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m-Chlorophenylpiperazine (m-CPP), a serotonin receptor agonist, is currently being investigated as a probe of serotonergic responsivity in various neuropsychiatric disorders. The safety of m-CPP in elderly populations and its potential usefulness in exploring possible serotonergic dysfunction in Alzheimer's disease and normal aging were assessed by examining the behavioral, neuroendocrine, and physiological effects of this agent in 15 elderly subjects (mean age 69 +/- 2 years): 9 Alzheimer patients and 6 healthy normal volunteers. Intravenous m-CPP (0.08 mg/kg) was well tolerated in all subjects and produced no serious adverse effects. The behavioral effects were modest; in particular, minimal anxiety was observed, a finding that contrasted to results from an earlier study reporting that intravenous m-CPP at a slightly higher dose induced marked anxiety and panic attacks in younger subjects. m-CPP produced significant increases in plasma cortisol and prolactin, and significant changes in blood pressure and temperature in these elderly subjects. The results of this preliminary study suggest that intravenous m-CPP is safe and well-tolerated in elderly subjects. Future studies at higher doses can now proceed to study more definitively the question of possible age- and disorder-related reductions in central nervous system (CNS) serotonergic responsivity.

Administration of fenfluramine to rats produced decreases in one-hour food intake and locomotor activity. Short-term (2-6 days) or long-term (21-25 days) treatment with the tricyclic antidepressant, imipramine, did not affect daily food intake, body weight gain or baseline locomotor activity when compared to saline treatment. However, long-term but not short-term imipramine treatment attenuated fenfluramine-induced decreases in one-hour food intake. On the other hand, neither short-term nor long-term imipramine treatment affected fenfluramine-induced decreases in locomotor activity. These findings demonstrate a differential effect of long-term imipramine treatment on fenfluramine-induced suppression of food intake and locomotor activity.

The outer membrane proteins (OMP) of fifteen strains of Yersinia were separated from the inner membrane (IMP) and intracytoplasmic (ICP) proteins. The molecular composition of these fractions was then analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The OMP of all fifteen strains exhibited a uniform pattern markedly distinct from the IMP and ICP. There was, however, heterogeneity in the OMP among the various bacteria, based on the apparent molecular weights of several of the major proteins. The two most prominent major proteins are easily distinguished because their apparent molecular weights varied substantially depending on the temperature at which the membranes were solubilized. Using the apparent molecular weights of these two proteins as a basis for comparison, the Yersinia organisms of serotype 3 presented a unique electrophoretic pattern, different from those of non-serotype 3 Yersinia organisms. Four of the nine serotype 3 organisms analyzed here were isolated from patients who developed arthritis subsequent to infection. However, no obviously unique features could be distinguished. A major focus of research effort is currently being devoted to the examination of the immune response generated against the Yersinia organisms by patients with Yersinia-induced arthritis. Most of the studies, so far, have utilized whole bacteria as the antigens. The data presented in this paper provide the basis of future analysis of such immune responses to individual molecules of Yersinia.

Progesterone-sterol pellets were made that porvided a zero-order release of progesterone for 80 days. 4-(14)C-Progesterone was used to measure the release in vitro and in vivo. The dissolution rate in vitro (distilled water as the desorbing medium) for progesterone-cholesterol (59:41 w/w) and the progesterone-beta-sitosterol (47:53 w/w) pellets was 72 microng/100 mm2/24 hr. The average in vivo absorption from subcutaneously implanted pellets in rabbits was 2 +/- 0.1 microng/ml of plasma/cm2 of surface area. Of this amount, 20-25% was progesterone; the remainder was progesterone metabolites and conjugates. Zero-order release (plasma levels) was obtained for approximately 80 days or until about 70% of the available progesterone was exhausted. During this time, the level of excreted radioactivity in urine continuously decreased, indicating that monitoring only this parameter would lead to erroneous conclusions. A long-term effect and increased effectiveness were obtained with a 5-20-mg progesterone equivalent dose, using gel prepared from 2% methylcellulose as the suspending medium.

An unusual incidence of a duodenal leiomyosarcoma in a 10-year-old boy is presented. The corrected diagnosis was made after a 27-month course of occult gastrointestinal bleeding, vague abdominal complaints, and anemia. Gastrointestinal radiography and upper gastrointestinal endoscopy were useful in localizing the lesion. The tumor was removed at exploratory surgery by simple excision. On frozen section, the tumor was thought to be benign, but fixed microscopic histological sections revealed a well-differentiated, malignant smooth muscle tumor. The presentation of this tumor in a child is compared to previously reported cases in adults, and the biological and clinical characteristics of malignant smooth muscle tumors of the gastrointestinal tract are reviewed.

Ion-selective electrodes designed in our laboratory have been employed to determine the characteristics of the changes in extracellular K+ and pH associated with acute coronary artery ligation and release. These studies have defined major inhomogeneities in the rate and magnitude of change of extracellular K+ and pH not only at the lateral margin of the ischemic zone but also between the subepicardium and subendocardium, between the subendocardium and endocardium, and even between closely spaced electrodes throughout the ischemic zone. The inhomogeneities during reperfusion were as great as or greater than those induced by coronary ligation. We have used papillary muscles of guinea pigs to determine the effect of the various combinations of extracellular pH and K+ observed at any point in time in an intact heart to study the anticipated changes in conduction and have found both a speeding and a slowing of conduction, which can be expected to occur simultaneously in an intact heart. These results indicate that significant inhomogeneities exist in the ionic and electrical consequences of acute coronary artery ligation and release and that these inhomogeneities can be expected to result in disorders of conduction leading to reentry.

To investigate the relationship between anxiety and regional cerebral blood flow, we administered behavioral challenges to 10 patients with obsessive-compulsive disorder while measuring regional cerebral blood flow with the xenon 133 inhalation technique. Each patient was studied under three conditions: relaxation, imaginal flooding, and in vivo (actual) exposure to the phobic stimulus. Subjective anxiety, obsessive-compulsive ratings, and autonomic measures (heart rate, blood pressure) increased significantly, but respiratory rate and PCO2 did not change across the three conditions. Regional cerebral blood flow increased slightly (in the temporal region) during imaginal flooding, but decreased markedly in several cortical regions during in vivo exposure, when anxiety was highest by subjective and peripheral autonomic measures. These results demonstrate that intense anxiety can be associated with decreased rather than increased cortical perfusion and that ostensibly related states of anxiety (eg, anticipatory and obsessional anxiety) may be associated with opposite effects on regional cerebral blood flow.

The effect of various doses of the 5-HT agonist m-chlorophenylpiperazine (MCPP) on neuroendocrine function (prolactin and corticosterone responses) were compared in three different rat strains: Wistar, Sprague-Dawley (SD), and Fawn-Hooded (FH) rats. Administration of various doses of MCPP produced increases in plasma concentrations of prolactin and corticosterone in all three rat strains. The prolactin responses of FH rats to MCPP were significantly smaller than that of either Wistar or SD rats, while corticosterone responses were equivalent across all three strains. On the other hand, baseline concentrations of corticosterone, but not of prolactin, were significantly higher in FH animals relative to both Wistar and SD animals. There was no significant difference in either baseline hypothalamic concentrations of serotonin, 5-hydroxyindoleacetic acid, norepinephrine, or dopamine or brain concentrations of MCPP among these three rat strains. These findings support some other data indicating that FH rats, a strain with a peripheral platelet serotonin storage pool disorder, also possess alterations in some neuroendocrine functions which are modulated by serotonin.

Total Intestinal Aganglionosis is a rare, uniformly fatal condition with absence of ganglia from the duodenum to the rectum. A neonate with this extreme form of Hirschsprung's disease is presented with a review of 12 previously reported cases. Smooth muscle strips from this infant's gastrointestinal tract demonstrated viable cholinergic receptors, absence of intrinsic neuronal innervation, and colonic contractile activity to the purported peptidergic neurotransmitter cholecystokinin. Four aspects of total intestinal aganglionosis are noteworthy: (1) one-third of patients presented between four and eight days of age after passing meconium on the first day of life; (2) at laparotomy, no intestinal distention, obstruction, or transition zone was evident; (3) hypertrophic nerve fibers seen in classic Hirschsprung's disease were absent in one-quarter of patients; and (4) a high incidence of affected siblings occurred in the previously reported cases. This form of Hirschsprung's disease may represent a distinct entity with autosomal recessive inheritance and significant risk for recurrence.

The serotonin agonist m-chlorophenylpiperazine (m-CPP) had greater anxiogenic and other mood and cognitive effects when administered intravenously (0.1 mg/kg) rather than orally (0.5 mg/kg) to healthy subjects. Nonetheless, similar elevations in peak plasma cortisol and prolactin concentrations were obtained with the two dosage regimens, and temperature elevations were greater after oral m-CPP. Plateau phase plasma concentrations of m-CPP at the times of the maximum neuroendocrine responses to intravenous and oral m-CPP were similar. Since all rodent and nonhuman primate studies have used parenterally administered m-CPP, and previous clinical investigations using intravenous rather than oral m-CPP have yielded somewhat discrepant results, our normative data should be useful for comparing results across different human studies and across species.

The food intake suppressant effects of three serotonin agonists, m-CPP (a selective 5-HT1B agonist), 8-OHDPAT (a selective 5-HT1A agonist) and fenfluramine (a 5-HT releasing agent) were compared in three different rat strains: Wistar, Sprague-Dawley (SD) and Fawn-Hooded (FH) rats. Administration of all three serotonin agonists produced dose-dependent decreases in 1 h food intake in all three strains. FH animals were significantly less sensitive to the food intake suppressant effects of all three serotonin agonists than either Wistar or SD rats. Body weight gain over the 9-week course of the study was also significantly less in FH animals than either Wistar or SD animals. These findings support some other data that Fawn Hooded rats, a strain with a peripheral platelet serotonin storage disorder, also possess altered central nervous system serotonergic function.

Intravenous administration of the 5-HT1B agonist, m-chlorophenylpiperazine (m-CPP) to rats produced increases in plasma prolactin (peak effect at 15 min), corticosterone (peak effect at 30 min) and a decrease in plasma growth hormone (peak effect at 15 min) concentrations. Short-term or long-term clorgyline treatment did not affect baseline levels of prolactin, corticosterone or growth hormone. Short-term clorgyline treatment attenuated m-CPP's effect on corticosterone but not on prolactin or growth hormone. On the other hand, long-term clorgyline treatment attenuated m-CPP's effect on prolactin but not on corticosterone or growth hormone. These findings are compatible with development of functional subsensitivity of 5-HT1B receptors mediating prolactin release following long-term clorgyline treatment. Attenuation of m-CPP's effect on corticosterone following short-term clorgyline treatment suggests either early adaptational changes in a 5-HT receptor subtype mediating corticosterone release, or clorgyline-induced increases in other neurotransmitters such as norepinephrine which may be responsible for attenuating m-CPP's effect on corticosterone.

Clinical and experimental investigations of intestinal atresia have reduced mortality and clarified etiology. However, the morbidity of this lesion remains excessive and its pathophysiology uncertain. The purpose of this project was to produce the first long-term model of intestinal atresia and thereby to study the motility of the adapting bowel. Intestinal atresia was induced in nine fetal lambs at midgestation by mesenteric avulsion. At term, this experimental group and eight control lambs underwent resection with anastomosis, decompression gastrostomy, and implantation of electrodes proximal and distal to the anastomosis. Vigorous resuscitation and constant intensive care were critical for survival. Slow wave activity (SWA) and spike potential activity (SPA) were recorded in the first 24 hours and every 48 hours thereafter for a 6-hour interval. Three of nine lambs with atresia and five of the eight control animals survived over 48 hours (chronic). Analysis of 220 hours of recording showed, in the first 24 hours of life, a statistically significantly different SWA of 16.4 cycles/min (+/- 1.15 SD) in the chronic atretic survivors compared with 13.1 cycles/min (+/- 2.6 SD) in the acute (died less than 48 hours) atretic group (P less than .05). The SWA of the chronic atretic survivors was similar to the SWA of the chronic nonatretic control animals, 15.1 cycles/min (+/- 1.4 SD). SPA was present on the first day of life in the microintestine of the chronic atresia group in contrast to the acute animals of this study and of Doolin and Hill's previous study. Delayed function has been attributed to the absence of SPA in the microintestine of acute models.(ABSTRACT TRUNCATED AT 250 WORDS)

The hyperphagic effects of two selective 5-HT1A agonists (8-OHDPAT and buspirone) in a free feeding paradigm and the locomotor suppressant effect of the serotonin agonist, m-chlorophenylpiperazine (m-CPP) were compared in three different rat strains: Wistar, Sprague-Dawley (SD), and Fawn-Hooded (FH) rats. Administration of various doses of 8-OHDPAT and buspirone produced significant increases in two-hour food intake only in Wistar and SD strains and not in the FH strain. Similarly, various doses of m-CPP produced significant decreases in locomotor activity only in Wistar and SD strains and not in the FH strain. Isolated FH animals gained significantly less body weight relative to both Wistar and SD animals. These findings demonstrate attenuated feeding and behavioral responses to serotonergic agonists in the FH strain relative to both Wistar and SD strains.

Rat pups, while separated from their littermates and placed in a novel environment, emit ultrasonic isolation calls. These ultrasonic calls decrease in number, power, and frequency following administration of the anxiolytic, diazepam (0.5 mg/kg). Pentylenetetrazol (20 mg/kg), which has been reported to be clinically anxiogenic, increases the number and the power of these calls. These changes following diazepam and pentylenetetrazol administration are dose dependent and do not appear to be secondary to nonspecific effects of these drugs on arousal or thermoregulation. The benzodiazepine receptor antagonist RO 15-1788, which has generally been reported to lack intrinsic activity at low doses, also decreases the number of rat pup isolation calls. These findings suggest that the benzodiazepine-GABA receptor-chloride channel complex may play a role in the physiologic mediation of the rat pup isolation call.

The technique and scoring system of 24-hr pH esophageal monitoring has been modified to evaluate gastroesophageal reflux in infants and children. The data from two pediatric controls and five clinical cases are presented and compared to normal adult values. This test has better objectivity, precision, sensitivity, and reliability than contrast studies, endoscopy, esophageal biopsy, acid perfusion, or acid reflux tests. The 24-hr pH monitoring assists the evaluation of sphincter maturation, pulmonary disease, and the significance of body position. With more experience, this technique could identify children at risk fo developing severe complications of reflux esophagitis and aid in the selection of candidates for surgical intervention.

To determine if collateral ventilation (CV) occurs in pigs and dogs during intermittent positive-pressure ventilation (IPPV) and high-frequency oscillation (HFO), seven pigs and seven dogs were studied by measuring Xenon 133 washout (XeW) from an occluded subsegmental bronchus. The rate constant/min (K) for Xe blood uptake (KXeb) was derived, and when subtracted from K for XeW (KXeW) gave K for removal of Xe by CV (KXecv). Pig XeW were single exponentials with mean KXew = 0.25/min during IPPV and 0.12/min with HFO. In pigs, mean K of XeW was no different from KXeb so that all XeW occurred by blood uptake and none by CV. XeW in dogs had two exponentials. Dogs had over 11 times greater mean KXeW than pigs during IPPV and over 24 times greater during HFO. In dogs, on average, 79% (IPPV) and 87% (HFO) of XeW occurred by CV. CV is a means of gas exchange during HFO and IPPV in dogs but not in pigs.

Intravenous administration of m-chlorophenylpiperazine (m-CPP, a serotonin agonist) to rats increased plasma prolactin and corticosterone concentrations. Long-term (21-day) and short-term (3-day) treatment with the tricyclic antidepressant, clomipramine, did not have any significant effect on baseline levels of either prolactin or corticosterone. Long-term but not short-term clomipramine treatment significantly potentiated m-CPP's effect on plasma prolactin. On the other hand, both long-term and short-term clomipramine treatment significantly attenuated m-CPP's effect on plasma corticosterone. These findings are consistent with other animal and clinical studies demonstrating a differential effect of antidepressant treatment on two different serotonin-mediated neuroendocrine functions.

The experiment conditions for the evaluation of Norethindrone (17 alpha-Ethynyl-17 beta-hydroxy-4-estren-3-one, NET) and Ethynyl-estradiol (17 alpha-ethynyl-1, 3, 5 (10) estratrien-3, 17 beta-diol, EE) by radioimmunoassay are described. A minimal quantity of 25 pg of these two steroids could be evaluated using different reduced metabolites of NET, very little cross reaction is observed with 200 pg of these metabolites. No effect was observed with estradiol for the EE-antiserum. The NET-antiserum was used to evaluate this steroid and ethynodiol diacetate after oral administration to female volunteers. Maximal values in the plasma (2-3% of the administered dose) was found between 1-3 h after administration and at 24 h a concentration of 0.1-0.3% still remained in the plasma.

Clomipramine is a potent serotonin reuptake blocker that decreases the symptoms of obsessive-compulsive disorder (OCD). To investigate whether clomipramine treatment in OCD affects brain serotonergic responsiveness, metachlorophenylpiperazine (mCPP), a selective serotonin agonist, and placebo were given under double-blind conditions to nine patients with OCD before and after treatment with clomipramine. Unlike our previous observations of a marked transient increase in obsessional symptoms and anxiety following 0.5 mg/kg of mCPP, readministration of mCPP after four months of treatment with clomipramine did not significantly increase obsessional symptoms and anxiety. Similarly, the hyperthermic effect of mCPP observed before treatment was eliminated after treatment with clomipramine. These findings are consistent with the development of adaptive subsensitivity to the serotonergic agonist mCPP during clomipramine treatment. A similar alteration in the response to endogenous serotonin may mediate clomipramine's antiobsessional effects.

Varying results have been reported with the use of acetylcholinesterase (AchE) staining to diagnose Hirschsprung's disease in rectal suction biopsy. We analyzed the histology and AchE staining of rectal biopsies from 10 patients with documented intestinal aganglionosis and 57 patients with ganglionic bowel. The results show that histologic identification of submucosal ganglion cells is reliable in excluding Hirschsprung's disease and that the absence of ganglion cells in an adequate suction biopsy is highly suggestive of intestinal aganglionosis. Four AchE staining patterns were recognized; the staining patterns overlap in some patients who have and some who lack ganglion cells. The AchE staining pattern did not correlate with sex or age of the patients, or with the length of the aganglionic segment. The acetylcholinesterase stain is not a reliable method of making or excluding a diagnosis of intestinal aganglionosis except when AchE-positive fibers are increased in both the lamina propria and muscularis mucosae. This AchE staining pattern occurred in 6 of our 10 patients with Hirschsprung's disease. In addition, eight segments of aganglionic colon were studied that included 2 cases of total colonic aganglionosis in which hypertrophic, AchE-positive nerve fibers were absent in all layers of bowel wall. This last finding suggests that an abnormality in the preganglionic cholinergic fiber or extrinsic neuron is involved in the pathogenesis of this unusual form of total colonic aganglionosis.

Continuous sampling of cerebrospinal fluid (CSF) over 24-h periods in 10 rhesus monkeys revealed a 2-fold, highly reproducible circadian rhythm in CRF concentrations. Peak CRF values of 77.9 +/- 6.4 pg/ml occurred in the evening at 1930 h, while the CRF nadir (38.4 +/- 4.2 pg/ml) occurred at 0745 h. Simultaneously sampled CSF cortisol peaked at 0913 h, with a nadir at 2226 h. Both CRF and cortisol rhythms closely fit sinusoidal circadian models, with r2 values of 0.94 and 0.92, respectively. While hypothalamic CRF is regarded as a major physiological regulator of pituitary ACTH secretion and, thereby, of the circadian and stress-related release of cortisol from the adrenal gland, CRF and CRF receptors are also widely distributed in other brain areas of primates and rodents. The marked difference in the circadian rhythm of CRF vs. that of cortisol suggests that CRF in CSF reflects or mediates some nonhypophysiotropic brain functions of this peptide.

The effect of tricyclic antidepressant drugs on the deamination of phenylethylamine and benzylamine by monoamine oxidase (MAO) type B was investigated in vitro in human brain cortex, human platelet, and rat brain preparations. These drugs inhibited MAO activity as expected; however, an atypical biphasic response was observed with the tertiary amine tricyclic, clomipramine, and, to a somewhat lesser extent, with two other tertiary amine tricyclics, imipramine and amitriptyline, when benzylamine was used as the substrate in human tissue preparations. This atypical biphasic pattern was not found when we used the secondary amine antidepressant drugs, desipramine, desmethylclomipramine, or fluoxetine, or used phenylethylamine as the substrate, or used rat rather than human brain tissue. For the tricyclics exhibiting normal inhibition patterns, the same rank order of inhibition was observed with benzylamine as a substrate in all three types of tissue; however with phenylethylamine, differences in inhibition were found between rat and human tissues. These tricyclic-MAO interactional data suggest that secondary and tertiary amine tricyclics interact differently with human MAO type B, that rat and human MAO type B are not functionally identical, and also support other data that phenylethylamine and benzylamine are deaminated by different mechanisms.

Administration of various doses of m-chlorophenylpiperazine (m-CPP, a 5-HT agonist) to rats produced dose-related decreases in food intake and locomotor activity. Long-term (21-25 days) but not short-term (3-7 days) lithium treatment attenuated m-CPP-induced decreases in food intake. However, neither short-term nor long-term lithium treatment had any significant effect on m-CPP-induced decreases in locomotor activity. These findings suggest development of functional subsensitivity of 5-HT1B receptors mediating decreases in food intake and provide further evidence that m-CPP's effects on food intake are mediated by different mechanisms from those regulating locomotor activity.

In groups of house mice (Mus musculus) an experimentally imposed sequence of experience led to the establishment of male territories in suitably designed observation pens. This sequence consisted of familiarization with the area followed by combat with and social dominance over another male who was then removed, and a final step in which defeat on the home ground of a similarly experienced male was coupled with victory over the latter on familiar ground.