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Journal Article 2002; 23(2): 95-100 PubMed PMID: 12011792 Citation  Keywords:  Adult, Aged, Analgesics, Opioid:pharmacology, Base Sequence, Down-Regulation:drug effects, Endothelium, Vascular:drug effects, Estrogen Receptor beta, Female, Gene Expression:drug effects, Humans, In Vitro Techniques, Male, Middle Aged, Molecular Sequence.   

UNLABELLED: Human vascular endothelial cells express the estrogen receptor-beta (ER-beta), which can be modulated by the opiate alkaloid morphine.

OBJECTIVES: To determine if morphine is capable of down regulating the ER-beta receptor in a similar fashion as the mu opiate receptor since they are both coupled to constitutive nitric oxide synthase derived nitric oxide release.

METHODS AND RESULTS: Endothelial cells obtain from human vascular tissues (saphenous vein, atria and primary saphenous vein cells) were treated with 1 uM morphine plus or minus the mu opiate receptor antagonist naloxone or CTOP (10 uM) for 24 h at 37 degrees C. Total RNA was isolated from treated and untreated primary endothelial cells, and specific primers and a probe were used to determine the ER-beta gene expression by real-time RT-PCR. Cells treated with morphine exhibited a down-regulation of ER-beta, whereas naloxone and CTOP were able to partially block the morphine effect. In addition, the 266 bp fragment generated by RT-PCR using the same primers as in the real-time PCR was sequenced and revealed a 100% sequence identity as the authentic ER-beta gene sequence.

CONCLUSIONS: These results indicate that ER-beta is expressed in human vascular endothelial cells, and morphine appears to regulate this receptor in a similar fashion as the mu opiate receptor....

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Journal Article 2002; 23(2): 85-93 PubMed PMID: 12011791 Citation  Keywords:  Adrenocorticotropic Hormone:physiology, Animals, Biological Evolution, Invertebrates:physiology, Opioid Peptides:physiology, Stress, Physiological:physiopathology,.   

: Through an extremely complicated equilibrium called homeostasis, all living organisms maintain their survival in the face of both externally and internally generated "stimuli". This apparent harmony is constantly challenged. Survival through successful adaptation is maintained as close to steady state as possible by adaptive responses, which may also be called perturbation responses since they have a constitutively defined dynamic capacity, i.e., an immediate limit, in a series of balancing and feedback activities reflecting an astounding array of biological, psychological and sociological behaviors. The broad spectrum of stimuli capable of engaging this protective response is remarkable. We define stress as a type of stimulation that is stronger and lasts for a longer duration, upsetting a typical perturbation response given its dynamic parameters. The stress response, which evolves out of the perturbation response, involves inducible signal molecules, i.e., cytokines. We surmise that the ability to exist in an ever-changing environment was a requirement for all life forms, including invertebrates and single celled organisms. It would be expected that these organisms exhibit both perturbation and stress responses. In this regard, we demonstrate that these organisms have mammalian-like signal molecule systems, i.e., opioid, and corresponding behaviors that are similar to those found in mammals with regard to both perturbation and stress responses. Thus, it would appear that these responses evolved first in simpler organisms and were then maintained and enhanced during evolution....

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Journal Article 2002; 23(2): 79-84 PubMed PMID: 12011790 Citation  Keywords:  Adolescent, Adult, Anxiety:physiopathology, Communication, Fear:physiology, Female, Humans, Hydrocortisone:analysis, Pheromones:physiology, Salivary Glands:chemistry, Smell:physiology,.   

: In this study we tried to find out if fear can be detected from human body odours. Female subjects wore under-arm axillary pads while watching a terrifying film. Saliva cortisol samples were taken before and after the film presentation as a hormonal measure for the fear response. The fear experience itself was measured by Spielberger's State-Trait Anxiety Inventory. A "neutral" film, shown one day after the "fear" film, was used as a control in a repeated measures design. In part two of the experiment, the axillary pads were presented to female subjects in a triple forced choice test. Results show that subjects were able to discriminate between fear and non-fear axillary pads, suggesting that women are indeed able to detect "the scent of fear". A direct correlation between induced fear, changes in cortisol levels and smell ratings could not be established. Thus cortisol levels are probably not the inducer of the scent of fear and a hypothetical fear pheromone could have other origins....

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Clinical Trial 2002; 23(1): 61-63 PubMed PMID: 11880864 Citation  Keywords:  Aged, Androgen Antagonists:therapeutic use, Anilides:therapeutic use, Humans, Levodopa, Male, Middle Aged, Nitriles, Prolactin:blood, Prostatic Neoplasms:blood, Tosyl Compounds,.   

OBJECTIVES: The secretion of prolactin (PRL), which is a growth factor for prostate cancer cell proliferation, has been proven to present profound alterations in advanced prostate cancer patients, consisting of abnormally elevated baseline levels and paradoxical response to L-dopa. Moreover, the efficacy of standard therapies for prostate cancer may be mediated at least in part by changes in PRL secretion. The present study was carried out to analyze the effects of the new antiandrogen agent bicalutamide on basal levels of PRL and on its response to L-dopa in metastatic prostate cancer patients.

MATERIAL & METHODS: The study included 10 metastatic prostate cancer patients. They were treated with bicalutamide at a dose of 50 mg/day orally. They were investigated with L-dopa test before therapy and after one month of treatment. L-dopa was given orally at 500 mg, by collecting blood samples before and at 60, 120 and 180 minutes after L-dopa administration. Serum levels of PRL were measured by the RIA method.

RESULTS: Abnormally basal levels of PRL were seen in 4/10 (40%) patients. Mean PRL basal levels decreased after bicalutamide therapy, without, however, significant differences. Before therapy, a paradoxical increase in PRL levels after L-dopa occurred in 4 patients, 3 of them showed basal concentrations of PRL within the normal range. Moreover, bicalutamide therapy significantly reduced PRL increase in response to L-dopa.

CONCLUSIONS: This study would suggest that the measurement of the only basal levels is not sufficient to define as normal the secretion of PRL in advanced prostate cancer, because of the possible existence of altered response to the dynamic tests for PRL secretion. Moreover, the study shows that the antitumor therapy with the new anti-androgen bicalutamide may reduce PRL secretion and improve its paradoxical secretion in response to L.-Dopa. Further studies will be required to better define the possible prognostic impact of changes in PRL secretion on the efficacy of treatments for metastatic prostate cancer....

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Clinical Trial 2002; 23(1): 55-60 PubMed PMID: 11880863 Citation  Keywords:  Aged, Aged, 80 and over, Anti-Anxiety Agents:administration & dosage, Benzodiazepines:administration & dosage, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Melatonin:therapeutic use, Middle Aged, Sleep:drug effects, Treatment Fai.   

OBJECTIVE: The present double blind-placebo controlled study was carried out to assess whether melatonin (3 mg p.o., fast release form) could be useful to reduce benzodiazepine dosage in old patients with minor sleep disturbance. The possible correlation of urinary excretion of 6-sulphatoxymelatonin (aMT6s) before starting treatment and outcome of treatment was also examined.

METHODS: Forty-five patients (36 females, 70.5 +/- 13.1 years old) regularly taking anxiolytic benzodiazepines in low doses were studied. Overall quality of morning freshness, daily alertness, sleep quality, and sleep onset and offset time were assessed from structured clinical interviews and from logs completed by the patients. Patients were randomized to receive either melatonin or placebo for 6 weeks. On day 14 of treatment, benzodiazepine dose was reduced by half and on day 28, it was halted. No significant modifications of sleep or wakefulness were detected after benzodiazepine withdrawal. As compared to basal, there was a general lack of changes in quality of wakefulness or sleep in patients taking melatonin or placebo. Sleep quality of patients taking melatonin during the first two weeks of treatment was significantly lower than that of placebo. Melatonin advanced sleep onset by 27.9 +/- 11.9 min and decreased significantly the variability of sleep onset time (p= 0.03). The urinary concentration of aMT6s prior to the study did not correlate with any parameter examined.

CONCLUSION: The present study does not support melatonin efficacy to reduce the use of benzodiazepines in low doses. This contrasted with the demonstrable effectiveness of melatonin to reduce benzodiazepine consumption in insomniac patients when used in hypnotic amounts....

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Journal Article 2002; 23(1): 49-53 PubMed PMID: 11880862 Citation  Keywords:  Aging:physiology, Animals, Circadian Rhythm, Freund's Adjuvant:administration & dosage, Hydroxyindoleacetic Acid:metabolism, Injections, Subcutaneous, Male, Melatonin:metabolism, Norepinephrine:metabolism, Pineal Gland:metabolism, Rats, Rats, Wistar, Sero.   

OBJECTIVES: This study was performed to search for changes in rat pineal function attributed to age and immunization with Freund's adjuvant.

METHODS: Young (2 months) and old (18-20 months) Wistar rats were injected s.c. with Freund's adjuvant or its vehicle. Eighteen days later, at the acute phase of arthritis, pineal concentration of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine (NE) and melatonin was measured by high pressure liquid chromatography at 4 different time intervals throughout the nocturnal activity span.

RESULTS: Old rats had the lowest pineal 5-HT and 5-HIAA content, the decrease in 5-HIAA exceeding that of 5-HT; consequently, old rats had the lowest 5-HIAA/5-HT ratio, an index of pineal 5-HT turnover. Although immunization did not affect globally pineal 5-HT or 5-HIAA levels, significant interactions "immunization x age" and "immunization x time" were found, i.e., immunization augmented pineal 5-HT content at the beginning of the activity span in young rats and at second half of the activity span in young and old rats, and increased pineal 5-HIAA concentration in young rats at the second part of the activity span only. Freund's adjuvant treatment increased pineal 5-HT turnover exclusively in old rats, an effect mainly seen during the second part of the activity span. Old rats exhibited the lowest pineal NE and melatonin levels, immunization further depressing them.

CONCLUSION: The effect of immunization with Freund's adjuvant on a number of pineal pre- and postsynaptic parameters are age-dependent....

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Journal Article 2002; 23(1): 45-48 PubMed PMID: 11880861 Citation  Keywords:  Attention Deficit Disorder with Hyperactivity:drug therapy, Attention Deficit and Disruptive Behavior Disorders:metabolism, Central Nervous System Stimulants:therapeutic use, Child, Dextroamphetamine:therapeutic use, Female, Humans, Hydrocortisone:metabol.   

OBJECTIVES: There is growing interest in the role of the hypothalamic-pituitary-adrenal (HPA) axis in neuropsychiatric disorders and there is some evidence that the HPA axis may be underfunctional in behaviorally disturbed children. However, co-morbidity is common in childhood neuropsychiatric disorders. Stimulant medication is widely used in the treatment of Attention-deficit hyperactivity disorder (ADHD) and can increase cortisol secretion when given acutely. We therefore set out to determine the whether salivary cortisol would be reduced in a group of children with ADHD/ODD (Oppositional-defiant disorder) and to examine the effect of stimulant medication on any such relationship.

DESIGN: Salivary cortisol was determined in thirty-two children with co-morbid ADHD and Oppositional-defiant disorder (ODD) according to DSM-IV criteria, compared to twenty-five healthy controls of similar age and ethnic background. Data were analysed according to prescription of stimulant medication in the patient group.

RESULTS: Salivary cortisol was significantly lower in the ADHD/ODD group than in the controls. Further analysis revealed that this reduction was restricted to the subgroup of patients not prescribed stimulant medication.

CONCLUSIONS: The results support the possibility of a dysfunction of control of the HPA axis in these behaviorally disturbed children. A reduction in salivary cortisol could reflect underarousal, an elevated threshold for detection of stressors or a subsensitivity of the HPA axis itself. It remains to be determined whether the ability of stimulant medications to negate the apparent deficit in cortisol secretion in these ADHD/ODD patients is an unrelated consequence of increased dopamine release or a reflection of their therapeutic benefit. The use of stimulant medication for co-existing ADHD should be taken into account in future studies of cortisol in behaviorally disturbed children....

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Journal Article 2002; 23(1): 33-44 PubMed PMID: 11880860 Citation  Keywords:  Adult, Aged, Arginine Vasopressin:antagonists & inhibitors, Aspartic Acid Endopeptidases:metabolism, Female, Glucocorticoids:therapeutic use, Humans, Hypothalamus:metabolism, Male, Middle Aged, Nerve Tissue Proteins:metabolism, Neuroendocrine Secretory Pr.   

OBJECTIVES: We reported earlier that vasopressin (AVP) peptide expression is significantly decreased in the postmortem hypothalamus of glucocorticoid (GC) treated patients, while such a decrease was not observed in AVP prohormone (proAVP) expression. This indicated a GC-induced suppression of AVP synthesis at the posttranslational level. Here, we investigated in detail whether this decreased levels of AVP expression in GC treated patients might be due to the down regulation of the prohormone convertases PC-1 and PC-2, and the molecular chaperone 7B2, as was reported previously in some AVP-related disorders.

MATERIALS & METHODS: An immunocytochemical study was performed on post-mortem hypothalami of GC exposed patients and controls, in which quantification of proAVP, AVP, neurophysin (NP) and oxytocin (OXT) expression were done along with the quantification of PC1, PC2 and 7B2 expression in the paraventricular nucleus, by using a computerized image analysis system.

RESULTS: Expression of processed AVP in GC exposed patients was significantly decreased (p=0.021), while the amount of proAVP expression was unchanged. Despite the strong correlation between AVP and NP (the other cleavage product of proAVP) expression in the GC group (r=0.917, p=0.004), the mean NP immunoreactivity did not show a significant decrease in this group. Also the OXT expression was similar in both groups. Although in most of the GC treated patients, the expression intensities of PC1 and PC2 were decreased parallel to the decrease in AVP, the mean expression levels of neither of PC1 and PC2, nor of 7B2 were statistically different between the groups (p=0.20-0.80).

CONCLUSION: We conclude that the suppression of AVP expression by GCs is not mediated solely by the down regulation of PC1, PC2 or 7B2. Other mechanisms, which may contribute to the GC-induced posttranslational suppression of AVP, are discussed....

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