Opioid peptides and dipeptidyl peptidase in autism.

It has been hypothesized that autism results from an 'opioid peptide excess'. The aims of this study were to (1) confirm the presence of opioid peptides in the urine of children with autism and (2) determine whether dipeptidyl peptidase IV (DPPIV/CD26) is defective in children with autism. Opioid peptides were not detected in either the urine of children with autism (10 children; nine males, one female; age range 2 years 6 months to 10 years 1 month) or their siblings (10 children; seven males, three females; age range 2 years 3 months to 12 years 7 months) using liquid chromatography-ultraviolet-mass spectrometric analysis (LC-UV-MS). Plasma from 11 normally developing adults (25 years 5 months to 55 years 5 months) was also tested. The amount and activity of DPPIV in the plasma were quantified by an ELISA and DPPIV enzyme assay respectively; DPPIV was not found to be defective. The percentage of mononuclear cells expressing DPPIV (as CD26) was determined by flow cytometry. Children with autism had a significantly lower percentage of cells expressing CD3 and CD26, suggesting that they had lower T-cell numbers than their siblings. In conclusion, this study failed to replicate the findings of others and questions the validity of the opioid peptide excess theory for the cause of autism.

Hemorrhagic complications of pancreatitis: radiologic evaluation with emphasis on CT imaging.

OBJECTIVE: To analyze and describe the incidence, pathophysiology, radiographic diagnosis and the initial management of hemorrhagic complications associated with pancreatitis. MATERIAL AND METHODS: Among 1,910 patients diagnosed of having pancreatitis in the last 10 years, 26 developed hemorrhagic complications (1.3%). These complications were detected from 2 months to 8 years after one or several episodes of pancreatitis with a mean of 2.3 years. Radiographic studies were reviewed and clinical management and outcome were recorded. RESULTS: Ten patients had CT evidence of pancreatic necrosis, 12 patients chronic pancreatitis, and 17 patients pancreatic pseudocysts. The cause of hemorrhage was bleeding pseudoaneurysm in 16 patients (61%), diffuse bleeding with pancreatic necrosis in 5 patients (19.5%) and hemorrhagic pseudocysts in 5 patients (19.5%). Intra-abdominal hemorrhage developed in 21 patients and gastro-intestinal bleeding in 5 patients. Arterial embolization was attempted in 12 patients and was successful in 9 patients (75%). Surgery was used in 16 patients and the overall mortality rate was 11%. CONCLUSIONS: Hemorrhagic complications are rarely seen and are usually late sequelae of pancreatitis. They develop because of leaking or ruptured pseudoaneurysms, diffuse bleeding in pancreatic necrosis, and hemorrhagic pseudocysts. Early detection followed by angiography, embolization and/or surgery has decreased mortality rates.

Translation and linguistic validation of a disease-specific quality of life measure for cystic fibrosis.

OBJECTIVE: To develop a conceptually and semantically valid English version of a French disease-specific measure of quality of life for children, adolescents, and adults with cystic fibrosis (CF). METHODS: Following a backward and forward translation of the measure, 60 participants, including 20 children, 20 parents, and 20 adolescents/young adults completed the Cystic Fibrosis Questionnaire (CFQ) and a series of cognitive probes evaluating their understanding of the items and response choices. RESULTS: Semantic and conceptual problems with the items were identified and modified for the second set of cognitive interviews. Response distributions across items and ages were adequate, and the predicted associations between disease severity and quality of life were obtained. CONCLUSIONS: The English version of the CFQ appears to be a linguistically valid measure of quality of life for patients with CF. A national validation study is now under way to test the psychometric properties of the measure.

Peer-Led Alcohol Education program: a pharmacy student-led program for seventh-graders.

OBJECTIVE: To delay or discourage the use of alcohol by seventh-grade students through peer-led education. Peer-Led Alcohol Education (PLAE) program objectives were to: (1) educate students about alcohol use and (2) assess the differences between pharmacy student presenters and high school student (peer) presenters. SETTING: Middle schools in rural Nebraska. DESIGN: PLAE focuses on normative beliefs, personal values, and pledging. Pharmacy students and high school students were trained to deliver alcohol education presentations to seventh-grade students. Evaluation results were compared among groups of seventh-grade students who received PLAE presentations from peer presenters and from pharmacy student presenters. RESULTS: PLAE presentations were made to 342 seventh-grade students at 11 schools. Evaluation results suggest that pharmacy students projected more confidence in their presentations, used more creative prop selections, and were more effective communicators. High-school presenters had a greater ability to "relate" to the seventh-graders and thus were deemed more on-target with the information. CONCLUSION: Evaluation findings suggest that rural seventh-grade students in Nebraska perceived that the PLAE program provides useful information to aid them in their decisions regarding alcohol use.

Predicting relapse to substance abuse as a function of personality dimensions.

The goal of the present study was to determine whether personality traits are related to return to heavy drinking or drug use following treatment for substance abuse. Personality characteristics of one hundred and eight patients residing on an inpatient substance abuse treatment program were assessed. Personality traits were examined using the 5-factor model of personality as measured by the NEO-Personality Inventory. These patients were then followed for 1 year after discharge from the treatment program. These substance abuse patients scored higher than the NEO-Personality Inventory normative sample on the personality domains of Neuroticism and Conscientiousness. A survival analysis showed that Neuroticism and Conscientiousness from the NEO-Personality Inventory were significant predictors of relapse. Odds ratios showed that the risk of relapsing was greatest for those patients who were both low in conscientiousness and high in neuroticism. The relevance of these two broad personality dimensions to the development and maintenance of addiction is discussed. Treatment implications for patients who possess these personality risk factors are outlined.

CNS actions of serotonin on cardiovascular function: nonadrenergic, noncholinergic mechanisms.

The present studies investigated the mechanisms mediating the cardiovascular changes induced by intracerebroventricular injection of serotonin (5-HT; 100 nmol) in conscious rats. At 5 min after 5-HT injection, arterial pressure and plasma levels of epinephrine were elevated and heart rate was reduced. The pressor response was abolished either by bilateral adrenalectomy or by pretreatment with chlorisondamine plus vasopressin V1 receptor antagonist. The bradycardic response was attenuated by pretreatment with chlorisondamine or a combination of methylatropine, propranolol, and vasopressin V1 receptor antagonist. At 20 min postinjection, arterial pressure and heart rate were both decreased. The reduction of heart rate at this time point was not blocked by the following pretreatments given alone or in combination: methylatropine, propranolol, vasopressin V1 and V2 receptor antagonists, adenosine A1 receptor antagonist, angiotensin-converting enzyme inhibitor, and chlorisondamine. These results suggest that immediately after intracerebroventricular injection of 5-HT, arterial pressure is elevated through the release of epinephrine and vasopressin and that heart rate is reduced via reciprocal changes in cardiac parasympathetic and sympathetic tone. In contrast, adrenergic, cholinergic, vasopressinergic, purinergic, and angiotensinergic mechanisms do not mediate the bradycardia observed at 20 min postinjection.

Cardiovascular activation by serotonergic stimulation: role of corticotropin-releasing factor.

Serotonin (5-HT) and serotonergic agonists stimulate the release of corticotropin-releasing factor (CRF) from hypophysiotropic neurons and thereby activate the pituitary-adrenal axis. Studies were performed to test the hypothesis that the release of CRF into central nervous system (CNS) sites where it influences cardiovascular function is likewise stimulated by serotonergic mechanisms. Experiments were thus designed to examine whether the cardiovascular effects of central administration of low doses of 5-HT and the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), are secondary to the release of CRF. Intracerebroventricular administration of 5-HT (1 nmol) and 8-OH-DPAT (3 nmol) produced cardiovascular responses similar to those evoked by CRF (0.15 nmol), i.e., simultaneous elevations of arterial pressure and heart rate, in conscious unrestrained rats. Coadministration of the CRF receptor antagonist, alpha-helical CRF-(9-41) (9 nmol), significantly attenuated the pressor and tachycardic responses to 5-HT and 8-OH-DPAT as well as those to injection of CRF. In contrast, coadministration of alpha-helical CRF-(9-41) did not alter the pressor and bradycardic responses to a high dose (100 nmol) of serotonin. It is concluded that the cardiovascular effects of low doses of 5-HT and 8-OH-DPAT are mediated in part through the release of CRF within the CNS.

Central actions of corticotropin-releasing factor on autonomic nervous activity and cardiovascular functioning.

The physiological role of corticotropin-releasing factor (CRF) in mediating stress-induced activation of the pituitary-adrenal axis, together with the neuroanatomical distribution of immunoreactive CRF and CRF receptors, provides a compelling rationale for investigating actions of CRF within the central nervous system (CNS) on autonomic nervous outflow and cardiovascular function. Evidence is reviewed showing that CRF acts within the CNS to elicit stress-like patterns of autonomic nervous outflow and cardiovascular changes in conscious animals. In addition, blockade of CRF-mediated neurotransmission is demonstrated to alter the expression of stress-induced autonomic nervous and cardiovascular responses. Together, the anatomical, pharmacological and physiological data support the hypothesis that the autonomic nervous and cardiovascular responses to selected stressful stimuli may be mediated in part by CRF-containing neuronal pathways.

Neuropeptides and the autonomic nervous system.

Peptides are a class of intercellular messengers that are found in virtually every bodily organ. Evidence is reviewed here that peptides may function physiologically in brain pathways that coordinate and integrate whole-organism responses. The focus is on selected peptides that produce complementary neuropharmacological actions on behavior, endocrine secretions and autonomic nervous activity.

Central and peripheral injections of the 5-HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, modify cardiovascular function through different mechanisms.

The mechanisms underlying the cardiovascular effects of central and peripheral administration of the 5-HT2 (serotonin) receptor agonist (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) were studied in conscious rats. Intravenous (10-1000 nmol/kg) and i.c.v. (3-300 nmol) administration of DOI produced dose-related elevations of arterial pressure without altering heart rate except after injection of the highest doses. Pretreatment with xylamidine tosylate, a 5-HT2 receptor antagonist that does not cross the blood-brain barrier, blocked the pressor response to i.v., but not i.c.v., administration of equivalent doses of DOI. Pretreatment with the vasopressin receptor antagonist d(CH2)5Tyr(Me)AVP significantly reduced the pressor response to i.c.v., but not i.v., administration of DOI. Prior ganglionic blockade with chlorisondamine amplified the pressor response to both i.v. and i.c.v. administration of DOI. Pretreatment with a combination of chlorisondamine, xylamidine and d(CH2)5Tyr(Me)AVP abolished the pressor response to i.c.v. administration of DOI. Thus, the pressor response to i.v. administration of DOI was mediated at sites outside the blood-brain barrier, most likely at vascular 5-HT2 receptors, and was not secondary to vasopressin release. Inappropriate heart rate changes attended the pressor responses to i.v. administration of DOI, suggesting an action at extravascular sites. The pressor response to i.c.v. administration of DOI resulted from a combination of vasopressin release, modulation of autonomic nervous outflow and some leakage into the periphery.

Differentiated hemodynamic responses to central versus peripheral administration of corticotropin-releasing factor in conscious rats.

Corticotropin-releasing factor (CRF) modifies cardiovascular function and hemodynamic status after administration into the central nervous system and into the peripheral circulation. The mechanisms by which CRF alters arterial pressure and heart rate have been examined in detail whereas little information exists regarding the processes mediating CRF-induced changes in regional blood flow. Therefore, studies were performed in conscious, unrestrained Sprague-Dawley rats to examine potential mechanisms underlying the regional hemodynamic effects of intracerebroventricular versus intravenous administration of CRF. Intracerebroventricular administration of CRF increased arterial pressure, heart rate, and mesenteric vascular resistance while decreasing iliac vascular resistance. Intravenous pretreatment with the CRF receptor antagonist, alpha-helical CRF9-41, did not alter the cardiovascular and hemodynamic responses to central administration of CRF. In contrast, prior ganglionic blockade prevented CRF-induced responses except for the reduction in iliac vascular resistance. Intravenous administration of CRF reduced arterial pressure and mesenteric vascular resistance, elevated heart rate, and transiently increased iliac vascular resistance. Intravenous pretreatment with alpha-helical CRF9-41 completely abolished the cardiovascular and hemodynamic responses to peripheral administration of CRF. Ganglionic blockade prior to intravenous administration of CRF augmented the reductions in arterial blood pressure and mesenteric vascular resistance, prevented the increase in heart rate, and unmasked a decrease in iliac vascular resistance. The divergent actions and mechanisms of action of CRF on regional hemodynamics when administered peripherally, as opposed to centrally, indicate that this peptide produces different hemodynamic effects that are specific to its site of action.

Central nervous actions of serotonin and a serotonin1A receptor agonist: cardiovascular excitation at low doses.

Studies were performed in conscious unrestrained rats to compare the cardiovascular effects of i.c.v. administration of serotonin (5-HT) and the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Low doses (less than 10 nmol) of 5-HT and 8-OH-DPAT elicited significant elevations of arterial pressure and heart rate. At doses greater than 10 nmol, 5-HT produced pressor responses attended by significant reductions of heart rate whereas 8-OH-DPAT produced significant depressor and bradycardiac responses. Concurrent i.c.v. administration of the nonselective 5-HT receptor antagonist, methiothepin, abolished the cardiovascular responses to a low (1 nmol) and a high (100 nmol) dose of 5-HT and a low (3 nmol) dose of 8-OH-DPAT. In contrast, methiothepin cotreatment did not prevent the reductions of arterial pressure and heart rate induced by a high (100 nmol) dose of 8-OH-DPAT. These results suggest that stimulation of central nervous system 5-HT1A receptors with low doses of 8-OH-DPAT produces cardiovascular activation.

Central regulation of stress responses: regulation of the autonomic nervous system and visceral function by corticotrophin releasing factor-41.

Our understanding of the role of CRF in mediating integrated endocrine, autonomic and visceral stress responses is rudimentary at best. Delineating the large number of neurochemical factors that influence the activity of CRF-containing hypophyseotrophic neurones offers one direction for future research in this area. Another approach might be to examine the neuropharmacological actions of transmitters which are co-localized within CRF-containing neurones. For example, CRF and dynorphin-related peptides coexist within a subpopulation of paraventricular neurones (Roth et al, 1983), suggesting the potential for their simultaneous release and possible functional interactions between them. Interestingly, CRF and dynorphin-related peptides exhibit reciprocal actions on the release of each other in vitro and in vivo. CRF stimulates the release of immunoreactive dynorphin from rat hypothalamic slices (Nikolarakis et al, 1986) while dynorphin A1-17 inhibits the basal secretion of immunoreactive CRF from rat hypothalami (Yajima et al, 1986). In vivo experiments demonstrate that i.c.v. administration of dynorphin A1-13 reduces basal and hypotension-induced secretion of CRF into hypophyseal portal blood (Plotsky, 1986). Recent studies suggest that, in addition to their interactions at the level of release, these peptides may also modify the CNS actions of each other on autonomic and cardiovascular function (Overton and Fisher, 1989b). Thus, CRF-induced elevations of arterial pressure, heart rate and plasma catecholamine levels are attenuated by co-administration of low doses of dynorphin A1-17. The reciprocal release actions and neuropharmacological interactions between CRF and dynorphin A1-17 suggest that local integration or perhaps feedback regulation of stress-induced autonomic and cardiovascular responses may be achieved by the co-release of multiple neurotransmitters from a single source. In summary, the combined anatomical, pharmacological and physiological data provide support for the involvement of CRF neuronal systems in mediating the integration of endocrine, autonomic, and visceral functions, particularly in response to stress. Future research in this area may contribute to our understanding of the neurobiology of CRF as well as the CNS mechanisms governing homeostasis.

Effects of exercise training on responses to central injection of CRF and noise stress.

The purpose of this study was to test the hypothesis that the cardiovascular and sympathoadrenal responses to acute environmental stress are attenuated by exercise training. Furthermore, we tested the hypothesis that the cardiovascular and sympathoadrenal responses to intracerebroventricular (ICV) administration of corticotropin-releasing factor (CRF) would be attenuated by training. Conscious, unrestrained, male Sprague-Dawley rats assigned to either a treadmill trained (16-26 m/min, 30-60 min/day, 5 days/week) or nontrained (16-26 m/min, 10 min/day, 1 day/week) group were studied. After 8-10 weeks of training, maximal oxygen uptake was significantly higher in the trained (108 +/- 3 ml/kg/min) vs. the nontrained (94 +/- 4 ml/min/kg) group. There were no significant differences in baseline mean arterial pressure, heart rate and plasma catecholamine levels associated with training. Trained rats exhibited significantly attenuated elevations in arterial pressure (20 +/- 3 vs. 36 +/- 2 mmHg for nontrained) and heart rate (-3 +/- 3 vs. 12 +/- 5 beats/min for nontrained) in response to acute noise stress. Twenty minutes after ICV administration of CRF, blood pressure (trained = 119 +/- 2 mmHg, nontrained = 127 +/- 2 mmHg), heart rate (trained = 408 +/- 8 beats/min, nontrained = 424 +/- 10 beats/min), plasma norepinephrine levels (trained = 757 +/- 54 pg/ml, nontrained = 775 +/- 100 pg/ml) and plasma epinephrine levels (trained = 266 +/- 29 pg/ml, nontrained = 225 +/- 42 pg/ml) were significantly elevated in both trained and nontrained groups. CRF-induced elevations of blood pressure, but not heart rate or plasma catecholamine levels, were significantly attenuated in the trained group.(ABSTRACT TRUNCATED AT 250 WORDS)

Central nervous effects of CRF and angiotensin II on cardiac output in conscious rats.

Studies were performed to determine whether the central nervous system actions of corticotropin-releasing factor (CRF) and angiotensin II (ANG II) on systemic arterial pressure are mediated, in part, through changes in cardiac output (CO). Changes in CO after intracerebroventricular administration of ANG II and CRF were assessed in conscious unrestrained rats bearing pulsed Doppler flow probes on the ascending aorta. Intracerebroventricular injection of CRF (0.15 nmol) increased arterial pressure (15-20 mmHg), heart rate (70-100 beats/min), and CO (25-35%) without significantly affecting total peripheral resistance. Intracerebroventricular injection of ANG II (0.1 nmol) produced similar elevations of arterial pressure (15-20 mmHg). However, the ANG II-induced pressor response was attended by significant decreases in heart rate (20 beats/min) and CO (10-15%) and significant increases in total peripheral resistance (30-40%). The results of these studies demonstrate that CO, as assessed by pulsed Doppler flow probe methodology, may be influenced significantly and differentially by central nervous system administration of CRF and ANG II.

Gastrointestinal motor effects of corticotropin-releasing factor in mice.

The present investigation examined the effects of centrally and peripherally administered corticotropin-releasing factor on gastric emptying and gastrointestinal transit in mice. Corticotropin-releasing factor, given either intracerebroventricularly or intrathecally, caused a dose-dependent inhibition of gastric emptyping and gastrointestinal transit. Intravenous or intraperitoneal administration of corticotropin-releasing factor, while 5- to 7-fold less potent than after central injection, produced an equivalent level of effect. alpha-Helical corticotropin-releasing factor, a corticotropin-releasing factor receptor antagonist, blocked the effects of intracerebroventricularly administered corticotropin-releasing factor when the antagonist was given concurrently by the intracerebroventricular, but not by the intraperitoneal, route. Conversely, corticotropin-releasing factor, when given peripherally, was antagonized equally well by intracerebroventricular or intraperitoneal administration of the antagonist. The inhibition of gastric emptying induced by corticotropin-releasing factor was reduced by pretreatment with the ganglionic blocking agent, chlorisondamine, and in adrenalectomized mice, but this effect was not antagonized by naloxone. These findings provide evidence for an action of corticotropin-releasing factor within the central nervous system, as well as a peripheral site of action, to inhibit gastric emptying in the mouse. The gastrointestinal motor effects of corticotropin-releasing factor are not mediated through opioid mechanisms although their full expression may require intact autonomic innervation and adrenal function.

Central nervous system cardiovascular actions of CRF in sinoaortic-denervated rats.

Studies were performed in unrestrained conscious Sprague-Dawley rats to examine the central nervous system (CNS) mechanism by which corticotropin-releasing factor (CRF) produces simultaneous elevations of arterial pressure and heart rate. To test the hypothesis that CRF inhibits ongoing impulse transmission through and/or transmitter release from the CNS terminations of baroreceptor afferents, the cardiovascular effects of intracerebroventricular administration of CRF were compared in rats subjected to prior sham surgery (Sham) or sinoaortic denervation (SAD). Resting levels of arterial pressure and heart rate were elevated after SAD. In addition, SAD resulted in greater chronotropic sympathetic tone and reduced chronotropic parasympathetic tone as assessed by intravenous injections of atropine methyl nitrate and DL-propranolol. Intracerebroventricular administration of CRF in both surgical groups elicited significant increases in arterial pressure and heart rate, although a tendency for reduced tachycardic responses after SAD was apparent. Pretreatment with atropine or propranolol revealed that both the parasympathetic and sympathetic nervous systems contribute to CRF-induced heart rate responses in both surgical groups. These results suggest that ongoing baroreceptor afferent transmission is not requisite for the expression of CRF-induced cardiovascular changes. Thus it is unlikely that CRF elevates arterial pressure and heart rate through an exclusive action at the CNS terminations of baroreceptor sensory fibers.