Late nonresponsiveness to steroids in children with the nephrotic syndrome.

Among 195 nephrotic children, ten developed resistance to prednisone therapy after responding to this drug on one or more occasions (late nonresponders). All were found to have "minimal lesions" on renal biopsy. Nine of these patients went into remission: one responded to further prednisone therapy, one went into remission while receiving azathioprine, and the remaining seven children responded to cyclophosphamide. Five of these seven patients subsequently relapsed; three of them have continued to respond to prednisone. The other two eventually became steroid resistant a second time, but in both instances a second course of cyclophosphamide again induced a remission. These nine patients have been followed for periods ranging from 6 months to 9.5 years (median = 53 months); all are doing well and have normal renal function. The tenth patient died from sepsis four months after the onset of steroid resistance.


Colonization by Enterobacteriaceae of the respiratory tract of children with cystic fibrosis of the pancreas and their antibody response.

Of 72 patients with fibrosis, 49 harbored Enterobacteriaceae in the respiratory tract, including Escherichia coli, Klebsiella, and Enterobacter. Colonization by two to four genera was documented in 29 subjects. Staphylococcus aureus was recovered from 44 of these 49 patients. The distribution of serogroups of E. coli was similar to that seen in patients with urinary tract infection. Antibody response against the O antigens of the patients' own Enterobacteriaceae was documented in 29 of these 49 children and encountered more often in patients with severe disease. Colonization by Enterobacteriaceae in the absence of Pseudomonas aeruginosa was seen more frequently in children with the mild form of the illness.


Evaluation of growth hormone release in children using arginine and L-dopa in combination.

L-Dopa in a dose ranging from 125-500 mg and arginine monochloride in a dose of 0.5 gm/kg were given simultaneously to 56 children with short stature (height less than third percentile). Sixteen of these children were subsequently diagnosed as having growth hormone deficiency. The diagnosis of hyposomatotropism was based on clinical findings and on responses to the combination test and to arginine and L-dopa administered as separate tests. All of the remaining 40 children had a normal GH response of greater than 6 ng/ml to the combination test. However, in this group, nine children were identified who responded to the combination test but who failed to respond to arginine and L-dopa in individual tests. The data suggest that a positive response to arginine and L-dopa in combination in children, who do not respond to the usual provocative tests when administered individually, may fail to identify children with partial GH deficiency who would benefit from treatment. The integrated stimulated GH response in the 31 children in whom a normal GH response to all three tests occurred suggests that the effects of L-dopa and arginine are additive.


Congenital fistula between an aberrant systemic artery and a pulmonary vein without sequestration. A report of three cases.

Three children had an arteriovenous fistula between an aberrant vessel from the descending aorta and a normal pulmonary vein in the posterior basal segment of a lung. The affected lung was otherwise normally developed. Only a few similar cases could be found in the literature.


Prenatal diagnosis of cystinosis.

Cystinosis was diagnosed in a small quantity of cultured amniotic cells from a 22-week-old fetus by a modified pulse-labeling technique in which intracellular 35SL-cystine retention was measured. As a result of the above finding, the pregnancy was terminated by administration of prostaglandin. The diagnosis was confirmed when the nonprotein-free cystine content of the kidney, liver, placenta, spleen, thymus, and gut, as well as that of a large amount of cultured amniotic cells, was found to be 100-fold higher than normal levels.


Comparison of the effectiveness of phototherapy and exchange transfusion in the management of nonhemolytic neonatal hyperbilirubinemia.

The relative effectiveness of phototherapy and exchange transfusion for nonhemolytic neonatal hyperbilirubinemia was compared in two closely matched groups of infants. Although the exchange transfusion achieved an immediate reduction of bilirubin level, the "rebound" was rapid and tended to offset this reduction. The more gradual and steady effect of phototherapy resulted in a significantly lower serum bilirubin level at 1, 2, and 3 days after commencement of therapy; the rebound after phototherapy was small. Phototherapy was demonstrated to be more effective than exchange transfusion in achieving prolonged reduction of bilirubin levels for nonhemolytic hyperbilirubinemia. With more efficient lamps delivering more energy in the desired spectrum, it would seem feasible to treat hyperbilirubinemia of whatever etiology with this safer and more convenient form of therapy, though sometimes only as in adjunct therapy.


Absorption of phenobarbital after the intramuscular administration of single doses in infants.

Blood concentrations of phenobarbital, following an intramuscular administration of a single large dose of approximately 10 mg/kg, were studied in 39 infants. A rapid rise was obtained with a mean concentration of 9.30 mug/ml at 30 minutes, 12.76 mug/ml at 90 minutes, and a mean peak concentration of 13.28 mug/ml, which was reached in most cases within 2 hours of injection or less. Cerebrospinal fluid values in 13 patients averaged half the blood phenobarbital concentrations.


Early asymptomatic lead exposure and development at school age.

Sixty-seven 7-year-old children, who had asymptomatic lead exposure between 1 and 3 years of age, were compared in their performance on a series of psychologic tests to 70 children of the same age and socioeconomic background who presumably did not have significant exposure to lead. Exposed children had deficits in global IQ and associative abilities, in visual and fine motor coordination, and in behavior. School failure due to learning and behavior problems was more frequent in the lead exposed than in the control group.


Further studies on deprivation/enhancement patterns.

Four studies were done to explore the construct validity of a previously established sex difference in TAT fantasy patterns. The results, both with various clinical groups and with normal children, support the notion that Deprivation/Enhancement fantasy patterns are meaningfully related to sexual identity and sex role development. The correlates of extreme D/E patterns are more clear for women than for men and involve elements of the "hysterical" character and cognitive style.


Self-perception of intrinsic and extrinsic motivation.

Self-perception theory predicts that intrinsic and extrinsic motivation do not combine additively but rather interact. To test this predicted interaction, intrinsic and extrinsic motivation were both manipulated as independent variables. The results revealed a significant interaction for task satisfaction and a trend for the interaction on a behavioral measure. These results are discussed in terms of a general approach to the self-perception of motivation.


Components of "authority" as determinants of compliance.

This study investigated factors affecting compliance, to orders from a formal authority. The design created a two-level status hierarchy in which subjects occupied identical low-status positions and responded to demands from a simulated high-status leader. Four components of authority-normativity,coervice power, collective justification, and success-failure-were manipulated as independent variables. Another component, the endorsement accorded the leader, was included in the design as a measured variable. Results indicated that compliance increased significantly when coervice power was high (rather than low), when justification was collective (rather than partisan), and when demands were normative (rather than counternormative). Contary ti the theoretical expectation, endorsement did not affect compliance by low-status members. The findings show that the normative aspect of legitimacy serves as a compliance-gaining base even when stripped of enforcing sanctions and under-lying goals and that the distinction between normativity and endorsement is valid for research on social power.


Nonverbal communication affect in children.

A paradign was tested for measuting the tendency of children to send accurate nonverbal signals to others via spontaneous facial expressions and gestures. This paradign was derived from studies on adults that suggest that women are more accurate nonverbal "sendres" than men in certain situations. Eighteeen male and 11 female preschoolers (aged 4 to 6 years) watched a series of emotionally loaded color slides while they were observed via a hidden television camera by their mothers. Results indicated that significant overall communciation occurred, with large individual differences in "sending ability" between children. There was no evidence of a large sex difference in sending ability in choldren, although on one measure girls were more accurate senders than boys when viewed by undergraduates. Sending ability was positively related to teacher's ratings of activity level, aggressiveness, impulsiveness, bossiness, sociability, etc., and negatively related ti shyness, cooperation, emotional inhibition and control, etc.


The facilitation of aggression by aggression: evidence against the catharsis hypothesis.

Nnety male subjects were either attacked or treated in a more neutral manner by a male confederate. On a subsequent maze-learning task, one third of the subjects shocked the confederate, one third observed as the experimenter shocked the confederate, and one third waited for a period of time during which the confederate was not shocked. Finally, all subjects shocked the confederate as part of a code-learning task. Subjects who had been attacked and had shocked the confederate during the maze task delivered shocks of greater intensity on the code task did subjects in the other two conditions, and the former subjects also experienced a greater reduction in diastolic blood pressure than did the latter. The results contradict the hypothesis of aggression catharsis and are discussed in terms of feelings of restraint against aggressing that a subject experiences after committing an aggressive act.


Effect of cognitive appraisal on d' and response bias to experimental stress.

The effects of an intellectualization-denial passage designed to modify cognitive appraisal of stressor stimuli (gory scences) were evaluated in terms of sensory-decision theory analysis. The passage was found to reduce "felt stress" ') for certain pairs of the stimuli addressed by the passage content but to less effective in reducing stress (Lx) was reduced rather than increased wi;h presentation of the passage for the included simuli only. Differences in d' between subjects classified within treatment groups as repressors versus sensitizers were obtained for certain stimulus pairs generally in the direction of lower sensitivity for repressors. Results are discussed in terms of the effects of altered cognitive appraisal on the "prevention of stress" and on "defensive"denial.


Conjugate lateral eye movements as an index of hemispheric activation.

Right handers moved their eyes leftward when solving spatial problems and rightward for verbal problems when the questioner sat behind them. When facing the questioner, the same subjects moved their eyes predominantly in only one direction, either right or left, regardless of problem type. The results indicate that the cerebral hemispheres, though specialized for problem type, are also preferentially activated within the same individuals.


Risky aggression in individuals and groups.

This study set out to investigate whether the risky shaft found in group consensus decisions as compared to group members' personal decisions extends to situations that combine risk and aggression. In a between-subjects design, subjects were exposed, either alone or as members of unisex triads, to an experimental task in which the risk entailed severe noxious consequences. The findings show that for both sexes, groups take significantly greater risks than individuals even when risk taking is mediated by aggressive means. The results are seen and discussed as limiting the explanatory scope of the risk-as-a-value hypothesis and as more consistent with the diffusion of responsibility hypothesis.


Aggression and heat: mediating effects of prior provocation and exposure to an aggressive model.

Sixty-four undergraduate males participated in an experiment designed to examine the effects of level of prior anger arousal, exposure to an aggressive model, and ambient temperature on physical aggression. On the basis of Bandura's social learning theory of aggression, it was predicted that uncomfortably hot environmental conditions would be most effective in facilitating later aggression when subjects had both witnessed the actions of the model and been exposed to strong provocation from the victim, but least effective in this regard when they had neither witnessed the actions of the model nor been exposed to prior instigation. In contrast to these predictions, results indicated that high ambient temperatures facilitated aggression by nonangered subjects but actually inhibited such behavior by those who had previously been provoked.


Causes and consequences of time perception differences in overweight and normal weight people.

Three experiments considered whether there are differences between overweight and normal weight subjects in time perception which represent the obese subjects' lack of internal responsiveness as well as heightened external reactivity in a noneating setting. In the first study, no time-relevant cues were provided, and overweight subjects were inaccurate in their temporal judgments and showed significantly higher group variability than did normals. In the second study, the effects of differential temporal information generated by interesting and boring cues was considered. The presentation of these time-relevant external cues reduced the judgment variability of the overweight subjects and influenced their perceived passage of time significantly more than normals. The third study examined the influence, on eating behavior, of differences in perceived passage of time as a consequence of manipulating cues for interest or boredom. When bored, overweight subjects perceived time to pass more slowly than did normals and thus ate sooner. Similarly, they delayed eating, judging time to have passed more quickly than it actually had, when they were attending to interesting cues. The implications of a generalized lack of internal sensitivity for a theory about the development and consequences of obesity are discussed.


Self-concept and attraction for similar and dissimilar others.

The present study investigated the role of self-concept as a moderator of the similarity-attraction relationship described by Byrne. Subjects conducted face-to-face interviews with confederates who played roles as job applicants. Similarity-dissimilarity was manipulated by the confederate roles as well as by the information given the subjects in accordance with the procedures described by Byrne. The hypothesis was tested and confirmed that persons with favorable self-concepts would be more attracted to others with similar attitudes than to others with dissimilar attitudes. Persons with negative self-concepts did not show a preference for similar others. It was suggested that earlier studies in this area suffered from methodological flaws and did not constitute an adequate test of the hypothesis. Suggestions for future work in the area were given.


Onset of audiogenic seizures in rodents after intake of near-toxic doses of rubidium chloride.

Rats and mice that were not genetically or otherwise predisposed toward audiogenic seizures were rendered susceptible to auditory stimuli by chronic treatment with large doses of rubidium chloride (RbCl). Animals given drinking water, 0.03 N with respect to RbCl, for four weeks responded with convulsive seizures when exposed to signals of 2 to 22 kHz and 74 dbA. The rate of development of audiosusceptibility was dose-related. Less rubidium was needed if the diet was deficient in potassium. No differences were found between tissue rubidium in treated rats which became audiosensitive and their counterparts which remained resistant to auditory stimuli.


Studies on the localization of central cough mechanism; site of action of antitussive drugs.

The localization of the central cough mechanism was studied by electrically stimulating the lower brainstem in cats lightly anesthetized with pentobarbital sodium or in unanesthetized midcollicular decerebrate preparations. Cough responses were recorded with the aid of a microphone. The cough responsive region was concentrated in an area dorsomedial to the trigeminal tract and nucleus. The sites of action of antitussive agents (dextromethorphan, codeine, clonazepam, diazepam and caramiphen) were studied on the centrally induced cough responses. Each of these drugs was administered intravenously to determine the dorsal levels for cough suppression. In other series, the threshold dose via the intravertebral route was determined first. Because the agent necessary to prevent cough via this route was so small in amount, recovery usually occurred in 20 to 90 minutes. Then the same agent was given intravenously in an attempt to obtain an effective dose which was close to the minimum dose for blocking the cough. The mean effective doses of these agents to abolish the cough via the vertebral artery were only about 1/20 of those required via intravenous injection. The findings suggest that these agents act centrally to suppress the cough responses. Clonazepam was found to be the most potent antitussive among these agents, the mean effective dose being about 1/35 of that of codeine. The antitussive potency of benzodiazepines is not well correlated with their muscle relaxant activity. For instance, clonazepam and diazepam have the same potency in depressing polysynaptic spinal reflexes, whereas the former is 6 times more potent than diazepam as an antitussive. This finding indicates that clonazepam has a high specificity as an antitussive.


Excitability modulation by taurine: action on axon membrane permeabilities.

Taurine, a ubiquitous sulfonic amino acid, has been described as a regulator of membrane activity in both normal and pathologic states of nerve and muscle. The common feature of its effects on brain activity and its interaction with muscle, can be summarized in terms of a stabilizing function on excitable membranes. In this paper, we report data on the ionic mechanisms by which taurine modulates membrane behavior of the lobster giant axon. Our data show that taurine increases membrane permeabilities to potassium and chloride but not to sodium. This increase is transient, showing membrane desensitization during taurine application. A reversal potential for the taurine response was observed at about -85 mV, causing the membrane potential to stabilize near the resting level. In addition, taurine causes a reduction of the action potential duration, resulting primarily from an acceleration of the depolarization phase. These ionic actions of taurine may explain its overall inhibitory effects in the central nervous system and in the retina and may account for its antiarrhythmic properties.


Extraneuronal monoamine oxidase in rat heart: biochemical characterization and electron microscopic localization.

Monoamine oxidase (MAO) increases in an age-weight relationship in the hearts of male rats. Accumulation of MAO is not related to the activities of such mitochondrial enzymes as succinic dehydrogenase or cytochrome oxidase which do not change with age. Our previous experiments, utilizing serotonin as a substrate, have determined that cardiac MAO in the young rat does not change after chemical sympathetectomy with 6-hydroxydopamine. In this study, rats of different ages were treated with 6-hydroxy-dopamine to investigate the neuronal vs. non-neuronal distribution of MAO in the heart. After sympathetectomy, various parts of the hearts and fractions of the hearts isolated by differential centrifugation were tested for changes in MAO activity with two different substrates (kynuramine and 14C-tryptamine). It was not possible to detect any changes in MAO activity in any parts or subcellular fractions of the heart as a result of denervation. Studies with clorgyline, the MAO inhibitor, in control and sympathetecomized animals revealed that rat cardiac MAO is mostly of the type A enzyme, which was originally thought to be neuronal. A histochemical technique for the electron microscopic demonstration of MAO with osmiophilic thiocarbamyl nitro blue tetrazolium was used in the rat heart in order to determine the ultrastructural location of the enzyme. Histochemical localization of MAO with the electron microscope using tryptamine as the substrate indicates that a substantial portion of rat cardiac MAO is located near the outer membranes of mitochondria within myocardial cells. This histochemical technique provides no evidence to support differential centrifugation data which suggests the presence of a sarcoplasmic reticular (microsomal) MAO in rat heart.


Multiple forms of amine oxidase in perfused rabbit lung.

The biogenic monoamines, phenylethylamine and 5-hydroxytryptamine are rapidly and extensively deaminated when perfused in Krebs' solution through rabbit lung. Deamination of phenylethylamine is inhibited approximately 70% by 10(-5) M pargyline and 30% by 10(-3) M semicarbazide. Deamination of this monoamine is unaffected by 10(-6) M harmaline whereas deamination of 5-hydroxytryptamine is inhibited about 75%. These data indicate that the intact perfused rabbit lung contains three forms of amine oxidase two of which are analogous to the A and B forms of the mitochondrial enzyme, monoamine oxidase described previously only in broken cell preparations of lung and other tissues. The third form of amine oxidase is similar to the enzyme found in plasma and several large arteries. Since uptake and metabolism of these amines, as well as loss of their deaminated metabolites, occurs very rapidly, it is suggested that all these forms of monoamine oxidase are associated with vascular endothelium.


The pharmacodynamics of 5-hydroxytryptamine uptake and metabolism by the isolated perfused rabbit lung.

We have investigated the dynamics for the removal of 5-hydroxytryptamine (5-HT) from the circulation using the isolated perfused rabbit lung. 5-HT was removed from the circulation at a constant rate and metabolized completely to 5-hydroxyindoleacetic acid which effluxed from the lung into the circulation. Two methods were developed to determine the constant rate of removal of 5-HT: (1) the constant rate is equal to the difference between the 5-HT concentration flowing into the lung and the 5-HT concentration in the effluent times the flow rate and (2) extrapolation of the rate of appearance of radioactivity in the effluent to zero time. With these methods, we have confirmed the 5-HT is removed by the lung by a carrier-mediated Na+-dependent transport system. Studies of transport systems in perfused organs required an adequate supply of the chemical to the lung. Supply rates less than removal rate will result in erroneous measurements of the constant removal rate. The relationships between the rate of removal, perfusate concentration and perfusion rate were analyzed.


Contractile responses of the guinea-pig trachea in vitro: modification by prostaglandin synthesis-inhibiting drugs.

Prostaglandins (PG) E2 and F2alpha, characterized by thin-layer chromatography and bioassay, were released from guinea-pig trachea contracted with acetylcholine or histamine. Inhibition of contraction with atropine or mepyramine, or by the removal of calcium, abolished the prostaglandin release. PGE2 and PGF2alpha were also released after gentle mechanical irritation of the mucosal surface, but not the adventitial surface, of the trachea. This release of prostaglandins occurred in the absence of calcium and was prevented by treatment of the trachea with indomethacin. Incubation (20 minutes) of tracheal spirals with indomethacin (0.6 mug/ml) 1) reduced the basal tension of the spiral; 2) reduced responses to low doses of histamine, serotonin, acetylcholine, barium or potassium; and 3) increased responses to high doses of these agonists. These effects lasted despite washout but were reversed by the addition of arachidonic acid. Subthresholdquantities of PGF2alpha after indomethacin treatment restored responses to minimally effective doses of the agonists. Aspirin (50 mug/ml), 5,8,11,14-eicosatetrayonic acid (2 mug/ml) and sodium salicylate (100 mug/ml) had effects similar to indomethacin (0.6 mug/ml). Alterations produced with 5,8,11,14-eicosatetrayonic acid and sodium salicylate were reversed with washing. Restoration of resting tension after indomethacin did not qualitatively change the results. Indomethacin at higher doses (greater than 30 mug/ml) inhibited responses to all histamine doses but this effect was reversible with washing. The results suggest that basal tension of the guinea-pig trachea may be due to an intramural production of PGF2alpha and that during the development of active tension, prostaglandins E2 and F2alpha are released which modulate the intensity of the contraction.


Saturable binding of dihydromorphine and naloxone to rat brain tissue in vitro.

The binding in vitro of an opiate agonist, 3H-dihydromorphine, was studied using a particulate fraction obtained from rat brain homogenates and compared with that of an opiate antagonist, 3H-naloxone. The binding of 3H-dihydromorphine may be separated into two components: one a saturable component and the other nonsaturable. The saturable binding may be calculated from the differences in binding observed in the absence and presence of high concentrations of levorphanol. The use of dextrorphan results in an artifactual separation of this component, although relative stereospecificity was observed for levorphanol and dextrorphan. There were marked regional differences in the distribution of saturable 3H-dihydromorphine binding in the brain. These were primarily due to the difference in the concentration of the saturable binding sites within various brain regions. It appeared that the saturable binding sites from various brain regions had similar affinities for dihydromorphine except for the binding site from cerebral cortex which had a higher affinity. In contrast, saturable binding sites for naloxone in various brain regions had different affinities for naloxone. It appears that naloxone has at least two types of saturable binding sites, one of which is not available to dihydromorphine. This is based on observations 1) that the total concentration of saturable binding sites for naloxone was greater than that for dihydromorphine in each brain region studied irrespective of the assay medium used and 2) that unlabeled dihydromorphine inhibited the 3H-naloxone binding in striatum but failed to alter it significantly in cerebellum, whereas unlabeled naloxone reduced 3H-naloxone binding significantly in both brain regions. The difference in concentrations of saturable binding sites for naloxone and dihydromorphine was relatively small in striatum but larger in cerebellum, indicating that the saturable binding sites in cerebellum are predominantly naloxone-specific, whereas those in striatum are capable of binding both naloxone and dihydromorphine. In cerebrospinal fluid or in simulated intracellular fluid, the apparent affinity for dihydromorphine was lower and that for naloxone was higher than in Tris-HCl buffer. It is concluded that naloxone binds to dihydromorphine binding site and to another site, which has a different affinity for naloxone and is not available to dihydromorphine. Studies in which opiate receptor binding was assayed in Tris-HCl buffer may need to be re-evaluated. Further, in studies where opiate binding in vitro is assessed following pharmacologic intervention, such binding should be estimated in a relevant physiological medium rather than in Tris-HCl buffer.


Effect of diuretics on oxidative phosphorylation of dog kidney mitochondria.

An effect of diuretics on cellular metabolism has been shown. In order to examine further the direct effect of diuretics on renal mitochondria, their effect on isolated cortical (C) and outer medullary (OM) mitochondrial respiration was examined. Oxygen consumption rate (QO2) was measured in a Gilson oxygraph utilizing either glutamate-malate or succinate as substrate. QO2, expressed in nanoatoms of O2 per milligram of protein per minute, was always higher in C than OM: 140.7 +/- 2.8 VS. 121.2 +/- 2.4 (P less than 0.001) with glutamate-malate and 181.1 +/- 6.3 vs. 129.7 +/- 5.2 (P less than 0.001) with succinate. A dose-response curve was constructed for each of the following: sodium ethacrynate, furosemide, chlorothiazide, acetazolamide and chlormerodrin. All diuretics inhibited C and OM equally. The 50% inhibitory molar concentration for EA was 6.2 times 10(-4); for furosemide 1.5 times 10(-3); for chlorothiazide 8.1 times 10(-3); for acetazolamide 10.8 times 10(-3); and for chlomerodrin 3.1 times 10(-5). Neither cysteine nor dithiothreitol inhibited the effect of EA. The effect of chlormerodrin was abolished by cysteine. These results demonstrate that while a difference exists between C and OM mitochondria during control studies, each of the diuretics examined exerted an equal inhibitory effect on mitochondrial respiration from both C and OM. Mercurials are the most potent inhibitors and presumably exert their effect by reacting with sulfhydryl groups. They are followed in potency by ethacrynic acid, furosemide, chlorothiazide and acetazolamide.


Cardiovascular effects of 1-benzylimidazole.

A derivative of imidazole, 1-benzylimidazole [(1-phenylmethyl)-H-imidazole], was found to have strong cardiotonic activity. In isolated ventricular strips of rabbits, 6.3 times 10(-5) M 1-benzylimidazole (BI) increased contractile force by 100%, and in the intact cat, 0.5 mg/kg of BI increased cardiac output by 30 to 40%. The increase was maintained in both preparations for 5 to 30 minutes. Heart rate was not changed in the atropine-pretreated cat. Basic cycle length, recorded intracellularly in rabbit sinoatrial nodal cells, was increased by 8%. Since BI had many actions similar to the cardiac glycosides, including the absence of effects on rate and resistance to adrenergic beta blockers, it was of interest to determine whether BI and ouabain could interact and modify, or enhance their respective actions. In combination, it was found that ouabain and BI had summative effects on contractility and maintained the frequency-force relationships.  In this respect, the action of BI is similar to that of glucagon and Ca++, but not to that of the catecholamines.


Altered intracardiac conduction after acute administration of ethanol in the dog.

Varying concentrations of ethyl alcohol were injected either into the left main coronary artery or intravenously in anesthetized intact dogs. Effects of alcohol on intracardiac conduction (by His bundle electrogram) were examined at spontaneous and paced (atrial) heart rates. Alcohol by the intracoronary route prolonged atrioventricular node and intraventricular conduction times by approximately 5 to 15%. These changes preceded a depression of left ventricular systolic pressure and of the rate of rise of left ventricular pressure and an elevation of left ventricular end-diastolic pressure. Intracoronary injections of contrast medium (sodium diatriozoate) or iso-osmolar solutions of sucrose and injections of similar amounts of alcohol in the ascending or descending aorta did not affect intracardiac conduction. Increasing atrial pacing rates resulted in prolongation of atrioventricular nodal conduction intervals, but did not influence intraventricular conduction time. At each pacing rate, alcohol depressed both atrioventricular nodal and intraventricular conduction. The data suggest that alcohol has a direct depressant effect on intracardiac conduction.


Self-actualization as a moderator of the relationship between attitude similarity and attraction.

It was hypothesized that self-actualization (SA) assessed by scores on the Personal Orientation Inventory should affect the salience of interpersonal stimuli and moderate the attitude similarity/dissimilarity relationship. Fifty-six American college students (28 males and 28 females), aged 18-21, were used as subjects. In Experiment I SA and proportion of attitude similarity were varied by use of Byrne's attraction paradigm in a between-Ss design. The personality variable failed to affect attraction. In Experiment II SA and proportion of attitude similarity were manipulated in a within-Ss design. SA Ss rated the stranger significantly higher in attraction at high levels of similarity and significantly lower in attraction at low levels of similarity when compared to non-SA individual (p smaller than .05). The results were discussed in terms of design differences in personality research and the potential mechanism (self-esteem) by which SA affects attraction.


Behavioral adjustment of psychiatric hospital patients and helping behavior.

This study investigated the relationship between behavioral adjustment of mental hospital patients and helping behavior in two distinctly different controlled situations. Forty hospitalized male patients between the ages of 20 and 45 were assigned to two groups of equal size according to ratings they received on the MACC Behavioral Adjustment Scale. Each subject was exposed to two separate and independent experimental situations calling for helping behavior. Helping in the first situation was defined as offering a confederate the use of an extra pencil, while in the second it was defined as offering to help a confederate in the hallway to pick up a box of pencils that had just been dropped. The results of both experiments confirmed the hypothesis that persons suffering more severe levels of disturbance and maladjustment perform significantly fewer helpful acts. Results were discussed in terms of empathy, self-concern, and response cost. Also some implications for treatment were discussed.


Selective effects of enucleation and transfer of heterologous nuclei on cytoplasmic organelles in Amoeba proteus.

The ultrastructural changes in the cytoplasm of lethal hybrids obtained by nuclear transplantation between different strains of Amoeba proteus were compared with those of enucleated amebae.  It was found that, whereas the Golgi complex and glycocalyx degenerated first in enucleated cells, mitochondria and endosymbiotes became abnormal first in the hybrids.  The selective effects are attributed to the presence of nucleic acids in the mitochondria and endosymbiotes and hence to the different interactions they would have with the nuclear genome.


Personality organization and language behavior: the imprint of psychological differentiation on language behavior in varying communication conditions.

The language behavior of field-independent (F-D) clinically normal, verbally resourceful femal college students was examined in three different communication conditions: Dialogue, Warm (vissually supportive) monologue, and Cold (visually nonsupportive and stressful) Monologue. F-I and F-D Ss produced similar amounts of the different types of language behavior evaluated in each of the three communicative conditions. However, they differed with respect to verbal output and length of sentence "packaging" unit in Monologue conditions. F-D Ss talked considerably less but at the same time produced different types of grammatically more elaborate language behavior in Warm and Cold Monologue compared to their Dialogue language behavior. F-I Ss talked considerably more but also showed a type of language autonomy. The pattern of language behavior which characterized F-I speech in Dialogue remained the same in both Monologue conditions.


A labour-saving manoeuvre.

Slow progress in the first stage of labour was treated in 792 mothers by digital dilatation. This manoeuvre is described. Partial dilatation was converted to complete dilatation in 94.4 per cent of all cases, the incidence of success being 90.0 per cent in primiparae and 96.0 per cent in multiparae. Difficulties are described, but serious complications were conspicuously absent.The manoeuvre was helpful with mothers unable to resist premature bearing down, and especially valuable for reducing delay before applying forceps for fetal distress. The early perinatal loss of 20 (in the first 200 cases) was reduced to 3.3 (in the last 599 births) after a change of technique.


The child with repeated injuries--a family problem.

Recurrent injuries in children should be regarded as a symptom complex rather than a diagnosis of ;accident proneness'. Investigation, which may include much listening will often reveal a family with emotional problems. The family doctor who can see the family as a whole is often best placed to offer or co-ordinate help.


Self-observation in general practice--the bleep method.

Recent trends in general practice towards working in multi-disciplinary teams from purpose-built premises have emphasised the need to study the ways in which doctors and other staff spend their working time.This paper describes a well-established work-study technique (activity sampling), which has been adapted to enable doctors to assess how they use their time. The method needs no observer and is cheap to operate. Five general practitioners undertook to record their surgeries for two separate weeks using the bleep method of activity sampling. The results they obtained show that the technique is both practicable in normal working conditions and is capable of providing information highly relevant to the management of general practice.


Community electrocardiography.

The report of the Joint Working Party on General Medical Services (1973) considered in detail the provision of electrocardiographic services for general practitioners. These are based either on primary health care teams using their own apparatus, or on hospitals offering open-access to their cardiac departments.In this survey I attempted to compare the proportions of general practitioners using their own electrocardiographs with those using hospital-based apparatus, and with those without direct access to any electrocardiograph facilities, and to evaluate the use made of such services, when available.


The place of the electrocardiograph in the study of cardiovascular problems in the elderly.

In a group of 64 patients (29 men and 35 women) all aged 65 or over referred for electrocardiography in this Department, there were 30 (16 men and 14 women) with no recorded clinical evidence of major cardiovascular disorders, past or present. Of these ;clinically negative' patients 19 (ten men and nine women) showed codable abnormalities when their electrocardiograms were read and classified according to the Minnesota code.In a group of 121 patients (63 men and 58 women) aged 42-64 only seven (six men and one woman of 58) ;clinically negative' patients showed codable abnormalities in their electrocardigrams. It is suggested that the high yield of codable abnormalities in the former group reflects incomplete and misleading cardiovascular histories or atypical clinical presentations in that group and a plea is made for a more widespread use of routine electrocardiography when trying to sort out the often multiple and confusing clinical problems of the elderly.


The relationship of urinary symptoms to significant bacteriuria.

Selected samples of healthy people (804 males, 796 non-pregnant females and 400 pregnant women) were questioned about present and previous urinary symptoms. Mid-stream specimens of urine were cultured quantitatively. Symptoms in the males occurred more frequently in the presence of ;significant bacteriuria', but the numbers were too small to allow statistical analysis. Among the non-pregnant females frequency or burning micturition was found more frequently in those who had significant bacteriuria than in those whose urinary bacterial counts were low; for nocturia this difference was statistically significant (p <0.001).Of the pregnant women, comparison of those who had significant bacteriuria with those whose urine was normal showed that diurnal and nocturnal frequency, and loin pain, occurred more frequently in those with significant bacteriuria (for each of these symptoms p <0.0.1).These results suggest that the recent onset of nocturia is the most reliable symptom of urinary tract infection. There remain, however, many people with urinary symptoms and with low urinary bacterial counts in whom other causes for the symptoms should be sought.


Induced ovulation in mature mice and developmental capacity of the embryos in vitro.

Embryos from gonadotrophin-treated mature mice were cultured from the two-cell to the early implantation stage. Their developmental capacity was very similar to that of spontaneously ovulated eggs.


The role of ovarian steroids in placental development and endovascular trophoblast migration in the golden hamster.

Pregnant hamsters were ovariectomized on Day 7 and daily supplements of progesterone or progesterone plus oestradiol benzoate were given. Fetal development and survival was 14% and 62% respectively. Histological examination indicated that failure of labyrinthine development in the placenta resulted in failure to form an adequate number of maternal arterial spaces communicating with the base of the trophospongium to allow trophoblast migration in the related maternal spiral arteries. Progesterone was essential at all stages of gestation to sustain decidualized tissues and allow survival of a minority of fetuses. Oestradiol supplementation significantly increased fetal survival, but not to normal levels, suggesting that other oestrogens may be essential for the maintenance of normal hamster pregnancy.


Effects of 5-hydroxytryptamine on fertility and luteal development following intravaginal administration in the rat.

Intravaginal administration of 5HT was effective in terminating pregnancy when given after implantation in the rat, provided that the tampon was allowed to remain in the vagina for 4 hr or more. Complete antifertility efficacy was associated with a prevention or reversal of the increase in ovarian weight, which occurs in untreated rats between Days 12 and 17 of pregnancy, and correlates with enlargement of the CL. Data from hysterectomized, ovariectomized and progesterone-implanted rats indicated that the effect on CL was not a cause of the antifertility effect. Intravaginal administration of 5HT was found to lead to general systemic effects.


Difficulty of obtaining reproducibility in the Franklin and Dukes test for the detection of sperm-agglutinating antibodies in human sera.

The Franklin and Dukes (FD) test is used as a screening test for the determination of sperm-agglutinating antibodies and as a proof of therapeutic effects in cases of infertility, but various parameters of the FD test remain unclear and the application of different techniques has revealed highly different results. To test the statistical evidence for the FD technique, conditions regarded as optimal prerequisites were applied: a sperm concentration of 20 times 10(6)/ml was produced with Baker's buffer and serum dilutions were made with Baker's buffer, starting at 1:4. Only the standard deviation of parallel tests with one serum sample and one semen sample on the same day was found to be within an acceptable range. Using ejaculates of the same donor and the same serum sample on different days gave results that were not reproducible. The FD test should not, therefore, be used for quantification of sperm-agglutination antibodies except for a comparison in one test with one semen sample on the same day. Although the FD test only allowed a qualitative evaluation of sperm-agglutinating antibodies the % sperm agglutination was more informative than agglutination titres. For quantification of sperm-agglutinating antibodies, the FD test should be replaced by other techniques.


A quantitative study of some lysosomal enzymes in the bovine endometrium during early pregnancy.

Endometrium was obtained from cattle slaughtered at various stages of early pregnancy and of the oestrous cycle. Analyses for protein, RNA, DNA, glucose and some lysosomal enzymes were carried out on this tissue. The results are considered with respect to the general influence of the hormonal status of pregnancy and the specific influence of the hormonal status of pregnancy and the specific influence of the blastocyst in one uterine horn.


The pattern of reproduction in female Columbian black-tailed deer, Odocoileus hemionus columbianus.

Ovarian cycles and the pattern of reproduction in female black-tailed deer in British Columbia were ascertained largely through examination of the ovaries from 444 females. Cyclic development and degeneration of single follicles of ovulatory size occurred several weeks before first ovulation. As the breeding season approached, a second or third large follicle developed in each cycle but in 48% of adult females the follicles were at different stages of maturation. Those failing to rupture at first ovulation luteinized 1 to 2 days thereafter. The first ovulation of the season, in November, never resulted in a lasting pregnancy even though some ova were penetrated by spermatozoa and began to cleave. First ovulation was apparently 'silent'  in five of seven females for their ova lacked spermatozoa. Of sixty-one pregnant females, fifty-nine conceived at second ovulation; the other two conceived at subsequent ovulations more widely spaced than the 8- to 9-day interval between first and second ovulations. The synchrony of ovulatory cycles among adult females was such that half of them ovulated for the second time in a span of 7 or 8 days. Primary CL that formed after first ovulation grew to an average maximum volume of only about 45 mm3, whereas those originating at second ovulation grew to twice that size within 5 to 8 days. First generation CL shrank from 35 mm3 to 10 mm3 within 2 days. They disappeared within 18 months but corpora albicantia persisted for the life of the female. The possible ecological significance of the reproductive pattern is discussed.


Isoelectric focusing of boar spermatozoa.

The isoelectric points of washed spermatozoa from intact boars and from boars after removal of the seminal vesicles were determined using isoelectric focusing on natural pH gradients. Normal boar spermatozoa focused at a higher pH than spermatozoa from boars without seminal vesicles. The isoelectric point of the latter was increased to a value approaching normal by preincubation in normal seminal plasma. This indicates that seminal plasma alters the membrane surface charge of boar spermatozoa on ejaculation.


Synthesis and pharmacological properties of [1-L-penicillamine,4-L-leucine]oxytocin.

For the synthesis of [1-L-penicillamine,4-L-leucine]oxytocin (2), Z-Tyr(Bzl)-Ile-Leu-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 was treated with anhydrous HBr, and the resulting partially deprotected octapeptide was coupled with Z-penicillamine(Bzl) in a condensation reaction mediated by dicyclohexylcarbodiimide and 1-hydroxybenzotriazole. The protected nonapeptide Z-penicillamine(Bzl)-Tyr-Ile-Leu-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 was treated with Na in NH3 and the resulting disulfhydryl compound was subjected to oxidative cyclization in H2O-CH3OH with ICH2CH2I, Purification of 2 was effected by partition chromatography and gel filtration. The analog possesses antioxytocic and antiavian vasodepressor pA2 values of 6.77 and 7.21, respectively, and has no antipressor or anti-ADH activity. Its biological activity spectrum is qualitatively identical with that of [1-penicillamine]oxytocin. In contrast to the marked natriuretic-diuretic and anti-antidiuretic activity of [Leu4]oxytocin, 2 exhibits none of these effects on the rat kidney.


(4-Phenylalanine)oxytocin, an inhibitor of the antidiuretic effect of 8-arginine-vasopressin.

[4-Phenylalanine]oxytocin was prepared from Z-Cys(Bzl)-Tyr(Bzl)-Ile-Phe-Asn-Cys(Bzl)-Pro-Leu-Gly-NG2 (4) by deprotection with Na in NH3 followed by cyclization of the resulting disulfhydryl compound with ICH2CH2I. The protected peptide 4 was prepared from Boc-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 by the stepwise solution method. Coupling was effected by a modification of the dicyclohexylcarbodiimide-1-hydroxybenzotriazole preactivation method wherein the precipitate of dicyclohexylurea is removed by filtration prior to mixing of the amino and carboxyl components. The analog was found to be an effective inhibitor of the antidiuretic (ADH) response to exogenous arginine-vasopressin. It produced marked diuresis in the anti-ADH assay at approximately the same dose level as does [Leu4]oxytocin but, in contrast to [Leu4]oxytocin, showed natriuretic activity only at relatively high dose levels. In addition, [Phe4]oxytocin exhibited 0.15% of the oxytocic potency of oxytocin, weak antiavian vasodepressor activity (pA2 = 6.93), and no measurable rat pressor activity.


Cycloalkanones. 7. Hypocholesterolemic activity of aliphatic compounds related to 2,8-dibenzylcyclooctanone.

A series of 19 aliphatic analogs of 2,8-dibenzylcyclooctanone and 1,5-diphenyl-2,4-dimethyl-3-pentanone was examined. Separation of hypocholesterolemic activity from the previously observed uterotropic and antifertility activities was achieved by simplification of the parent compound to 2-octanone. There was no loss of hypocholesterolemic activity. Reduction of serum cholesterol levels in male rats to less than 50% of control values was obtained at a dose of 10 mg/kg/day.


Preparation of nitroso-13N-labeled nitrosoureas.

A method is described for the preparation of 13N-labeled N-nitrosoureas, specifically 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. The 13N is generated as ammonia by the 12C(d,n)13N reaction on methane gas. The product is selectively trapped and subsequently oxidized to nitrous acid which reacts with the parent urea in solution to form the 13N-labeled nitrosourea.


Trans-2-Acetoxycyclobutyltrimethylammonium iodide, a cyclobutane analog of "trans-ACTM".

The (+/-) title compound was prepared to evaluate prior observations that certain acetylcholine congeners derived from cyclobutane are devoid of muscarinic effects. It was prepared by a multistep sequence from trans-2-carbomethoxycyclobutyl methyl ketone. In a guinea pig ileum assay, it was 0.02 times as active as AcCh, and in a dog blood pressure assay, it was 0.09 times as active. In these assays, its (+/-)-cyclopropane congener and AcCh were equally active. This is the first cyclobutane-derived AcCh congener possessing significant muscarinic effect.


3-Hydroxymethyl-s-triazolo[3,4-a]phthalazine, a novel urinary hydralazine metabolite in man.

The elucidation of the structure of a new major metabolic product of hydralazine, 3-hydroxymethyl-s-triazolo[3,4-a]-phthalazine, is described. The structures of several other previously described metabolites of the drug, phthalazone, s-triazolo[3,4-a]phthalazine, and 3-methyl-s-triazolo[3,4-a]phthalazine, are confirmed. A metabolic pathway of hydralazine is also proposed.


Preparation and analgesic activity of 3,6-diacetylnormorphine and 6-acetylnormorphine.

3,6-Diacetylnormorphine (norheroin) and 6-acetylnormorphine have been prepared in excellent yield through the 3,N-bis(tert-butoxycarbonyl) derivative of normorphine via acetylation and selective removal of protecting groups. This general procedure would be applicable to the preparation of various 3,6-diesters or 6-monoesters of normorphine. The analgesic potency of norheroin was found to be the same as that of 6-acetylnormorphine, about 0.05 that of heroin. The onset, peak, and duration of action of these compounds were nearly identical and comparable with morphine.


Analgetic activity and in vitro binding constants of some N-alkyl-3-benzazocines.

A homologous series of 3-alkyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6-methyl-3-benzazocines (2) has been synthesized. Analgetic activity and binding constants for the opiate receptor for 2 and for an analogous series of benzomorphans (1 and 3) are reported. In 1, hot-plate analgesic activity is lost on increase of the N-alkyl chain length from ethyl through butyl (lc-e) and regained with amyl (lf) and hexyl (lg). Compounds lc-e show that antagonist properties and binding constants are similar throughout the series. With 2, where there has been loss of steric constraints through removal of the 2,6-methano bridge of 1 and 3, greatly diminished analgetic activity and receptor affinity and no antagonist properties were observed. Like 1, however, greatest agonist activity was shown by the N-methyl (2c), amyl (2g), hexyl (2h), and heptyl (2i) homologs and there is a parallel of in vitro binding strength and analgetic activity.


Synthesis of tritium- and deuterium-labeled 9-beta-D-arabinofuranosyladenine and the tritium-labeled 5'-monophosphate ester with increased metabolic stability.

Preparation of both a 5'-deuterium and a 5'-tritium-labeled 9-beta-D-arabinofuranosyladenine (6a and 6b) by reduction of the protected 5'-aldehyde 4 is described. Conversion of 6b to the 5'-tritium-labeled 5'-monophosphate 7b was effected directly with a phosphoryl chloride-formic acid reagent. The product 7b exhibited consistently higher blood levels of nonvolatile tritium than the 2-labeled compound when tested in dogs.


(1-Beta-mercaptopropionic acid, 2-(3,5-dibromo-L-tyrosine))oxytocin, a potent inhibitor of oxytocin.

[1-Beta-Mercaptopropionic acid,2-(3,5-dibromo-L-tyrosine)]oxytocin was synthesized from a protected polypeptide intermediate that had been prepared by the condensation of S-ethylcarbamoyl-beta-mercaptopropionyl-3,5-dibromotyrosine with H-Ile-Gln-Asn-Cys(Ec)-Pro-Leu-Gly-NH2, using dicyclohexylcarbodiimide in dimethylformamide. The ethylcarbamoyl (Ec) protecting groups were removed by refluxing NH3, and the resulting disulfhydryl peptide was oxidatively cyclized to the corresponding disulfide by ICH2CH2I. Purification of the analog was effected by partition chromatography and gel filtration. The analog possesses antioxytocic (pA2 = 7.05) and antiavian vasodepressor (pA2 = 7.44) activities but has neither agonist nor antagonist activity in the rat pressor assay.


Non-computer approach to structure-activity study. An expanded Fibonacci search applied to structurally diverse types of compounds.

The Fibonacci search technique, first applied to a structure-activity study by Bustard, has been expanded to allow the analysis of a broad class of structural types of compounds. The compounds are first arranged in order of increasing value of a molecular property of the analogs such as log P, Sigmapi, Sigmasigma, or Rm. A successful Fibonacci search of the compounds will find the most active analog in a small, predetermined number of steps. Examples are given where insight as to mechanism of action is indicated by the combination of various parameters such as log P and pKa. Additional examples illustrate the use of Fibonacci search to establish the parabolic dependence of the biological activity of lipophilicity and sigma, where such dependency had not been observed initially. This technique allows the treatment of a variety of structurally diverse types of compounds simultaneously. It is to be stressed that Fibonacci search can be applied to structure-activity studies without the use of a computer.


The role of anionic, imidic, and amidic forms in structure-activity relationships. Correlation of electronic indices and bacteriostatic activity in sulfonamides.

The problem of structure-activity relationships in sulfonamide type compounds is tackled on the ground that both bacteriostatic activities and structural indices must be referred to the specific individual forms assumed by sulfa drugs in the active solutions. The frequency value of the symmetric stretching mode of the sulfonyl group upsilons (SO2) is chosen as a suitable electronic index and measured for the individual active forms in aqueous and Me2SO solutions. The linear correlation that exists between bacteriostatic parameter and vibration frequency (over the complete range of data at present available) proves a strict relationship between electronic structure and bacteriostatic activity in this class of drugs. Furthermore, it justifies the assumption used for the calculation of the bacteriostatic activity of the anionic form; i.e., in equilibrium with a very active species (the anion) a less active species (the neutral form) gives a negligible contribution or does not contribute at all to the total activity. The results can be summarized as follows: the lower the frequency of the symmetric stretching mode of the SO2 group of any active species of sulfonamide type compounds, the higher its bacteriostatic activity. The existence of a clear structure-activity correlation demonstrates that the whole class of compounds, whatever their form, has a single mechanism of action, while incontrovertible deviations from the general trend indicate differences or complications in the mechanism itself, but does not demonstrate that the group on which the structural index is localized plays a dominant role in the biological process. The usefulness of pKa and NH2 proton chemical shift of precursor amine as indirect indices of the electronic structure of the anionic forms is explored on extensive sets of available data.


Inhibitors of nucleoside transport. A structure-activity study using human erythrocytes.

The passage of nucleosides across the plasma membrane of erythrocytes is a membrane-mediated process which is strongly inhibited by derivatives of 9-beta-D-ribofuranosylpurine (1) with S, O, or N atoms at the purine 6 position bearing variously substituted arylalkyl groups. In this structure-activity study, nucleoside derivatives were compared in respect to their ability to inhibit a transport-dependent aspect of nucleoside metabolism in erythrocytes, the synthesis of inosine from external guanosine and hypoxanthine. 6-Benzylthio, 6-benzylamino, and 6-benzyloxy derivatives of 1 were inhibitory at 10(-5)-10(-6) M and the similarity of their activities suggested that alkylation of the transporter as the mechanism of transport inhibition was unlikely. The hydrophobicity of the 6-position substituents appeared to contribute importantly to inhibitory activity. Although replacement of the ribofuranose moiety by other sugars reduced inhibitory activity, compounds with 9-butyl groups were inhibitory. 6-[(2-Hydroxy-5-nitrobenzyl)thio] derivatives of 1 were the most potent of the inhibitors tested, being active at about 10(-7) M.


Synthesis and central nervous system effects of 8.9-dihydro(1)benzazepino(3,2.1-ak)(1,4)benzodiazepin-1(2H)-ones and (1) binzazepino(3,2,1-jk)(1,4)benzodiazepin-1(2H)-ones.

A series of 4-alkyl-8,9-dihydro[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives was synthesized. Two approaches for the synthesis of 4-alkyl[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives are described. All compounds were evaluated for CNS activity. None showed significant activity. The results obtained indicate that in the case of the 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one a phenyl group at the 1 position causes a fall in CNS activity not only when it is free but also when fused to the benzodiazepine system.


Stereoisomeric 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphans, strong analgesics with non-morphine-like action profiles.

The eight optically active stereoisomers and the corresponding four racemic forms of 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan (1) have been prepared. Depending on their configurations these compounds are potent analgesics or inactive substances in mice. The analgesics attain potencies up to about a hundred times that of morphine but they do not show morphine-like side effects in mice nor do they suppress abstinence in withdrawn morphine dependent monkeys. Their therapeutic ratios are favorable and, in the case of la-1 and la-2, exceptionally good. Configuration-activity relationships are discussed. R configuration of the N-tetrahydrofurfuryl group is a major prerequisite for high analgesic potency.


9-Chloro-2,3-dihydro-5H-1,4-dioxepino(6,5-b)benzofuran, a novel antilipidemic agent structurally related to clofibrate.

The synthesis and antilipidemic activity of 9-chloro-2,3-dihydro-5H-1,4-dioxepino[6,5-b]benzofuran (3), a novel enol lactone which is considerably more resistant to serum esterase hydrolysis than clofibrate (1), are discussed. Whereas both 3 and 1 reduced hypercholesterolemic and hypertriglyceridemic serum levels in the Triton WR-1339 induced hyperlipidemic Sprague-Dawley rat to normal, the hydrolysis product of 3, namely 5-chloro-3(2'-hydroxyethoxy)-2-benzofurancarboxylic acid (4), was found to be inactive. Further, 3 is comparable to the hydrolysis product of 1 when both were assessed for their ability to block norepinephrine (NE) induced lipolysis in vitro. 4 is inactive at comparable concentrations (5 times 10(-4)-10(-3) M). The antilipidemic action of 3 and 1 may, in part, be due to their ability to block NE-induced lipolysis.


Microbial models of mammalian metabolism. O-Dealkylation of 10,11-dimethoxyaporphine.

Microbial transformations of 10,11-dimethoxyaporphine were studied to determine the potential of microorganisms to produce monomethoxyaporphines. Ten microorganisms were identified as being capable of yielding apocodeine and/or isoapocodeine as the major metabolite in 24 and 20% yield, respectively. Cunninghamella blakesleeana (ATCC 9245) converted 10,11-dimethoxyaporphine quantitatively into isapocodeine. O-Dealkylation of this aporphine system is a facile microbial transformation, and the 10-methoxyl group is more susceptible to metabolic cleavage than the sterically hindered 11-methoxyl group. Selectivity in O-dealkylation may be accomplished with different microorganisms. This is the first report dealing with the microbial transformation of an aporphine system.


Organic disulfides and related substances. 38. Some disulfide and trisulfide sulfinate salts as antiradiation drugs.

The trisulfide disulfinate [Na32S(CH2)4S]2S (2) is an antiradiation drug which is atypical in having no nitrogen function. At low dose levels of 37.5 and 18.5 mg/kg intraperitoneally (ip), 2 protected respectively about 82 and 35% of lethally irradiated mice. By the oral route (po), 150 mg/kg of 2 protected about 73%, and 75 mg/kg protected about 20%. The LD50 either ip or po exceeded 900 mg/kg. Although a 2,3-diacetoxy analog 3 was inactive, cyclic disulfide and trisulfide sulfinate analogs showed promice. Among these, a sulfinate moiety is related to a di- or trisulfie moiety in the sense of 1,8 in a naphthyl system (4,5), 2,2' in a biphenyl system (6-9), and alpha,alpha' in an o-xylyl system (10,11). The 1,8-naphthyl disulfide sulfinate 4 was not tested biologically because a marked neighboring group effect of -SO2Na on -SS- caused rapid cyclization to the parent disulfide dioxide 14; the corresponding trisulfide 5 was more stable but only slightly protective. Other analogs lacking the coplanarity of 4 also were more stable. The biphenyl compounds 6 and 7 were quite active ip (e.g., 7 led to 90% survival at 4.6 mg/kg, with LD50 EQUALS 130 mg/kg, although protection with 6 and 7 at the doses given po was only fair). Dichloro counterparts 8 and 9 offered no advantages over 6 and 7. The xylylene compounds 10 and 11 were roughly comparable to each other by ip and op routes (e.g., given ip, 10 led to 93-100% survival at 75 mg/kg, with LD50 GREATER THAN 950 mg/kg; given po, 10 gave 100% survival at 60 mg/kg, with LD50 GREATER THAN 900 mg/kg). Compounds 7 and 11 join 2 as promising antiradiation drugs that lack the usual nitrogen function. The fact that sulfinate salts show activity, both ip and po, suggests that the -SO2Na moiety deserves more attention in medicinal chemistry. Hydration of sulfinate salts often made analytical characterization difficult. Confirmatory evidence for typical structures is given.


Hydroxy derivates of S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate and related compounds as antiradiation agents.

The high antiradiation activity and low toxicity of sodium 3-amino-2-hydroxypropyl hydrogen phosphorothioate (1) suggested the introduction of hydroxyl groups into other types of radioprotective phosphorothioates. A number of such compounds were synthesized, including S-3-(3-aminopropylamino)-2-hydroxypropyl dihydrogen phosphorothioate (11, n equals 3), S-2-(3-amino-2-hydroxypropylamino)ethyl dihydrogen phosphorothioate (20) and its propyl homolog 26, N,N'-(2-hydroxytrimethylene)bis(S-2-aminoethyl dihydrogen phosphorothioate) (40), S-2-[3-(2-hydroxyethylamino)propylaminoi1ethyl dihydrogen phosphorothioate (44), and sodium S-2-amino-2-(hydroxymethyl)-3-hydroxypropyl hydrogen phosphorothioate (49). Compounds 11 (n equals 3), 20, 26, and 49 were highly protective when administered intraperitoneally but were generally ineffective when given perorally, as were the other hydroxylated phosphorothioates prepared. The introduction of hydroxyl groups significantly enhanced the radioprotective properties of nonhydroxylated parent compounds, however, only in the case of intraperitoneally administered.


Antitumor agents. 16. Steroidal alpha-methylene-gamma-lactones.

Several novel steroidal alpha-methylene-gamma-lactones and related derivatives have been synthesized as potential steroid alkylating antitumor agents. The synthesis of these compounds involved the convenient Reformatsky-type reaction between ethyl-alpha-(bromomethyl)acrylate and the proper steroidal ketones. In vitro assay for the cytotoxicity of these compounds against the growth of tissue culture cells originating from human epidermoid carcinoma of the larynx (H.Ep.-2) has shown significant activity. Cytotoxicity was improved at least sixfold with the introduction of lipophilic steroidal character. Preliminary in vivo tumor assay also indicated that these compounds were active against Walker 256 carcinosarcoma in rats and were inactive against both L1210 lymphoid leukemia and Ehrlich ascites carcinoma in mice. However, the simple alpha-methylene-beta,beta-dicarbethoxy-gamma-butyrolactone significantly inhibited Ehrlich ascites tumor growth.


7alpha-Carboalkoxy steroidal spirolactones as aldosterone antagonists.

A variety of esters of 17-hydroxy-3-oxo-17alpha-pregn-4-ene-7alpha,21-dicarboxylic acid-gamma-lactone (7a) was synthetized in a sequence using the corresponding 3-oxo-4,6-diene (2) as starting material. The methyl (5), ethyl (7c), and isopropyl (7e) esters as well as the C-1 unsaturated methyl ester (8a) showed good oral and subcutaneous activity (MED less than or equal to 0.41 mg). Some general observations on structure-activity relationships are made.


Potential latentiation forms of biologically active compounds based on action of leucine aminopeptidase. Dipeptide derivatives of the tricycloaliphatic alpha-amino acid, adamantanine.

Some glycine, leucine and phenylalanine dipeptide derivatives of the transport inhibitory, tricycloaliphatic alpha-amino acid, adamantanine (1), have been synthesized using classical methods of peptide synthesis with the aim of improving the latter's bioavailability. Although test doses of glycyladamantanine and L-leucyladamantanine appeared to be absorbed in vivo as evidenced by its appearance in the uring following intraperitoneal administration, they were not hydrolyzed by a purified preparation of leucine aminopeptidase in vitro. Indeed, they were inhibitors of this enzyme. Adamantanylglycine, adamantanyl-L-leucine, and adamantanyl-L-phenylalanine were also not hydrolyzed by leucine aminopeptidase.


Hypolipidemic imidazoles.

A series of analogs of N-benzylimidazole was prepared and tested for hypolipidemic activity. Both plasma cholesterol and triglyceride-lowering activity were found in several members of the series. The most active compounds were N-3-methoxy-, N-4-methoxy-, and N-4-methylbenzylimidazole. Structure-activity relationships are discussed.


Structure-activity relationships in reactivators of organophosphorus-inhibited acetylcholinesterase. 9. N-Heterocyclic acraldoximes methiodides.

N-Heterocyclic acraldoximes methiodides, where the heterocyclic residues are 2-, 3-, and 4-pyridyl, 2-(1-methyl)imidazolyl or 4-pyrimidyl, were prepared and tested for their reactivating potency on acetylcholinesterase inhibited from diisopropylphosphorofluoridate (DFP). The in vitro testing revealed that the new compounds are good reactivators of the phosphorylated electric eel cholinesterase. The structure-activity relationships are briefly discussed.


Structure-activity relationships in cinnamamides. 1. Synthesis and pharmacological evaluation of some (E)- and (Z)-N-alkyl-alpha,beta-dimethylcinnamamides.

Two series of (E)- and (Z)-N-alkyl-alpha,beta-dimethylcinnamamide derivatives were prepared and the biological activity of these compounds was investigated in a series of pharmacological tests. All compounds tested had clear activity on the CNS; generally, this was depressant with E isomers, while Z isomers always caused marked stimulation (tremors and convulsions). Some of the E isomers also had a clear-cut anticonvulsant activity as shown by the antagonistic effect on pentylenetetrazole-induced seizures in the mouse. The NMR spectra of these compounds, which confirm their configurations, are discussed.


Potential central nervous system antitumor agents. Hydantoin derivatives.

Hydantoin derivatives of varying lipophilic character were prepared as nitrogen mustard carriers for CNS antitumor evaluation. Activity was studied in the murine ependymoblastoma brain tumor system. Multiple cures were observed for three of the four analogs examined. The compounds were also active in the intraperitoneal leukemia L1210 and P388 systems as well as in B16 melanoma and Lewis lung carcinoma.


Synthesis and antiarrhythmic activity of substituted (2-pyrimidinylthio)acetamidoximes.

A series of (2-pyrimidinylthiomethyl)carbonitriles and -carboxamidoximes was synthesized and the antiarrhythmic effects were evaluated against ventricular arrhythmias as measured by the electrical fibrillatory threshold in the anesthetized dog. Structure-activity studies indicated 2-[4-(p-chlorobenzylamino)-6-methyl-2-pyrimidinylthio]acetamidoxime dihydrochloride (6a) and 2-[4-(1,3-benzodioxol-5-ylmethylamino-6-propyl-2-pyrimidinylthio]acetamidoxime (6g) to be the most potent members of the series.


Synthesis and analgesic activities of 2,5-dimethyl-2'-hydroxy-9alpha- and -beta-propyl-6,7-benzomorphans.

The 2,5-dimethyl-2'-hydroxy-9alpha- and-beta-propyl-6,7-benzomorphans were synthesized from 4-methyl-3-propylpyridine in five steps, in an overall yield of 14 and 5%, respectively. The required 4-methyl-3-propylpyridine was prepared in an overally yield of 34% by a four-step sequence. The benzomorphans were about as potent as, or more potent than, morphine in vivo.


Calculation of hydrophobic constant (log P) from pi and f constants.

The highest level of confidence can be placed in calculated log P values when (1) the log P of a parent solute is known, (2) pi constants for the required substituent(s) are available, and (3) the substituents either do not have an effect on groups already present in the parent or else this effect has been previously determined. In some instances there are no values available for any related structures which could serve as a parent; then, rather than substitute groups for hydrogen, it is easier to begin "from scratch", as suggested by Nys and Rekker, and assemble the structure from fragments, each of which has been assigned a hydrophobic value. In the present paper some new log P values for the lower alkanes and the inert gases are analyzed with the view of separating hydrophobic effects according to volume (including branching and flexibility) and polarity. Modified fragment values appear to enable reliable calculations to be made for a wider range of structures than was possible with the originally proposed constants.


Rm values of phenols. Their relationship with log P values and activity.

The experimental Rm values for a series of phenols were obtained by a reversed-phase TLC system. The extrapolation from a range of linear relationship between experimental Rm values and acetone concentration provided a set of extrapolated Rm values. This were used for studying the relationship between structure and activity in vitro and in vivo. The possibility to obtain by means of the extrapolation technique the Rm values in a standard system for serveral series of chemotherapeutic agents is pointed out.


Rm values of steroids as an expression of their lipophilic character in structure-activity studies.

The chromatographic Rm values of three series of steroids were determined by means of a reversed-phase system. The Rm values at 45% acetone in the mobile phase were shown to be correlated with the partition coefficients in an ether-water system. However, an almost equally good correlation was found when using extrapolated Rm values. The extrapolation technique could provide a standard system. The relationship between biological data and Rm values pointed out the important role of the lipophilic character in regulating the activity of steroids. In particular, the dependence of protein binding absorption and biotransformation on lipophilic character might strongly influence the availability of steroids at the site of action.


Regression analysis of the relationship between physical properties and the in vitro inhibition of monoamine oxidase by propynylamines.

Regression analysis of the potency of inhibition of monoamine oxidase by 47 propynylamines revealed that there are three determinants of inhibitory potency: (1) the smallest substituent on the nitrogen must be methyl or hydrogen in order for any activity to be observed; (2) potency is parabolically related to pKa-the optimum pKa is 6.2; and (3) ortho-substituted benzylamine analogs are ten times more potent than predicted on the basis of pKa values. The optimum pKa cannot be explained by differences in fraction ionized but rather in terms of the multistep sequence whereby these compounds inhibit MAO. A very slight positive effect of hydrophobicity on potency was found. The potency of several analogs not included in the original analysis was predicted.


Ergot alkaloids. Synthesis of 6-methyl-8-ergolenes as inhibitors of prolactin release.

A general synthetic route from elymoclavine (4a) to a variety of C-17 substituted 8-ergolenes has been established. [The C-17 position is the carbon attached to C-8 of the ergoline (1) skeleton as indicated in structure 2.] This route involves displacement reactions on the allylic chloride (4h) prepared from 4a by reaction with thionyl chloride. Conversion of the naturally occurring tricyclic clavines, chanoclavine I (5a) and isochanoclavine I (5b), to the tetracyclic clavine, agroclavine (4i), has been achieved. The new compounds prepared were tested for prolactin-inhibiting ability and were found to possess activity. One of the compounds prepared, 6-methyl-8-ergolenylacetamide (4k), was very potent, comparing favorably in activity to the best prolactin inhibitors reported to date.


Studies in potential filaricides. 6. Synthesis of 3,8-disubstituted 1,3,8-triazabicyclo(4.4.0)decan-2-ones and -thiones.

1,3,8-Triazabicyclo[4.4.0]decan-2-ones and -thiones varying substituents at positions 3 and 8 have been synthesized. When tested in cotton rats for their antifilarial activity against Litomosoides carinii, some of the compounds showed moderate microfilaricidal activity.


Potential bioreductive alkylating agents. 5. Antineoplastic activity of quinoline-5,8-diones, naphthazarins, and naphthoquinones.

A number of 2-chloromethyl and 2-bromomethyl derivatives of naphthoquinones, quinolinediones, and naphthazarins were designed and synthesized as potential bioreductive alkylating agents, and the antitumor activity of these compounds was assessed in mice bearing Sarcoma 180 ascites cells. The results indicated that, with the exception of 3-benzamido-2-chloromethyl-1,4-naphthoquinone, which was inactive, all newly synthesized naphthoquinones possessed strong antitumor activity against this neoplasm. 6,7-Bis(bromomethyl)quinoline-5,8-dione had moderate inhibitory activity against Sarcoma 180 at its optimal daily dosage level of 15 mg/kg. 3-Bromo-2-bromomethyl- and 3-bromo-2-chloromethylnaphthazarin produced a moderate extension of the life span of tumor-bearing mice; whereas, in contrast, 6,7-dimethyl analogs of these agents were inactive when employed in daily doses up to 40 mg/kg body weight.


Studies in antifertility agents. 8. Seco steroids. 2. 5,6-Secoestradiol and some related compounds.

Three ring beta-secoestradiols, 2alpha,3beta- and 2beta,3beta-2-ethyl-3-(p-hydroxyphenyl)-6beta-methyl-trans-bicyclo[4.3.0]nonan-7beta-ols, have been synthesized and some of them shown to possess significant antiimplantation activity in rats.


Oxanilic acids, a new series of orally active antiallergic agents.

A large number of oxanilic acid esters and N-heteroaryl oxamic acid esters were prepared and found to have antiallergic activity using the rat passive cutaneous anaphylaxis (PCA) test. Many of the oxanilic acid esters are active orally, with the most active species having an aryl 2'-carbamoyl group and a 3'-methoxy group. Hydrolysis of the ester from the oxanilic ester moiety causes a loss of oral activity.


Synthesis of ethyl 6-substituted-chroman- and -chromone-2-carboxylates. A comparative structure-activity study employing the 6-phenyl and phenoxy analogs in the triton hyperlipidemic rat model.

To explore the effect of lipophilicity on antilipidemic activity in the Triton WR-1339 induced hyperlipidemic rat model we synthesized the 6-cyclohexyl, phenyl, and phenoxy analogs of ethyl chroman-2-carboxylate. Results obtained were analyzed in light of the biological activity observed for the 6-chloro-substituted and unsubstituted chromans, the 6-chlorochroman-4-one ester, and the 6-chloro-, phenyl-, and phenoxychromone esters. The suggestion is made that chromones likely exert their antilipidemic effects by a somewhat different set of mechanisms than do the chromans and clofibrate. Whereas the 6-chlorochromanone ester is inactive, the 6-chlorochromone ester is active in both normal and hyperlipidemic Sprague-Dawley rats. The major differential effect was observed for ethyl 6-cyclohexylchroman-2-carboxylate which did not lower cholesterol levels but returned triglyceride levels to normal in hyperlipidemic rats.


Inhibitors of polyamine biosynthesis. 3. (+/-)-5-Amino-2-hydrazine-2-methylpentanoic acid, an inhibitor of ornithine decarboxylase.

(+/-)-5-Amino-2-hydrazino-2-methylpentanoic acid [alpha-hydrazino-alpha-methyl-(+/-)-ornithine] was obtained from 1-phthalimidopentan-4-one by treatment with hydrazine and KCN followed by acid hydrolysis. The title compound was found in vitro to be a potent competitive inhibitor of ornithine decarboxylase obtained from the prostate glands of rats. This inhibition was abolished at high concentrations of pyridoxal phosphate. The title compound also blocked the increase in putrescine levels normally observed in bovine lymphocytes transformed by conconavalin A.


Structure-activity relationship in synthetic fibrinolytics. 2-Phenethynylcyclopropanecarboxylates.

The fibrinolytic activity of nine 2-phenethynylcyclopropanecarboxylates was measured in the hanging clot test. The structure-activity relationship is given by log 1/C equals 0.54 log P + 2.01 where P is the octanol-water partition coefficient of the carboxylate ion pair and C is the molar concentration of the drug. The equation obtained for the cyclopropanecarboxylates is compared with similar equations for benzoates, salicylates, and N-phenylanthranilates.


Benzoxocin and benzoxonin derivatives, Novel groups of terpenophenols with central nervous system activity. A correction.

The structure of a compound previously reported as 2,3,4,5,6,7-hexahydro-2,2-dimethyl-8-hydroxy-6-methyl-10-pentyl-3,7-methano-1-benzoxonin (1) is shown to be actually 3,4,5,6-tetrahydro-7-hydroxy-2-methyl-5-isopropyl-9-pentyl-2,6-methano-2H-1-benzoxocin (2a).


Synthesis and hypoglycemic activity of phenacyltriphenylphosphoranes and phosphonium salts.

Phenacyl-riphenylphosphorane (1a) and several analogs substituted in the meta position of the phenacyl group lowered blood glucose levels in 48-hr fasted rats. The corresponding phosphonium salts had comparable hypoglycemic activity. Two compounds (1a and 1b) were also hypoglycemic in fed rats, but hypoglycemia could not be elicited in another species.


Retention by sex and race of 1968-1972 U.S. medical school entrants.

With expanding class sizes and increased proportions of women and minority group medical students, questions are frequently asked concerning recent trends in retention and graduation rates. In this article the authors report on a national Association of American Medical Colleges study of new entrants in the 1968 through 1972 first-year classes of U.S. medical schools and place this study in historical perspective. They note that recent attrition rates are only about half that of the 9 percent reported in the last national AAMC study of 1949-1958 entrants. Although the retention rate for women and for underrepresented minorities is still slightly less than that for white males, the gap appears to be narrowing. Suggestions for optimum retention include: (a) enlarging the pool of minority applicants, (b) improving the techniques of student selection, and (c) increasing the flexibility of academic programs in the medical schools.


Traditional criteria as predictors of minority student success in medical school.

There have been many reports stating that the traditional criteria of the Medical College Admission Test (MCAT) and undergraduate grade-point average (GPA) have little, if any, value in predicting success in the preclinical years of medical school among students from underrepresented (racial and ethnic) minority groups. In contrast to previous articles this report emphasizes that traditional criteria and the quality of the undergraduate college attended are of some statistical value in predicting success in the preclinical years of medical school among accepted students from under represented minority groups. Of these criteria, the one with the greatest predictive value is the selectivity of the undergraduate college attended.


An attempt to predict graduation from medical school.

Although there is less attrition from medical school now than in prior years, 500 or more students can be expected to withdraw from American medical schools during each academic year. Continuing study of the problem is, therefore, warranted. Personality inventory, cognitive, and application data, all gathered at the time of admission, were examined for 1,014 graduates and 57 dropouts; separate analyses were conducted for the 17 who departed for academic reasons and the 40 whose attrition was attributable to other causes. Correlational analyses were also conducted in which graduates, nonacademic dropouts, and academic dropouts were scaled in a 4-3-1 continuum. The best predictor of this graduation versus dropout hierarchy was given by a six-variable combination, including scores on the Quantitative ability subtest of the Medical College Admission Test and premedical grades for the last two terms, with positive weightings; personality inventory scales for status potential, socialization, and communality, also with positive weightings; and a personality scale for conformist achievement drive, weighted negatively.


Student evaluations of professors: are they of value?

Recent studies of the validity of student ratings of teaching leave much to be desired. Five of these studies are evaluated on the basis of adequacy of design, validity, and generalizability; and one of the studies is used as a model for further inquiry in this area. It is then argued that student evaluations of teaching can provide useful information relevant to the improvement of instruction. However, in order to use such evaluations, improved methods of data collection and analysis are needed. A primary improvement would be in the area of generalizability. A plan for expanding the use of student evaluations from personal utility to general applicability is outlined.


Continuity of care in a university-based practice.

Effects of changes in a pediatric practice--expansion of the number of pediatricians and incorporation into a university hospital setting--on continuity of care and utilization were examined by means of a longitudinal study of a sample of 63 families. Continuity of care was measured by the following index: the number of visits with own physician divided by the total number of pediatric visits per year. Although continuity of well-child visits remained unchanged at the university setting, the continuity of sick visits declined markedly. An increased use of doctor visits for illness care was observed; its relationship with the decline in continuity is analyzed and discussed. While continuity is inherent in a small partnership practice, it is not so in a larger medical organization, particularly when involvement in patient care is part time. In such an organization, deliberate arrangements that enable patients with acute needs to receive care from their own doctors are needed.


The progression and evaluation of hetatologic and serum biochemical values in the chimpanzee.

Summary statistics of various hematologic and serum biochemical measures are presented for a colony of 74 chimpanzees (Pan troglodytes). Covariance analysis of longitudinal values revealed a progression of some measures with maturity. Equations for evaluating these measures as they relate to the health of individual colony members and new additions to the colony were formulated. From these equations, confidence bounds (95%), which can be regarded as normative ranges, were established for each of the measures. The literature on hematologic and serum biochemical values in the chimpanzee, especially as they pertain to the evaluation and progression of values, is reviewed.


Cation effects on volume and water permeability in the halophilic algae Dunaliella parva.

Rates of change of cell volume were measured in suspensions of the halophilic green algae Dunaliella parva subjected to changes in cation composition and concentration of the outside medium. Measurements were made with a particle size analyzer and results were checked by direct microphotography. For any one salt solution, changes in cell volume with concentration were consistent with the Boyle-Van't Hoff model of an osmometer. Nonosmotic volume comprised 60-80% of total cell volume and was sensitive to the nature of the cation, increasing in the order Cs less than K less than Na less than Ca less than Mg. Kinetics of volume change in response to changes in outside salt concentration are best described by two kinetic coefficients differing by one order of magnitude and dependent on the nature of the outside cation (decreasing in order Cs greater than K greater than Na greater than Mg) as well as on direction of water flow.


Axonal surface charges: evidence for phosphate structure.

The effect of different extracellular alkaline-earth cations (Ca2+, Mg2+, Sr2+, Ba2+) upon the threshold membrane potential for spike initiation in crayfish axon has been studied by means of intracellular microelectrodes. This was done at the following extracellular concentrations of the divalent uranyl ion (UO2/2+): 1.0 X 10(-6) M, 3.0 X 10(-6) M, and 9.0 X 10(-6) M. At each concentration employed, extensive neutralization of axonal surface charges by UO2/2+ was evidenced by the fact that equal concentrations (50 mM) of alkaline-earth cations did not have the same effect on the threshold potential. The selectivity sequences observed at the different uranyl-ion concentrations were: 1.0 X 10(-6) M UO2/2+, Ca2+ greater than Mg2+ greater than Sr2+ greater than Ba2+; 3.0 X 10(-6) M UO2/2+, Ca2+ greater than Mg2+ greater than Ba2+ larger than or equal to Sr2+; 9.0 X 10(-6) M UO2/2+, Ca2+ approximately Ba2+ greater than Sr2+ greater than Mg2+. These selectivity sequences are in accord with the equilibrium selectivity theory for alkaline-earth cations. At each of the concentrations used, uranyl ion did not have any detectable effect on the actual shape of the action potential itself. It is concluded that many (if not most) of the surface acidic groups in the region of the sodium gates represent phosphate groups of membrane phospholipids, but that the m gates themselves are probably protein-aceous in structure.


Ionic fluxes in isolated epithelial cells of the abdominal skin of the frog Leptodactylus ocellatus.

Unidirectional ion fluxes are measured in cells isolated by a trypsination-dissection method from the epithelium of the frog Leptodactylus ocellatus. Potassium seems to be contained in a single cellular compartment. The influx of potassium is 0.0068 mumole min-1 mg-1 of dry weight and is carried by a ouabain-sensitive pump. Sodium seems to be contained in two cellular compartments, one of which does not exchange its Na within the experimental period. The possibility that these compartments reflect the existence of different types of cells is not discarded. 49% of the rate constant for the Na efflux is ouabain-sensitive and 23% is ethacrynic-sensitive. Under control conditions the permeability to potassium (PK), sodium (PNa) and chloride (PC1) are 7.6 X 10(-5), 2.6 X 10(-5) and 2.8 X 10(-5) liters/min mg, respectively. The value of PNa is much higher than predicted by current electrical models of the epithelium. The discrepancy might offer some insight into the nature of the "inner facing barrier" of the skin.


Sodium-calcium exchange and calcium-calcium exchange in internally dialyzed squid giant axons.

The influx and efflux of calcium (as 45Ca) and influx of sodium (as 24Na) were studied in internally dialyzed squid giant axons. The axons were poisoned with cyanide and ATP was omitted from the dialysis fluid. The internal ionized Ca2+ concentration ([Ca2+]i) was controlled with Ca-EGTA buffers. With [Ca2+]i greater than 0.5 muM, 45Ca efflux was largely dependent upon external Na and Ca. The Nao-dependent Ca efflux into Ca-free media appeared to saturate as [Ca2+]i was increased to 160 muM; the half-saturation concentration was about 8 muM Ca2+. In two experiments 24Na influx was measured; when [Ca2+]i was decreased from 160 muM to less than 0.5 muM, Na influx declined by about 5 pmoles/cm2 sec. The Nao-dependent Ca efflux averaged 1.6 pmoles/cm2 sec in axons with a [Ca2+]i of 160 muM, and was negligible in axons with a [Ca2+]i of less than 0.5 muM. Taken together, the Na influx and Ca efflux data may indicate that the fluxes are coupled with a stoichiometry of about 3 Na+-to-1 Ca2+. Ca efflux into Na-free media required the presence of both Ca and an alkali metal ion (but not Cs) in the external medium. Ca influx from Li-containing media was greatly reduced when [Ca2+]i was decreased from 160 to 0.23 muM, or when external Li was replaced by choline. These data provide evidence for a Ca-Ca exchange mechanism which is activated by certain alkali metal ions. The observations are consistent with a mobile carrier mechanism which can exchange Ca2+ ions from the axoplasm for either 3 Na+ ions, or one Ca2+ and an alkali metal ion (but not Cs) from the external medium. This mechanism may utilize energy from the Na electrochemical gradient to help extrude Ca against an electrochemical gradient.


Comparison of some permeability properties of rat liver slices, liver cells in suspension, and in vivo-produced aggregates of dispersed liver cells.

It has been reported earlier that when rat liver is dispersed to a single cell  suspension, the parenchymal cells lose the ability to take up pyrimidine bases but acquire the ability to take up RNAase and macromolecular nucleic acids. It is now shown that these changes are largely reversed on intraperitoneal reaggregation of the parenchymal cells and that, in these respects, the aggregates behave more like the organized tissue than like the dispersed cells.


Effect of cell concentration on the uptake of amino acids by rat liver parenchymal cells in suspension.

The accumulation of several amino acids in the acid-soluble fraction and their incorporation into protein in rat liver parenchymal cell suspensions, has been shown to depend on the concentration of cells in the incubation medium; the uptake, both in the acid-soluble and the acid-insoluble fractions, decreased as the cell concentration increased from 0.03 X 10(6) cells/ml upwards, reaching a plateau at high cell concentrations (3-5 X 10(6) cells/ml). The uptake values at high cell concentrations were the same as those obtained in liver slices in which a similar effect was not observed. Evidence is presented which suggests that this phenomenon is mediated by a material released from the cells in suspension, which is inhibitory to enhancement of the uptake of amino acids by these cells over and above the value obtained in normal, adult liver slices.


The post-natal development of holocrine epidermal specializations in gekkonid lizards.

The abdominal escutcheon, and certain aspects of pre-anal organ morphology, have been studied in Sphaerodactylus spp. and Gekko vittatus respectively. These epidermal modifications are male characteristics. The sphaerodactyline escutcheon becomes larger by the peripheral addition of specialized scales with increasing size of the individuals: this relationship is much more clearcut in S. cinereus than in the notatus species group (sensu Shreves, '68), and the possible reasons for this are discussed. The number of pre-anal organs varies between populations of G. vittatus, but within populations remains constant throughout life. Individual organs increase steadily in size throughout life. These data are discussed with reference to current interpretations of gekkonid gland evolution, and of factors controlling epidermal cell proliferation and differentiation.


Morphology of lymphoid organs in a cichlid teleost, Tilapia mossambica (Peters).

In Tilapia mossambica organized lymphoid tissues are present in the thymus, head-kidney and spleen, whereas they are lacking in pericardial tissue, liver, mesonephros, intestine and rectum. No lymphoid tissue was observed in the chondrocranium and cartilaginous viscerocranium of young adults. The thymus in Tilapia is encapsulated by thin strands of collagen fibers and consists of outer, middle and inner zones. While middle and inner zones are comparable to the thymic cortex and medulla of higher vertebrates, the homology of the outer zone is not clear. At the anterior end of the thymus, a loose aggregation of lymphocytes without a definite boundary has been observed. The head-kidney is characterized by the presence of lymphoid follicles, a subcapsular sinus, a hilus-like area and lymphatic vessels. The spleen is grossly divisible into white pulp and red pulp; the white pulp contains only a reticular area without definite lymphoid centers and the latter contains predominantly erythrocytes. Morphological changes in the lymphoid organs associated with immune response have been discussed.


The microscopic anatomy of epidermal glands in two species of gekkonine lizards, with some observations on testicular activity.

The gross and microscopic anatomy of epidermal glands has been studied in laboratory maintained tokays (Gekko gecko), and house geckos (Hemidactylus bowringii) captured from the wild throughout the year. Annual testicular activity in the house gecko has also been studied. While no significant differences in glandular development at various times have been observed in G. gecko, there are clear-cut annual cycles in H. bowringii. The evolution of epidermal glands in gekkonid lizards is reviewed; the cellular dynamics of beta-glands are compared with those of unspecialized epidermis; the possibility that gekkonine epidermal glands respond to quantitative variation in circulating testosterone titers is discussed.


An ultrastructural study of adhesive junctions in reaggregates of unincubated chick embryos.

Cell suspensions obtained by the dissociation of unincubated chick embryo blastoderms were allowed to reaggregate on a gyratory shaker for 24-48 hours. The reaggregates which form during this period consist of an inner phase of tightly packed cohesive cells surrounded by an external phase of loosely packed cells. This sorted out arrangement achieves its definitive form between 24 and 48 hours of rotation culture. It was determined that the external phase consists of primitive ectoderm and that the internal phase consists of primitive endoderm. Both 24- and 48-hour reaggregates were examined in the electron microscope and observations were directed to areas of close membrane apposition between cells. In 48-hour reaggregates, primitive endoderm cells were joined by many specialized junctions (desmosomes). The formation of desmosomes in reaggregates of dissociated unincubated chick embryo cells was correlated with the sorting out process.