excretion of sodium and water, renal venous plasma renin activity and renin secretion rate were measured during the administration of furosemide (5 mg/kg) to 10 anesthetized dogs, previously subjected to unilateral splanchnicotomy ("renal denervation"). Denervation diuresis and natriuresis, observed during control periods, did not occur when the diuretic was given and there were no significant changes in glomerular filtration rate or renal plasma flow in either the intact or denervated kidneys. Despite the abolition of denervation natriuresis with furosemide, plasma renin activity and renin secretion rate were depressed by splanchnicotomy. Thus, changes in the sodium load to the macula densa do not seem to play a decisive role in decreasing renin release following renal denervation.


Compensatory adaptation of bicarbonate excretion following acute contralateral kidney exclusion in the dog. Changes in the excretion of bicarbonate, sodium and potassium in one kidney after exclusion (complete sudden ligation of renal pedicle) of its partner have been studied in 16 dogs undergoing bicarbonate diuresis. Fluid balance, haematocrit, plasma electrolyte and protein concentrations were maintained constant throughout the experiment. Acute contralateral renal pedicle ligation lead to an immediate increase in bicarbonate as well as water, sodium and potassium excretion by the remaining kidney. The rapid and immediate increase in the fractional and absolute rates of bicarbonate excretion was observed at varying levels of bicarbonate loading, with the greatest response occurring at the highest infusion rate. Sodium, potassium and water excretion also increased in parallel with urinary bicarbonate loss. The increase in bicarbonate exposition, glomerular filtration rate, effective renal plasma flow, aldosterone and vasopressin. In 8 sham-operated animals, no abrupt increase in sodium and bicarbonate excretion occurred despite similar continued infusion of sodium bicarbonate. It was concluded that exclusion of one kidney induces immediate adaptive excretory changes for sodium and bicarbonate in the remaining kidney, and that these changes are not accounted for by any of the known factors normally regulating sodium and bicarbonate excretion.


Effects of angiotensin II and noradrenaline on intrarenal haemodynamics in the rat. The haemodynamic effects of angiotensin II and noradrenaline were studied in the rat kidney. These pressors were given by intravenous infusion in stepwise increasing doses. Intrarenal haemodynamics were analyzed by the 133xenon washout technique, 85krypton autoradiography and silastic casting of the renal vascular tree. Angiotensin II induced significant changes in intrarenal haemodynamics before any changes in systemic blood pressure were detected. The decrease in mean renal blood flow (2.91 ml.min-1.g-1 in controls, 1.76 ml.min-1.g-1 in rats given 50 mug of angiotensin II.kg-1.h-1) reflects a reduction in component I blood flow rate (from 3.9 to 2.9 ml.min-1.g-1) as well as a decrease in the fraction of total renal blood flow supplied to component I of the washout curve (from 84% to 62%). With noradrenaline an increase in total renal resistance occurred simultaneously with the elevation of mean arterial blood pressure. The resulting reduction in mean renal blood flow (from 2.76 ml.min-1.g-1 in controls to 1.55 ml.min-1.g-1 in rats given 1000 mug of noradrenaline kg-1.h-1) reflects a decrease in component I blood flow rate with lower infusion rates and a drop in component I flow fraction (from 82% to 52%) whith higher doses. In contrast to canine kidneys, no evidence for a patchy cortical vasoconstriction was found in the rat. Using autoradiography it was possible to attribute component I to the renal cortex and subcortical area of the kidney.


The effect of meal feeding and of sham-feeding on insulin secretion in dogs. After feeding intact conscious dogs 1000 g mashed meat, peripheral venous immunoreactive insulin activity (IRI) increases before any enhancement of amino nitrogen concentration. This course of IRI is paralleled by a decrease of free fatty acids. Meal feeding in dogs, whose pancreatic juice is completely diverted from the gut by a fistula, is followed by a similar IRI increase without a distinct enhancement of amino nitrogen. In oesophagus fistula dogs, sham-feeding meat in 9 out of 15 experiments results in a considerable early IRI increase which is correlated with a small but a significant decrease of blood glucose and free fatty acid concentrations. In these tests there was no amino nitrogen alteration either.


Observations on lipid metabolism in chronic renal failure, during conservative and haemodialysis therapy. The main variables of glycolipid metabolism (blood non-esterified fatty acids, triglycerides, cholesterol, insulin, glucose) have been measured in basal conditions in uraemic patients on conservative treatment and on dialysis of different duration and bath glucose concentration (no glucose, 1 g/l, 2 g/l). Basal values for the patients on conservative dietary treatment are not different from normal. In dialysed patients, the blood non-esterified fatty acid and triglyceride concentrations are increased (p less than 0.001) while cholesterol glucose and insulin levels are unchanged. No significant difference is found between the various types of dialysis, having different duration and bath glucose concentration


Lecithin: cholesterol acyltransferase activity and cholestyramine resin therapy in man. The effect of the bile-acid-sequestering agent cholestyramine on esterification of plasma cholesterol has been studied in vitro. No change in the activity of plasma lecithin: cholesterol acyltransferase was found by either of the two assay methods employed. Similarly the resin did not produce any significant change in the ability of plasma to act as substrate for a given lecithin:cholesterol acyltransferase source. It is concluded that the frequently reported relationship between plasma cholesterol concentration and lecithin:cholesterol acyltransferase activity does not represent cause and effect. Also other variables influenced by bile-acid-sequestering agents, such as hepatic cholesterol synthesis, are unlikely to be major determinants of plasma lecithin: cholesterol acyltransferase activity.


Comparison of the pharmacokinetics of intravenous dl-propranolol in borderline and permanent hypertension. In borderline and permanent hypertensives after rapid i.v. injection of dl-propranolol 0.2 mg/kg plasma levels were measured and were fitted to a two-compartment open-model. In borderline patients, characterized by a high basal cardiac output (CO), plasma levels were always lower than in permanent hypertensives. The biological half-life was reduced and the central volume of distribution, volume of distribution at pseudo-equilibrium and total clearance (TC) were markedly increased. In the overall population, there was a significant positive correlation between CO and TC. Rapid achievement of a predetermined plateau in each group constituted experimental proof of the validity of the two-compartment open-model for kinetic analysis of propranolol i.v. If kinetic parameters from permanent hypertensive were applied to borderline hypertensives a lower plateau was obtained. Thus, in so far as beta-blockade is related to plasma level of propranolol, an increased intravenous dose may be required in patients with high CO.


Studies on hydralazine. III. Bioavailability of hydralazine in man. The bioavailability of orally administered hydralazine was assessed in 4 healthy subjects after separate administration of a single oral or intravenous dose (0.3 mg-kg-1). Comparison of the areas under the serum concentration-time curves showed that 26-55% of the oral dose was available to the systemic circulation as unchanged drug. The 0-24 h excretion of the drug in urine was rapid: 11.4-14.1% of the dose after intravenous administration, and 2.0-3.6% after an oral dose. Acetylation of hydralazine leads to formation of 3-methyl-s-triazolo-3,4, aphthalazine (MTP) and a gas-liquid-chromatographic method for its measurement in urine was developed. After oral and intravenous administration, 0.8-1.2% and 1.4-2.3% of the dose, respectively, were recovered within 24 hours from urine as MTP. After oral administration there was a relative increase in the amount of MTP in every subject, which indicates route-dependent metabolism. The lower bioavailability of oral hydralazine could be explained in terms of first-pass metabolism.


Lack of relationship between serum free fatty acids and impaired plasma protein binding of diphenylhydantoin in chronic renal failure. The plasma protein binding of diphenyldantoin (DPH) in 13 patients with varying degrees of renal failure was considerably less than in normal healthy subjects confirming early studies. The fraction of unbound DPH was correlated with serum creatinine (r = 0.81, p less than 0.001), but there was no significant correlation with the serum concentration of free fatty acids, triglycerides or cholesterol.


The pharmacokinetics of chlormethiazole following intravenous administration in the aged. Eight healthy aged subjects were administered 1.2 g of chlormethiazole by constant-rate intravenous infusion. The disposition of the drug was found to be multi-exponential in character. Fits of plasma level-time data to two- and three-compartment open models were assessed with the aid of statistical tests. For three of the subjects the experimental data were adequately fitted to a two-compartment pharmakcokinetic model, however a three-compartment model was necessary to fit the data observed for a further four subjects. An anomalous chlormethiazole plasma concentration-time curve was obtained for the remaining subject. The disposition half-life of chlormethiazole was 8.49 +/- 3.28 h and the plasma clearance was 16.14 +/- 5.00 ml/min/kg. These values were significantly different to those reported earlier for young adult subjects and the clinical implications have been discussed. The blood/plasma concentration ratio of chlormethiazole was found to be approximately one with some evidence for concentration dependence.


Bioavailability of beta-acetyldigoxin after single and repeated doses of tablets and solution. In eight healthy volunteers the bioavailability of beta-acetyldigoxin solution and tablets was measured after single and multiple doses. Plasma and urine data were used to calculate bioavailability by four different methods. The differences obtained and the interindividual variations suggested that different and independent methods should be employed to assess "absolute" and "true" bioavailability. There was no significant difference between the regimens and both preparations had similar bioavailability; mean values (+/- SD) for the solution were 68.3 +/- 8.7% (single dose) and 68.6 +/- 5.9% (multiple doses), and for the tablets 72.8 +/- 7.5% and 66.1 +/- 6.0%, respectively. For routine measurements, single dose studies with plasma and urine sampling for 24 hours and 48 hours, respectively were an accurate and practicable procedure.


Simple model to explain effects of plasma protein binding and tissue binding on calculated volumes of distribution, apparent elimination rate constants and clearances. A simple pharmacokinetic model, incorporating linear plasma protein binding, linear tissue binding, and first order elimination of free (unbound) drug, was studied. If Clp is the plasma clearance, Vf is the "true" volume of distribution of free drug, beta is the apparent elimination rate constant, sigma is the fraction of the drug which is free in plasma, f is the fraction of the drug which is free in the entire body, kf is the intrinsic elimination rate constant for free drug, and AoTB is the initial amount of drug which is bound to tissues, then the model indicates that the following relationships hold: (1) Clp = Vfsigma kf; (2) beta = f kf; and Vdext = (sigma/f) Vf. Only sigma, and not f, can be measured experimentally. Dividing Clp by sigma provides an estimate of the intrinsic clearance of free drug, Vfkf. A plot of Vdext versus sigma has an intercept equal to Vf, and the ratio of the slope/intercept is an estimate of AoTB/Aof, where Aof is the initial amount of free drug (equal to Vf times initial concentration of free drug in plasma). Thus, an estimate of AoTB may be obtained. Dividing the intrinsic clearance by Vf provides an estimate of kf. Thus, theoretically, estimates of Vf, kf, AoTB and f may be obtained. The variables are not separated when beta is plotted versus sigma, and curvature of such plots is expected; no useful information is obtained from such plots.


General derivation of the ideal intravenous drug input required to achieve and maintain a constant plasma drug concentration. Theoretical application to lignocaine therapy. A constant plasma drug concentration can be achieved and maintained by the intravenous administration of an initial bolus loading dose in conjunction with a constant rate and an exponential intravenous drug infusion. The drug input required to achieve a constant plasma drug concentration is derived without making any assumptions about the nature of drug distribution within the body or elimination from the body.


Reconstitution of genetically regulated responses against random and ordered synthetic polypeptides by methylated bovine serum albumin as analyzed by isoelectric focusing. In previous publications it was shown by avidity measurements, cross-reactivity patterns and genetic analyses, that the tetrapeptide T-T-G-G is the immuno-dominant epitope of the synthetic polypeptide (T, G)-A--L. In the present study this close immunological relationship between the random multichain copolymer (T, G)-A--L and the ordered analogue (T-T-G-G)-A--L is extended by two additional criteria. First, the immune response against (T-T-G-G)-A--L in H-2k nonresponder mouse strains can be reconstituted to high antibody levels by complexing this antigen to methylated bovine serum albumin, as was tested earlier for (T,G)-A--L. The antibodies elicited upon reconstitution in both antigenic systems are directed mainly against the same determinant, T-T-G-G. Second, isoelectric focusing analysis of specific antisera developed with radiolabeled antigen revealed restricted 7 S IgG antibody populations in high responder and reconstituted high and low responder mice. The spectra were found to be of similar complexity in the (T,G)-A--L and in the (T-T-G-G)-A--L system. From these data it was concluded that the repertoires of specific B cells to T-T-G-G are very similar in high and low responder strains, and the defect in the H-2k low responder systems should be located at the level of T-B cell cooperation.


Nonparallel changes in brain monoamines of pyridoxine-deficient growing rats. The effects of a large number of neurotropic drugs have been attributed to changes in the metabolism of 5-hydroxytryptamine. The aromatic amino acid decarboxylase considered to decarboxylate both dihydroxyphenylalanine and 5-hydroxytryptophan requires pyridoxal phosphate as coenzyme. Thus, in pyridoxine deficiency one would expect a decrease of serotonin as well as the catecholamines of the brain. In the present study we have found a very significant decrease in brain serotonin of the pyridoxine-deficient growing rat. However, the brain levels of norepinephrine and dopamine were not altered. This decrease in serotonin does not result from a decrease either in the brain level of trytophan or the activity of tryptophan hydroxylase. Increased degradation of serotonin measured by the levels of its metabolite, 5-hydroxyindoleacetic acid is also excluded, thus suggesting the possibility that the decarboxylation of 5-hydroxytryptophan is decreased in pyridoxine deficiency.


Horizontal vestibular nystagmus. I. Identification of medial vestibular neurones. 1. The properities of inputs from the horizontal semi-circular canal to neurones of the medial vestibular nucleus have been studied intracellularly in the unanaesthetized encéphale isolé cat. 2. Secondary neurones of the bestibulo-abducens reflex arc were identified by their orthodromic response to labyrinthine stimulation and by antidromic excitation from the contralateral abducens nucleus. 3. The responses of medial vestibular cells receiving only labyrinthine in puts are also described. These were seen to be predominantly excitatory though IPSPs were observed in a few cases. 4. Identified vestibular neurones were intracellularly injected with procion yellow and showed different morphological characteristics correlated with function.


Horizontal vestibular nystagmus. II. Activity patterns of medial vestibular neurones during nystagmus. 1. Identified medial vestibular neurones were studied before, during and after nystagmogenic labyrinthine stimulation in the Encéphale isolé cat. Motor discharges were simultaneously recorded from the contralateral abducens nerve. 2. 87.9% of the recorded neurones showed changes in tonic firing frequency during repetitibe labyrinthine stimulation with no nystagmic modulation in behaviour. 3. The secondary vestibular neurones projecting monosynaptically to the contralateral abducens motoneurones were included in this non-rhythmic population. 4. Only 2% of the recorded population fired rhythmically both during nystagmogenic stimulation and poststimulation nystagmus. These neurones showed plasticity in behaviour regarding the phases of nystagmus recorded from the contralateral abducens nerve. 5. The remaining 10.1% of the medial vestibular neurones were excited or inhibited by repetitive stimulation of the labyrinth but showed burst firing pattersn correlated with poststimulation nystagmic discharges.


Abortion utilization: does travel distance matter? The further a woman must travel in order to obtain an abortion, the less likely she is to get one. Distance is especially disadvantageous to blacks, and most so to black teenagers. Distance discourages use among rural as well as urban women. Opening new clinics increases abortion use in nearby communities.


[Primary structure of the casein macropeptide of porcine and human kappa caseins]. The amino acid sequence of porcine and human caseinomacropeptides (CMP), the C-terminal glycopeptide released from kappa-casein by chymosin at the initial step of milk coagulation, have been investigated. The complete amino acid sequence of porcine CMP and that of the first 59 amino acid residues of human CMP have been determined. Porcine and human CMPs contain 71 and likely 65 amino acid residues respectively. The extra hexapeptide 38-43 found in porcine CMP arises obviously from the duplication of the DNA fragment coding for the 6 preceding amino acids.


The diagnosis and treatment of amenorrheas. Correct diagnosis and treatment of amenorrhea is a challenging problem to the clinician. A systematic approach to the differential diagnosis and treatment, based on functional activity along the hypothalamic-pituitary-ovarian axis, is presented. By obtaining a detailed history, performing a meticulous physical examination, and utilizing several simple clinical and laboratory tests, a correct diagnosis can be reached for the majority of patients. Treatment is relatively simple and geared to the patient's desires. In most instances, understanding of the basic problem helps the patient to cope with it and no treatment is needed. If lack of menses is a problem, cyclic bleeding at regular intervals can be induced. When fertility is a problem, ovulation can be induced, provided that there is no ovarian failure. By spending sufficient time with the patient, paying attention to detail, and giving some thought, a correct diagnosis can be reached and adequate treatment given to most amenorrheic patients.


Induction of midtrimester abortion by the combined method of continuous extravovular infusion of prostaglandin F2alpha and intracervical laminaria tents. Midtrimester abortion was successfully induced in 55 of 60 patients with continuous extraovular infusion of prostaglandin F2alpha (PGF2alpha) following the insertion of intracervical laminaria tents. Intravenous oxytocin was also used in 38 (63%) of the 60 patients. The mean induction-abortion time (IAT) was 11.72 hours +/- 1.06 SD). Abortion was completed in 40% within 8 hours, 80% within 16 hours, and 93% within 24 hours. The mean total dose of PGF2alpha was 41.9 mg. There was no significant difference in IAT between the parous patients (13.40 hours +/- 1.90 SD) and the nulliparous patients (10.41 hours +/- 1.13 SD). There was no apparent correlation between IAT and the stages of gestation (12 to 22 weeks). The five patients who failed to abort within 24 to 36 hours underwent uterine evacuation, which was easily accomplished because there was a marked degree of cervical dilatation. Side effects and complications of the technique were few. Endometritis occurred in three patients, two of whom had had intrauterine devices in situ until just prior to the procedure. It appears that this method has a high success rate, an acceptable safety factor, good patient tolerance, and relatively few side effects.


The abortifacient effectiveness and plasma prostaglandin concentrations with 15(S)-15-methyl prostaglandin F2alpha methyl ester-containing vaginal silastic devices. The abortifacient effectiveness of three intravaginal Silastic devices impregnated with 15(S)-15-methyl prostaglandin F2alpha (15(S)-Me-PGF2alpha) methyl ester in concentrations of 0.25%, 0.5%, and 1.0% was investigated. Each concentration was tested in 10 patients with gestations ranging from 8 to 19 weeks. Abortion was successfully induced by prostaglandin alone in 6 patients with the 0.25% device, in 9 patients with the 0.5% device, and all 10 patients treated with the 1.0% device. Additionally, three patients treated with the 0.25% device and one patient treated with the 0.5% device aborted with concomitant, continuous, intravenous oxytocin therapy. The mean abortion time with the 0.25% device was 16.43 hours; with the 0.5% device, 16.49 hours; and with the 1.0% device, 10.18 hours. The peripheral plasma levels of 15(S)-Me-PGF2alpha methyl ester were the most variable with the 0.5% device. The plasma levels of 15(S)-Me-PGF2alpha methyl ester of patients receiving the 0.25% device were similar to the levels of patients receiving the 1.0% device. The intravaginal Silastic device impregnated with 15(S)-Me-PGF2alpha methyl ester appears to be an effective abortifacient, but further study is indicated to determine the most efficient device with the fewest side effects.


Intra-amniotic prostaglandin F2alpha and urea for midtrimester abortion. Intra-amniotic prostaglandin F2alpha, in doses of 2.5 to 20 mg, combined with 80 gm of urea, was an effective, safe, simple, and economical midtrimester abortifacient in 115 patients. The mean abortal time, 15.8 hours, was significantly less than that in prior series in which intra-amniotic hypertonic saline or urea was administered together with constant, intravenous oxytocin infusion. The use of intracervical laminaria tents did not shorten the abortal time. Only eight patients had not aborted within 30 hours; only two had not aborted within 36 hours; and only six received a second intra-amniotic injection. Operative removal of the placenta, when necessary, was accomplished under intravenous sedation in a treatment room. The incidence of infection, nausea, vomiting, and other complications was low.


An intravaginal contraceptive diaphragm made of collagen sponge: new old principle. This study presents a theoretical background for a new intravaginal contraceptive. A highly resilient and liquid-absorbent collagen sponge in the form of a cup is self-administered in the upper vault of the vagina, where it is retained for several days to form a mechanical barrier against sperm. The high fluid-binding capacity contributes to the trapping and immobilization of sperm within the sponge. Other methods enhancing the retention and spermicidal effect of the sponge are discussed. Clinical testing of the sponge is in progress.


The acceptance of the collagen sponge diaphragm as an intravaginal contraceptive in human volunteers. Two types of highly resilient and liquid-absorbent collagen sponge contraceptives (CSC) in the shape of cylindrical cups (6 cm wide and 2.5 cm thick) were evaluated for acceptance as an intravaginal contraceptive method for a period of 3 months in 27 volunteers. Parameters such as retention, odor, irritation, itching, discharge, and convenience for the user and her sexual partner were tested. Average retention time was 7 to 9 days (range, 2 to 28 days); still, most sexually active volunteers preferred to remove the CSC every 3 to 4 days, rinse them in tap water, and reinsert them. Odor was noticed by users in 4% of the tested sponges and in 30% of all volunteers by medical personnel at the time of removal of the CSC from the vagina. No irritation, itching, or discharge was reported. The CSC alone did not cause any inconvenience to the user or partner, while the CSC with inserted rubber ring was felt by both partners and was found to be dislocated. This study indicates good acceptance of the CSC in intravaginal use. Studies to evaluate the efficacy of collagen sponges as mechanical contraceptive barriers are in progress.


Puerperal Weck clip sterilization: study I (first study of two consecutive studies). One hundred and four puerperal applications have been performed using the (original) Weck pistol-grip applicator and applying the large Weck clip in the inverted V configuration. Follow-up varied from 37 to 42 months. The corrected failure rate was 8.7%. Mechanical difficulties were encountered with the jaws and metal sleeve of the (original) Weck pistol-grip applicator. Recovered clip configuration and tubal tissue histology are presented. Histologic changes suggest possible reversibility.


Puerperal weck clip sterilization: study II (second study of two consecutive studies). Forty-five puerperal inverted V Weck clip applications have been completed with either the Samuel's or (modified) Weck pistol-grip applicator. Of the 45 applications, 31 have been followed for 25 to 36 months (69%), 12 have been followed for 13 to 25 months (27%), and 2 have been followed for 9 to 12 months (4%). The failure rate thus far is 2.2%. No mechanical difficulties were encountered with the Samuel's or the (modified) Weck pistol-grip applicator. Reversibility has been observed in one interval patient, while pre-admission evaluation of a puerperal patient suggests postremoval tubal patency.


Accuracy of basal body temperature for ovulation detection. In 30 normally menstruating women, ages 19 to 41 (mean 24), gravida 0 to 5 (mean 0.7), basal body temperature (BBT) was correlated with serum luteinizing hormone (LH), progesterone, and estradiol or urinary estrogen levels assayed serially during one menstrual cycle. In 21 subjects (70%), a biphasic BBT correlated with an ovulatory hormonal pattern. Six women (20%) had a monophasic BBT but demonstrated a preovulatory estrogen peak, a midcycle LH surge, and a significant rise in serum progesterone levels during the luteal phase. The remaining three women (10%) showed anovulatory cycles (two women) or a deficient luteal phase (one woman) as determined by BBT and hormonal assays. The results indicate that in approximately 20% of ovulatory cycles the BBT failed to demonstrate ovulation.


Microscopic appearance of the human fallopian tube following a reanastomosis procedure. Microscopic evaluation of a human fallopian tube following end-to-end anastomosis over a polyethylene stent was performed 10 days after the initial surgical procedure. The stent was removed on the 3rd postoperative day. Examination of the excised tube revealed a patent lumen without any evidence of mucosal compromise. The submucosa adjacent to the anastomotic site revealed a mild polymorphonuclear leukocytic infiltration, although a marked inflammatory response was observed around the 5-0 chromic sutures used in the reanastomosis. This case and recent animal studies suggest that early removal of the stent does not appear to jeopardize the patency of the tube and may be preferable to removal after 3 to 4 months.


Hyperprolactinemic male infertility.

Hyperprolactinemic male infertility. Serum prolactin was studied in 25 fertile and 127 infertile men. The latter included 91 oligospermic, 27 azoospermic, and 9 hypogonadotropic hypogonadal men. The mean prolactin level in all three groups of infertile men was significantly above that of the fertile group. There was no correlation among serum levels of follicle-stimulating hormone, luteinizing hormone, sperm count, and serum prolactin values. Hyperprolactinemia was found in five patients (two oligospermic, one azoospermic, and two hypogonadotropic hypogonadal men). Bromocriptine, 2.5 mg twice daily, suppressed hyperprolactinemia. In one man with hyperprolactinemic oligospermia, treatment with bromocriptine yielded significant improvement in sperm count (to normal values).


Histones instead of protamines in terminal germ cells of infertile, oligospermic men. A study was carried out, by means of polyacrylamide gel electrophoresis, of the nucleoproteins of spermatozoa from infertile, oligospermic patients affected by partial idiopathic spermatidic arrest. Results in a normal group of men, in agreement with previous reports, showed the presence of protamines in mature spermatozoa. Data relative to nucleoproteins in "spermatozoa" from the infertile patients showed that, in these cells, no protamines were detectable, but histones exclusively. These findings suggest that in our patients a maturational defect of spermatogenesis exists both at the meiotic level (a DNA content double that of spermatozoa) and during spermatidic maturation (no substitution of histones by protamines). Therefore, the nuclear maturation of these terminal germ cells is that typical of that of primary spermatocytes.


Androgen levels in intact and vasectomized rams during the breeding and nonbreeding seasons. Plasma androgen profiles were studied in two intact and two vasectomized rams in October (over a 12-hour period) and in a similar number in February (over a 25-hour period). No significant differences were found between intact animals and those vasectomized 4, 6, and 7 months previously. All intact and vasectomized animals showed a marked difference in profiles between October and February. The response to an intravenous injection of 4500 IU of human chorionic gonadotropin was also studied in February and no significant difference was observed in the subsequent pattern of plasma androgens.


Participation of membrane sulfhydryl groups in the epididymal maturation of human and rabbit spermatozoa. Changes in the concentration of -SH groups on the human and rabbit spermatozoal membrane and during epididymal maturation were studied by means of a new fluorescent probe, carboxyphenylmaleimide (CPhM), which reacts specifically with -SH groups. Binding of CPhM did not modify oxygen uptake, motility, or viability of the sperm cells used, but produced a characteristic increase in fluorescence. By analysis of this increase it was possible to calculate the presence of 35 +/- 4.2 and 55 +/- 8 nmoles of exposed -SH groups/10(8) rabbit and human ejaculated spermatozoa, respectively. Caput epididymal cells bound significantly more CPhM than did cauda epididymal cells or ejaculated spermatozoa (155 +/- 22, 78 +/- 11, and 35 +/- 4.2 nmoles/10(8) cells, respectively, in rabbit cells; and 184, 110 +/- 18, and 55 +/- 8 nmoles/10(8) cells, respectively, in humans cells). In addition to the differences in number of exposed -SH groups observed between human and rabbit sperm cells, the behavior of these membrane-reactive groups when ethylenediaminetetraacetate and/or zinc were added to the incubation media indicates that the participation of membrane--SH groups in sperm physiology is species-specific.


[An unusual case of herpes circinata (author's transl)]. A 61-year-old patient presented with an eczematous patch on the left wrist, suspect of a contact dermatitis to his watch. This lesion did not respond to the usual topical treatment. On the contrary, new lesions appeared on both forearms. A fungous culture was positive and confirmed the diagnosis of tinea circinata. Appropriate treatment allowed a complete cure within 1 month.


[Cutaneous leishmaniasis: an autochtonous case in Switzerland?]. Different kinds of Phlebotomus, which are responsible for the infectiousness of cutaneous leishmaniasis, have been identified at different places in Europe. The pathogenic agent, Leishmania tropica, essentially linked to climatic circumstances, seems slowly to gain ground north of the Mediterranean Sea. The chance of having an autochthonous case in Ticino (Southern Switzerland) is existing. A treatment with Rifampicin has been successful.


[Radiotherapy of precancerous lesions and carcinoma of the head (author's transl)]. On the basis of results and check-ups gained at the clinic of Zurich, it can be demonstrated, once more, that radiotherapy of precancerous lesions and tumors, even critically considered, is still a very valuable and safe method of treatment with lasting success in 90 to 99% of the cases. At the same time this method safeguards the essential functions, even in the case of particularly difficult areas.


[A follow-up of x-ray-treated tuberous hemangiomas after 15-20 years (author.s transl)]. The treatment of hemangiomas with X-rays has been sharply criticized because of their tendency to involute spontaneously. It has been the aim of this catamnestic study to re-examine for X-ray injury those patients, whose hemangiomas were irradiated 15-20 years ago. The findings indicate that signs of roentgenoderma can appear already with 800 r and increase rapidly over 1,500 r. The observed irreversible damages, however, were mostly not grave, but admonish a certain amount of restraint. An assessment of the effectiveness of low X-ray doses still requires verification considering a faster spontaneous involution.


[Studies on the effect of vitamin A acid in experimentally induced follicular keratosis (author's transl)]. Topical application of Benzoxazole to the inner surface of the ear of the rabbit induced a considerable and histologically verified follicular keratosis. This effect could be intensified by a preceding treatment of the animal with androgens. Vitamin A acid, applied topically, is able to eliminate this follicular keratosis.


[Round-headed spermatozoa (author's transl)]. The light microscopic diagnosis of round-headed spermatozoa is shown to comprise different pathomorphogenetic types that are only distinguishable by electron microscopy. Two types are described, one of them corresponding to the type that was initially characterized by SCHIRREN and HOLSTEIN by its globular nucleus and its lack of the acrosomal cap; the other one, with normally shaped nucleus and acrosome in an enlarged headpiece, reveals signs of a primary maturing inhibition.


The use of new polymethylmethacrylate adjuvants for split influenza vaccines. Split influenza virus vaccines with varying antigen content were adjuvated with polymethylmethacrylate particles, produced by polymerizing monomeric methylmethacrylate in the presence of the subunits, or by addition of the subunits to previously polymerized methacrylate particles. Both adjuvants yielded higher antibody titers than aluminum hydroxide or fluid vaccines. The character of the antigen-adjuvant conjugate of both types of polymer adjuvants is discussed.


Occurrence of plasmocytoid cells in long-term blood-cell cultures from a patient with 'hairy cell' leukemia. Cells from the peripheral blood of a patient with 'hairy cell' leukemia were cultivated in long-term cultures. They grew with a monolayer growth pattern and consisted of at least two cell populations. The electron microscopic morphology of the cultivated cells revealed cells resembling 'hairy cells' showing the typical cytoplasmic protrusions and cells with structural characteristics of plasma cells.


Morphologic and molecular changes in target cells during in vitro interaction with macrophages. Recent work has indicated that macrophages can affect eukaryote cells in a variety of ways. The inhibitory or enhancing effects on target cell proliferation are mediated by soluble factors released from macrophages and appear to affect every replicating cells. Macrophages have also been shown to affect target cell viability and this destructive potential was initially considered to be tumor-specific. The present work further assesses these macrophage effects on targets by morphologic and fluorimetric methods. Morphologic analysis of the interaction between activated nonimmune macrophages (AM) and tumor cells attests to close cell-to-cell contact as an important factor in the mediation of target cell damage. All evidence suggests that damaged targets progressively disintegrate, and residues of target cell cytoplasma and/or nucleus are then engulfed as a secondary event. Analysis by impulse cytophotometry of the alterations in the DNA distribution occurring during interaction with AM revealed a marked decrease in the number of nuclei with higher DNA content. This effect was virtually identical irrespective of whether target cells were derived from normal or transformed tissues. Analysis of the consequences of AM/target cell interaction by cytofluorimetry showed that a large proportion of tumor cells lyse in the course of the interaction. However, no such killing occurred in recent explants derived from normal tissues interacted with AM; the majority of these targets were arrested in G1.


Effect of age and sex on lesions of the esophagus in Buffalo strain rats ingesting diethylnitrosamine. Inbred Buffalo male and female rats, 4, 12, 24, and 52 weeks of age, ingested 0.0114% diethylnitrosamine in a semisynthetic diet. Both age and sex were important in the development of preneoplastic and neoplastic lesions of the esophagus. The 4-week-old male rats had notably more carcinomas of the esophagus than female rats of the same age; whereas, 12-week-old male rats had only slightly more carcinomas than the females. The incidence of esophageal lesions was about the same in 24-week-old males and females. Rats 52 weeks of age were not susceptible to esophageal carcinogenesis.


Clara cells in the llama.

Clara cells in the llama. A study was made by light and electron microscopy of the Clara cells of two llamas born and bred at an altitude of 4,720 m in the Peruvian Andes. The Clara cells were numerous and prominent with big apical caps, many of which had been extruded into the terminal bronchioles. On electron microscopy the caps were found to contain vesicular endoplasmic reticulum. Previous studies have shown this to contain dipalmitoyl lecithin, a known pulmonary surfactant. Acute exposure to a simulated altitude of 4,270 m has been reported to increase surface tension in lung extracts of mice. Hence it may be that an animal, such as the llama, chronically exposed to high altitude requires a persistent secretion of pulmonary surfactant.


Estrogen receptor in human myoma tissue. The occurrence and characteristics of an estrogen receptor in the cytosol of myoma samples from human uteri were investigated employing dextran-coated charcoal and density gradient centrifugation techniques. Receptor binding site concentrations in 24 myoma specimens ranged from 23 to 515 fmol/mg cytosol protein (98+/-108, mean+/-S.D.). In one myoma sample no receptor was found. The apparent equilibrium dissociation constant (Kd) was 1.3 X 10(-10) mol/l for estradiol-17beta. On sucrose density gradient centrifugation, [3H]estradiol was bound by macromolecules with sedimentation rates of 4 and 8 S. The latter component was specific for estrogens, whereas the former contained specific and nonspecific binding sites. Ligand specificity studies were carried out utilizing 30 different steroidal compounds. A good correlation was found between the in vitro binding affinity and the in vivo estrogenic potency of the compounds tested. The cytosol estrogen receptor from myoma had a ligand specificity which closely resembled that of the corresponding receptor in normal human myometrium and endometrium as well as in human breast carcinoma. The myoma estrogen receptor level was compared to that in normal myometrium and endometrium in 13 uterine specimens. The receptor concentrations in cytosol fractions from myoma and myometrium correlated significantly (P less than 0.05), whereas no correlation existed between the receptor levels in endometrial and myoma cytosols. Furthermore, the estrogen receptor content in myoma samples did not correlate to estradiol-17beta levels in the myoma cytosol or serum of the same patient.


Interactions of glucagon and fructose in the control of glycogenolysis in perfused rat liver. By measuring the specific radioactivity of glucose released from isolated perfused livers of normal, fed rats in the presence of [U-14C]fructose, the gluconeogenetic and glycogenolytic contributions to glucose production were estimated. After 20 min of perfusion with 4 mM fructose, glycogenolysis was inhibited by 40% in the absence and by 70% in the presence of glucagon (3 nM). Glucagon decreased the release of lactate plus pyruvate and enhanced glucose formation from fructose without affecting its uptake. Glycerol (4 mM) and xylitol (3 mM) had qualitatively similar, but smaller effects on glucagon-stimulated glycogenolysis. The glucagon-mediated phosphorylase b to a conversion was not altered by fructose, indicating that glycogenolysis was decreased as a consequence of an inhibition of phosphorylase a. During the first minutes after the addition of fructose, decreased ATP/AMP ratios and tissue Pi levels correlated with a transient increase of phosphorylase a activity. It was concluded that the effects of fructose on the control of hepatic glycogenolysis and glucose production were the result of a complex interplay between a transient b to a conversion of phosphorylase and an inhibition of the a-form of the enzyme, possibly by fructose 1-phosphate and other phosphorylated metabolites.