Intestinal metabolism of plasma free fatty acids. Intracellular compartmentation and mechanisms of control. Fatty acid metabolism in intestinal mucosa has been examined primarily in regard to lipid absorption. Since earlier studies suggested intestinal utilization of plasma free fatty acids (FFA), we investigated mucosal metabolism of plasma FFA in rats. Mucosal radioactivity (1 per cent of administered) was maximal 2 min after i.v. [14C]palmitate. Of mucosal 14C, 42 percent was in water-soluble metabolites, including CO2 and ketoacids, 28 percent in phospholipids, and only 16 per cent in triglycerides. The specific activity of mucosal triglyceride fatty acids (TGFA) was 11 times that of serum TGFA, confirming in situ synthesis. Double isotope experiments showed marked differences in the metabolism of fatty acids entering mucosa simultaneously from lumen and plasma. Whereas luminal fatty acids were chiefly esterified to triglyceride, plasma FFA were preferentially oxidized and incorporated into phospholipids. Crypts did not differ from villi, indicating that intestinal metabolism of plasma FFA is related to their site of entry into epithelial cells. Mucosal metabolism of i.v. [14C]palmitate was minimally affected by glucose administration. However, intraduodenal isocaloric ethanol inhibited mucosal oxidation of FFA by 60 per cent, and increased incorporation into triglycerides nearly twofold. During lipid absorption, mucosal uptake of plasma FFA doubled and incorporation into intestinal lymph triglycerides was increased sixfold. These studies demonstrate an intracellular compartmentation of fatty acids in the intestinal epithelium. In contrast to absorbed luminal fatty acids, plasma FFA in the fasting state are both an energy source and a substrate for the synthesis of tissue phospholipid. The fasting contribution of plasma FFA to mucosal and lymph triglyceride is minimal, but it increases during ethanol administration and fat absorption.


Marrow erythroid and neutrophil cellularity in the dog. This paper describes a method for determining the number of marrow erythroid and neutrophil cells in which the cellularity of marrow sections was related to that of the total marrow by radioiron dilution. Tissue sections were prepared from methacrylate-embedded dog marrow biopsies, and neutrophils were identified by staining of their primary granules. After correction of direct section counts for multiple counting error, accurate neutrophil-erythroid ratios were established with a coefficient of variation of less than 10 percent when 10-4 cells were examined. An average neutrophil-erythroid ratio of 1.2 was found in six normal dogs. The total number of nucleated red cells in the dog was 5.48 plus or minus 0.78 times 10-9/kg (plus or minus 1 SD), and the corresponding erythron iron turnover was 0.90 plus or minus 0.11 mg Fe/100 ml whole blood/day. The total number of marrow neutrophils, derived from the neutrophil-erythroid ratio, was 6.6 plus or minus 0.59 times 10-9 cells/kg, of which 1.4 were promyelocytes and myelocytes, 2.3 were metamyelocytes and bands, and 3.0 were segmented neutrophils. Leukopheresis studies were carried out in six dogs to confirm the accuracy of these cellular measurements. Marrow counts showed a mean decrease of 22.7 times 10-9 cells or 35 percent of the postmitotic neutrophil pool, and it was calculated that 10.2 times 10-9 additional cells had been taken from already circulating blood. This estimated deficit of 32.9 times 10-9 was almost identical to the 33 times 10-9 cells actually counted in the removed blood.


Neutrophil kinetics in the dog.

Neutrophil kinetics in the dog. The production of neutrophils in dogs has been estimated from the number of postmitotic neutrophils in the marrow and the transit time of a [3H]-thymidine pulse. The number of postmitotic neutrophils was derived from the erythron iron turnover measurement of erythroid number and the neutrophil-erythroid ratio in bone marrow sections. The mean value for marrow postmitotic neutrophils in dogs was 5.61 plus or minus 0.56 times 10-9 cells/kg. The mean transit time of these neutrophils was calculated to be 82.1 h. A marrow production of 1.65 times 10-9 neutrophils/kg/day was calculated from these data. The turnover of circulating neutrophils was measured by [3H]thymidine and [32P]diisopropylphospho-fluoridate (DF32P) labeling of blood neutrophils. [3H]-Thymidine labeling gave a calculated recovery of 65 per cent, a t1/2 disappearance time of 6.7 h, and a calculated turnover of 1.66 times 10-9 cells/kg/day. Corresponding results with DF32P tagging were 51 per cent, 5.4 h, and 2.89 times 10-9 cells/kg/day. The discrepancy between these two tags persisted in doubly tagged cells and was considered to be due to elution of DF32P.


Hearing in the parakeet (Melopsittacus undulatus): absolute thresholds, critical ratios, frequency difference limens, and vocalizations. Avoidance conditioning and the method of limits were used to measure absolute auditory thresholds, masked thresholds, and critical ratios in 4 parakeets. The same procedure was then used to study frequency difference limens in 6 additional animals. The power spectrum and "constancy of intonation" of the parakeet call were also measured and related to the absolute and differential frequency sensitivity. The mechanism of frequency analysis in the parakeet ear was considered in relation to the present results and to the anatomical and functional differences between the avian and mammalian auditory systems.


The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. The effects of insulin on the renal handling of sodium, potassium, calcium, and phosphate were studied in man while maintaining the blood glucose concentration at the fasting level by negative feedback servocontrol of a variable glucose infusion. In studies on six water-loaded normal subjects in a steady state of water diuresis, insulin was administered i.v. to raise the plasma insulin concentration to between 98 and 193 muU/ml and infused at a constant rate of 2 mU/kg body weight per min over a total period of 120 min. The blood glucose concentration was not significantly altered, and there was no change in the filtered load of glucose; glomerular filtration rate (CIN) and renal plasma flow (CPAH) were unchanged. Urinary sodium excretion (UNaV) decreased from 401 plus or minus 46 (SEM) to 213 plus or minus 18 mueq/min during insulin administration, the change becoming significant (P smaller than 0.02) within the 30-60 min collection period. Free water clearance (CH2O) increased from 10.6 plus or minus 0.6 to 13 plus or minus 0.5 ml/min (P smaller than 0.025); osmolar clearance decreased and urine flow was unchanged. There was no change in plasma aldosterone concentration, which was low throughout the studies, and a slight reduction was observed in plasma glucagon concentration. Urinary potassium (UKV) and phosphate (UPV) excretion were also both decreased during insulin administration; UKV decreased from 66 plus or minus 9 to 21 plus or minus 1 mueq/min (P smaller than 0.005), and tupv decreased from 504 plus or minus 93 to 230 plus or minus 43 mug/min (P smaller than 0.01). The change in UKV was associated with a significant reduction in plasma potassium concentration. There was also a statistically significant but small reduction in plasma phosphate concentration which was not considered sufficient alone to account for the large reduction in UPV. Urinary calcium excretion (UCaV) increased from 126 plus or minus 24 to 200 plus or minus 17 mug/min (P smaller than 0.01). These studies demonstrate a reduction in UNaV associated with insulin administration that occurs in the absence of changes in the filtered load of glucose, glomerular filtration rate, renal blood flow, and plasma aldosterone concentration. The effect of insulin on CH2O suggests that insulin's effect on sodium excretion is due to enhancement of sodium reabsorption in the diluting segment of the distal nephron.


Discriminability and the contrafreeloading phenomenon. According to previous reports of the "contrafreeloading phenomenon," animals will work for a reward, and sometimes work quite hard, in the presence of the same reward available freely. With rats as the subjects two experiments are presented which suggest that the contrafreeloading data are explainable with a basic learning principle, discriminability and its accompanying response decrement. For some animals the change in stimulus conditions with introduction of free water was made more highly discriminable by a change in earned reinforcement conditions. The other animals remained on the same earned reinforcement conditions under which all the animals had been trained. The results demonstrated that the discriminability between the conditions of working and freeloading is a most important factor contributing to the continued responding in the presence of free rewards.


Relative similarity of rotated and reversed figures to the original figures as a function of children's age. Four rotated and 2 (left-right and up-down) reversed replicas of 11 random figures and a capital letter, F, were ranked for similarity to the originals by 7 age groups, 5-19 yr. in mean age, each consisting of 23-39 normal boys and girls. For both the random figures and the letter, the left-right reversals were judged as the most similar to the originals at ages 5-7, while the 45 degrees rotations were judged so at ages 12-19. The age of 10 was the boundary between these 2 tendencies. These results indicate that young children have already differentiated spatial orientations and directions to a considerable degree, but differently from older children and adults.


Electrophysiological and behavioral reactivity to photic stimuli following septal lesions and pharmacological treatments in rats. Analysis of behavioral reactivity and cortical visual evoked response (VER) to photic stimulation revealed 2 patterns of lesion-induced changes. One pattern of VERs reflected a hypoarousal electrophysiological condition. This pattern, present initially under all conditions, could be simulated with administration of scopolamine. A second pattern of VERs developed gradually and appeared to reflect a hyperaroused electrophysiological condition. This pattern could be simulated with d-amphetamine. While both lesion-induced electrophysiological patterns were associated with augmented behavioral reactivity to flashes, the hyperarousal pattern related to more intense conditions of stimulation and more sustained behavioral reactivity. Scopolamine, as opposed to d-amphetamine, reproduced the heightened behavioral reactivity to the flashes. These results were interpreted in terms of a "hypoarousal hypothesis" of sensory hyperreactivity.


Classical differential and operant conditioning in rabbits (Oryctolagus cuniculus) with septal lesions. Normal rabbits and rabbits with septal lesions received classical differential conditioning of the nictitating membrane response (NMR), followed by auditory generalization tests run in extinction. Although rate of acquisition and asymptotic responding to positive conditioned stimuli did not differ, septals responded more than normals to nonreinforced stimuli. Resultant decrements in differential conditioning could not be attributed to changes in auditory or shock thresholds or to increased spontaneous NMRs. Septals also responded at higher rates in both operant conditioning (bar presses reinforced with food pellets on a variable interval schedule) and extinction sessions. No difference in suppression in a passive avoidance task was found. Results are discussed in relation to McCleary's response disinhibition analysis of septal function, and an habituation hypothesis is considered.


Hypoglycemic conditioned reflex in rats: preliminary study of its mechanism. It was found that a nervous mechanism is involved in eliciting a hypoglycemic response in rats. A conditioned reflex was established after a series of reinforcements in which an insulin injection (unconditioned stimulus) was associated with the sound of a bell (conditioning stimulus). The hypoglycemic conditioned response was statistically similar to that of insulin. The latency of the beginning of the hypoglycemic response to insulin was between 4 and 6 min. The latency of the conditioned hypoglycemic response to the conditioning stimulus was about 1 min. Blood extracted from a conditioned rat during the test of conditioning produced a hypoglycemic effect when injected into a nonconditioned receptor rat.


Osmosensitive neurons in the rat's preoptic area: medial-lateral comparison. For the first time, brain-recording data were brought to bear directly on the question of a critical osmosensitive zone in the lateral preoptic area as specifically delimited in the rat by Blass and Epstein, and in the rabbit by Peck and Novin. Our data clearly showed that this critical zone in the lateral preoptic area of the rat contains cells that are osmosensitive. Simultaneous recording from cell populations (a) inside the critical zone and (b) in a zone medial to it showed that the net acceleratory response to challenge for the former was much greater than it was for the latter. These findings constitute new evidence for the critical importance of the lateral preoptic area in cellular dehydration thirst.


Neurochemical coding for feeding in sheep and steers. Feeding responses of sheep and steers were compared following intraventricular injection of alpha-adrenergic agonists and antagonists in 2-hr. tests. In sheep, injection of the alpha-agonist 1-norepinephrine (1-NE) (140-1,120 nmoles) increased feed intakes 288% and 388% compared with intakes following synthetic cerebrospinal fluid. This response was blocked by the alpha-antagonist phenoxybenzamine, whereas the antagonist alone decreased feed intake. The beta-adrenergic antagonist propranolol did not modify the 1-NE response. A purer but weaker alpha-agonist, 1-phenylephrine, also resulted in increased feed intake that was blocked by phenoxybenzamine. In contrast to the feeding responses of sheep, 1-NE caused hypophagia in steers, reducing intakes as much as 58% in 2-hr. tests over doses ranging 42-27,800 nmoles. Phenoxybenzamine blocked the 1-NE-induced hypophagia in steers; when injected alone, it increased feed intakes 181% of control values. Changes in feeding following 1-NE injections are probably not attributable to changes in temperature, fat mobilization, or stupor. The data support the hypothesis of an alpha-adrenergic-coded system for feeding in sheep and for satiety in steers.


Some effects of ovarian hormones on food intake and body weight in female rats. Ovarian steroids affect the food intake and body weight of rats. These effects are probably mediated by estradiol and progesterone, since these 2 hormones are more effective than their principal metabolites (estrone and 5alpha-pregnane-3,20-dione, respectively) in altering the food intake and body weight of ovariectomized rats. Estradiol seems to affect food intake by lowering the set point about which body weight is regulated in a dose-dependent fashion. These actions of estradiol can be attenuated or completely blocked by concurrent injections of progesterone. Estradiol-treated ovariectomized rats are far more responsive to the weight- and appetite-promoting actions of progesterone than are ovariectomized-adrenalectomized rats, suggesting that the principal action of progesterone on energy balance may be to interfere with the effects of estradiol.


Influence of ovarian hormones on the recovery period following lateral hypothalamic lesions. The effects of ovariectomy and its interaction with body weight on the recovery period following lateral hypothalamic lesions were examined. The results of the experiments indicated that body weight set point prior to lesioning, liable to be influenced by hormonal and metabolic factors, is a more important variable in modifying the recovery process after lateral hypothalamic lesions than is absolute body weight, while absolute body weight determines the amount of weight loss that follows lesions of the lateral hypothalamus.


Chronically reduced body weight in rats sustaining lesions of the lateral hypothalamus and maintained on palatable diets and drinking solutions. Male rats sustaining lateral hypothalamic (LH) lesions regulated their body weight at a reduced level when maintained for 1 mo. postlesion upon a wet mash diet. Thereafter, for a period of 84 days, half of these animals were offered a high fat dies whereas the remaining animals continued to receive wet mash. A series of palatable drinking solutions were also offered. Body weight remained at reduced levels relative to intact control animals regardless of the diet offered, even under conditions of high fluid intake generated by the palatable drinking solutions. These results contradict the interpretation of Mufson and Wampler that the lower body weight observed in LH-lesioned animals is secondary to lesion-produced "finickiness" and/or dehydration resulting from hypodipsia. Rather, a primary shift in the set point for body weight appears to underlie the reduced levels of weight maintenance in LH-lesioned animals.


Differential effects of amphetamine and food deprivation of self-stimulation of the lateral hypothalamus and medial frontal cortex. Intracranial self-stimulation of the lateral hypothalamus of the rat was markedly increased by d-amphetamine administration and by food deprivation. In contrast, similar self-stimulation response rates obtained in the same animals from the medial frontal cortex were unaffected by food deprivation and only slightly increased by d-amphetamine administration. Furthermore, a large difference between d- vs. l-amphetamine on response rate was obtained for lateral hypothalamic but not for medial frontal cortex self-stimulation. The results of this study were consistent with a noradrenergic self-stimulation system for the lateral hypothalamus. Medial frontal cortex self-stimulation, however, appears to be mediated by a neuroanatomical and neurochemical system different from that of the lateral hypothalamus.


Production of satiety with small intraduodenal infusions in the rat. Rats equipped with chronic intragastric and intraduodenal catheters received small infusions of various solutions through one catheter during spontaneous meals. Regardless of which compartment or which solution was infused, the animals maintained a constant daily nutrient intake. However, all hypertonic solutions reduced mean meal size and increased the frequency of feeding when injected intraduodenally, while only nutritive solutions reduced mean meal size when infused intragastically. Water ingestion varied with the effective osmotic pressure of the injected solutions, but there were no differences in water ingestion as a function of the compartment infused. These data suggest both the presence of a duodenal satiety mechanism and the validity of interpreting the meal patterns of vagotomized rats eating a liquid diet as resulting from the rapid emptying of the diet into the duodenum.


Neonatal androstenedione and adult sexual behavior in golden hamsters. Male rats castrated and given androstenedione neonatally can show high levels of both masculine and femine copulatory behavior in adulthood. In the present study, intact female and male hamsters castrated at birth were treated for their first 20 days with oil, free testosterone, or androstenedione. All neonatal androgen treatments mimicked the naturally occurring developmental process of the male in that all androgenized groups were capable of high levels of male behavior (males but not females showing ejaculation patterns) as well as moderate levels of lordotic receptivity. There were no significant differences in effect among neonatal androgen treatments. The results were discussed as they relate to species differences, sex differences, hamster "bisexuality," and posthormone copulatory performance.


Influence of testosterone propionate administered neonatally on puberty and bisexual behavior in female hamsters. Female hamsters were treated with oil, 3-mug., 30-mug., or 300-mug. testosterone propionate (TP) as neonates. Neonatal TP treatment delayed the onset of puberty by 4.5 days to an age near that previously reported for the male hamster. In addition, neonatal TP altered genital morphology, induced the capacity for mounting behavior, and at the highest dosage, disrupted the ability to bear and rear young. Vaginal and behavioral estrous cycles, however, were not influenced by neonatal TP. In a second experiment, 600-mug. TP administered neonatally blocked estrous cyclicity, but did not eliminate the capacity to display feminine sexual behavior. These results imply that "masculinization" and "defeminization" are separate aspects of neurobehavioral sexual differentiation, and the "defeminization" includes several independent physiological processes.


Estrogen-progesterone regulation of nest-building and incubation behavior in ovariectomized ring doves (Streptopelia risoria). The role of ovarian hormones in the induction of nest-building (tucking) and incubation behavior in female doves (Streptopelia risoria) was determined by systemic injections of estrogen, or progesterione, or estrogen combined with progesterone, or oil in reproductively experienced ovariectomized females. Combined estrogen and progesterone treatment was the most effective hormone regimen for eliciting both behavior patterns in females and also facilitated these behaviors in their untreated mates. Differences in role of the gonadal progesterone in male and female doves were discussed.


Androgens and the organization of sex differences in active avoidance behavior in the rat. A series of experiments was performed to clarify the role of androgens in the development of sex differences in the acquisition of active avoidance behavior. Gonadectomy in adulthood did not affect the performance of either sex regardless of the length of the postoperative recovery interval. Neonatal castration also failed to improve the avoidance performance of males, but prenatal exposure to the antiandrogen cyproterone acetate combined with neonatal gonadectomy produced males whose avoidance acquisition and open field activity scores were indistinguishable from those of control females. Prenatal exposure to endogenous of normal males, but there is no compelling evidence that exposure to androgens during the prenatal period is critical to this effect.


Effects of hippocampal microinjections of D-amphetamine and scopolamine on active avoidance behavior in rats. Rats received bilateral injections of 20 or 40 mug. of d-amphetamine or scopolamine into the dorsal or ventral hippocampus prior to each of 8 daily training sessions in a discriminated Y-maze active avoidance task. Scopolamine, but not d-amphetamine, facilitated avoidance responding in both sites, with the effect being greatest following administration of 20 mug. into the dorsal hippocampus. On Days 9 and 10, all animals received saline injections and were tested for transfer of responding to the nondrug state. A decrement of performance occurred irrespective of whether the drug had facilitated avoidance responding. The performance changes were greater following termination of scopolamine than d-amphetamine injections, and in no case were so great as those previously reported following peripheral injections of the drugs.


Relationship between hippocampal theta activity and running speed in the rat. The frequency of occurrence and amplitude of hippocampal theta waves induced by forced locomotion is proportional to speed of movement on a treadmill. Although induction of hippocampal theta waves is related to the initiation of movement, it is not dependent upon proprioceptive feedback because it persists in the resting animal after a bout of running. It is possible to obtain cortical theta waves in the absence of hippocampal theta activity.


Hippocampal ablation prolongs immobility response in rabbits (Oryctolagus cuniculus). The present study was performed to test the hypothesis that damage to the hippocampus reduces tonic immobility in rabbits. Two measures were used: the number of successful inductions of tonic immobility in a test session and the duration of each successful immobilization. Both of these measures were found to increase in rabbits with hippocampal lesions rather than to decrease as expected. It is suggested that the hippocampus may act to suppress any ongoing dominant or prepotent response, whether the response involves movement or cessation of movement.


Attenuation of "acute" habituation by scopolamine in the black-tailed prairie dog (Cynomys ludovicianus). The hypothesis after scopolamine attenuates habituation occurring within a training session as well as that occurring between training sessions was tested and confirmed. Scopolamine injections (.5 mg/kg) reduced spontaneous wheel running in the prairie dog. The same dosage did not affect the threshold for wheen running induced by electrical brain stimulation (EBS). Another experiment demonstrated that EBS-induced running declined during a 10-min. stimulation period and indicated that the decline was habituative since the response was repeatedly dishabituated. In a final experiment .5 mg/kg of scopolamine reduced habituation of EBS-induced wheel running during 10-min. sessions.


Delayed alternation learning under electrical (blocking) stimulation of the caudate nucleus in the cat. Of 9 cats with electrodes implanted in the dorsolateral caudate nucleus, 4 had previously reached criterion on a delayed alternation task. Tested under alternating conditions of stimulation and nonstimulation, these 4 animals showed a significant performance decline with stimulation. When a marker was placed on one response panel, performance under stimulation did not decline. Stimulation did not affect the learning of a visual discrimination. The remaining 5 cats were trained on delayed alternation with alternating stimulation and nonstimulation conditions. Under stimulation, performance remained near chance levels. These animals were tested on position learning and reversal, and under unilateral stimulation. The results support the view that the caudate nucleus and prefrontal cortex mediate separate aspects of delayed response behavior.


Time-dependent changes in amphetamine self-administration following frontal cortex ablations in rats. Rats were trained to intravenously self-administer d-amphetamine (.01 mg/kg/reward infusion) during daily 1-hr. testing sessions. Following removal of frontal cortex, rates of d-amphetamine self-administration were higher at early (3-5 days) postoperative intervals but lower at later (2-4 wk.) postoperative intervals. These and other results indicated that, as a function of time after surgery, frontal rats are first hyposensitive and then become increasingly hypersensitive to the rewarding effect of d-amphetamine.


Emotional behavior in feral cats with ablations of prefrontal cortex and subsequent lesions in amygdala. Bilateral ablations of gyrus proreus in 6 feral cats did not significantly alter either the intensity or the pattern of flight behavior during confrontation with a human. The scores for defense behavior were reduced in only 2 animals. Subsequent lesions in the rostral part of the basolateral nuclei of amygdala reduced flight and transiently decreased defense scores in all cats. The prefrontal cortex does not seem necessary for the flight and defense responding observed in feral cats. The role of amygdala in the regulation of these behaviors was confirmed.


Direct contact with enriched environment is required to alter cerebral weights in rats. To test the relative effectiveness of direct vs. indirect interaction with an enriched environment, some rats were housed in groups of 12 in large enriched condition (EC) cages while littermate "observer" (OC) rats were placed singly in small wire-mesh cages within EC. A third group was housed singly in an impoverished condition (IC) where stimulation was minimal. After 30 days, the animals were killed and the brains dissected. In both experiments the usual pattern of EC-IC differences in brain weights appeared, whereas OC showed no significant differences from IC. On measures of exploratory behavior taken during the last 2 days of the second experiment, IC fell significantly below EC, and OC was somewhat below IC. Thus EC differen from both IC and OC in brain and in behavior. Active contact with an enriched environment appears necessary for development of EC effects.


Interocular transfer of lateral mirror-image discriminations by cats: evidence of species differences. Interocular transfer of mirror-image discriminations has been shown to be paradoxical in split-chiasm monkeys tested in a lighted Wisconsin General Test Apparatus (WGTA) with 3-dimensional forms, but veridical in split-chiasm cats tested in a darkened 2-choice discrimination box with transilluminated patterns. In the present study, 8 split-chiasm cats showed veridical interocular transfer of a mirror-image and a non-mirror-image discrimination in a WGTA or a 2-choice discrimination box. On the basis of the testing parameters used, it is argued that the discrepancy in the literature arises from a species difference (having a behavioral rather than a gross neurological basis), and not from differences in behavioral testing apparatus or mode of stimulus presentation.


Color pecking preferences in White Leghorn chicks. Studies of color pecking preferences in newly hatched chicks (Gallus domesticus) have shown unimodal preference in the orange region of the spectrum or bimodal preferences at blue and orange. In the present study, dark-harched White Leghorn chicks were tested in darkness with targets illuminated at 1 or 3 radiant intensity levels. Results showed the least amount of pecking at green (541 nm.) and peak preferences in blue-violet and orange-red regions. Findings were similar when other dark-hatched chicks were tested in the light (Experiment 2). Overall, findings suggest unlearned pecking preferences for short and long wavelengths, with minimums at green. Possible evolutionary and photochemical bases for such a bimodal wavelength preference function were discussed. Since bimodality was unaffected by target intensity and background, these variables probably do not account for the unimodal function reported by others.


Early experience in domestication.

Early experience in domestication. Two experiments using domestic and wild rats (Rattus norvegicus) were conducted to assess the ontogenetic as well as phylogenetic influences of early experience on domestication. Experiment 1 was a factorial, reciprocal cross-foster study. Experiment 2 was a factorial assessment of the combined effects of preweaning handling and postweaning enriched environments. These experiments on rat domesticatoin showed that preweaning handling has a strong influence on the ontogenetic development of the rat in terms of reduced emotionality. Handled wild rats became much more like domestic rats in their behavior. This finding for handling contrasted with minimal effects for cross fostering and enriched environments.


Disinhibition and spontaneous recovery of response decrements produced by free reinforcement in rats. Spontaneous recovery and disinhibition were studied in 3 experiments in which, after rats had been trained to bar press on a variable interval schedule of reinforcement, response rates were reduced by the introduction either of extinction or of a response-independent (free) reinforcement schedule. Spontaneous recovery was consistently obtained in extinction, especially when session durations were long. Under free reinforcement conditions there was little sign of spontaneous recovery, even when with high reinforcement rates response reduction was almost as rapid as in extinction. In disinhibition tests the introduction of noise produced increased responding under free reinforcement conditions, but not in extinction. The results are interpreted as demonstrating a dissociation between spontaneous recovery and disinhibition.


Second-order conditioning with food unconditioned stimulus. Three experiments investigating second-order conditioning were conducted with rat subjects. An appetitive Pavlovian conditioning situation was employed in which the response measure was the amount of general activity. Experiment 1 provided a well-controlled demonstration of substantial second-order conditioning. In Experiment 2 extinction of the first-order conditioned stimulus (CS) has no effect upon the response to the second-order CS. Experiment 3 examined the relationship of the second-order conditioning paradigm to that of conditioned inhibition. Both phenomena could be observed simultaneously in the same setting. Implications for second-order conditioning and related conditioning phenomena are discussed.


Functional decortication by cortical spreading depression does not prevent forced extinction of conditioned saccharin aversion in rats. Conditioned taste aversion established in rats by association of saccharin drinking with subsequent lithium chloride intoxication decreased saccharin intake to 22% of normal consumption. Force-feeding saccharin to intact and functionally decorticate trained rats returned saccharin consumption on the next day to 62% (n equals 18) and 77% (n equals 19), respectively. Over-trained conditioned saccharin aversion was affected by forced extinction in a similar way (saccharin intake increased from 28% to 50% and 63%, respectively). Intact brain rats refused to swallow saccharin during forced feeding. while functionally decorticate animals showed no signs of aversion; but extinction was almost equal in both cases. Application of lithium chloride after forced feeding of saccharin in functionally decorticate rats neither prevented extinction of conditioned taste aversion nor reestablished the aversion habit extinguished earlier with intact brain. It is concluded that acquisition of the conditioned taste aversion requires cortical input to a short-term memory file, whereas decorticate extinction can be induced by subcortical gustatory processing analogous to the mechanism controlling feeding behavior during the preweaning period.


Conditioned drinking as avoidance learning. Blocking the robust conditioned drinking response following conditioning eliminates the isotonic procaine conditioned response (CR) but not the hypertonic procaine CR. Rats allowed to drink in the box during conditioning form a larger CR than rats merely injected with hypertonic or isotonic procain who are prevented from drinking in the box: response blocking during extinction eliminated if no experience of drinking water in the box occurs either during baseline or during conditioning. Blocking the drinking response, like blocking shock avoidance, markedly reduces its high resistance to extinction. This suggests that rats overdrink to avoid anticipated illness, and fail to extinguish partially because they are never exposed to the fact that no illness will occur even if no drinking occurs.


Stimulus control of defensive reactions in the albino rat. A series of studies are reported, examining the characteristics of stimuli that produce unconditioned defensive reactions in the rat. These studies show that neither the sound nor the smell of a cat, or the sight or a dead cat, will produce freezing, but either a moving cat or dog, or the abrupt and rapid movement of an inanimate card, will result in freezing and failure to approach the stimulus object. It is suggested that movement is a major factor in the initiation of defensive responses and that movement of a neutral stimulus may enhance the acquistion of defensive responses to that stimulus.


Effort as a dimension of spontaneous activity in rats. The relationship between effort and voluntary activity was studied in a braked running wheel and a voluntary treadmill. Effort was manipulated by varying the torque required to turn the wheel and by changing the angle of inclination of the treadmill. In both situations distance run was a linear decreasing function of effort, and work accomplished was a nonmonotonic increasing function of effort. These findings are discussed in relation to responsivity and regulatory views of the genesis of spontaneous activity.


Methionine hydroxy analog supplementation of low protein calf rations. Thirty-six Holstein calves were randomly assigned at 3 days of age to one of three complete calf rations: ration A, B, C containing 0, .25, or .50% methionine hydroxy analog. All three rations were isonitrogenous at 13.5% crude protein (dry basis) and were offered adlibitum until calves were 12 wk of age. Calves were fed 3.64 kg whole milk oncedaily for 4 wk. Average daily gains (kg) and dry matter intakes (kg) from 4 to 12 wk were .88, 2.49; .77, 2.50; and .56, 1.98 for calves fed A, B, and C. Weight gains differed between all rations while intake was higher for A and B than for C. Dry matter intakes (kg per kg gain) from 4 to 12 wk were 2.85, 3.32, and 3.54. Serum amino acids for five calves on each treatment were similar for A and B. Calves fed C had lower serum values for all individual essential amino acids compared to A and B and 28% lower circulating total essential amino acids. Serum cysteine increased as dietary methionine hydroxy analog increased. Anamino acid imbalance or toxicity may have been produced which severely reduced gain, intake, and serum amino acids on ration C but only reduced gain on ration B.


Intravenous isoproterenol: rationale for bronchial asthma. Intravenous isoproterenol was infused into 7 adult asthmatic patients with refractory bronchial obstruction. Over a dose range of 0.0375 to 0.225 mug per kilogram per minute, maximal bronchodilator effect (or reversal of effect) occurred within 2 to 5 minutes of starting (or stopping) the infusion. Obstruction to airflow improved with each increment of dose. Average heart rate reached a maximum at 0.075 mug per kilogram per minute. Over the lower dose range alveolar to arterial oxygen gradients widened and heart rate increased; over the higher dose range, as heart rate plateaued, bronchodilator effect continued and oxygen gradient narrowed. When combined with adequate oxygenation and continual monitoring of cardiac rhythm and blood pressure, intravenous isoproterenol appears safe for asthmatic patients. Major advantages are (1) administration of bronchodilator to airways not reached by inhalation, (2) prompt onset and offset of effects, and (3) reversal of undesirable side effects. The use of intravenous isoproterenol may obviate the need for intubation and  ventilatory assist.


Measurement of IgE antibodies by the radioallergosorbent test. II. Analyses of quantitative relationships in the test. IgE antibodies have been measured by the radioallergosorbent test (RAST) and the relative amounts present in serum determined by comparison with reference standards. In this study we analyzed the quantitative aspects of the binding of IgE antibody to solid-phase ragweed antigens. With the volumes of allergic serum usually tested, IgE antibodies are in excess in the first step of the RAST. The inability of solid-phase antigens to remove IgE antibody appeared to be due to an insufficient quantity of antigen on the particles rather than steric interference with binding of IgE antibody. Dose-response curves with serums from several ragweed-sensitive subjects were not parallel when plotted on a semilog scale. In contrast, log-log plots of dose-response curves with serums from ragweed-sensitive subjects were nearly parallel. Log-log plots of dose-response curves with serums from subjects with ragweed and grass sensitivity and tested with the appropriate solid-phase antigens also were nearly parallel. Because of the latter finding, RAST could be standardized using a reference serum in every assay and plotting the results on a log-log scale. Finally, because IgE antibody is in excess in the RAST as it is usually performed, the final result reflects both the quantity and the affinity of the IgE antibody.


The administration of radiographic contrast media to patients with a history of a previous reaction. Ninety-five patients were seen in consultation for previous reactions which their physicians considered as possible contraindications for the use of radiographic contrast media (RCM). Twenty-seven patients received no further studies because of a lack of sufficient indication to do them. The previous incidents in 26 were such that they were not classified as immediate generalized reactions (IGRs). Two of these patients had IGRs with repeat RCM (7.7%). Forty-two patients had previous reactions considered to be IGRs and medical problems such that repeat administration of RCM appeared essential for diagnosis. After pretreatment with diphenhydramine, 43 repeat procedures were performed in these patients followed by reactions, generally mild, in 7 (16%). Five of these were classified as IGRs (11.8%). The data on 264 similar patients in the literature were also reviewed. There appeared to be a higher incidence of IGRs to RCM in patients with a good history of a previous reaction than in the general population, but no severe reactions or fatalitics occurred in this entire series. The results showed that repeat studies in patients with previous reactions to RCM may be done, provided that there is careful evaluation of the initial reaction, the need for the diagnostic study, and provided appropriate precautions are taken prior to the procedure.


Life-span and the inheritance of longevity of inbred mice. Measures of life-span were obtained for male and female A/J, BALB/cJ, C57BL/6J, and DBA/2J inbred mouse strains and the six possible hybrid combinations (N equals 500, 10 groups, 25 male and 25 female per group). C57BL/6J mice were long lived, while A/J, BALB/cJ and DBA/2J mice were short lived, with the exception of female BALB/cJ mice, which lived as long as C57BL/6J mice. Female BALB/cJ and two female hybrid mouse groups with a BALB/cJ parent lived longer than males, but significant sex differences were not obtained for other groups. In general, the mode of inheritance of longevity was overdominant. For a second study (N equals 400) of the longevity of A/J and C57BL/6J strains and F1 and F2 hybrids it was estimated that one genetic factor was associated with longevity and the coefficient of genetic determination for longevity was estimated as between .48 and .79.


The effect of estrogen on protein and RNA concentration and on de novo synthesis of RNA in the uterus of aging ovariectomized mice. A study was made of RNA concentration and de novo synthesis and protein concentration in the uterus of ovariectomized C57BL/6J mice with and without estrogen treatment. Young adult animals (4 to 7 mo.) were compared with mice during the age period of reproductive decline (11 and 15 mo.). Concentration of RNA was significantly lower in 15-mo.-old  mice than in 4- to 7- and 11-mo.-old animals. De novo RNA synthesis, as indicated by incorporation of 3H-uridine, was also lower in 15-mo.-old mice than in young adults. Estradiol -17beta increased RNA concentration at all ages studied and the percentage increase did not decline with age. De novo synthesis of RNA was also increased in response to estrogen treatment, but the response was less in 15-mo.-old mice. Protein concentration did not change with age, but the concentration decreased in the estrogen treated mice. The biochemical changes in the uterus may be associated with the declining ability of this organ to support pregnancy as it grows older.


Norepinephrine uptake by the mycoardium of the senescent mouse in vitro. Age-related delays in the uptake of norepinephrine (NE) by the rat myocardium were observed after subcutaneous injection of NE (Gey, Burkard, and Pletscher, 1965). We report here that in vitro uptake of 3H-NE by myocardial slices from healthy C57BL/6J male mice is not impaired by aging (8-28 mo.) at 0.1 ng/ml, 2.0 ng/ml, 1000 ng/ml of NE. Additionally, no age-related changes of inulin space in myocardial slices were observed. Hence, the delayed uptake observed in vivo by Gey et al. may be attributed to age-related changes in the absorption from the subcutaneous site.


A study of the effect of diet on the life-span of Nasonia vitripennis (Walk.) (Hymenoptera, Pteromalidae). The effect of diet on the life-span of female Nasonia vitripennis (Walk.) has been investigated. Life-tables were constructed for these insects fed on dipteran puparia and on 10% sucrose; Further experiments were performed involving the transfer of females from the sucrose diet to puparia at different ages. The converse experiment was also carried out. From this work it was shown that the insect is capable of a greatly extended life if fed sucrose for all, or part of its life-span. However, transfer from puparia to sucrose after 15 days allows an increased survival for only a small percentage of the population. The results are discussed with regard for the age at transfer and to the reproductive physiology of the insect.


Comparison of speech and swallowing function in patients with tremor disorders and in normal geriatric patients: a cinefluorographic study. In a study of vocal tract and esophageal function during speech and swallowing, unmedicated Parkinson patients were found to have specific disorders in oral and esophageal stages of deglutition and a predictable sequence of deterioration in speech. To determine whether these disorders are exclusive to parkinsonism or are typical of all patients with tremor or of geriatric patients in general, a cinefluoroscopic study was initiated to examine the physiology of speech and swallowing in these other patients. Subjects were 10 normal geriatric patients and 10 patients with essential tremor. Results of the studies for these two groups were compared with data from earlier studies on unmedicated Parkinson patients. Parkinson patients showed most severely disordered swallowing and speech function. Patients with essential tremor showed only slight slowing in esophageal transit during swallowing and vocal tremor during speech, but no progressive deterioration. Normal geriatric patients revealed no swallowing or speech disturbances.


Albumin metabolism in elderly patients.

Albumin metabolism in elderly patients. Hypoalbuminemia, without any apparent cause, is occasionally seen in elderly patients. Eleven patients (6 with plasma albumin of over 3 gm% and 5 with plasma albumin of 3 gm% or less), who had no evidence of liver disease or nephrosis and whose dietic history suggested that they were taking adequate amounts of protein were investigated, using 131I human serum albumin. None were acutely ill and their age ranged from 70 to 86 years. It was found that elderly subjects with plasma albumin level of 3 gm% or less had significantly reduced albumin pools and an increased fractional catabolic rate. It is suggested that this may be due to an impairment of the control of degradation in these patients. There was no increased gut loss of albumin in 3 hypoalbuminemic patients investigated with 131I-PVP.


Age differences in backward monoptic visual noise masking. An investigation of age differences in backward monoptic visual noise masking was carried out with young and old adult subjects. It was found that the older subjects were susceptible to the backward masking effect over significantly longer delays between the target and masking stimulus. The masking effect seems to be, at least in part, attributable to age changes in the central mechanisms concerned with perceptual processing which limit the rate at which stimuli can be "cleared" through the nervous system. Backward masking studies of different types seem to hold considerable promise for assessment of the peripheral and central components of age change in visual perceptual processing.


Age, word imagery, and delay interval: effects on short-term and long-term retention. Effects of word imagery and delay interval (0 or 20 sec.) on short-term and long-term retention were explored in subjects 18-27, 65-79, and 80-94 years old. Four high or low imagery words presented visually were recalled after either 0 or 20 sec. delay. Free recall and recognition for all words were also tested after 24 hours. Age group, imagery, and delay were all significant effects on immediate recall, while age group and imagery level affected 24-hour recall and recognition. The proportion of those words recalled in immediate memory which were also recalled by the same subject after 24 hours varied strongly as a function of age. This finding was discussed in relation to age group differences in susceptibility to interference.


Aging and interference with memory.

Aging and interference with memory. Input and output interference in both short-term and long-term memory were measured in three age groups (aged 20-39, 40-59, 60-80 years). A paired-associate probe technique was used, which, by factorially combining the positions of the pairs at presentation and recall, allowed an examination of output interference for all positions in the input list. No differential output interference or input interference due to age was found for items assumed to be recalled from long-term memory. Evidence, however, did indicate that adult aging primarily affects long-term memory, since no differences between groups were found for items assumed to be recalled from short-term memory.


Temporal information processing by young and senior adults and patients with senile dementia. Temporal discrimination by healthy young and senior adults and patients with senile dementia was studied using the measure of transmitted information and two psychophysical methods (single-stimulus-ranking and pair-comparison). The patients with senile dementia showed very severe impairment on both methods and performed much less efficiently than the healthy adults of the same age; thus the former revealed a deficit in both memory and discrimination. The healthy seniors showed less alteration of temporal judgment with significant loss only with the single-stimulus method, which reflects memory deficit alone. Temporal cognition is very sensitive to changes in brain function.


Developing a system for assigning individuals into an appropriate residential setting. With the goal of maximizing the most suitable placement of elderly persons into different types of residential settings, a mathematical system is being developed, using discriminant function analysis, for replicating interdisciplinary clinical team judgments concerning case specific appropriateness for (1) an institutional setting; (2) an apartment in sheltered housing (providing at least the major meal of the day plus housekeeping services); and (3) an apartment in more traditional housing for the elderly. Two discriminant function systems are being developed--the first for separating elderly persons into those needing institutionalization and those requiring a less supervised setting and the second for separting persons judged not to be in need of institutionalization into those requiring either sheltered housing or some other more independent residency situation. While the first function is considered more fully developed at this time, the second is nevertheless useful in that is suggests forces (variables) predictive of such judgments.


A multi-dimensional, multiple method analysis of attitudes toward the elderly. An attitude questionnaire was employed to assess youths' attitudes toward a "representative" 25-year-old and a "representative" 70-year-old along various dimensions, which resulted in their rating the elderly in a more negative fashion. A sample of these subjects judged specific target persons on the basis of autobiographical sketches which were equated for social desirability value but differed with respect to age of target (either 25 or 70 years old). On this measure college students judged the 70-year-old more favorably than the 25-year-old. A comparison of prejudicial responding among the various attitude dimensions and across differing measurement methods was made.


Longitudinal study of age and cohort influences on dietary patterns. Dietary data from weighed food intake records were obtained from 35 women 29 years old and older during 4 studies from 1948 to 1966. Longitudinal data were analyzed by the use of a multiple linear-regression model with year of birth and age as independent variables. With increasing age, mean intakes declined significantly for fat, saturated fatty acids, and oleic acid, and increased significantly for calcium. After accounting for cohort effects, no significant changes occurred in mean intakes of food energy, carbohydrate, protein, phosphorus, iron, thiamin, riboflavin, preformed niacin, vitamin A, and ascorbic acid. For successive year of birth, mean intakes increased significantly for protein, calcium, phosphorus, riboflavin, preformed niacin, and linoleic acid. The regression model used explained approximately 20% of the variability in intakes of food energy and most nutrients examined.


Community complexity and knowledge of facilities. This research examines the relationships among three sets of variables: the amount of differentiation (or complexity) of a community, individual characteristics of its residents, and residents' knowledge of available facilities. A sample of 144 communities in upstate New York was drawn. Community differentiation was measured by means of the Medical Specialties Scale. A subsample of 32 communities was drawn, and in each of these a random sample of 40 noninstitutionalized men and women was interviewed. Multiple regression analysis was the statistical procedure used to test the hypothesis of the study. The findings uncovered an interaction effect, i.e., the relationship between community complexity and knowledge is different within different categories of communities. There is a negative relationship between community complexity and knowledge of facilities for rural communities, but for large cities the relationship is positive. The findings are interpreted as resulting from different sources of knowledge in different types of communities.


Allergic encephalomyelitis in the reputedly resistant Brown Norway strain of rats. Brown Norway (BN) rats are much less susceptible to experimental allergic encephalomyelitis (EAE) than Lewis rats. Nevertheless, BN rats developed severe EAE, even paralysis, when immunized with rat spinal cord and carbonyl iron adjuvant. Complete Freund's adjuvant (CFA) was much less effective. The use of both CFA and pertussis vaccine with rat cord was moderately, but not consistently, effective. Guinea pig spinal cord was weakly encephalitogenic to BN rats with all adjuvant combinations. We were not able to produce EAE in BN rats with purified myelin basic protein from either rat or guinea pig. Inoculations directly into lymph nodes or into the blood stream proved that the low susceptibility of BN rats was not due to lack of absorption from the site of inoculation, but may be related to peculiarities of processing antigen in draining lymph nodes. The severity of EAE in F1 hybrids was intermediate between the BN and Lewis parental strains when tested with an immunizing procedure of appropriate strength. The fact that F1 hybrids were less reactive than Lewis mandates modification of the theory that susceptibility to EAE is inherited through a single autosomal dominant gene.


Inhibition of lymphocyte trapping by cell-free ascitic fluids cultivated in syngeneic mice. Several cellfree ascitic fluids were tested for their influence on the trapping of lymphocytes in peripheral lymph nodes after subcutaneous antigen administration. Fluid from three ascitic tumors cultivated in syngeneic mice diminished the trapping response significantly. Fluid from one of these ascitic tumors cultivated in allogeneic mice showed no inhibition of trapping. Syngeneic normal mouse serum did not significantly affect the trapping phenomenon. It was concluded that syngeneic ascitic fluids contain a substance capable of inhibiting lymphocyte trapping.


Lymphoid cell adenylate cyclase activity after x-irradiation and cortisone treatment. Cortisone injection and x-irradiation of normal mice lead to extensive destruction of thymus and spleen lymphocytes. The lymphocytes resistant to these treatments have basal adenylate cyclase activities that are the same as or slightly lower than the cells of untreated animals. On the other hand, the ability of the cyclase of the cortisone-resistant and radioresistant lymphocytes to respond to stimulation by epinephrine is greatly diminished. The results provide an explanation for the previously observed lack of epinephrine sensitivity of the cyclase of lymphoid cells of immunodeficient pituitary dwarf mice and suggest that the depressed lymphoid cell population of the dwarf is the result of an inability to recover from stress-related lymphoid involution. It is also suggested that the more mature population of lymphoid cells of normal mice is less responsive to hormonal influences.


Antibody response by cells cultured on dialysis membrane in disposable plastic vessels. Plastic vessels were used to culture mouse spleen cells by the technique of Marbrook (1967) and good primary antibody responses were obtained. These vessels some advantages over glassware, which may allow a wider use of this technique.


Quantitative immunoautoradiography at the cellular level. I. Design of a microphotometric method to quantitate membrane antigens on single cells using 125I-labeled antibodies. Iodine-125 has become a commonly-used radioisotope, especially for immunoautoradiographic investigations. Microphotometry of grain density, a well-established method in autoradiography with tritium and carbon-14, was applied to nucleated cells with 125I-labeled membranes. Geometric and absorption factors of radiation were investigated in order to find suitable conditions for quantitative evaluation. A preparatory device is given and a set-up of appropriate measuring conditions is presented. With these prerequisites the reflected-light bright-field photometry of immunoautoradiographs permits to determine automatically the content of surface antigens of single cells. Measurement examples were demonstrated.


Hemoglobin E, an oxidatively unstable mutation. When bloods from 3,159 individuals from the United States, Iran, Ethiopia, and South Vietnam were examined for erythrocytic enzyme deficiencies with a new test utilizing the visible reduction of 2,6-dichlorophenolindophenol by glutathione, gross turbidity was observed in 81 samples. All were from Southeast Asia and 78 contained hemoglobin E. The precipitation rates of various hemoglogins in hemolysates incubated with dichlorophenolindophenol were: Hb EE greater than Hb AE greater than other hemoglobins (A, S, C, D, A2, F, O-Arabia, Rush). Hemoglobin E is an oxidatively unstable hemoglobin, possibly with weakened alpha 1 beta 1 contact; it may result in increased susceptibility to oxidative hemolysis and can be simply detected and differentiated from both Hb C and Hb O-Arabia.


Investigation of small bowel transit time in man utilizing pulmonary hydrogen (H2) measurements. Pulmonary H2 excretion was used to quantitate the small bowel transit time in man. This technique is based on the observation that H2 is produced when carbohydrate is fermented by colonic bacteria and that this H2 production is reflected by a concomitant increase in breath H2 excretion. The time, therefore, between ingestion of the unabsorbable disaccharide, lactulose, and the rise in breath H2 represents the small intestinal transit time of the head of the lactulose load as it passes through the gut. Following ingestion of a mixture of polyethylene glycol (PEG) and lactulose by 9 subjects, transit time measured by H2 excretion correlated closely with the simultaneously determined time for PEG to reach the distal ileum (r equals 0.97). The ileal appearance of PEG preceded the rise in H2 excretion by a mean of 7.6 minutes. Transit time of 19 Gm. of lactulose in 40 healthy subjects averaged 72 minutes (range 25 to 118). Studies repeated 3 to 5 times in 6 subjects showed good individual reproducibility with subsequent measurements differing from initial by a mean of plus or minus 14 per cent. There was an inverse relation between transit time and dose of lactulose ingested by 9 subjects with 5, 10 and 20 Gm. of lactulose having mean transit times of 128 plus or minus 19, 94 plus or minus 15, and 40 plus or minus 8 (S$M.) minutes, respectively. This technique appears to provide a simple, safe, and noninvasive means of studying small bowel transit time in man.


Serum dopamine-beta-hydroxylase activity in parents and children. Dopamine-beta-hydroxylase (DBH), an enxyme catalyzing the final step in the synthesis of norepinephrine, is released with norepinephrine on stimulation of the sympathetic nervous system. In this study an enzymatic colorimetric method was used to assay serum DBH activity in 196 individuals of whom 169 were either the parents or children in 29 families. We examined the association of DBH with age and with hypertension and the faamilial pattern of distribution of serum DBH activity. Serum DBH activity was highest in te groups 10 to 14, 40 to 49, and over 60 years. There was no significant difference in serum DBH activity between normal subjects and individuals with hypertension in any age group. tfurthermore, there was no significant correlation of mean blood pressure with serum DBH activity with or without correction of DBH for age differences; Highly significant correlations of serum DBH activity were found in sibling-sibling pairs and in mean parent-child pairs. No significant correlations were found for father-mother pairs. These observations suggest that the contribution of heredity is more important that shared environment in determining the familial pattern of distribution of serum DBH activity. Serum DBH activity did not have a bimodal distribution in the population. Noevidence was found for a maternal influence or for sex linkage in the transmission of this trait. Our data, derived from this study restricted to families with only two generations, are not adequate to specify with confidence the mode of inheritance of DBH activity in the general population.


Defective regulation of chemotaxis in cirrhosis. The presence of a severe leukotactic defect in cirrhotic patients has been confirmed. This defect is due to the presence of abnormally high levels of the chemotactic factor inactivator (CFI) in serums of patients with hepatic cirrhosis. This inactivator inhibits each of three different chemotactic factors tested and does so in an irreversible manner. As would be predicted by these results, generation of chemotactic activity in cirrhotic serums by a complement-activating agent is markedly impaired. Physicochemical features of CFI in cirrhotic serum differ slightly from that found in normal human serum. These results indicate the nature of the chemotactic defect in cirrhotic patients and may explain the increased susceptibility of these patients to bacterial infections and some of their reported defected in expression of cellular immunity.


Studies on crystal-induced chemotactic factor. II. Role of phagocytosis. The interaction of polymorphonuclear leukocytes (PMN's) and urate crystal leads to the formation of a chemotactic factor. The purpose of this study was to determine the need for ingestion of crystals by the cells in the generation of the chemotactic factor. Our studies showed that when PMN's were incubated with cytochalasin B, an inhibitor of phagocytosis, and urate crystals, no chemotactic activity appeared in the lysosomal extract of the cells. Likewise, no chemotactic activity was present in the media of PMN's incubated with crystals although lysosomal enzyme activity was increased. These findings indicate that phagocytosis is required for chemotactic activity to appear. Our studies also show that cytochalasin B increases the release of lysosomal enzyme B-glucuronidase but not of cytoplasmic enzyme lactic dehydrogenase from PMN's when the cell encounters urate crystals.


Control of plasma renin activity in chronic stable renal disease. Plasma renin activity (PRA) was determined on 70 subjects in clinical salt and water balance with stable glomerular filtration rate (GFR) ranging from 4 to 189 ml. per minute. Average 24-hour urine sodium excretion was obtained for 3 to 5 days prior to the study. The relationship between PRA and daily sodium excretion present in the low GFR group (GFR less than 80 ml. per minute) was similar to that obtained in the high GFR group (GFR greater than 80 ml. per minute). Hypertensive and normotensive subjects also demonstrated a relationship between PRA and daily sodium excretion although the values for PRA tended to be lower in the hypertensive subjects. In 32 subjects, following water hydration, a hypotonic saline load was administered. PRA values fell in 26 subjects, remained unchanged in 5, and increased in 1 subject. The decrease in PRA was not related to the level of GFR and was similar in the normotensive and hypertensive low GFR group. The level of PRA before or after the saline load did not relate to the level of distal sodium supply as estimated by CH2O/GFR + CNA/GFR. In subjects with chronic stable renal disease PRA responds appropriately to variations in daily salt intake and acute volume expansion with saline. Hypertensive subjects with impaired renal function appear to be able to vary PRA levels as do normotensive subjects with impaired renal function.


Pseudohyperkalemia and extreme leukocytosis. Two patients with chronic lymphocytic leukemia and pseudolhyperkalemia are described. Both patients had white blood cell counts exceeding 600,000 per cubic millimeter. Routine determinations of serum potassium were elevated while normal values were obtained when plasma and serum were separated within 30 minutes of venipuncture. Incubation of clotted and heparinized specimens for 6 hours was accompanied by a marked increase of potassium levels. This study indicates that extreme leukocytosis alone can give rise to apparent hyperkalemiamtrue values can be obtained if the determinations are performed quickly after venipuncture.


Placental acid hydrolase purification on concanavalin A-sepharose. Crude human placental extract was chromatographed on concanavalin A-Sepharose. Using a single procedure, 20- to over 300-fold purification of six acid glycohydrolases was achieved, in most cases with a good yield. Improved yield of individual enzymes could be achieved by modifications of the method of elution. The capacity of concanavalin A-Sepharose to bind glycohydrolases from placenta was very large, and will provice a useful procedure for the large-scale purification of the human enzymes.


A precise catecholamine assay for small plasma samples. The time, temperature, and pH of the trihydroxyindole reaction were controlled to minimize interference between norepinephrine (NE) and epinephrine (E) so that, in plasma catecholamine assay within normal human physiologic range, NE contributes less than 1 per cent to the fluorescence produced from E, and E contributes only 0.5 to 10 per cent to NE fluorescence; assay and blank measurements show superior stability. Elution from alumina and instrumental factors, such as optical filters, were optimized so that a single 5 ml. plasma sample sufficed for triplicate analyses of both NE and E, with duplicate blanks for each. This triplicate fluorescence assay was combined with duplicate recovery measurements of radioactive catecholamines added in tracer quantities to the plasma so as to make possible reliable estimates of the precision of measurement of each individual sample. The mean levels found for men aged 40 to 60 years from antecubital vein blood drawn during the subject's working hours (but after a brief rest) were, for NE 0.38 ng. per milliliter, range 0.15 to 0.54 ng. per millilter, and for E 0.09 ng./ml, range 0.01 to 0.27 ng. per millilter. The high precision and small amounts of blood required by this method made possible the measurement of basal plasma levels of E and NE in rats under two-stage phenobarbital anesthesia. The mean levels for 13 male and 4 female Long-Evans-stain rats weighing 250 to 350 grams were, for NE 0.26 ng. per millilter, range 0.16 to 0.37 ng. per millilter, and for E 0.36 ng. per millilter, range 0.14 to ng. per millilter. These rat values are called basal because they are only 1/5 to 1/10 as large as values obtained on plasma secured by single-stage pentobarbital anesthesia or from unanesthetized rats. Eight to 11 ml. of whole blood obtained from each rat were sufficient for individual analyses, an improvement over most other reported methods which require blood from a number of animals to be pooled. The average precision of an individual determination of NE was plus or minus 10 per cent in the range of 0.20 to 0.40 ng. per millilter. The average recovery for NE was 65 per cent and for E it was 55 per cent. Major factors influencing recovery were quantitatively investigated and discussed.


Enzymatic determination of carbamyl phosphate in blood. A specific assay for determination of carbamyl phosphate (carbamyl P) in blood has been developed using the enzymatic conversion of carbamyl P to citrulline by ornithine carbamyl transferase (OCT). This assay, for evaluation of bioavailability of carbamyl P, is necessary for study of the in vivo and in vitro effects of carbamyl P as an antisickling agent. The recovery of carbamyl P as citrulline was 88 to 92 per cent. Carbamyl P in whole dog blood in vitro decomposed with first-order kinetics with a t-1/2 of 42 minutes, the same as the t-1/2 reported for decomposition of carbamyl P to cyanate in buffers at physiologic temperature and pH. When carbamyl P (190 mg. per kilogram) was injected intraperitoneally into mice, it appeared in the blood, with a maximum concentration of 0.2 mM observed between 1 and 5 minutes after injection, followed by a rapid decrease within 10 minutes. The clearance of carbamyl P from dog blood after intravenous injection was first-order, with a t-1/2 of approximately 2.2 minutes. The rapid disappearance of carbamyl P in vivo may possibly by explained by the action of tissue acyl phosphatases which have been reported to hydrolyze carbamyl P.


An automatic device for the isolated rabbit heart preparation for testing cardioactive drugs. An automatic device for the isolated rabbit heart is described. Test solutions are perfused from reservoirs via valves, the sequence and time of opening of which is controlled by a programmable unit. The perfusate was pushed through the heart at a constant flow-rate, with pressure measurement serving as an indicator of preparation stability. The system worked well giving reproducible results without tedious, repetitive manual work. The results obtained with caffeine were in line with those reported in the literature, there being a dose-dependent increase in rate and force of contraction.


The uncoating of native and reconstituted TMV by dimethylsulphoxide: the polarity of stripping. The effect of increasing concentrations of dimethylsulphoxide (DMSO) on the stability of native and reconstituted tobacco mosaic virus (TMV) has been investigated by means of electron microscopy and infectivity assay. The removal of protein subunits from TMV by DMSO was found to be a stepwise process. Subunits are first removed from the 3'OH end of the rod but at about 72% DMSO the site at which uncoating occurs shifts to the 5' end. Studies with reconstituted and partially reconstituted TMV confirm the stepwise nature of the uncoating process. Complete uncoating of reconstituted TMV was found to occur at smaller DMSO concentrations than that of native TMV.


Radioactive labelling of borme mosaic virus. Brome mosaic virus (BMV) can be radioactively labelled by allowing virus synthesis to take place in barley leaves whose cut ends are placed in solutions of radio active precursors of BMV. When barley plants are infected by inoculation of the first emerging leaf, the rate of incorporation of both [14C]-leucine and [32P]-ortho-phosphate into virus particles was found to be maximal in the second leaf, cut and labelled 4 to 5 days after inoculation. The rate of incorporation declined when the labelling or the cutting and labelling were delayed, even though assembly of particles still took place from pre-formed components. An exposure of 72 h to an appropriate amount of 32P yielded highly radioactive BMV RNA for possible sequencing studies. A specific radioactivity (32P) of the order of 1 mCi/mg RNA can be obtained readily.


The Tantalus Ration--a scaffolding for some personality-core vectors. The two opposing vectors which are the core of our personality theory are "participation" and "separation." By participation we mean one's identification of his ego with a person(s), an object, or a symbolic construct outside himself, and his striving to lose his separate identity by fusion with this other object or symbol. Separation, of course, is the opposite vector. We use these opposing vectors of unification--fusion nad separation--isolation as the main axis of our theory in conjunction with three major developmental phages. The first is the process of birth. The second is the crystallization of an individual ego by the molding of the "ego boundary." The third phase of separation is a corollary of socialization when one reaches one's "ego identity" (12). The strain to overcome the separating and dividing pressures never leaves the human individual. The striving to partake in a pantheistic whole is ever present and it takes many forms; if one avenue towards its realization is blocked, it surges out from another channel. An illustrative case is the achievement motive which is a participation surrogate. Actual participation is unattainable by definition. The objective impossibility of participation is augmented by the countering separating vectors, both instinctual and interactive. At any given moment of our lives there would be a disjuncture, a gap between our desires for participation and our subjectively defined distance from our participatory aims. We have denoted this gap the Tantalus Ratio which is the relationship between the longed for participatory goal and the distance from it as perceived by ego. The Tantalus Ratio is dependent on, interalia, the strength of the participatory vectors, as determined by the age distances from the developmental stages of birth, ego boundary, and ego identity.


Differential transfer in poor and normal readers. It has been suggested that children who sustain specific reading disability experience difficulty in abstracting and generalizing the invariant components of words containing redundant elements because of basic dysfunction in categorical processing. This hypothesis was assessed by comparing independent samples of poor and normal readers on transfer of training tasks of two different types: a visual-verbal association task which simulated the reading process, and a visual-visual association task unlike reading. It was predicted that poor readers would perform significantly below normal readers on both initial learning and transfer under the visual-verbal association conditions. In contrast, it was expected that the performance of similar groups of poor and normal readers would be comparable under the visual-visual training and transfer conditions. The results supported these predictions, and it was concluded that the generalization problems observed in poor readers in early word learning are, most likely, attributable to transfer difficulties associated with specific disorder in visual-verbal integration, rather than primary or basic disorder in categorization ability.


Children's evaluations of temporally distant outcomes. Forty 4th grade boys indicated their perceptions of value and of excitement at the expected receipt, either immediately or a week later, of good- and bad-tasting foods. They also chose between receiving immediately either the food originally expected immediately, or the one expected in a week's time. Delayed bad-tasting foods were judged less aversive and chosen more often than immediately expected ones. Evaluations and choices of good-tasting foods revealed similar, although weaker, trends. These findings are interpreted as reflecting the 10-year-old's confusion of subjective excitement and objective value, which arises from inadequate attention to the effects of delay. The findings are compared with results obtained in a similar study with 7th grade boys.


The relation of reflection-impulsivity to field dependence-independence and internal-external control in children. First- and third-grade black children were administered Kagan's Matching Familiar Figures Test, Karp and Konstadt's Children's Embedded Figures Test (CEFT), and Shore, Milgram, and Malasky's Locus of Control Interview (LCI). It was hypothesized that  reflective children would be (a) more field-independent and (b) more internal than their impulsive counterparts. The first hypothesis was supported and discussed in terms of the task demands of the CEFT. The failure to find strong support for the second hypothesis was attributed to the generalized nature of the LCI.


Reflection-impulsivity and locus of conflict in emotionally disturbed children. Forty-four emotionally disturbed children were administered the Matching Familiar Figures Test by one examiner, and the 13 most impulsive and 13 most reflective children were chosen. The teachers of these 26 children were asked to fill out a Locus of Conflict Rating Scale by which each child was designated as either an internalizer or externalizer. Impulsive children were found to be externalizers, while reflective children were internalizers. The implications of these results for the etiology and treatment of maladaptive behaviors of emotionally disturbed children were discussed.


Academic achievement, situational stress, and problem-solving flexibility. Academic overachieving (n equals 12) and underachieving (n equals 10) tenth grade boys were randomly assigned, with their parents, to either a success or a failure treatment in a problem solving task to determine the effects of induced stress on problem solving flexibility. For the underachievers, Ss in the success treatment were the most flexible, while for the overachievers, Ss in the failure treatment were the most flexible. A curvilinear proposition, consistent with Hebb's cue-arousal postulate was proposed to explain the results and also to explain the apparent discrepancies in the literature as to whether situational stress increases or decreases flexibility in problem solving. An implication of the proposition is that for persons with feelings of personal inadequacy, increases in situation stress result in decreased problem solving flexibility, but for persons with feelings of personal adequacy such increases enhance their problem solving flexibility.


Catecholamine histofluorescence in the median eminence of female rabbits activated by mating. Mating was used in the rabbit as a physiological trigger, easily definable in time, for the activation of gonadotropic hypothalamic structures. Using the histochemical fluorescence technique of Falck and Hillarp, it has been attempted to determine whether, in relation to mating, clearly distinuishable and reproducible changes in histofluorescence occur in the tuberoinfundibular dopaminergic system in combination with hypothalamic hypophysiotropic hormone release. Between 20-30 min post-coitum an increase in DA turnover was noted in the external layer of the median eminence. The characteristics of this reaction were studied by administration of reserpine and alpha-methyl-paratyrosine. Immediately after coitus, a paradoxical fluorescence reactivation was observed in the median eminence in female rabbits in which tyrosine-hydroxylase activity was inhibited for 5 hours.


Influence of stress on regional brain serotonin metabolism after progesterone treatment and upon plasma progesterone in the rat. The effect of progesterone upon stress altered serotonin (5-HT) metabolism in various regions of the rat brain was investigated with regard to a possible connection with premenstrual and post-partum depression. When electric footshock was administered to ovariectomized rats pretreated with progesterone or its vehicle, there were generally higher 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations after progesterone. 5-HT levels were significantly higher in thalamus, hippocampus, raphe, and frontal cortex, 5-HIAA rose significantly in hippocampus, raphe, and frontal cortex. Whereas after electric footshock alone the septum showed highest increases of 5-HT and 5-HIAA and hippocampus ranged last, after pretreatment with progesterone increases of 5-HT and 5-HIAA were least pronounced in septum but rather high in hippocampus. Electric footshock administered to ovariectomized rats also resulted in an increase of plasma progesterone concentration.


Antagonism by haloperidol of the L-DOPA-induced disruption of a successive discrimination in the rat. Male rats were trained to perform a conditioned avoidance response combined with a successive discrimination in a shuttle-box. The administration of L-DOPA, 100 mg/kg i.p., after inhibition of peripheral dopa decarboxylase, disrupts the discrimination but not the acoidance behaviour, whereas the administration of the antipsychotic agent haloperidol (HPD), 0.125 mg/kg i.p., disrupts the avoidance behaviour but not the discrimination. The L-DOPA-induced disruption of the successive discrimination was completely antagonized by 0.25 mg/kg of HPD. The present data show that administration of the antipsychotic agent HPD not only inhibits behaviour but also can improve the behaviour in animals with a disturbed function.


Hydroxyindole-O-methyl-transferase activity in the pineal gland of the rabbit. Rabbit pineal HIOMT activity shows a diurnal rhythm. The highest values are observed at night and the lowest during the daytime. Animals kept in permanent darkness show higher values than those in constant light. Bilateral superior cervical ganglionectomy results in a tenfold decrease in pineal HIOMT activity.


Separation of pineal extracts by gelfiltration. II. Identification and isolation of two indoles from sheep pineal glands. After separation of aqueous extracts of sheep pineal bodies and sheep cerebral cortex on Sephadex G-25, a high fluorescence peak showing an excitation maximum at 305 leads to 310 nm and a fluorescence maximum at 350 leads to 355 nm was observed in pineal extracts, which could not be detected in cerebral cortex extracts. Separation of this pineal fluorescence peak on Sephadix G-10 with water elution, followed by gradient elution of water and NaOH, gave rise to several highly fluorescent peaks. From one of these it was possible to isolate a substance with Rf-values, using thinlayer chromatographic, fluorescence and mass spectra studies, identical with synthetic 5-hydroxyindole-3-acetic acid. From another peak a substance, idential with synthetic 5-methoxyindole-3-acetic acid, could be isolated. The results are compared with those obtained in previous studies.


The effect of porphyrin precursors on monosynaptic reflex activity in the isolated hemisected frog spinal cord. The porphyrin precursors beta-aminolevulinic acid (beta-ALA) and porphobilinogen (PBG) which accumulate, and are excreted in the urine in increased amounts during acute attacks of porphyria, were tested for their effects on reflex activity in the isolated hemisected spinal cords of Xenopus laevis. The two compounds were found to exert an inhibitory effect on monosynaptic ventral root responses, as well as on dorsal root responses (DRR) and dorsal root potentials (DRP). The latent period for inhibition of the monosynaptic response was longer than that for the DRR and DRP. The sensitivity of the preparations to the effect of the porphyrin precursors was subject to some seasonal variation. BETA-ALA and PBG did not effect conduction in isolated sciatic nerves at a concentration of 1 mg/ml.


Development of a "blood-brain barrier" to methadone in the newborn rat. The chronic administration of dl-methadone to female rats during gestation results in the simultaneous administration of the drug to the unborn fetus. The tissue concentration of methadone in fetal brain is several-fold greater than in maternal brain. Methadone concentration in other maternal tissues studied was higher than in their fetal counterpart. Similar brain concentrations of methadone were seen in 19- to 21-day fetal rats, taken from mothers who had been treated with methadone, as was found in 1-day-old pups which were given an i.p. injection of methadone directly. The amount of methadone concentrating in the brain from a single 5 mg/kg dose increased with increasing postnatal age until about day 15 and then decreased to near adult levels by days 30 to 35. The blood concentration of methadone was more or less constant with all age groups and was significantly lower than brain concentrated at all time periods studied prior to day 30. The data presented would suggest that there is no true blood-brain barrier to methadone in either the young or the adult rat. However, there is some process which limits the brain content of methadone in the adult which is absent in the young animal. This process appears to be developed by about 30 to 35 days after birth. The apparent delay in the developmental processes seen in the pups born to and nursed by mothers chronically treated with methadone is not statistically significant.


Uptake into brain proteins of 35S-methionine during morphine tolerance. Effect of morphine sulfate on protein synthesis in rat brain was evaluated in tolerant and nontolerant rats. Male Wistar-Lewis rats were randomly distributed to control, tolerant and nontolerant groups. The rats were made tolerant by giving morphine sulfate (25 mg/kg b.i.d.) for either 42 or 84 days. An aqueous solution of 35S-methionine (0.5 muc/g b.w.t.) was administered i.v. Rats from each group were then sacrificed at 20 minutes, 1 hour and 2 hours after 35S-methionine. The 35S-activity in trichloroacetic acid-precipitated proteins and supernatant fractions from cortex, hypothalamus, putamen, corpus callosum, thalamus, cerebellum, kidney and liver was determined. In addition the amounts of label in lipid, saline-soluble and insoluble proteins of whole brain for tolerant and control rats were determined. The 35S-activity in brain proteins of non-tolerant rats did not differ from those of controls. The six brain areas in tolerant rats 1 and 2 hours after injection of 35S-methionine showed a 15 percent, then 30 percent increase in radioactivity (disintegrations per minute per milligram of protein). Proteins from putamen and corpus callosum had w/w 60 percent of the 35S-activity found in hypothalamus and cortex. There was no difference in 35S-activity in kidney and liver between control and tolerant rats. The radioactivity of the brain lipids was 2 percent of that found in proteins in both tolerant and control groups. Protein synthesis in morphine tolerant rat brain is significantly (P smaller than .01) increased as judged by incorporation of 35S-methionine.


Antagonism of the convulsant effects of heroin, d-propoxyphene, meperidine, normeperidine and thebaine by naloxone in mice. Naloxone antagonized convulsions produced by tail vein infusions of d-propoxyphene, heroin, meperidine, normeperidine and thebaine in mice in a dose-related manner. Pretreatment with naloxone (60 mg/kg i.p.) produced a 200 percent increase of the dose of d-propoxyphene or heroin needed to produce a seizure. A 40 percent increase in the convulsant dose of meperidine was observed after naloxone pretreatment (30 mg/kg i.p.). Naloxone (15 mg/kg i.p.) produced a 30 percent increase in the convulsant dose of normeperidine; however, larger doses of naloxone did not produce any further increase in the convulsant dose of either normeperidine or meperidine. Larger doses of naloxone were needed to antagonize convulsions produced by thebaine. Heroin, d-propoxyphene and meperidine produced nonlethal clonic seizures, whereas normeperidine and thebaine produced tonic-clonic seizures which were followed by death. These data suggest that there may be two mechanisms by which narcotic analgesics and their congeners produce convulsions.


Tolerance characteristics produced during the maximally tolerable chronic pentobarbital dosing in the cat. The method of "maximally tolerable" dosing technique for establishing a reproducible state of barbiturate dependence in cats was used for the study. The development of tolerance in animals treated by this method has been quantitatively assessed. Sodium pentobarbital was administered morning and evening for 35 days via a plastic tube implanted into the stomach through the abdominal wall. A range of neurological signs of intoxication was scored before and after each dose and during the day at certain preset intervals. Based on the scoring of neurological impairment, each cat was given the maximally tolerable anesthetic dose of sodium pentobarbital. All of the animals treated by this method exhibited severe withdrawal signs upon abrupt withdrawal of the drug. For each cat, blood pentobarbital concentrations were determined every day before and 1 to 11/4 hours after the morning dose. Also, a complete blood pentobarbital elimination study was made on days 1, 7, 14, 21, 28 and 35 of the regimen. These results distinguished between dispositional and functional tolerance. The dispositional tolerance developed maximally within a week and was maintained at that level as long as the treatment was continued. The functional tolerance, on the other hand, developed more gradually and progressed with continued treatment.


Effects of chronic ethanol treatment and thyroxine administration on ethanol metabolism and liver oxidative capacity. Chronic administration of ethanol to rats leads to an increase in the rate of ethanol metabolism in vivo and in vitro. In vitro studies in liver slices showed that ouabain, an inhibitor of the Na++K+-activated adenosine triphosphatase, can completely block the extra ethanol metabolism in the livers of the treated animals only in the presence of ouabain. Administration of thyroxine led to an increase in the rate of ethanol metabolism when measured both in vitro and in vivo. This effect was biphasic; an activation occurred only with low doses of thyroxine but disappeared after administration of larger doses. Alcohol dehydrogenase activity in the liver of the animals treated with large doses of thyroxine was found to be significantly reduced. With the doses used (50-1000 mug/kg), thyroxine also increased the rate of oxygen consumption as measured in liver slices. However, a biphasic effect did not occur; a near maximum activation on the rate of oxygen consumption occurred with low doses of thyroxine (100 mug/kg). Oxygen consumption was also found to be increased in the liver of animals chronically treated with ethanol. A maximal effect was produced after 18 to 21 days of treatment. For both ethanol and thyroxine-treated animals, an increased rate of oxygen consumption occurred with a concomitant loss of dinitrophenol effect. Mitochondrial alpha-glycerophosphate oxidase was found to be increased in the liver of animals treated with ethanol or with thyroxine. In these two groups, this enzymatic activity appeared to be less affected by the treatment than the dinitrophenol-activated respiration.


Biliary excretion of colchicine.

Biliary excretion of colchicine. After intravenous administration of 3H-colchicine (0.2 mg/kg) to rats, 68 percent was excreted in the feces in 48 hours suggesting bile might be the major route of excretion for colchicine. Rats with cannulated bile ducts excreted 50 percent of a 2 mg/kg dose into the bile within 2 hours; half of this was colchicine, and the rest was desmethylcolchicine and more polar metabolites. Colchicine was excreted into the bile of the rat against a bile/plasma concentration gradient of 800 which resulted from a liver/plasma ratio of 15 and a bile/liver ratio of 60. The biliary excretion of colchicine varied widely among the hamster, dog and rabbit. Of the administered colchicine, 32, 20 and 16 percent were excreted by the hamster, dog and rabbit, respectively, within 2 hours. There was also a species difference in the percentage of the radioactivity present in bile as the parent drug. In the hamster, dog and rabbit, the percentage of radioactivity excreted into the bile as colchicine was 45, 34 and 72 percent, respectively. These species excreted colchicine into the bile against a bile/plasma gradient ranging from 19 to 870. Partition of these gradients between liver/plasma and bile/liver ratios demonstrated that both ratios were greater than one, suggesting that colchicine is excreted by an active process. The liver/bile gradient was always the larger of the two ratios.


Effect of biliary stasis and hepatotoxins on the excretion of iopanoate in the rat. In rats, hepatic dysfunction was induced with CCl4, SKF 525-A, taurolithocholic acid and alpha-naphthylisothiocyanate and by acute and chronic surgical ligation of the bile duct. Biliary and urinary excretion of 125I-labeled iopanoate was measured after a standard i.v. dose. In the absence of normal biliary excretion, the amount excreted in the urine varied over a wide range (0.25-11.2 percent of the dose), with highest rates of urinary excretion occurring after alpha-naphthylisothiocyanate and chronic stasis. Drug disposition was further determined by tissue analysis of liver and kidney. The results indicate that, for a drug that is normally almost exclusively excreted by the bile, in the presence of hepatic dysfunction the amount excreted by the alternate urinary route depends on the type of the induced hepatic disorder. The intrarenal distribution of 125I-radioactivity is strongly influenced by its plasma concentration rather than just by the rate of excretion in the urine.


Inhibition of chondromucoprotein synthesis: an extraneuronal effect of nerve growth factor. Nerve growth factor (NGF) is probably made by many extraneural tissues and some mesenchymal tumors. The present study investigated the effects of NGF on the in vitro synthesis of macromolecules by embryonic chicken cartilage. Cartilage deoxyribonucleic acid and ribonucleic acid synthesis as estimated by radioactive thymidine and uridine incorporation were unaltered by NGF. Chondromucoprotein synthesis as determined by 35SO4 incorporation into cartilage proteins was significantly inhibited by as little as 2 mug/ml of NGF and markedly inhibited (65-82 percent) by 20 mug/ml. Total cartilage protein synthesis as indicated by the incorporation of radioactive leucine was slightly (14 percent) but significantly inhibited by NGF. Fractionation of cartilage proteins into collagen-rich and chondromucoprotein-rich fractions and further purification by polyacrylamide gel electrophoresis demonstrated that all of the inhibition of leucine incorporation was due to the inhibition of chondromucoprotein synthesis. Thus NGF causes a selective and unique inhibition of cartilage chondromucoprotein synthesis.


The effect of caffeine on barbiturate sleeping time and brain level. The effect of caffeine and coffee on the sleeping time induced by barbital was tested in rats. It was found that caffeine pretreatment shortened barbital-induced sleeping time and that coffee had an effect in direct proportion to its caffeine content; decaffeinated coffee was without effect. It was hypothesized that the shortening was due to an interaction at the brain level. This hypothesis was tested using hexobarbital which is metabolized by the liver whereas barbital is only negligibly so metabolized. Pretreatment with caffeine was found to shorten the hexobarbital sleeping time even though the brain concentration of the latter was actually elevated. It was also shown that caffeine pretreatment was much less effective than phenobarbital pretreatment in stimulating the enzyme systems in the liver which metabolize hexobarbital, aminopyrine and ethylmorphine (in vitro). Consequently, it is concluded that caffeine stimulation of liver metabolism is a relatively minor factor in the shortening of barbiturate sleeping time by caffeine in comparison to the brain interaction of these two drugs.


D-amphetamine-induced release of "newly synthesized" and "stored" dopamine from the caudate nucleus in vivo. The lateral and third ventricles of anesthetized cats were perfused continuously with artificial cerebrospinal fluid (CSF) containing 3H-tyrosine and the perfusate was analyzed for 3H-catecholamines. The addition of d-amphetamine sulfate to the perfusing CSF for 2 hours, beginning 2 hours after the start of the 3H-tyrosine perfusion, caused an immediate increase in the efflux of 3H-dopamine. The efflux of this amine declined subsequently despite the continued presence of amphetamine in the CSF. The addition of alpha-methyltyrosine to the CSF concurrently with the d-amphetamine did not markedly alter the immediate increase but accelerated the subsequent decline in the efflux of 3H-dopamine. This suggests that ampetamine initially releases dopamine from a "strong pool," but continuous release is dependent upon ongoing amine synthesis. The addition of d-amphetamine to the 3H-tyrosine containing CSF at the start of perfusion immediately increased the efflux of 3H-dopamine. This response was completely blocked by the presence of alpha-methyltyrosine in the CSF. Pretreatment of cats with reserpine effectively depleted the caudate nucleus of endogenous and 3H-dopamine, but did not alter the ability of d-amphetamine to increase the efflux of 3H-dopamine. Indeed, the amount of 3H-dopamine released during each collection period by either intraventricular or intravenous administration of d-amphetamine was higher than the content of the labeled amine remaining in the whole caudate nucleus. These results suggest that damphetamine can release both "stored" and "newly synthesized" 3H-dopamine from the caudate nucleus, but that the maintenance of the amphetamine-induced release of dopamine is dependent upon the newly synthetized pool.