[Ultrastructural variations of synapses in the normal human cerebral cortex].

The numerous synapses in the normal human brain cortex display various aspects. The authors have also observed some electronic type synapses which are more numerous around the pericaryons. The cortical synapses are classed according to their synaptic vesicle richness : synapses with very few vesicles, synapses very rich in vesicles and synapses with a middling vesicular density. With the help of observations on these aspects and on variations of the synaptic cleft and that of the postsynaptic density, the authors advance an hypothesis on synaptic plasticity, the synaptic structures going from a simple intercellular contact (probably non functional) to a completly formed synapse and vice versa.


[Dendroarchitectonic study of the inferior colliculus in the cat].

A network analysis of dendritic fields of the cells of the inferior colliculus has been performed in the adult cat. The cells of the dorso-medial nucleus have a smaller volume, less terminal segments and more dendritic spines than the cells of the ventral lateral nucleus. The bifurcation ratio of the different cells makes it possible to separate two different types of cells: order 2 cells with a strictly monochotomous branching on random segment and order 3 cells which dendrites grown by terminal branching on random pendant arcs.


[The internal remodeling of compact bone in children].

The internal remodeling of bone in children is characterized by the presence of large osteones with irregular undermineralized deposits and large Havers canals. These Havers canals undergo a lateral displacement by progressive erosion of their internal side. These remodeling units decrease progressively in number and in dimensions and disappear after the age of 12 years. The metabolic necessities of childhood would explain the importance of the remodeling. The decentred form evokes a relation to strains imposed on the bone.


Behavior of mallard ducklings from parents fed 3 ppm DDE.

Mallard ducks fed a diet containing 3 ppm DDE (equal to about 0.6 ppm in a natural succulent diet) laid eggs that contained an average of 5.8 ppm DDE; ducklings that hatched from these eggs differed from controls in behavioral tests designed to measure responses to a maternal call and to a frightening stimulus. In response to the maternal call, ducklings from parents fed DDE were hyper-responsive; compared to controls, a greater percentage approached the call and a greater percentage of those that approached remained near the call for the remainder of the test. In a test of avoidance behavior, ducklings whose parents were fed DDE traveled shorter distances from the firghtening stimulus than did controls.


Effects of lead nitrate ingestion on open-field behavior of mallard ducklings.

Mallard ducklings were fed a control diet or a diet containing 5, 50, or 500 ppm lead as lead nitrate, ad libitum, and their open-field behavior was tested after either 3 or 8 days on treatments. Differences in open-field performances among treatments were not significant. Percentage weight gain differed significantly among treatment groups over an 8 day period, with the least growth occurring in the 5 ppm treatment group.


Venous carbon dioxide tensions in chronic obstructive lung disease.

Eighteen patients with severe chronic obstructive lung disease (arterial PCO2 greater than 45 mmHg arterial PCO2 less than 55 mmHg) were studied during a stable period of their disease. Samples of arterial blood and blood from the main pulmonary artery, internal jugular vein, hepatic vein, renal vein and femoral vein were taken by manipulating a Cournand catheter to each of these sites in rapid succession. An estimate of the regional distribution of blood flow was derived from the arterio-venous oxygen content difference of each organ. Expired air was collected into a spirometer. There was a redistribution of blood flow in these patients with chronic lung disease in accord with the observations made by others in the past. Carbon dioxide concentration in the venous blood depends on 1. the blood flow to an organ, and 2. the carbon dioxide production by the organ. The total body CO2 production was within normal limits and there is no reason to suspect any alteration in carbon dioxide production by individual organs in these resting patients. Thus the venous CO2 levels are intimately linked with organ blood flow but even a substantial increase in organ blood flow cannot always compensate for the disorder in the lung. The exact role of CO2 in regulating the peripheral circulation cannot be assessed from this study but they do emphasize the importance of regional blood flow in regulating the concentration of CO2 in the venous blood and presumably in the tissues making up the organ.


Acid-base changes in acute exacerbation of chronic hypercapnia in man.

Acid-base parameters were studied in 10 adult patients with chronic respiratory failure during spontaneous acute exacerbations of chronic hypercapnia and after return and stabilization of PaCO2 values at previous levels with improvement of clinical conditions. All factors interfering with acid-base equilibrium were carefully avoided. The results of this investigation confirm qualitatively those obtained by GOLDSTEIN et al. [7] in dog studies and those of INGRAM et al. [9]in human studies: increasing degrees of chronic hypercapnia tend to minimize the pH reduction induced by acute PACO2 changes. From a quantitative standpoint INGRAM's data in humans are considerably different from GOLDSTEIN's data obtained in dogs. Our data, although numerically limited, confirm the acute deltaH+/deltaPaCO2 slope obtained from dogs by GOLDSTEIN et al. As data are not yet sufficient, definitive conclusions cannot be drawn. However the pattern of acid-base equilibrium changes in man in this situation seems to be similar to that observed by GOLDSTEIN et al. in the dog and could be described with reasonable accuracy by the theoretical model of LEUENBERGER et al.[13].


[Effects of long term hypercapnia on plasma amino acids in the rat (author's transl)].

Rats have been placed for periods from two hours to 22 days in a chamber, the atmosphere of which was enriched in CO2 (FICO2: 0.10). The acute phase of hypercapnia induces multidirectional changes of many plasma amino acids. Some of these changes lessen or become of an opposite direction during the first days of exposure; most of them disappear when the hypercapnic acidosis is partly compensated. The variety of these reactions seems due to the fact that CO2 brings into play various mechanisms of synthesis, circulation and catabolism.


[Intermediates of erythrocyte glycolysis during three days hypercapnia in the dog (author's transl)].

Ten mongrel dogs (mean weight: 27 kg) awake and with an implanted femoral catheter have been maintained for three days in a controlled chamber (10% CO2 and 21% O2). Arterial blood samples, taken before admission and after one, two, four, six, 24, 48 and 72 hours of exposure, allowed to study blood gases and acid-base equilibrium. Glycemia, phosphatemia, erythrocyte concentration of glucose-6-phosphate (G-6-P), fructose-6-phosphate (F-6-P), fructose-1,6-diphosphate (F-1,6-DP), 2,3-diphosphoglycerate (2,3-DPG), pyruvate, lactate and ATP were also titrated by various enzymatic methods. In addition, nine reference subjects were studied in air (without CO2). During the hypercapnia, [H+] rapidly increases to 70 nmol/1, then progressively decreases after 24 hours, while [HCO3-] slowly rises. The glycemia stays high during the whole exposure. There is also an increase in inorganic phosphate, G-6-P and F-6-P, but during the first 24 hours only. F-1,6-DP, pyruvate and lactate remain lowered during the whole exposure. The 2,3-DPG diminishes after the sixth hour. These phenomena, related to the acidosis and probably to the phosphofructokinase inhibition don't arise in the reference subjects. However the latter present after a two and four hour-stay in the chamber a small decrease in pyruvicemia and lactacidemia.


[Metabolism during exercise in young men breathing 4% CO2 (author's transl)].

Fourteen young men (on the average 25 years), well trained (maximal oxygen consumption, VO2 max., between 2.7 to 3.5 1) have been studied at two different levels of exercise: 90 and 140 watts (about 40 and 70% of VO2 max.) in chamber, where the atmosphere was regulated. The subjects performed the exercise after a sojourn of six hours in the chamber, at the same level, either in air or in hypercapnic conditions (FICO2: 0.04; FIO2: 0.21); the order of the exercise tests was determined at random. The rise of total ventilation (VE) during exercise in CO2 atmosphere was particularly related to the increased tidal volume (VT). In spite of the larger increase of VE in hypercapnia, CO2 output (VCO2) and respiratory quotient (R) were lower while PaCO2 was elevated (48 at rest and 54 mmHg during exercise). Oxygen consumption during exercise was the same in both conditions. Values of arterial lactic acid concentration were not different at 90 watts level. On the contrary, at the level of 140 watts, the lactic acid concentration was significantly lower in CO2 atmosphere. The well known changes during exercise of other electrolytes (rise of Na+, K+ and total Ca) was similar in air and in CO2. Only the inorganic phosphorus was higher in CO2 atmosphere at 140 watts.


[Iliac crest bone CO2 and CO2/Ca ratio in man during respiratory failure (author's transl)].

The bone is often considered as a slow exchanger and bone sampling from the iliac crest, by needle-biopsy, is a commonly used and atraumatic technique; therefore the significance of the evolution of CO2 stores has been investigated in iliac crest in respiratory failure. Samples are taken before ventilation and on the first, second, and in some cases third days after ventilation. The results show that ageing is to be considered, since the CO2/Ca ratio varies according to the age group (0.84 at 30 years and 1.35 at 60 years). Patients with respiratory failure may be distributed into two main categories: hypoxic patients without hypercapnia, and patients with predominant hypercapnia. Hypercapnic patients may be differentiated from the hypoxic ones, both before assisted ventilation and on account of the dynamic phenomena that come into play during respiratory support in this group of patients. If the equilibrium state (at least five days with rigorously steady gazometry), before assisted ventilation, remains unknown, it is not possible to distribute the patients in one of these two groups. The results' significance is discussed, as well as the possible therapeutic applications.


[CO2 storage in various organs during chronic experimental hypercapnia (author's transl)].

The total CO2 is titrated in liver, abdominal and leg's muscles, brain and thigh-bone of rats exposed to 8 +/- 1% of carbon dioxide under normoxic (20-23% of O2) and normobaric conditions during zero, two, four or six weeks. Total (H2Ot) and extracellular (H2Oe) water is measured in these organs by the 3H-inulin method. The CO2 storage in organs is expressed in relation to the PaCO2 increase (mmol-kg-1 fresh tissue-torr-1). During a four week hypercapnia, this CO2 increase is very important in bone and brain compared with that of other organs and of the whole body. With regard to the whole body, the bone CO2 content is still increasing after four weeks. The increase in extracellular bicarbonate (delta[HCO3-e]/delta PaCO2) is negligible (1/100 th) in comparison with the whole carbonic increase (delta CO2/delta PaCO2). The bone extracellular compartment diminishes in relation with the experimentation duration, without any significant change in H2Oi (Student's analysis). A factorial analysis (BENZECRI) shows that the weight of H2Oe in the information diminishes for all organs, both with the duration of normal subjects observation (ageing) and with the hypercapnia duration.


[Bone electrolytes in experimental chronic hypercapnia (author's transl)].

The role of the skeleton in electrolyte equilibrium, well known for various diseases, remains difficult to understand during chronic hypercapnia. An experimental study of normoxic (O2:21%) hypercapnia (CO2:8 +/- 1%) was carried out for two, four and six weeks, followed by a systematic quantitative determination, in thigh-bone samples of Na+, K+, Ca++, PO4--, N2 and CO2 in 72 rats, and of total H2O and extracellular H2O (H2Oe) in 129 rats. Considering the mean values of groups (from 16 to 42 subjects for each group), at various times of hypercapnia, bone K+ was increased during hypercapnia (+3 to 4 X 10(-3) mEq/g fresh tissue), Ca++ diminished (--12.5 to 15.4 mEq). PO4-- and Na+ temporarily decreased at two and four weeks of hypercapnia. On account of the scatter of individual results, only the variation of K+ was statistically significant (at two weeks). This increase in bone K+, accompanying a partially compensated acidaemia, is to compare with the significant hyperkaliemia observed at two and four weeks, whereas this period is characterized by a decrease in K+ in skeletal muscle, as shown in a previous work. In a group of 72 rats, the analysis of correspondances and correlations points out the bone CO2 as a very significant variable, opposite to the variable H2Oe. PO4--is positively correlated to Na+. The complexity of the results does not permit a decisive interpretation of the phenomenon. On the other hand, this study corroborates the bone calcium loss and reveals the gain in bone potassium during hypercapnia.


[CO2 "wash-out" : a factor contributing to increase myocardial performance in the face of hypoxia (author's transl)].

The cardiovascular system of the anaesthetized dog has been used as an experimental model for studying the mechanisms of the haemodynamic responses to hypoxia. Together with aortic and left circumflex coronary artery blood flow (electromagnetic flow transducers), aortic and left ventricular pressures have been recorded and blood has been sampled from the aorta and the coronary sinus (PO2, PCO2, pH). During short periods of hypoxia an improvement of myocardial performance has been observed both before and after administration of a beta-adrenergic receptor blocker and a marked reduction of coronary sinus PCO2 has been noted. When hypoxia was caused by a mixture of nitrogen (95%) and CO2 (5%) an improvement of performance was observed only before administration of the beta-blocker. The slope of the relationship between PCSCO2 and cardiac performance was found to be similar before and after administration of the beta-blocker and also similar to that observed in studies of the response of the isolated heart muscle to acute hypocapnia. Besides beta-adrenergic receptor stimulation, a reduction of coronary sinus PCO2 (CO2 wash-out due to an increase of coronary blood flow) could be a factor contributing to the maintenance of myocardial performance in the face of hypoxia.


[Acute hypercapnia and bile. Experimental studies in the rat (author's transl)].

The bile acid-base parameters are analyzed in 42 male Wistar rats under pentobarbital anaesthesia, in normal conditions of blood acid-base equilibrium. The reproducibility of the results is emphasized. In acute hypercapnia (FICO2 : 0.12 for 15 min) without hypoxia, and for the same increase in PCO2, and pH variation is lesser in bile than in blood, thus showing an high buffer capacity. In vitro and in vivo comparative studies show that bile buffer capacity is about five times higher in vivo, independently of a possible increase in choleresis. Comparative studies of bile-acid-base equilibrium are effected during perfusions of dehydrocholate, sodium taurocholate, secretin and acetazolamide. Sodium and chlorine remain stable during hypercapnia both in blood and in bile ; potassium concentration is increased in the two media. To explain these results, the role of the liver is still to specify.


Carbon dioxide and liver blood flow.

This study was designed to determine blood flow to the liver during hypercapnia and combined hypercapnia-hypoxia with the portal vein and hepatic artery intact except for placement of an electromagnetic flow probe around these vessels. Twenty mongrel dogs weighing 30-45 kg were anesthetized with pentobarbital and flow probes and occluders were surgically implanted. Ten of these dogs were subjected to hypercapnia alone. During inspiration of 6% CO2 in room air, portal vein flow increased from 588 +/- 73 ml/min to 731 +/- 113 ml/min (p less than .05), while hepatic artery flow did not change significantly from its control mean of 221 +/- 38 ml/min. In the remaining dogs, inhalation of 6% O2 resulted in a reduction of portal blood flow within 30 min from 527 +/- 55 ml/min to 381 +/- 41 ml/min (p less than .01). Again, mean hepatic artery flow did not increase significantly above its control of 273 +/- 43 ml/min. Subsequent inhalation of 6% CO2 plus 6% O2 (combined hypercapniahypoxia) for 30 min in these same animals resulted in a significant increase of portal vein blood flow from 514 +/- 46 ml/min to 716 +/- 116 ml/min (p less than .05). Thus, hypercapnia alone increases total liver blood flow, primarily by an increase in portal vein flow. Hypoxia results in a decrease in portal vein flow. The superimposition of hypercapnia on hypoxia restores blood flow to a level close to that found with hypercapnia alone. Hypercapnia in the range of 63 +/- 4 mmHg PCO2 overwhelms the tendency toward a reduction of portal vein blood flow induced by an arterial PO2 of 42 +/- 5 mmHg in the presence of mild hypocapnia (PCO2 : 30.2 +/- 1 mmHg).


[Variation of effective compliance with respiratory frequency. Test of inhomogeneity of the ventilatory mechanical system (author's transl)].

A decrease in effective compliance (Ce) with increase in respiratory frequency (f) is considered as representing an inhomogeneity in the distribution of the pulmonary time constants. The Ce variation in relation with f reflects the inadequacy of the first order linear mono-alveolar model usually used to describe the ventilatory mechanical properties. Such an assertion is widely accepted, but few attempts have been done to validate this point in patients and to determine the various components likely to affect the Ce, f relationship. In 171 patients, selected in order to sample different types of lesions of some pulmonary structures, the authors calculated the next functional parameters : VC/theoretical VC ratio, RV by dilution method and by plethysmography, airway resistance and distribution index of inspired gas. Moreover, by means of a computerised system, the effective compliance and its variation with respiratory frequency have been calculated. After discussion of the procedure and of the method used to express the compliance-frequency relationship (linear regression), the authors develop the arguments which allow to assert that despite the elementary type of expression the relation is a good discriminative parameter. Its signification is discussed by analysing results obtained in patients and by simulating a mathematical model of the ventilatory mechanics where the mechanical parameters are distributed. It seems likely that a negative slope of the compliance-frequency relationship expresses an important mechanical inhomogeneity. Taking into account the fact that the whole frequency-compliance relationship gives little information, at this moment, in the face of an unpleasant test for the patients, the authors propose a simplified procedure, adapted to the usual practice.


The effect of inhalation hypercapnia in healthy subjects on the acidity of gastric juice.

The pathogenesis of gastroduodenal ulcer associated with chronic pulmonary obstructive disease is complicated, as is the pathogenesis of these two disease entities separately. It is evident that a multifactorial dependence is involved which has not yet been resolved completely. Hence, there is no "magna cause morbi" but rather a multiform and dynamically variable chain of causes, consequences and conditions, some of which may be of genetic dependence. In the possible complex of causes leading to the genesis of gastroduodenal ulcer associated with chronic pulmonary obstructive disease, the author investigated the effect of isolated hypercapnia on the acidity of gastric juice and mucous membrane in 18 healthy normacid subjects. The results of this study that in healthy subjects isolated hypercapnia leads to a statistically significant increase in acidity of gastric juice and mucous membrane.


Mucociliary transport in central and intermediate size airways: effect of aminophyllin.

Mucociliary transport and the percentage of ciliated cells were studied in large and intermediate sized airways (generations 0-3) of anesthetized mongrel dogs before and after aminophyllin administration. The mean percentage of ciliated cells decreased respectively from 22.0% and 25.4% in the trachea and main bronchi to 8.0% in the lobar and 2.7% in the segmental bronchi. The fastest mean mucous velocity was found in the trachea (4.9 mm/min, S.E. 1.0). Mucous velocity decreased 38% from the trachea to the main bronchi, 55% to the lobar bronchi, and 66% to the segmental bronchi. A positive correlation (r = 0.75) was demonstrated between mucous velocity and the percentage of ciliated cells. After aminophyllin administration, mucous velocity increased 59% in the trachea and 27% in the main bronchi. No statistical difference in mucous velocity could be demonstrated in the smaller airways after aminophyllin, probably due to relative insensitivity of the method in short bronchi with low mucous velocities.


Disturbances in pulmonary gaseous exchange in primary hyperlipoproteinemias.

Carbon monoxide diffusion (DLCO), blood gas analysis at rest and after exercise, distribution of ventilation and perfusion by Xenon 133 were carried out in 43 hyperlipidemic patients, Fredrickson's types I, IIA, IIB, and IV. DLCO was significantly reduced in hypertriglyceridemic and to a lesser degree in hypercholesterolemic patients. A significant negative correlation was found between DLCO and triglyceride values. Significantly lower basal PaO2 values, which improved after exercise, were observed in both type IIA and type IV hyperlipemic patients. The ventilation/perfusion ratio distribution (V/Q) did not increase from the basal to the apical segments of the lungs in hyperlipidemic patients as it did in normals. The hypothesis of an alteration in pulmonary surface-active lipoprotein, directly related to hyperlipoproteinemia or indirectly caused by fat microembolism, may explain the reduced DLCO, the loss of V/Q gradient, and the decrease in PaO2 (which improves after exercise) observed in hyperlipemic patients. Disturbances in pulmonary gas exchange and PaO2 reduction could play an important role in the pathogenesis of both angina pain due to ischaemic heart disease, which is frequently observed in hyperlipemic patients, and the postprandial angina syndrome.


[Value and reproducibility of TLCO, TMCO and Vc in healthy subjects (author's transl)].

Transfer factor (TLCO) and its components (TMCO and Vc) have been measured in 47 healthy subjects. The regressions with respect to age and body surface were close to those found in the literature. The reproducibility of these indices has been investigated in a sub-group of 5 subjects, examined at two days intervals, for 24 to 42 days. For TLCO measured with a 16% O2 mixture, the reproducibility was good (coefficient of variation of 5%). For Vc and TMCO, the dispersion was more important and varied among the subjects. The lack of reproducibility appeared to be due, among other factors, to reading errors on the variables, and more frequently FACO. Four among these 5 subjects were asked to keep alveolar pressure close to atmospheric during the apnea; the coefficient of variation decreased from 23.5 to 7.5% for Vc and from 25.9 to 12.4% for TMCO.


[Effect of atmospheric pollution on respiratory function in children from Venice (author's transl)].

The respiratory function has been compared in two standard school populations. A sample, of 700 children from the industrial quarters of Venice (highly polluted) and 350 children from the Historic Center (not polluted), has been subjected to a respiratory questionnaire, clinical investigation and plethysmographic functional testing with measurement of airways resistance by the panting method. The changes in the airways resistance were related to the residing area and to the bronchitic episodes in the past, while the family's socio-economic situation and the living area did not play any role.


Brain organic acids during hypercapnia.

Experiments in rats during acute and prolonged periods of hypercapnia show important changes in the glutamate and glutamine content of the brain. Compartmentation studies using labelled glutamate intracisternally injected show an increased turnover of the small glutamate compartment. The possible pathophysiological significance of these observations is discussed.


Early detection of airway abnormalities in a selected group of population.

Functional data were collected from 5,746 males from a country region, whose ages ranged from 14 to 65 years. Out of this population we excluded a group of 466 males (9%) who had abnormal results of traditional pulmonary function screening tests (FVC less than 80% reference values or FEV1% FVC less than 70%) and chose a group of 1,092 males (19%) with normal values for the above two parameters but with abnormal forced mid-expiratory flow. In randomly selected persons of the second group we found frequency dependent dynamic compliance (100%), abnormal maximum expiratory flow at 25% of vital capacity (98%), increased residual volume (76%), decreased maximum expiratory flow at 50% of vital capacity (67%), and increased closing capacity (57%); on the contrary static complicane and airway resistance were normal. To account for these results we suppose that measurement of forced mid-expiratory flow, abnormal values of which we obtained in practically one fifth of the experimental population, could represent, in agreement with other reports, a suitable screening test for first or early detection of airway abnormalities.


[Differential diagnosis of chronic obstructive lung disease, A statistical analysis of the discriminating power of various lung function tests (author's transl)].

Among 65 patients admitted to the hospital for chronic obstructive lung disease, the following pulmonary tests were systematically performed : spirometric vital capacity and total lung capacity, FEV1, functional residual capacity and total lung capacity measured by body plethysmography, airway resistance and specific conductance, CO diffusion capacity measured by single-breath test, N2 clearance by single breath oxygen dilution, and blood gases. The patients were divided into bronchitics, emphysematous and broncho-emphysematous, according to the clinical and radiological Nash's score, and to another personal score derived from the former. The simple and multiple correlations between the clinico-radiological score and the functional results are low. The clustering analysis groups the 65 patients into four clouds of points, around two principal axes : the volume axis and the overinflation axis. This study indicates that the most suggestive results for emphysema diagnosis are increased FRC and TLC and low Tlco/V'a. The clinical score is not dominant for the clustering of the patients into the dynamic clouds. Beneath the bronchitic, the broncho-emphysematous and the emphysematous groups, the clustering analysis individualizes a fourth group of cases characterized by chronic asthma, and which were not isolated by Nash's score.


Emphysema as possible explanation for the alteration of expiratory PO2 and PCO2 curves.

The present explanation of the shape of deformed expiratory partial pressure curves of O2, CO2, N2 and foreign gases as being caused by sequential convective emptying of compartments with decreasing VA/Q is put into question, since the same deformation can be observed in healthy subjects during simultaneous breathing of helium and SF6, where the SF6 curve is deformed and the helium curve has a normal shape. The high molecular weight of SF6 causes a delay of its gaseous diffusion from the peripheral air spaces of the lung. A similar delay can be caused by emphysematous changes such as a longer distance for diffusion, an increased alveolar volume and a reduction of the number of small airways, where the gas has to pass through. Different data from cross-sectional and longitudinal studies, from induced changes of bronchomotor tone, from comparison of patients with relatively pure emphysema and patients with airway obstruction and from autopsy suggest that stratification and serial inhomogeneities, caused by emphysema, are at least a reasonable, if not a better explanation for the deformation than the VA/Q concept with sequential emptying of parallel units.


[Relationship between the initial dimensions of bronchial ring and its contraction after acetylcholine (author's transl)].

Contractions produced by comulative doses of acetylcholine were studied in isolated canine bronchical rings from 2 to 10 mm internal diameter. The maximal active tension achieved was directly related to the initial caliber of the ring and to the amount of smooth  muscle. The maximal decrease in caliber was relatively greater (--39%) in the smaller than in the larger bronchi (--17%). However the corresponding increase in airway resistance may be predicted to be more important in the larger resistive bronchi.


A sampling method for mean alveolar gas in normal subjects and patients with respiratory disease.

The paper describes an alveolar gas sampling method based on the criterion of equality of mean alveolar (RA) and expired (RE) respiratory quotients. Expired gas is sampled at an expired volume equal to VT/2 + VD by means of a mechanical sampler controlled by an analog computer. Eleven normal subjects and 50 patients with cardiopulmonary disease have been tested. When the difference between mean alveolar and expired respiratory quotients did not exceed 0.05, the result was considered to be satisfactory. Such results have been obtained in 40 patients and all of the normal subjects. For the remaining 10 patients, either experimental error and/or particular non-homogeneities in ventilation seemed to be the cause of the unsatisfactory results. Arterial to alveolar PCO2 differences have been calculated. The mean difference in normal subjects was never negative (1.86 +/- 1.58 torr).


[Radiological indices of pulmonary hypertension in chronic obstructive pulmonary disease (author's transl)].

This study attempted to correlate mean pulmonary arterial pressure with four radiological indices of pulmonary hypertension in 159 patients with chronic obstructive pulmonary disease. The mean pulmonary arterial pressure at rest (PAPR) and with exercise (PAPE) and four indices measured from the plain chest radiograph were considered. The measurements were: 1) DIP: the distance between the bifurcation of the right and left main pulmonary arteries, 2) DIP/T X 100 where T is a maximal thoracic diameter, 3) R: the diameter of the right descending pulmonary artery, and 4) R/h x 100 where h is T/2. The mean index values +/- SD obtained from three observers were: DIP = 11.4 +/- 1 cm, DIP/T x 100 = 36.1 +/- 3.5 R = 1.9 +/- 4cm, R/h x 100 = 12 +/- 2.7. An analysis of variation demonstrated that the interobserver error was unacceptable for R and R/h x 100 but small for DIP and DIP/T x 100. Increased PAP does not implicate high index values but high values specify abnormal PAP. The results suggest that DIP greater than 13 cm or DIP/T x 100 greater than 42 are diagnostic. A minority presented such values, but in 20 to 30% of these cases this preceded clinical or electrocardiographic manifestations of cor pulmonale.


Respiratory function of infants in relation to subsequent respiratory disease: an epidemiological study.

Crying ventilatory function was measured in 487 infants shortly after birth. Over the following five years 129 infants suffered attacks of pneumonia or bronchitis. Their initial crying ventilatory function was compared with that of the 358 infants who escaped these illnesses. No statistically significant differences were found in crying ventilatory function between these two groups of infants. This has been interpreted as indicating that newborn infants who subsequently suffer attacks of pneumonia or bronchitis do not start life with deficits in their ventilatory function. In the same study crying ventilatory function was measured in 550 infants at their first birthday; 70 had suffered attacks of pneumonia or bronchitis by that age and made a clinical recovery. Their crying ventilatory function showed no consistent difference from the 480 infants who escaped their illnesses. The reasons for the lack of a difference in crying ventilatory function is discussed.


[Reference values of pulmonary compliance (author's transl)].

Pulmonary compliance has been measured, using a classical method in 156 healthy subjects aged between 18 and 74 years, breathing spontaneously. Pulmonary compliance (ml-cmH2O-1) was related to height in meters (H) by an allometric relationship such as C = aHb. As b was not significantly different from three, than C/H3 ratio was studied. This ratio was not dependent on age so that it was possible to establish that, in men, C (ml-cmH2O-1) = 36.6 H3 (m) and in women, C (ml-cmH2O-1) = 33.3 H3 (m). These two relationships were significantly different. From these relationships and from reference values of pulmonary volumes, specific pulmonary compliance could be calculated but since confidence limits were very wide, their utilization is limited. Furthermore, it is difficult to apply specific compliance in respiratory impairment.


Rebreathing and single breath pulmonary CO diffusing capacity in man at rest and exercise studied by C18O isotope.

The pulmonary diffusing capacity for carbon monoxide, Dco, was estimated in normal subjects, using both a single breath technique (DcoSB) and a rebreathing technique (DcoRB). In order to measure CO by mass spectrometry, the stable isotope C(18)O was used. In three normal subjects Dco was measured at different lung volumes at rest, and at different levels of bicycle exercise. DcoRB was found on the average 30% higher than DcoSB when compared at the same mean lung volume, and both increased slightly during exercise. The advantages and drawbacks of the rebreathing method are critically discussed.


Diurnal variations and reproducibility of the N2 closing volume test in healthy subjects.

To assess the diurnal variation of closing volume measurements, 11 non-smokers and 10 somkers, all healthy, were tested with the single-breath nitrogen test. In each subject, 3 satisfactory tracings were recorded at 9:a.m., 11:a.m., 1:p.m., 3:p.m. and 5:p.m. on each of two consecutive days. Duplicate copies of the tracings were read in radom order by two independent observers. The "best+ and the mean values of closing volume to vital capacity ratio (CV/VC or phase 4/VC) and of the slppe of phase 3 were calculated. The study shows that: (1) the time of the day may be a source of variation of the closing volume measurements. Meals and cigarette smoke did not appear to be responsible for this diurnal variation, (2) values obtained with the "best" tracing method can, at least in some readers, give systematic differences with the mean of several traces, (3) individual variations in CV/VC and in the slope of phase 3 are the highest with the "best" trace analysis, and (4) the vlaues obtained by two independent readers may significantly differ. The differences observed between hours, although significant, were nevertheless small in magnitude and did not explain most of the variation of the measurements. Variations in trace aspect were small in some subjects. The reproducibility of the test was remarkable in them, at least when the junction of phase 4 with phase 3 was well defined. In other subjects, the coefficient of variation was high mainly because of varying curve shape and/or poorly defined departure of phase 4. This explains for a great part the intra-and interreader variations observed in this study.


Ventilatory impairment and hypoxemia in chronic non-specific lung disease.

The relation between arterial oxygen tension at rest (Pao2) and ventilatory performance (VC and FEV1.0) was studied (198 determinations) in a group of 156 patients (11 females) aged 31 to 76 (mean 52.1) years, with chronic non-specific lung disease (asthmatics non included). The average results were 72.7 mmHg for Pao2, 2.87 1 for VC, 1.32 1 for FEV1.0 and 44.9 % for the FEV1.0/VC ratio. Ninety per cent of the patients had ventilatory impairment (FEV1.0 less than 81 % predicted) and 2/3 had hypoxemia (Pao2 less than 75 mmHg). The Pao2 - spirometric variables linear correlation coefficients were of medium value (0.35 to 0.51), but highly significant due to the large number of observations. The correlation was high in patients with severe ventilatory defect (FEV1.0 less than 40% pred.), weak in those with moderate (FEV1.0 41-60 % pred.) and absent in those with minor or absent ventilatory impairment. In respect to the clinical type of obstructive disease, Pao2 and FEV1.0 showed a high correlation (r=0.69) in "bronchitics", a looser one (r=0.45) in "intermediate" patients, and no correlation for "emphysema" patients. The regression equation relating Pao2 and FEV1.0 (Pao2=64.4 + 5.9 X litres) had too high a standard error of estimate (20 % of the mean) to be of practical value.


[Rheology of bronchial secretions and mucociliary transport (author's transl)].

Optimal relationships between mucociliary clearance and rheological properties of bronchial secretions expectorated by patients with chronic bronchitis have been analysed by successive measurements of visco-elasticity with a rotational rheometer and of transport velocity on frog palate mucosa. It appears that the role of the elastic component is predominent. Sputum characterized by very low strain recovery (SR less than 4 units) or conversely by very high elasticity (SR greater than 20 units) is transported at a low rate in comparison to that of the control frog mucus (relative transport rate less than 0.5). Pronounced hyperviscosity of sputum (no greater than 200 poises) appears also as a limiting factor to the mucociliary transport. The best transported secretions (relative transport rate greater than 0.7) are characterized by a relative elasticity (SR) of 4 to 13 units and a viscosity (no) of 25 to 200 poises. Under the action of mucolytic agents such as N-acetylcysteine, sputum initially characterized by low strain recovery (SR less than 4 units) is transported at a much slower rate which is related to the increased loss of elasticity. These results indicate that mucolytic drugs must be administered with great care in patients with chronic bronchitis. Moreover, they should not be used in patients with very low visco-elastic secretions which reflect the non-functional state of the bronchial mucosa.


[Hyperalaninaemia during acute hypoxia in the anesthetized rabbit (author's transl)].

Blood alanine (Ala), an important glucose precursor, has been demonstrated to result mainly from the transamination of pyruvate derived from glucose in muscle [10]. A positive relationship between blood pyruvate and blood alanine was reported during muscular exercise and fasting. The alanine/pyruvate relationship in arterial blood has been studied in male fasted anesthetized rabbits before, during and after a short term hypoxic stress (50 minutes). Three groups of animals were studied : normoxic control (FIO2 = 0.28 ; n = 3) (C), hypoxic hypoxia (FIO2 = 0.10 ; n = 4) (HH) and hypoxia induced by respiring the animals with a carbon monoxide containing gas mixture (FIO2 = 0.28, FICO = 0.002 ; n = 6) (HCO). The hypoxic stress was of similar magnitude in HH and HCO groups. During the hypoxic periods an increase of [Ala] was observed along with hyperlactatemia and hyperpyruvatemia. Hyperalaninemia and hyperlactatemia was higher in HH than in HCO groups and hyperglycemia was observed only in HH group (adrenergic stimulation). In normoxic conditions [Ala] correlates positively with pyruvate. This relationship vanishes during the hypoxic and post hypoxic periods. The percentage increase of [Ala] during hypoxia was larger than that of pyruvate. These data, as well as recent reports in the literature, suggest that elevated [Ala] during hypoxia may result from increased muscular production from glycolytic pyruvate and other amino acids and decreased hepatic utilization (gluconeogenesis).


Neurophysiology of pain-peripheral aspects. Speculation concerning the possibility of a unitary peripheral cutaneous input system for pressure, hot, cold and tissue damage.

The gate theory of pain is criticized at three levels: (1) at the dorsal horn "gate", where pre-synaptic inhibition in the primary afferent endings may go beyond mere reduction of synaptic power at the afferent endings and induce antidromic impulses (dorsal root reflexes) that may modulate peripherally by blocking; (2) central to the "gate", where postsynaptic neuronal repetitive (epileptiform) firing is believed to be an important underlying mechanism in clinical chronic pain syndromes; and, (3) in the periphery, where there is more to input coding than a balance between the ratio of large and smaller fiber inputs. Contrary to the belief of many sensory neurophysiologists, the present authors contend that pattern theory is viable; and that specificity, while important and not to be ignored, should be considered as only a partially evolved refinement superimposed on a basic underlying spatial and temporal patterning of input that probably requires central decoding, which begins in the dorsal horn.


Technique for accurate localization with the CT scanner.

A method for accurate localization of intracranial lesions on CT scans is described, using a marker wire and a radiograph exposed by the CT scanner.


A brief trial of phenytoin therapy for thalamic pain.

Phenytoin was given in full dosage to eight patients with thalamic pain and two others with intractable pain resistant to other forms of treatment. Serum levels were monitored and correlated with dosage levels. Three patients improved markedly, two improved only minimally, two were unchanged, and three were worse. Those patients who had improved noted return of original pain on stopping phenytoin. The results indicate the need for a further study of the drug in thalamic and other chronic pain states.


The management of the patient with calcium stones.

Results of investigation of 800 patients with renal calculi are presented. The high incidence of medullary sponge kidneys (tubular ectasia) in patients of either sex is stressed as is the low incidence of idiopathic hypercalciuria in the female. Hydrochlorothiazide has been found to be highly effective in preventing recurrence of calcium stones in our personal experience with over 300 patients who have been treated for as long as 14 years with this agent. The efficacy and mode of action of other measures advocated for stone prevention is reviewed.


Size of renal calculi, recurrence rate and follow-up.

Stones smaller than 5 mm in diameter seldom need any operation other than the use of the stone-basket. Stones larger than 10 mm in diameter usually need an operation, are more often accompanied by infection, and have a higher recurrence rate. The size of the stone is unrelated to the level of urinary calcium or to body surface area. In planning the follow-up of patients with calculi the size of the first stone is a useful guide.


Recurrence of infected calculi following postoperative renal irrigation with stone solvent.

Renacidin has been shown to dissolve small fragments of infected renal calculi in vitro. 34 patients with infected calculi have undergone pyelolithotomy and postoperative renal irrigation with Renacidin. 30 patients were women and Proteus was the commonest infecting organism. Renal irrigation appears to be safe if closely monitored and covered by antibiotic therapy. 24.4% of calculi had recurred at a mean follow-up of 42 months. The rate of recurrence or unilateral calculi was much less than that of bilateral calculi (15% vs. 40%). Persistent postoperative urinary tract infections later led to recurrent stone formation.


Primary hyperparathyroidism---a review of cases in the Sheffield area.

73 patients with primary hyperparathyroidism are reviewed. The elevated serum calcium was the main diagnostic index but estimation of the parathyroid hormone was useful confirmatory evidence when raised. A normal level does not exclude the diagnosis being found in 32% of patients. Intravenous methylene blue was a useful adjunct to surgery. 95% of the patients had relief of their hypercalcaemia after a single operation. 78% of patients had stones and there was a marked reduction in further stone formation after surgery.


Reflux induced pelvi-ureteric obstruction.

The phenomenon of pelvi-ureteric obstruction which is induced by vesico-ureteric reflux is well documented but ill understood. The radiographic findings can be impressive to an extent that obstruction is probably often over-diagnosed. Before considering a pyeloplasty it is essential to confirm the true obstructive nature of the problem. Where the urogram is not suggestive of an obstruction a re-implantation of the ureter will usually stop the gross pelvic dilatation. It is suggested that the obstruction is at least partially an active process.


Occupational bladder tumour cases identified during ten years' interviewing of patients.

All patients attending the Royal Marsden Hospital with urothelial tumours have their occupational histories taken. About 10% of histories suggest a possibility of past exposure to urinary carcinogens, and on examination 4% indicate definite exposures justifying claims for Prescribed Industrial Disease benefit.


Inverted papilloma of the lower urinary tract.

A study of 35 cases of inverted papilloma of urothelium confirms that it is a distinctive entity and typically benign. These lesions occur mainly in males, may be multiple, and are sometimes situated elsewhere than in or near the trigone, which is their characteristic site. Their precise histogenesis remains uncertain. It must be stressed that not all transitional cell tumours of inverted pattern are of this type; some will have the appearance of and behave as malignant tumours. The same diagnostic criteria of malignancy established for the more common exophytic papillary neoplasms must be applied also to the inverted papillary tumours herein described.


The value of lymphography in the management of bladder cancer.

228 bilateral pedal lymphograms in patients with bladder cancer have been correlated with the features of the primary bladder tumour and patient survival. In 70 cases, radiographic findings were correlated with operative node histology. The results show that it is not possible to predict accurately which cases have lymphatic spread without this investigation. Positive lymphograms were found in 91 cases, and were associated with a very poor prognosis. Only 6% of patients with unilaterally involved iliac nodes survived 5 years, and all patients with bilateral iliac or para-aortic disease died within 3 years. Histological correlation was found in 90% of cases, and the results indicate that this investigation slightly underestimates the incidence and extent of microscopic lymphatic metastases. It is concluded that this investigation is essential in planning the treatment of infiltrating bladder tumours.


Radiotherapy in the treatment of recurrent bladder cancer.

A retrospective review of 1,518 cases of transitional cell carcinoma treated by supervoltage irradiation is presented. The majority of patients had recurrent disease after previous treatment. An appreciable salvage rate has been achieved. A "high risk" group for distant metastases has been identified (T3) and the suggestion is made that adjunctive therapy be employed to deal with occult metastases. The place of preoperative irradiation in Stage T2 tumours has been referred to. It is recognised that this is an ageing population. Many die not of their cancer but from other causes. It is difficult to compare these results with others published because of problems in selection and differences in staging the tumours.


Hyperthermia in the treatment of bladder tumours.

High temperature bladder irrigation was employed in 4 men as an alternative to cystectomy because of their age and frailty. Hyperthermic irrigation of the bladder from 63 degree C for 70 minutes to 82 degree C for 25 minutes caused partial, but not total, necrosis of the bladder. Transitional cell carcinoma appears to be resistant in vivo, in some cases, to heating at temperatures that destroy adjacent normal structures. Hyperthermic irrigation of the bladder at these high temperatures may be hazardous. In view of these findings we cannot recommend high temperature bladder irrigation as an alternative to cystectomy even in poor risk patients.


Treatment of advanced bladder cancer with adriamycin and 5-fluorouracil.

The cytotoxic drug combination of adriamycin and 5-fluorouracil has resulted in a 35% objective response in 20 patients with advanced bladder cancer. This has been achieved with minimal toxicity and on an out-patient basis. If the survival rate of patients with invasive bladder cancer is to be improved it seems likely that some form of systemic treatment will need to be added to the local measures currently in use. Further studies of different chemotherapeutic agents should help to define an effective and safe form of adjunvant therapy.


The endemic bladder stones of Indonesia---epidemiology and clinical features.

Bladder stone is a relatively common disease of childhood in West Sumatra with an incidence of 8.3/100,000 population per year. We have studied 87 cases with a peak age of onset of 2-4 years and a male/female ratio of 12:1. The majority of these are from poor families with a diet low in protein and phosphate. Diarrhoea is common. The composition of the stones is primarily ammonium acid urate. Patients with sterile urine have shown significantly higher levels of urinary ammonia than controls, and only approximately 50% of patients' urine were infected. This is consistent with excretion of a high acid load, due both to an acidogenic rice diet and diarrhoea, combined with a low level of phosphate. This condition was once endemic in Europe but is now confined to a belt of countries from the Balkans through Asia.


Distension therapy for the unstable bladder: later results including an assessment of repeat distensions.

51 patients with urgency and urge incontinence of urine and enuresis have been treated by prolonged bladder distension. At recent follow-up, 16 patients were symptom free, 25 substantially improved and 10 symptomatically unchanged, at a mean of 13 months after distension. 13 patients whose symptoms relapsed after a previous distension or who failed to obtain a satisfactory improvement have had a further distension for a more prolonged period. The early results in this group are not as good as for patients having first distensions, although 2 patients have become symptom free, and 6 have shown a substantial symptomatic improvement.


Clinical and experimental studies on the action of prostaglandins and their synthesis inhibitors on detrusor muscle in vitro and in vivo.

Experiments on muscle strips have shown that prostaglandin is naturally produced by the detrusor, and acts to increase the tone and spontaneous activity. An intimate relation between acetylcholine and prostaglandin has been demonstrated. Therapeutic application of prostaglandins has been successful in the treatment of chronic retention in women.


Anti-reflux surgery in the congenital neuropathic bladder.

42 refluxing ureters were re-implanted into the bladder in 28 children with neuropathy. In each case other measures directed at enhancing bladder emptying were employed. Reflux was cured in 36 of 38 ureters investigated after operation. The incidence of contralateral reflux following unilateral re-implantation was 50%. 1 of 12 undilated units showed late post-operative deterioration. 22 of 28 initially hydroureteronephrotic units either improved or stabilised  at a satisfactory level. In 6 children urinary diversion was subsequently performed because of persistent reflux (2 cases), postoperative deterioration (1 case) or failure of severely dilated upper tracts to improve (3 cases). Since reflux from a high pressure bladder can rapidly cause severe renal damage, cystography is indicated when there is clinical or pyelographic suspicion of its existence. Operative cure is needed when reflux is of major degree or if, when of lesser severity, it does not stop spontaneously following improved bladder emptying resulting from therapeutic lessening of the urethral resistance.


The assessment of sphincteric activity in patients following trans-sphincteric urethral reconstruction.

12 patients who had previously undergone trans-sphincteric urethral reconstruction were studied with regard to their sphincter mechanisms. The method of study was by urethral pressure profile and urethral voluntary sphincteric pressure increment. This study showed that patients may undergo trans-sphincteric urethral reconstruction with preservation of normal profiles and voluntary pressure increases indicating preservation of the "external" sphincter mechanism.


An assessment of surgical treatment of vesical outlet obstruction in spinal cord injury: a review of 471 cases.

An assessment of 139 cases of outlet obstruction following spinal cord injury, in a consecutive series of 471 patients, is presented. The figures in relation to the level and extent of the spinal lesion and the type of operation (transurethral resection and external sphincterotomy), are reviewed. The incidence of repeat operation is recorded and assessed. It is concluded that transurethral resection and external sphincterotomy, either alone or combined, will relieve outlet obstruction in most cases of neuropathic bladder following spinal cord injury.


A simple artificial implantable sphincter.

A device is presented for the cure of urinary incontinence in males. 16 cases have been operated on, 10 have been cured, 1 improved and 5 failed. Most of the failures were due to sepsis. Despite this small number of cases the results are extremely encouraging. The device, because of its simplicity, both in construction and ease of insertion, is considered worthy of extensive trials.


Excretion urography in the investigation of prostatism.

The excretion urogram and urodynamic studies of 201 patients presenting with prostatism were reviewed. The urographic features of trabeculation and diverticula were found to be associated with bladder instability as shown on inflow cystometry but not to be associated with outflow obstruction as shown by the pressure-flow analysis of micturition. The bladder shadow on the preliminary film and the bladder size on the post-evacuation film were associated with the measured residual urine and with outflow obstruction. The basal prostatic filling defect was also associated with outflow obstruction.


Lymphography and pelvic lymphadenectomy in carcinoma of the prostate.

20 of 45 new patients with prostatic carcinoma have undergone lymphography and lymphadenectomy to determine the N-category. The overall accuracy of lymphography was 75%. Lymphadenectomy was a safe procedure with minimal morbidity. Although it would be premature to recommend its universal adoption in the management of this disease, its further application and study seems desirable. Full TNM classification has proved to be of considerable value in the management of these patients. This study confirms that 50% of T3 MO tumours are free of lymph node metastases.


Hypospadias--problems of postoperative fistulae formation and a modified 2-stage procedure to reduce these.

A retrospective review of hypospadias repair reveals a high incidence of postoperative fistula nad stenosis. Further studies using Silicone casts have revealed a potential cause for the occurrence of these complications. The close co-operation between urologists and plastic surgeons has resulted in a grea er awareness of the surgical problems and the development of a simplified 2-stage technique which it is hoped will reduce these.


Plasma gonadotrophic hormones, testicular biopsy and seminal analysis in the men of infertile marriages.

The first step in the investigation of infertile men is to obtain 2 seminal analyses 3 days after the previous ejaculation. Clinical assessment of testicular size is an unreliable means of assessing spermatogenesis and is best done by performing bilateral testicular biopsies. Azoospermic men with grossly elevated FSH levels should be advised to consider AID or adoption. Those with normal or mildly elevated FSH levels should undergo testicular exploration in an attempt to correct an obstructive lesion. Azoospermic men with subnormal FSH levels may have an isolated hormone defect which will respond to treatment with Pergonal. Different treatment programmes for oligozoospermic men depending on the results of the FSH and LH assays may lead to a more rational approach to therapy. Infertility associated with varicocele may possibly be associated with a local disturbance of "inhibin" and FSH concentrations.


The development of the isthmo-optic nucleus.

The nucleus of origin of centrifugal fibers to the retina (the so-called isthmo-optic nucleus - ION) has been used as a model for the study of the major features of neural development, from the period of cell proliferation until after the formation of its afferent and efferent connections. 3H-thymidine autoradiography has established that in the chick cells of the ION are generated (i.e., become post-mitotic) between the middle of the 5th and the end of the 7th days of incubation. The first-formed cells are found in the ventrolateral part of the nucleus, while those that are generated at successively later stages come to occupy progressively more medial and dorsal positions within the nucleus. The anlage of the ION can be identified on the 8th day of incubation, and by the 11th day, when it is numerically complete, it occupies a prominent position in the caudo-dorsal part of the midbrain tegmentum at the level of the IVth nerve nucleus. At this stage the nucleus contains about 22,000 neurons, and shows no signs of cytoarchitectonic differentiation. Between the 13th and 17th days of incubation, about 60% of the neurons in the nucleus degenerate; as a result of this degeneration, the arrival of afferent fibers, and the growth of the cells' processes, the nucleus comes to have its characteristic adult form of a complex, folded, bilaminar sheet, in which each part of the retina is precisely represented. Experiments based on the retrograde transport of horseradish peroxidase (HRP) from the eye indicate that the first centrifugal fibers, in the isthmo-optic tract (IOT), reach the retina on the 10 day of incubation, and by the 12th day all but about 5% of the neurons in the ION can be retrogradely labeled in this way...


Brain circuits for consciousness.

The question is explored of the location of consciousness in the human brain. The author's own studies of defects of consciousness as the result of the splitting of the corpus callosum are described and disorders of consciousness associated with damage to other specific areas of the brain, are reviewed. A circuit spanning the brain is described which stretches from the parietal lobe at one side to the parietal lobe at the other and includes the splenium of the corpus callosum. The medial banks of the hemispheres, the callosal as well as the cingulate areas, are also thought to be involved.


Telencephalon of the lizard Gekko gecko (Linnaeus): some connections of the cortex and dorsal ventricular ridge.

Interhemispheric connections of the telencephalon in the lizard, Gekko, were studied with anterograde degeneration methods following lesions variously placed in the medial, dorsal, and lateral cortices and/or the dorsal ventricular ridge (D.V.R.). After lesions involving dorsal cortex, the medial wall, and the DVR, the majority of degenerated fibers decussate in the hippocampal commissure and terminate in the septum, medial wall, dorsal cortex, and the lateral edge of the DVR contralaterally. Lesions confined to dorsal cortex result in a similar pattern of degeneration, while lesions confined to the lateral wall result in degeneration in the contralateral lateral cortex, DVR and striatum, mainly via the anterior commissure. Some variation has been reported on the pattern of interhemispheric projections among reptiles studied to date; two possible interpretations of the data are that (1) dorsal cortex may be homologous as a field to parts of both neocortex and the hippocampal formation of mammals or (2) only the lateral part of dorsal cortex may be homologous to neocortex.


Behavioral correlates of 'tectal compression' in goldfish. I. Intensity and pattern discrimination.

Goldfish were trained to perform visual intensity and pattern discriminations. Three groups of fish had bilateral ablation of the caudal optic tectum, a fourth consisted of unoperated controls and a fifth group consisted of sham-operated controls. The fish were tested after various postoperative intervals ranging from 19 to 147 days. The lesions produced modest deficits in intensity discrimination irrespective of postoperative interval. The fish that began training on the pattern discrimination after 14-18 postoperative days showed no improvement in performance. Fish that began training after 39 postoperative days showed improvements in performance after about 65 postoperative days. The group that began training 158-160 postoperative days showed steady and persistent improvements in discrimination performance. The results suggest that improvements in pattern vision after partial tectal ablation follow the same time course as compression of the retinotectal map after partial ablation of the tectum.


Behavioral correlates of 'tectal compression' in goldfish. II. Visual acuity.

Visual acuity was measured in three normal goldfish and two goldfish in which the caudal optic tectum had been ablated bilaterally. Compression of the retinotectal map was assumed to have occurred in the two operated fish, which were tested more than 200 days after surgery. The results indicated that the visual acuity of the normal fish ranged from 0.94 to 0.95 degrees of visual angle. The visual acuity of the fish with presumed compression of their retinotectal maps ranged from 1.91 to 2.07 degrees. The results suggest that compression of the retinotectal map occurs at the expense of the spatial-resolution ability of the visual system.


The mineral dust load of human lungs.

Studies of the dust content of lungs from non-industrially exposed city dwellers have shown that many people build up during life a total dust load of 2 grammes or more. This dust load may include up to 17 X 10(6) mineral fibres large enough to be visible with the light microscope and 360 X 10(8) fibres visible only by electron-microscopy. All lungs examined contained a small percentage of fibres that appeared structurally similar to chrysotile asbestos. It was found that the total dust content and content of light microscope sized mineral fibres was much lower in a non-industrialised city than in one with a high level of heavy industry, but levels of electron-microscope sized fibres did not differ markedly between the two groups. It would appear that these very small fibres are part of a general mineralogical background rather than resulting from industrial atmospheric pollution. This was further indicated by the fact that many of the dust particles, including large numbers of the fibrous ones proved to be derived from diatom skeletons.


Isoelectric points and molecular weights of salt-extractable ribosomal proteins.

Rat liver ribosomes prepared in low salt buffer contain basic and acidic proteins not found on ribosomes washed in high salt buffer. Proteins extracted from liver ribosomes by 500 mM KCL were characterized by acid urea-polyacrylamide gel electrophoresis, sodium dodecyl sulfate - polyacrylamide gel electrophoresis and gel isoelectric focusing. The salt-solubilized proteins contain 12 polypeptides with a molecular weight over 67000, several polypeptides with molecular weights less than 67 000, and three polypeptides whose molecular weight exceeded 130 000. Ten to 12 of the proteins were basic, and about 24 acidic proteins were partially or wholly extracted from the ribosomes. Four of the acidic proteins have isoelectric points less than 4.5.


Preparation of active run-off 80S ribosomes and their subunits from mouse liver.

A method is described for the preparation of active "run-off" 80S ribosomes and 40S and 60S subunits of mouse liver. A polysome preparation was incubated at 37 degrees C for 10 min under the condition for protein synthesis (4 mM Mg2+, 100 mM KCL). Puromycin (10 mM)and 2 M KCL were added to a final concentration of 0.1 mM and 500 mM, respectively, and the reaction mixture was further incubated at 37 degrees C for 10 min. This latter treatment destabilized small polysomes and "stuck" 80S particles, which were remaining after the first incubation, leading to complete release of 40S and 60S particles. Thus, the present method minimized variations in yield of subunits due to polysome preparations and preincubation conditions. The subunits were separated by sucrose density-gradient centrifugation or recovered by precipitation following reassociation into 80S particles (run-off 80S). The reformation of 80S particles from the subunits occurred spontaneously at 5 mM Mg2+ and 100mM KCL. The isolated 40S and 60S subunits, separately, showed low phenylalanine-incorporating activity in the presence of poly(U), but when recombined, polymerized up to 10 phenylalanine residues per couple.


Purine catabolism in man: inhibition of 5'-phosphomonesterase activities from placental microsomes.

The 5'-phosphomonoesterase activity of 5'-nucleotidase (EC 3.1.3.5) and alkaline phosphatase (EC 3.1.3.5) participates in the catabolism of purine ribonucleotides to uric acid in humans. Initial velocity studies of 5'-nucleotidase suggest a sequential mechanism of interaction between AMP nad MgCl2, with a Km of 14 and 3 muM, respectively. With product inhibition studies the apparent Ki's for adenosine, inosine, cytidine, and inorganic phosphate were 0.4, 3.0, 5.0, and 42 mM, respectively. A large number of nucleoside mono-, di-, and tri-phosphate compounds were inhibitors of the enzyme. Allopurinol ribonucleotide, ADP, or ATP were competitive inhititors when AMP was the substrate, with a Ki slope of 120 muM. The phosphomonoesterase activity of human placental microsomal alkaline phosphatase had a pH optimum of 10.0 and had only 18% of maximum activity at pH 7.4. Substrates and inhibitors included almost any phosphorylated compound. The Km for AMP was 0.4 mM and the apparent Ki for Pi was 0.6 mM. Activity was increased only 19% by 5 mM MgCl2. These observations suggest that 5'-nucleotidase and alkaline phosphatase may be inhibited by ATP and Pi, respectively, under normal intracellular conditions, and that AMP may be preferentially hydrolyzed by 5'-nucleotidase.


Decreased uptake of orotate in kidney tumors.

The uptake of isotope by three transplanted kidney tumors after i.p. injection of 3H-labeled orotate was less than 5% of that in the host kidney cortex. A decrease of similar magnitude in the uptake into the acid-soluble tissue fractions from the kidney tumors was observed with very low incorporation into RNA relative to the host kidney cortex. Total uptake of orotate-3H and incorporation into RNA were several fold higher in the normal kidney cortex than in the kidney medulla and for the kidney cortex both parameters were less in young than in old rats. The uptake of uracil-3H by two kidney tumors was approximately 40% of that in the kidney cortex of host rats. Although the uptake of orotate-3H in kidney cortex was greater than that for uracil-3H the reverse situation was observed with kidney tumors, indicating that renal neoplasia in the rat is accompanied by an altered pattern of uptake of these metabolites.


Shapes of carcinogenic benz[alpha]anthracenes: an x-ray crystal structure analysis of 12-methylbenz[alpha]anthracene.

The crystal structure of the moderately active carcinogen 12-methylbenz[alpha]anthracene (12-MBA) has been determined by application of direct methods to X-ray single-crystal diffraction data. Least-squares refinement to a residual R = 0.09 over 929 independent reflections enabled carbon positions to be established with apparent e.s.d.s. of atomic coordinates about 0.008 A. Deviation from planarity is exemplified by the 15.5 degrees inclination of the benz ring (A) to the anthracene nucleus and by the 0.89 A distance of the methyl carbon out of the best plane through the whole benzanthracene nucleus. Comparison with the structure of the highly carcinogenic 7,12-dimethylbenz[alpha]anthracene (7,12-DMBA), and with the recently solved structures of the weak carcinogen 1-MBA and the extremely weak carcinogen 1,12-DMBA, shows a close similarity in the anthracene parts; in 1-MBA, and 1,12-DMBA, the phenanthrenic K-region bond is close to 1.34 A and the M-region bond about 1.38 A. In 12-MBA, overcrowding in the 'bay' region causes the central anthracene ring C and the benz ring A each to be bent about 10 degrees in opposite directions from the phenanthrenic B ring, much as in 1-MBA and 7,12-DMBA, but less than in 1,12-DMBA; the 12-methyl carbon lies about the same distance (0.55 A) above the anthracene plane in 12-MBA as in 1,12-MBA and 7,12-DMBA.


Temporal changes in chromatin isolated from Friend virus-infected mouse spleens.

Differences noted in enzyme II directed RNA synthesis under varying salt conditions in nuclei isolated from uninfected and Friend virus (FV)-infected spleen cells, have been attributed to chromosomal modifications (Babcock and Rich 1973). This investigation was undertaken to determine if compositional changes occur in the chromatin of FV-infected spleens, which correlate with an altered rate of synthesis by enzyme II. A quantitative study of the chromatin constituents at various times after infection indicated that they vary in the same temporal manner as the rate of RNA synthesis in isolated nuclei. Relative to DNA, RNA, histone, and nonhistone protein reached a maximum at 14 days postinfection. This was followed by a gradual decrease during the remainder of the infection. Chromatin endogenous DNA-dependent RNA polymerase activity varied in the same manner, suggesting that RNA synthesis directed by enzyme II is modulated by chromosomal proteins.


Theoretical prediction of mutagenicity and carcinogenicity of chemical substances.

The pseudopotential with respect to free electrons has been calculated for a series of chemical substances. These potentials are different for carcinogenic, mutagenic-carcinogenic, and mutagenic substances thus allowing the theoretical prediction of their biological activity. The reaction mechanism is discussed on the basis of the interaction potential.


Minimizing false negatives in electron microscope searches for virus or other specific features of cancer cells.

Electron microscopic searches for virus particles and other specific features of cancer cells involve exceptionally poor sampling statistics. It is probable that most searches conducted in the past were of limited value in establishing whether such viruses or special features are associated with one or more tumor types. On the other hand, in a few cases, the electron microscope has provided the first, or even the only, evidence of virus particles. A radical change in the way the electron microscope is applied to this problem is suggested whereby a high-voltage microscope is used to examine thicker sections and an image-processing arrangement is used to focus and select images and to search the images for virus particles. It is suggested that it is important to distinguish virus producers amongst oncogenic viral genome carriers since these may be in a more advanced state of tumor induction and may be capable of transmitting the virus to others.


Behavior of rat liver catalase during electrophoresis in a pH gradient.

Investigations were conducted on the distribution of rat liver catalase subsequent to electrofocusing in a pH gradient. Differences were observed depending on the enzyme being extracted from the total mitochondrial fraction, from the supernatant of the homogenate or from purified peroxisomes. Catalase solubilized from the total mitochondrial fraction exhibits an apparent isoelectric point lower than that of catalase derived from the supernatant. Catalase released from purified peroxisomes shows a behavior similar to that of the supernatant catalase. It has been concluded that, in a total mitochondrial fraction, a factor is present that alters the electric charge of the catalase molecule during or after the extraction of the enzyme. This factor is probably associated with lysosomes existing together with peroxisomes and mitochondria in a total mitochondrial fraction. As a matter of fact, the addition of an extract of purified lysosomes to purified peroxisomes or to supernatant will cause a shift towards a more acid pH of catalase distribution subsequent to electrofocalization.


Transfer RNA and aminoacyl tRNA synthetases in hormone dependent and independent mammary tumors of GR mice: II. Isoacceptor tRNA's in hormone dependent and independent mammary tumors of GR mice.

The chromatographic elution profiles of 15 aminoacyl tRNA's from dependent and independent mammary tumors of GR mice have been studied using the reversed phase chromatography (RPC 5). The seryl tRNA from the dependent tumor displayed three isoacceptor peaks while only two isoacceptor peaks were observed in the case of the independent tumor when the tRNA's were charged in the presence of the GR mice liver enzyme. Charging of the tRNA's with radioactive leucine by homologous and heterologous enzyme revealed major differences in the leucyl isoacceptor species. The homologous dependent tumor system charges five leucyl tRNA species while the independent system only charges four. The leucyl tRNA from the dependent tumor has a new peak which is only recognized by its own enzyme, but this peak is either suppressed or completely absent in the independent tumor.


Carcinogenic effects of different nitroso-compounds in chinese hamsters: N-dibutylnitrosamine and N-nitrosomethylurea.

Three hundred and twenty Chinese hamsters (Cricetulus griseus) (CH) were subcutaneously (s.c.) treated with 1/5, 1/10 or 1/20 the mean lethal dose (LD50) of N-dibutylnitrosamine (DBN) or N-nitrosomethylurea (NMU). In several respects these two substances produced the same organotropy in the CH as in the Syrian golden (SGH) and European hamsters (EH). DBN prolonged lung tumours and neoplasms of the injection site. NMU induced tumours of the injection site only.


Polycyclic aromatic hydrocarbons in human bronchial carcinoma.

A study was made to determine whether and to what extent polycyclic aromatic hydrocarbons (PAH) are present in human bronchial carcinoma. Twenty-four carcinomas, obtained from surgical operations and autopsies, were examined. The samples were tested for 12 PAH; these were determined by direct fluorescence analysis on thin-layer plates. Only 4 of the 12 PAH were detected in the cancerous tissue: benzo(a)pyrene, fluoranthene, benzo(ghi)perylene. Beno(a)pyrene was found in all carcinomas. The reasons for increased concentration of the detected PAH in cancerous tissue are discussed with respect to deposition and elimination of inhaled particles as well as the metabolism of these compounds.


A further pancreatic carcinogen in Syrian golden hamsters: N-nitroso-bis(2-acetoxypropyl)amine.

Weekly subcutaneous injection of N-nitroso-bis(2-acetoxypropyl)amine (BAP) for 20 weeks to Syrian golden hamsters induced pancreatic neoplasms in 50% of the animals, as early as 15 weeks from the start of treatment. The carcinogenic potency and organotropic spectrum of BAP were similar to those of N-nitroso-bis(2-hydroxypropyl)amine (BHP). Metabolism studies indicated that BAP was readily converted in vivo to BHP and that BHP was also the major urinary metabolite.


Human breast carcinoma: heterotransplantation to newborn rats.

Cultured cells from a human breast carcinoma (HBC) were injected subcutaneously in newborn cortisone-treated Sprague-Dawley rats (CNBR). Tumors of predominantly epithelial nature appeared in all within 30 days, and wipespread metastases occured often. Cells cultured from these tumors rapidly produced similar tumors in CNBR. Rat-to-rat passage by implanting fragments of tumor tissue was 100% successful in CNBR. The in vivo model described is simple and inexpensive.


Tumorgenicity of L cell derivatives and hybrid cells derived from them.

Hybridization studies on high and low malignant L cell derivatives support our previous conclusions, in showing that crosses between highly tumorigenic and poorly tumorigenic lines to a marked suppression of the malignant phenotype. Malignant behaviour is not, however, suppressed when cells from one highly tumorigenic line are crossed with those of another tumorigenic line. The present results show further that these rules apply even when all the cells crossed are closely related derivatives of one cell line.


Investigations on esophageal carcinogenicity by methyl-phenyl-nitrosamine and ethyl alcohol in rats.

Methyl-phenyl-nitrosamine was administered subcutaneously or orally to Sprague-Dawley rats. Carcinomas of the esophagus were found in 46-87% of the animals. The induction period of tumors was 170-290 days. Simultaneous application of 25% ethyl alcohol given instead of drinking water did not alter tumor incidences and induction periods. Hepatotoxic effects of ethyl alcohol were not observed. Mean life expectancies of animals were not reduced.


Vaccinia virus: the possibilities of its oncogenicity in humans.

Contrary to the earlier generally accepted view that vaccinia virus replicates in the cytoplasm only of suitable target cells, steadily accumulating data show that the viral genome spends a limited period of time in the nucleus. This, together with the many cases where a close association has been suspected or established between skin cancer and vaccination, suggests that vaccinia virus may, under certain yet undefined physiological conditions, act as an oncogenic virus in humans.


Early membrane alterations in isolated cells treated in vitro with chemical carcinogens.

Membrane alterations were detected in isolated epithelial cells treated in vitro with 5 x 10(-4) M dibutylnitrosamine (DBN) or 1.2 x 10(-9) M diethylstilbestrol (DES) for 30 min. Addition of DBN to bladder cells and DES to endometrial cells elicited a striking increment in Con A-mediated hemadsorption, but not Con A binding, to the treated cells as compared to those not treated with carcinogens. Concomitantly, release of the lysosomal proteinase, cathepsin B1, to the extracellular medium was essentially doubled in the preparations exposed to the carcinogens, as compared to corresponding controls. The increased cellular hemagglutination in response to carcinogen treatment was significantly reduced by prior incubation of the epithelial cells with ovomucoid, a proteinase inhibitor that suppresses the activity of cathepsin B1.


Modification of photocarcinogenesis by two immunosuppressive agents.

The carcinogenic effect of ultraviolet radiation (UVR) on the skin of hairless (hr) mice was modified by two immunosuppressive agents, rabbit anti-mouse lymphocytic serum (ALS), and 6-mercaptopurine (6MP). Daily exposure of mice to UVR resulted in multiple tumor production. Carcinogenesis was measured in terms of affected mice (prevalence) and numbers of tumors produced. By both criteria, photocarcinogenesis was enhanced by ALS but inhibited by 6MP.


Carcinogenic effects of a single dose of diethylnitrosamine in three unrelated strains of mice: genetic dependence of the induced tumor types and incidence.

The carcinogenic effects of a single dose of diethylnitrosamine (DEN) were studied in three inbred strains of mice. The most predominant tumors observed were lung adenomas, leukemia, and liver tumors. Mice of strain AKR/J developed both leukemia and lung tumors; SWR/J mice were most susceptible to lung tumor development; and in C57BL/6J mice liver lesions including liver tumors occurred. The influence of the genetic background on the organ susceptibility to DEN-carcinogenesis is discussed.


Proliferation of endocrine (APUD-type) cells during early N-diethylnitrosamine-induced lung carcinogenesis in hamsters.

Pronounced proliferation of amine precursor uptake and decarboxylase activity (APUD-type) cells was found in the segmental bronchi and bronchioles of Syrian golden hamsters during N-diethylnitrosamine (DEN)-induced lung carcinogenesis. Since similar epithelial alterations did not occur in previous experiments after benzo(a)pyrene (B(a)P) treatment, it is concluded that the initial stages of lung carcinogenesis differ with respect to the carcinogen administered.


DNA damage and repair in intact animals. Single-stranded regions in rat liver DNA following administration of dimethylnitrosamine.

Rat liver DNA was radioactively labelled by administration of [3H]thymidine following partial hepatectomy. Two weeks later, the rats were treated with the carcinogen, dimethylnitrosamine. DNA was isolated and fractionated by elution from benzoylated DEAE-cellulose with NaCl and caffeine solution. The caffeine-eluted fraction was increased by administration of dimethylnitrosamine. This increase was proportional to the dose of carcinogen injected and persisted for at least 24 h after administration of the carcinogen. These data, together with the results of hydroxyapatite chromatography, suggest that the DNA contains short single-stranded sections associated with much longer regions of native DNA.


On the carcinogenic polycyclic aromatic hydrocarbon benzo(a)pyrene in volcano exhausts.

The content of benzo(a)pyrene in the juvenile ashes of the volcano Tyatya (Kunashir Island, Kuriles) and in the soil, vegetation and volcanic mud collected near volcanos in Kamchatka was studied. It was concluded that volcanic activity does not play a large role in forming the background level of this carcinogen in the human environment.


Stimulatory effect of staphylococcal leukocidin on granulopoiesis disturbed by cytostatic agents.

Functional tests of granulopoiesis (leukocytosis, bone marrow picture, incubation in vitro of bone marrow with [3H]thymidine followed by radioautography and counting of labeled promyelocytes and myelocytes, serum muramidase level, liberation of granulocyte bone marrow reserve, Nitro-BT reduction in blood granulocytes, enzyme cytochemistry, and phagocytosis) were performed in rabbits given bubulphan (10 mg/kg) or 5-fluorouracil (200 mg/kg). Determinations were carried on serially during treatment with cytostatics. Some of the cytostatic-treated animals received intravenous (i.v.) injections of purified staphylococcal leukocidin in daily doses of 0.1 mg/kg. In control animals, theleukocidin resulted in stimulation of granulopoiesis (leukocytosis, increased number of [3H]thymidine-labeled myelocytes, elevated serum muramidase level). Animals receiving cytostatics suffered from marked inhibition of granulopoiesis accompanied by decrease of bone marrow granulocyte reserve. Injection of staphylococcal leukocidin during the period of myelosuppression evoked by cytostatics resulted in partial protection of granylopoiesis and faster regeneration of the leukocyte system.


Decreased transforming ability of a temperature-sensitive mutant of human adenovirus type 12.

A mutant of human adenovirus type 12, temperature-sensitive for virus replication an for the enhancement of thymidine incorporation in resting human embryonic kidney cells, is described. The mutant was also temperature-sensitive for transformation of rat cells. The results indicate that a viral gene required for the virus growth cycle is also required for transformation.


Random repression, immunological surveillance and hyperthermia.

A theoretical model of random repression of genetic information in a cancer cell is related to the efficiency of the immune system in removing cancer cells. It is suggested that at some elevated temperature, binding of a certain repressor molecule to the genome ceases and that the cell loses its random properties. We conclude with the idea that elevated temperature increases the efficiency of the immune system.


Effect of sodium ascorbate on tumor induction in rats treated with morpholine and sodium nitrite, and with nitrosomorpholine.

Groups of male MRC Wistar rats were treated for 2 years either with morpholine (10 g/kg food) together with sodium nitrite (3 g/l drinking water) or with N-nitrosomorpholine (NM, 0.15g/l drinking water). In both cases, a group of rats was given sodium ascorbate (22.7 g/kg food) in addition to these treatments. When ascorbate was present, the liver tumors induced by morpholine and nitrite showed a 1.7-fold longer induction period, a slightly lower incidence, and an absence of metastases in the lungs, indicating that ascorbate had inhibited the in vivo formation of NM. Ascorbate did not affect liver tumor induction by the performed NM. The group treated with morpholine, nitrite, and ascorbate had a 54% incidence of forestomach tumors, including an 18% incidence of squamous cell carcinomas, possibly because ascorbate promoted NM action in this organ.


Skin tumor initiating ability of benzo(a)pyrene 4,5- 7,5- and 7,8-diol-9,10-epoxides and 7,8-diol.

The skin tumor initiating abilities of both K-region and non-K-region epoxides of benzo(a)pyrene(BP) were determined in mice using a two-stage system of tumorigenesis. BP-4,5-epoxide and BP-7,8-dihydrodiol-9,10-epoxide (anti) were found to be weak tumor initiators whereas BP-7,8-epoxide had about a third of the activity as the parent hydrocarbon, BP. However, the 7,8-dihydrodiol of BP was found to be approximately as potent as BP suggesting that it may be a proximate carcinogen.


The effect of withaferin A on human peripheral blood lymphocytes. An electron-microscope study.

Cultures of normal human peripheral blood lymphocytes stimulated by phytohaemagglutinin (PHA) were treated with withaferin A and examined by an electron microscope. The compound was found to affect the spindle microtubules of cells in metaphase. There were no intact pole-to-pole microtubules or pole-to-kinetochore microtubules found in the treated cells; the centrioles were located in the center. Furthermore, cells at interphase were also affected, the membrane system of the cells being damaged.


The effect of withaferin A, a natural steroidal lactone, on the fine structure of S-180 tumor cells.

Mouse sarcoma 180 (S-180) solid and ascites tumor cells were treated in vivo and in vitro with withaferin A and observed with the electron microscope. The compound was found to effect this spindle microtubules of cells in metaphase. An interesting finding was the double membranes surrounding the chromosomes in the treated cells; probably the nuclei were reconstructed directly from the metaphase stage in the in vivo withaferin A-treated cells. In addition the membranes of the cells in interphase were affected by in vivo or in vitro treatment with the compound.


Effect of chronic administration of dimethylnitrosamine on the excision of O6-methylguanine from rat liver DNA.

Rats were exposed chronically to unlabelled N,N-dimethylnitrosamine (25 ppm in the drinking water) then given a single dose of N-[3H]methyl-N-nitrosourea (10 mg/kg body weight). The rates of loss of tritium-labeled 7-methylguanine, O6-methylguanine and 3-methyladenine from the liver DNA in control and dimethylnitrosamine-treated rats were found not to be significantly different. Thus, under the conditions used, inhibition of the O6-methylguanine excision repair system does not seem to be a factor in the induction of liver tumours by chronic DMN application.


Induction of renal pelvic tumours in Sprague-Dawley rats by di-isopropanolnitrosamine.

Transitional cell papillomas and carcinomas of the renal pelvis were observed in Sprague-Dawley rats after subcutaneous (s.c.) treatment with di-isopropranolnitrosamine (DIPN). These tumours occurred unilaterally and appeared as early as 24 weeks after the commencement of treatment. The tumours frequently filled the entire renal pelvis and compressed the kidney parenchyma. The malignant neoplasms demonstrated infiltrative growth into the adjacent medullary parenchyma.


Echocardiographic evaluation of adriamycin cardiotoxicity in children.

Thirty children with malignant solid tumors receiving adriamycin had serial evaluation of left ventricular (LV) function by echocardiography. The echocardiographic studies showed a progressive decrease in myocardial contractility as evidenced by changes in several parameters of LV function with increasing cumulative doses of the drug. Using the patients as their own controls, serial echocardiography appears to be a reliable method for detecting early alteration of cardiac function in the asymptomatic patient. This technique may prove useful to prevent cardiomyopathy secondary to adriamycin and to prolong therapy beyond the currently established limits.


Studies of the effects of cyclophosphamide, vincristine, and prednisone on some hepatic oxidations and conjugations.

The effects of low and high doses of three anticancer agents, cyclophosphamide, vincristine, and prednisone (given individually or in various combinations), on oxidative and conjugation pathways were studied in Sprague-Dawley male rats. Cyclophosphamide used alone at low doses decreased aniline hydroxylase and ethylmorphine demethylase activities by about 20% and at high doses produced a 30%-50% decrease in the specific activities of several microsomal mixed-function oxygenase activities, in the contents of cytochromes P-450 and b5, and in the magnitudes of type I and II drug-binding spectrum. The levels of microsomal glucouronidase, glucuronyl transferase, and sulfatase per gram of liver were also decreased (30%-50%) by the high dose of cyclophosphamide. The high dose of cyclophosphamide in conjunction with either vincristine or prednisone also produced a noticeable decrease in several activities tested; however, when cyclophosphamide was given at either low or high doses in combination with vincristine and prednisone, the activities tested were comparable to those seen in untreated controls. The mechanism of this protection is presently unknown. Vincristine, at both low and high doses, produced little effect on oxidative pathways; however, at low doses it caused a significant increase (80%) in the specific activity of hepatic microsomal sulfatase. This effect was also discernible when vincristine was given in combination with cyclophosphamide and prednisone. Other than producing a 15% decrease in liver weight and a 40% decrease in the specific activity of microsomal glucuronidase, the high dose of prednisone used had no effect on various activities tested. Results of these studies indicate a potential for drug interaction among anticancer agents and supportive drugs used in combination cancer chemotherapy.


Survival and cycle-progression delay of human lymphoma cells in vitro exposed to VP-16-213.

The lethal and kinetic effects of VP-16-213 were analyzed in a human lymphoid cell line (T1 cells) in vitro. When asynchronous T1 cells were exposed to increasing concentrations of VP-16-213 for 1 hour, an exponential survival curve with a Do (mean lethal dose equal to the concentration required to reduce survival by 63% on the exponential part of the survival curve) of 3 mug/ml was obtained. Increasing exposure time also reduced survival exponentially. Synchronized cells showed age-dependent sensitivity to VP-16-213 with the greatest lethal damage experienced by cells treated in S and G2 phase. The major kinetic response of the T1 cells to VP-16-213 was a delay in G2 phase, the extent and duration of which was a function of drug concentration, exposure time, and cell cycle stage of drug addition; thus, cells in S phase were most effectively blocked in the subsequent G2 phase. Continuous treatment with concentrations of VP-16-213 (greater than 0.5 mug/ml for greater than 3 hours) caused a retardation of S-phase transit with prompt recovery after drug release. Treatment with 10.0 mug/ml for greater than 3 hours resulted in a "frozen state" of the whole life cycle, inducing only minor compartment changes. DNA synthesis was inhibited in the majority of cells with an S-phase DNA content. There was no correlation between the extent of perturbation and lethal effects after treatment with VP-16-213.


Studies with 2,5-piperazinedione, 3,6-bis(5-chloro-2-piperidyl)-,dihydrochloride. II. Effects on macromolecular synthesis in cell culture and evidence for alkylating activity.

2,5-Piperazinedione, 3,6-bis(5-chloro-2-piperidyl)-,dihydrochloride (NSC-135758) inhibited DNA synthesis but not RNA and protein synthesis in Adenocarcinoma 755 cells in culture. The expression of such inhibition was delayed in time; it was necessary to expose tumor cells to NSC-135758 for 10-12 hours before measuring the macromolecular synthesis in order to demonstrate selective inhibition of DNA synthesis. Inhibition of DNA synthesis was demonstrated to be irreversible in human epidermoid carcinoma cells in culture. Exposure of cells in suspension culture to NSC-135758 or to melphalan for 1-4 hours, and then incubation of cells in the absence of an inhibitor for 20 hours, resulted in preferential inhibition of DNA synthesis; inhibition of RNA synthesis was observed under these conditions but was less pronounced. Chemical evidence for alkylating activity of NSC-135758 and of the bis-aziridine derived from it (NSC-201424) was obtained by demonstrating their reaction with 4-(p-nitrobenzyl)pyridine. NSC-135758 was more potent as a cytotoxic agent than was its derivative, a result which suggests that NSC-135758 is the active alkylating agent. Reaction of NSC-135758 with diethylamine was examined; the product obtained upon alkylation of diethylamine by NSC-135758 was identified from its proton magnetic resonance spectrum and by field desorption mass spectral analysis. These results support the view that NSC-135758 acts as an alkylating agent in inhibiting DNA synthesis and cell proliferation of tumor cells in culture.


Studies with 2,5-piperazinedione, 3,6-bis(5-chloro-2-piperidyl)-,dihydrochloride. III. Biochemical and therapeutic effects in L1210 leukemias sensitive and resistant to alkylating agents: comparison with melphalan, cyclophosphamide, and BCNU.

2,5-Piperazinedione, 3,6-bis(5-chloro-2-piperidyl)-,dihydrochloride (NSC-135758) selectively inhibits DNA synthesis in L1210/0 leukemia and in cyclophosphamide-resistant L1210 (L1210/CPA). Melphalan (L-PAM) inhibits nucleic-acid synthesis but not protein synthesis in L1210/0 and L1210/CPA. CPA selectively inhibits DNA synthesis in L1210/0 but does not inhibit DNA synthesis in L1210/CPA. NSC-135758 is as active in vivo against L1210/CPA and BCNU-resistant L1210 (L1210/BCNU) as it is against L1210/0. It is inactive against ic implanted L1210/0. These data clearly indicate important differences in the biologic activity of this compound compared to either CPA or BCNU. L-PAM is similar to NSC-135758 in activity against L1210/CPA and L1210/BCNU.


Amino acid-conferred resistance to melphalan. I. Structure-activity relationship in cultured murine L1210 leukemia cells.

Melphalan cytotoxicity to murine L1210 leukemia cells in culture was reduced in growth medium containing amino acids. Investigation of the effect of single amino acids revealed that the L-isomers of glutamine and leucine, but not the D-isomers, were the most active in decreasing cytotoxicity. Protection was concentration dependent, with maximum protection occurring at approximately 0.25 mM, a physiologic concentration. The LD90 for melphalan in the presence of 0.1 mM L-glutamine or L-leucine was increased by 7.3- and 10.8-fold respectively, under conditions where the cells had been pre-incubated with the amino acids. These results are interpreted to suggest that melphalan transport by the L1210 leukemia cell is mediated by a system also responsible for the transport of glutamine and leucine and that interaction with such a system may play a significant role in the chemotherapeutic activity of this alkylating agent.


Synthesis of 2-acetamido-2-deoxy-3-O-beta-D-mannopyranosyl-D-glucose.

Condensation of 4,6-di-O-acetyl-2,3-O-carbonyl-alpha-D-mannopyranosyl bromide with benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-alpha-D-glucopyranoside (2) gave an alpha-D-linked disaccharide, further transformed by removal of the carbonyl and benzylidene groups and acetylation into the previously reported benzyl 2-acetamido-4,6-O-benzylidene groups and acetylation into the previously reported benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl)-alpha-D-glucopyranoside. Condensation of 3,4,6-tri-O-benzyl-1,2,-O-(l-ethoxyethylidene)-alpha-D-glucopyranose or 2-O-acetyl-3,4,6-tri-O-benzyl-alpha-D-glucopyranosyl bromide with 2 gave benzyl 2-acetamido-3-O-(2 O-acetyl-3,4,6-tri-O-benzyl-beta-D-glucopyranosyl)-4,6-O-benzylidene-2-deoxy-alpha-D-glucopyranoside. Removal of the acetyl group at O-2, followed by oxidation with acetic anhydride-dimethyl sulfoxide, gave the beta-D-arabino-hexosid-2-ulose 14. Reduction with sodium borohydride, and removal of the protective groups, gave 2-acetamido-2-deoxy-3-O-beta-D-mannopyranosyl-D-glucose, which was characterized as the heptaacetate. The anomeric configuration of the glycosidic linkage was ascertained by comparison with the alpha-D-linked analog.