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Journal Article 2008; 29(6): 1033-107 PubMed PMID: 19112393 Citation  Keywords:  ACTH-Secreting Pituitary Adenoma:metabolism, Adenoma:classification, Adult, Apoptosis Regulatory Proteins:metabolism, Female, Growth Hormone-Secreting Pituitary Adenoma:metabolism, Humans, Inhibitor of Apoptosis Proteins, Male, Microtubule-Associated Prot.   

OBJECTIVES: Survivin is a member of the inhibitor of apoptosis protein family, which was recently showed to be expressed by different benign and malignant human tumors. Still very little is known about survivin expression in pituitary tumors. In spite of the fact that pituitary tumors in histological examination are usually benign, in the clinical process a certain number of pituitary adenomas is capable of aggressive growth, recurrence and invasion of the surrounding structures. The aim of the present study was to assess the presence of survivin transcripts and protein in different types of pituitary tumors and to evaluate survivin expression levels in invasive and non-invasive pituitary tumors.

DESIGN AND METHODS: The analyzed material consisted of tumor tissue samples obtained during standard neurosurgical removal of the tumor from 23 patients in whom acromegaly (n=14), non-functioning pituitary tumor (n=6), prolactinoma (n=2) and corticotropinoma (n=1) were diagnosed. As a control of the study normal pituitary tissue obtained at autopsy was used. Amplification of survivin gene using sequence specific primers and qRT-PCR method and immunohistochemical staining with primary polyclonal antibodies against human survivin were performed.

RESULTS: Our study demonstrated the presence of survivin mRNA in all 23 analyzed pituitary tumors. Survivin expression was also observed in normal pituitary, but the level of its expression was 6-fold lower than in tumors tissue when studied by real time RT-PCR. The difference between the levels of survivin expression in invasive and non-invasive tumors was not statistically significant. Immunohistochemical analyses revealed the presence of the protein in both normal and tumor tissue of pituitary. Immunostaining of tumor tissue was not uniform. Survivin was observed mainly in the nuclei of cells collected in clusters. The presence of the protein in normal pituitary was restricted to small population of cells.

CONCLUSIONS: The present study showed that overexpression of survivin is characteristic for pituitary tumors. Further analysis of this protein expression profile should demonstrate whether survivin might be use as a prognostic marker in diagnosis and therapy of pituitary adenomas....

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Journal Article 2008; 29(6): 995-998 PubMed PMID: 19112392 Citation  Keywords:  Adult, Age Distribution, Aged, Aged, 80 and over, Antipsychotic Agents:adverse effects, Basal Ganglia Diseases:chemically induced, Cohort Studies, Czech Republic:epidemiology, Dyskinesia, Drug-Induced:epidemiology, Female, Humans, Incidence, Male, Middle .   

BACKGROUND: The second generation antipsychotics (SGA) is considered to have contributed to the decrease of the risk of TD in comparison with the first generation antipsychotics (FGA). Using the multiple regression analysis, we compared the predictive strength of the FGA/SGA distinction with the predictive strength of the duration of treatment, patients' age and sex. The difference between sedative (sed) and incisive (inc) antipsychotics was added as the fifth predictor.

METHOD: A cohort of patients treated with antipsychotic drugs for less than 5 years and who were free from TD was followed for one year and examined regularly by the abnormal involuntary motor scale (AIMS).

RESULTS: From a sample of 98 patients, 6 patients developed TD after six months. The duration of treatment, age and sex of the patients were the main determinants of its emergence. The drugs used did not play a statistically significant role. After one year, 15 patients developed TD. Age and sex lost their statistically provable influence on its emergence. The difference between the treatment with sedative or incisive antipsychotics became the variable with the highest statistical significance. The relationship of the risk of TD to the FGA/SGA distinction was not statistically significant. 14.4% of the variability in the increase of the risk of TD during the second half of the one year observational period could be explained by the predictors. The stepwise regression showed that both, SG/FG and sed/inc distinction remained statistically significant....

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Comparative Study 2008; 29(6): 971-976 PubMed PMID: 19112391 Citation  Keywords:  Adolescent, Adult, Amyloid beta-Peptides:cerebrospinal fluid, Biomarkers:cerebrospinal fluid, Case-Control Studies, Demyelinating Diseases:cerebrospinal fluid, Female, Humans, Male, Middle Aged, Multiple Sclerosis:cerebrospinal fluid, Peptide Fragments:ce.   

OBJECTIVES: The presented study focuses on the importance of measurement of beta-amyloid42 (Abeta-42) levels, total tau protein, and phosphorylated tau (p-tau) protein in the cerebrospinal fluid (CSF) of cerebrospinal multiple sclerosis (MS) and clinically isolated syndrome (CIS) which represents an early phase of multiple sclerosis.

METHODS: A total of 23 patients with clinically isolated syndrome and suspected MS were enrolled into the study. Of this number, 14 patients met the criteria for definitive MS according to McDonald. The control group consisted of 40 patients examined for the possibility of organic damage to the brain, which was not confirmed. We used method of enzyme immunoanalysis to examine concentrations of tau protein, p- tau protein, and beta amyloid42. Differences between the respective groups were examined by test statistics. In addition, dependence of the total tau protein, p-tau protein, and beta-amyloid42 levels on demographic variables, diagnosis and duration of disease was examined by correlation analysis. Correlation of the concentrations obtained in the measurements was evaluated based on the calculated correlation coefficient (r) and level of significance (p).

RESULTS: Compared to the control group, no statistically significant difference was found in the levels of tau protein and p-tau protein between the CIS group and definitive MS group. A significant increase was found only for beta-amyloid42 levels in patients with diagnosed MS vs. control group. We demonstrated no correlation between the beta-amyloid42 and tau protein levels, p-tau protein and age of patients and duration of disease in patients with MS, CIS and the control group.

CONCLUSION: Results of our study show that use of tau protein, p-tau protein and beta-amyloid42 in the diagnosis of multiple sclerosis seems to be non-beneficial. We confirmed no importance for the differential diagnosis of an early stage MS....

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Journal Article 2008; 29(6): 1038-144 PubMed PMID: 19112390 Citation  Keywords:  Acromegaly:blood, Adenoma:complications, Adult, Aged, Follow-Up Studies, Humans, Insulin-Like Growth Factor I:analysis, Male, Middle Aged, Pituitary Neoplasms:complications, Somatostatin:analogs & derivatives, Treatment Outcome,.   

OBJECTIVE: The aim of our study was to investigate the characteristics of acromegalic patients diagnosed at a tertiary University Hospital and to evaluate the results of the recommended treatment protocols.

PATIENTS AND METHODS: All our acromegalic patients were included (n=48; 27 women). Demographic, hormonal, visual and imaging data at diagnosis and during follow-up were recorded, as well as the treatments applied.

RESULTS:&nbsp;In 73.0% of the patients, acromegaly was due to a pituitary macroadenoma. From those under periodic surveillance, 68.2% underwent surgery and 36.4% had radiotherapy. At the time of the study 88.6% of the patients were receiving medical therapy, 28.2% of them as first-line treatment. Applying current criteria, only one patient was cured by surgery. Considering normal age and sex-matched concentrations of IGF-I as a control criteria, surgery resulted in disease control in 10% of the patients who had surgery, while medical treatment controlled the disease in 76.9% (P <0.05). Of those who receive medical therapy as first-line treatment, tumour size decreased in 45.5%, while in the rest no significant changes were observed during follow-up.

CONCLUSIONS:&nbsp;Not all centres obtain the results reported in the literature in terms of disease control and morbidity after surgical treatment of growth hormone-secreting tumours. It is possible that in some hospitals first-line medical treatment should be chosen, unless the patient has visual disturbances, as long as it is not clear that partial surgical removal of the tumour significantly improves response to medical therapy or reduces its costs....

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Comparative Study 2008; 29(6): 999-1006 PubMed PMID: 19112389 Citation  Keywords:  Analysis of Variance, Animals, Arcuate Nucleus of Hypothalamus:drug effects, Female, Follicle Stimulating Hormone:blood, Injections, Intraventricular, Leptin:administration & dosage, Luteinizing Hormone:blood, Rats, Rats, Wistar, Statistics, Nonparametric.   

OBJECTIVES:&nbsp;This study is an attempt to determine, the in vivo action of leptin on this hypophysiotropic hypothalamic area, by evaluating the concentrations of luteinizing hormone (LH) and follicular stimulating hormone (FSH) in the serum.

METHODS:&nbsp;The experiments were done by stereotaxic injection of recombinant rat leptin (rrleptin) into the third cerebral ventricle (V3) of adult female Wistar rats. Subjects were divided into five groups. Group A included normal intact animals. In Group B, the rats were stereotaxically administered with rrleptin in the V3. The rats, in Groups C, D and E, were subjected to electrolytic lesion of the arcuate nucleus (ARC), of the ventromedial nucleus (VMH) and of both of these hypothalamic nuclei, respectively. Immediately after the electric lesion, they were intracranially injected with rrleptin. Blood samplings for serum LH and FSH levels estimation were performed three times: 1) just before any stereotaxic procedure, 2) six hours, and 3) twenty-four hours after leptin administration.

RESULTS:&nbsp;The results showed that serum LH levels increased dramatically in group B, six hours after leptin administration. The LH levels in Groups C, D and E presented the same pattern with a lower peak. The FSH levels were doubled six hours after leptin administration in all groups without any exception. Both LH and FSH serum levels reverted to the initial basic levels after 24 hours.

DISCUSSION:&nbsp;The significant conclusion derived from this study is that ARC and VMH, which are responsible for controlling the tonic secretion of gonadotropins, respond in a different way for the FSH and LH secretion. This also suggests that some other mechanism(s) or factor(s) may additionally participate in the control of the tonic component of FSH secretion....

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Evaluation Studies 2008; 29(6): 1007-114 PubMed PMID: 19112388 Citation  Keywords:  Animals, Antioxidants:pharmacology, Electron Spin Resonance Spectroscopy:veterinary, Free Radicals:analysis, Hydroxyl Radical:analysis, Male, Nitrogen Oxides:analysis, Pain:metabolism, Pain Measurement:instrumentation, Pain Threshold:drug effects, Rats, R.   

OBJECTIVES:&nbsp;The aim of the study was to demonstrate the ability to measure free radicals and singlet oxygen, using EPR methods, in the tail of anaesthetized rats. The advantage of this method lies in the potential for continuous evaluation of free radicals and singlet oxygen during nociceptive processes.

METHODS:&nbsp;Electron paramagnetic (spin) resonance (EPR/ESR) was used. DMPO and PBN as spin traps and thermal mechanical pulp (TMP) as a spin detector of singlet oxygen were used. Thirty-one adult male (Wistar) rats were used for the experiments. They were housed according to principles of good laboratory practice. The animals were stimulated for 10 minutes on 5 consecutive days by using clamps on the hind limbs. During the EPR measurement they were anaesthetized with a mixture of ketamine and xylazine. Hydroxyl and nitroxide free radicals, as well as singlet oxygen were measured.

RESULTS:&nbsp;After nociceptive stimulation, free hydroxyl radicals were increased as well as free nitroxide radicals. Singlet oxygen was also increased after nociceptive stimulation. Antioxidants significantly decreased the increase in hydroxyl radicals after nociceptive stimulation.

CONCLUSIONS:&nbsp;Our results confirmed an increase in free radicals and singlet oxygen after nociceptive stimulation and a reduced increase after application of antioxidants. Direct EPR methods were first used in the tail of anaesthetized rats and represent an extremely useful tool for the evaluation of pain intensity in living animals....

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Comparative Study 2008; 29(6): 929-938 PubMed PMID: 19112387 Citation  Keywords:  Adenoma:classification, Gene Expression Regulation, Neoplastic:physiology, Ghrelin:genetics, Humans, Immunohistochemistry, Pituitary Neoplasms:classification, RNA, Messenger:analysis, Somatotrophs:metabolism,.   

OBJECTIVES:&nbsp;It has been suggested that ghrelin synthesized locally in pituitary regulates the function and growth of pituitary cells in autocrine/paracrine way and might be an important factor of pituitary tumorogenesis. The expression of ghrelin receptor in neoplastic cells of pituitary adenomas has also been demonstrated. In vitro studies confirmed that ghrelin stimulates the proliferation of somatotroph cells in GH3 cell line. The presence of both ghrelin mRNA and protein was detected in a number of benign and malignant neoplasms as well as in neoplastic cells of the tissues which do not express ghrelin in physiological conditions. This study showed the presence of ghrelin mRNA and its protein in different types of pituitary adenomas.

DESIGN:&nbsp;The samples of 37 pituitary adenomas were obtained during standard neurosurgical tumor removal. The study tissues included 20 somatotroph tumors (15 patients treated and 5 patients untreated with octreotide LAR before the surgery), 12 nonfunctioning adenomas, 4 prolactinomas and 1 ACTH-secreting tumor. The control included samples of normal mucous membrane of the stomach and normal pituitaries. Expression of ghrelin mRNA was studied in 28 pituitary adenomas by RT-PCR. Immunohistochemical evaluation of ghrelin presence was performed in 34 tumors.

RESULTS:&nbsp;The presence of ghrelin gene transcripts was demonstrated in 10 out of 15 examined somatotroph tumors (obtained from patients treated with octreotide LAR before the surgery) and also in 2 out of 4 samples of prolactinomas, 7 out of 8 of nonfunctioning tumors and in 2 samples of normal pituitary. Immunohistochemical analyses revealed the presence of the protein in all 5 examined somatotroph tumors obtained from patients not treated prior to the surgery and in 10 out of 15 tumors obtained from patients treated with octreotide LAR. The peptide was detected also in 10 out of 12 examined nonfunctioning tumors and in 2 examined PRL-secreting tumors. The immunostaining for ghrelin was not shown in normal pituitaries.

CONCLUSIONS:&nbsp;The study demonstrated that ghrelin gene is expressed in somatotroph adenomas, both treated and untreated with octreotide LAR before the surgery, and also in other types of pituitary adenomas (prolactinomas and nonfunctioning adenomas)....

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Journal Article 2008; 29(6): 846-851 PubMed PMID: 19112386 Citation  Keywords:  Animals, Contraception, Humans, Kisspeptins, Ovulation Induction, Receptors, G-Protein-Coupled:physiology, Reproduction:physiology, Sexual Maturation:physiology, Tumor Suppressor Proteins:physiology,.   

:&nbsp;KISS1 encodes the kisspeptin (KP) family of peptides which were originally characterised as potent antimetastatic agents in breast cancer and malignant melanoma cells. One member of this family of arginine-phenylalanine amide peptides, KP-54, was subsequently identified as the natural ligand for the G-protein coupled receptor-54 (GPR54). In addition to its importance as a metastatic suppressor, KP has been found to play a major neuroregulatory role in governing endogenous gonadotropin release by its modulation of the hypothalamic-pituitary-gonadal (HPG) axis. In humans, KISS1 mRNA has been localised to the hypothalamic anteroventral periventricular nucleus and arcuate nucleus. Although GPR54 is expressed in human pituitary cells, it is not presently known if gonadotrope cells themselves are targets for significant KP activity. It was recently shown that full disruption of the KP/GPR54 complex resulted in hypogonadotropic hypogonadism. Indeed, evidence now suggests that KP/GPR54 signalling during gestation is necessary for sexual differentiation and implicates activation of the KP/GPR54 complex as the single most important upstream event regulating GnRH release. Several compelling studies have placed KP as the leading candidate molecule responsible for initiating puberty, making this receptor-ligand complex of fundamental importance to the neuroendocrinology of reproduction. Here, we discuss key KP/GPR54 discovery events and present an evolution of KP biology in the context of recent animal and human experimental work. With evidence pointing to proper KP/GPR54 signalling as the principal trigger for activation of GnRH neurons and subsequent ovulation, elucidation of how this pathway is modulated is likely to bring novel pharmacologic strategies for fertility treatment (and contraception) within reach. Because the physiological significance KP is now acknowledged to extend well beyond cancer biology (and may also contribute to the pathophysiology of pre-eclampsia), KP represents an exciting research theme in human reproductive biology and neuroendocrinology....

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