Neuro Endocrinology Letters

The identification of a non-atherogenic and an atherogenic lipoprotein profile, non-athero phenotype A vs. athero phenotype B, in a group of hypercholesterolemic subjects reveals newly discovered non-atherogenic hypercholesterolemia. Individuals with this type of hypercholesterolemia, or hyper-betalipoproteinemia LDL1,2, are probably not at increased risk to develop a premature atherothrombosis or a sudden cardiovascular event. Examined individuals with hyper-betalipoproteinemia LDL1,2 were divided into two subgroups: individuals under 40 years of age, and older individuals between 46 and 71 years of age. Subjects in the under 40 years of age group did not have any apparent clinical or laboratory-proven impairment of the cardiovascular system. The older subjects with hyper-betalipoproteinemia and a non-atherogenic lipoprotein profile had only mild signs of clinically irrelevant aortic valve sclerosis. A quantitative analysis of the lipoprotein spectrum in plasma in a group of hypercholesterolemic subjects was performed. An innovative electrophoresis method on polyacrylamide gel (PAG) was used for the analysis of plasma lipoproteins and for the identification of atherogenic vs. non-atherogenic lipoproteins in plasma. With regard to lipids, total cholesterol and triglycerides in plasma were analyzed with an enzymatic CHOD PAP method (Roche Diagnostics, FRG). A new parameter, the score for anti-atherogenic Risk (SAAR), was calculated as the ratio between non-atherogenic to atherogenic plasma lipoproteins in the examined subjects. There was a high concentration of LDL1, and LDL2 subfractions (p<0.0001), and an extremely low concentration of LDL3-7 (p<0.0001) in the non-atherogenic lipoprotein profile of hyper-betalipoproteinemia LDL1,2 compared to the control group. Higher concentrations (p<0.0001) of lipids and lipoproteins in the non-atherogenic hypercholesterolemia, compared to the control group, were also found. The hyper-betalipoproteinemia LDL1,2 was also characterized by high SAAR values. There was found a higher concentration of HDL large and HDL intermediate subfractions in hypercholesterolemic subjects. The advantages of this new diagnostic method include: (i) identification of the existence of a non-atherogenic hyper-betalipoproteinemia LDL1,2 in examined hypercholesterolemic subjects with untreated hypercholesterolemia (ii) introduction of a new risk measure, the score for anti-atherogenic risk (SAAR), for the estimation of atherogenic/anti-atherogenic risk. (iii) the presence of small dense LDL in plasma is decisive for the declaration of an atherogenic lipoprotein profile. It is valid for hyperlipidemia and for normolipidemia as well.
Candida tropicalis yeast is a microorganism that possesses high tolerance for phenol and shows strong phenol degrading activity. This yeast is capable of utilizing phenol as the sole carbon and energy source. While the enzyme participating on the first step of phenol biodegradation, NADPH-dependent phenol hydroxylase, has already been characterized, information on the enzyme participating in the second step of its degradation, catechol 1,2-dioxygenase, is scarce. The development of the procedure suitable for catechol 1,2-dioxygenase isolation and partial characterization of this enzyme are the aims of this study. Combination of chromatography on DEAE-Sepharose and gel-permeation chromatography on Sephadex G-100 was used for isolation of cytosolic catechol 1,2-dioxygenase from C. tropicalis yeast. The sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and gel chromatography on Sephadex G-100 were used to evaluate the molecular mass of the enzyme. The enzyme activity was followed by HPLC (catechol consumption and/or cis,cis-muconic acid formation). Using the isolation procedure consisting of chromatography and re-chromatography on a column of DEAE-Sepharose and gel filtration on Sephadex G-100, catechol 1,2-dioxygenase was purified from C. tropicalis cytosol to homogeneity. Catechol 1,2-dioxygenase was found to be a homodimer with a subunit molecular mass of 30000 +/- 5000. The enzyme oxidized catechol producing cis,cis-muconic acid. The optimal temperature and pH were 30 degrees C and 7.7, respectively. The data are the first report showing the isolation of eukaryotic catechol 1,2-dioxygenase from C. tropicalis to homogeneity and its partial characterization.
The examples of spontaneously active pineal cells: A—multicellular activity; B—"slow" type cell in intact rat (regular spikes); C—"fast" type cell in colon tumor-bearing rat (regular spikes); D—"slow" type patterns in colon tumor-bearing rat cell. 
Spontaneously active pineal cells frequency comparison in intact and colon tumor-bearing rats. 
The ratio of different cell types in intact and colon tumor-bearing rats
The group of 4 interacting pineal cells in colon tumor- 
OBJECTIVES: Intact rats and rats with 1,2-dimethylhydrazine induced tumors of large intestine were used in experiments. Previously, blood melatonin concentration in these tumor-bearing rats was shown to increase at night, but not in the daytime. METHODS: The extracellular microelectrode registration of rat daytime pineal gland activity was performed. RESULTS: The existence of different types of pinealocytes in the pineal gland was confirmed. Tumor-bearing rats, in comparison to intact, demonstrated higher spike frequency due to cells switching from regular to pattern (4-6 times gain) activity and appearance of "fast" cells (>5Hz frequency). CONSLUSIONS: The literature about pinealocytes points to the correlation between electrical and secretory processes in pinealocytes; thus we suppose the groups of interacting cells, detected in tumor-bearing rats, to reflect cascade cells activation while pineal gland secretion increases. The results indicate, that in the daytime pinealocytes are secreting substances (not melatonin) in dependence with hormonal background.
The diurnal changes of 5-HIAA (ng/mg protein) in the SCN, PA and ME of hypothalamus in control rats and after morning (11 a.m.) and evening (11 p.m.) administration of DM(n=6-10). X-axis-time (hr). ¨-the points repeating the control values at given hours. 
Our data on the contents of norepinephrine (NE), dopamine (DA) and the metabolite of serotonin 5-hydroxyindoleacetic acid (5-HIAA) measured in the suprachiasmatic nuclei (SCN), preoptic area (PA) and median eminence (ME) of hypothalamus of rats after single subcutaneous injection of 1,2-dimethylhydrazine (DMH) as well as the effect of this carcinogen on formation of reactive oxygen species (ROS) in the PA are presented in this paper. Diurnal changes of DA in all studied brain structures and of NE in the PA have been observed in the control group. Their morning levels were higher than evening ones. Rhythms of 5-HIAA in the SCN and diurnal changes of ROS formation have been shown to have contrary changes in control. Both the morning (11 a.m.) and evening (11 p.m.) subcutaneous administration of DMH at the dose of 21 mg/kg of body weight resulted in changes of all rhythms observed in control. In some cases a phase shift was found, in others the rhythms of neurotransmitters and ROS formation disappeared entirely. The data obtained confirm the idea of dopaminergic and serotoninergic systems taking part in mechanisms of a response of the hypothalamic nuclei to non-photic stimuli. It is suggested that the effect of DMH on the content and diurnal rhythms of neurotransmitters in the hypothalamic structures under study is due to its affecting activities of the enzymes of biogenic amines synthesis, synaptic transmission, melatonin synthesis and secretion rhythms. The change in ROS formation that is caused by administration of DMH is likely to be due to a disturbance of diurnal rhythms of neurotransmitters that are one of the sources of formation of free radicals in the brain.
Objectives: Effect of long-term oral administration of three different concentrations (0.5, 1.0, and 2.0%) of micronized β-1.3/1.6-D-glucan derived from oyster mushroom (Pleurotus ostreatus, Hiratake) on biometrical, haematological, biochemical, and immunological indices of half-year-old rainbow trout (Oncorhynchus mykiss) was assessed in the study. Design: Rainbow trout were feed commercial feed pellets containing β-1.3/1.6-D-glucan in the concentrations of 0.5, 1.0, and 2.0% for 85 days. Biometrical indices consisted in total and standard length, body and liver weight, from which derived somatic parameters such as Fulton´s condition factor and hepatosomatic index were calculated. Haematological parameters were evaluated according to unified methods for haematological examination in fish. Plasma biochemical profile was analysed using biochemical analyser Konelab 20i and Easy Lyte Analyzer. A phagocyte cells metabolic activity (induced chemiluminescence of phagocytes) was determined as an immunological parameter by a microplate luminometric method on Immunotech LM-01T. Results: No clinical signs of behavioral, respiratory, or neurologic distress were observed in rainbow trout. Fish showed normal feeding behavior. As for biometric parameters, no significant changes in total and standard length, body weight, liver weight, as well as in condition factor and hepatosomatic index of experimental and control fish were found. In the course of the study, weight gains in rainbow trout were similar and continuous. Shifts in PCV (p<0.05), haemoglobin (p<0.05), and MCHC (p<0.01) were found within haematological indices. Plasma concentration of glucose, lactate, total protein, cholesterol, calcium, natrium, potassium (all p<0.05), albumins and chlorides (both p<0.01), as well as catalytic activities of ALT and AST (both p<0.05) were changed in the course of the study. A phagocyte cells metabolic activity (luminol-induced chemiluminescence) in rainbow trout was not altered by oyster mushroom β-1.3/1.6-D-glucan administration. Conclusion: After long-term oral administration of three concentrations of micronized β-1.3/1.6-D-glucan derived from oyster mushroom (Pleurotus ostreatus, Hiratake) shifts in haematological and biochemical profiling were found in half-year-old rainbow trout (O. mykiss) in environmental conditions of a commercial rainbow trout fishery. Biometrical indices were not found significantly altered. No specific effect of β-glucan on immune system response of rainbow trout was found in the study. The use of β-glucan in prosperous, clinically healthy aquaculture is still an issue, nevertheless, its use in breedings endangered by stress stimuli, infectious diseases or adverse environmental factors is indisputable.
Effect of Forbush Decrease (FD) in cosmic ray intensity on mortality from myocardial infarction (MI) in Minnesota* 
Magnetic storms trigger myocardial infarctions with mechanisms relating to heart rate variability. Solar cycle-to-solar cycle differences and solar cycle stage dependence shown herein may resolve prior controversy and serve to advocate coordinated worldwide systematically aligned biological and physical monitoring. * This paper was originally invited by the historian-geophysicist Wilfried SCHRöDER of Bremen, Germany, for his biographical "Encounters," and is to serve as an update on the project on the BIOsphere and the Cosmos (BIOCOS) and its offspring ICEHRV (Dr. Kuniaki Otsuka's International Chronome Ecologic Study of Heart Rate Variability). It is intended for distribution at a NATO conference on space weather hazards, organized by Dr. Ioannis Daglis, June 18-29, 2000.
The aim of the study is to asses blood plasma concentrations of S-100B protein and Tissue Polypeptide Antigen (TPA) in patients with confirmed ischemic stroke and to correlate these concentrations with stroke severity. S-100B protein and TPA blood plasma concentrations were determined in 47 patients with acute ischemic infarction and in the control population. S-100B protein was assessed on the 1th day, TPA on the 1th, 7th and 14th day. The clinical status was documented using Scandinavian Stroke Scale. The functional deficit after the stroke was scored by Barthel Index. The analysis of the entire examined group in relation to the control population showed elevated concentrations of S-100B protein (0.47 ng/ml vs. 0.19 g/ml). The highest concentrations were in the severe stroke group (0.89 ng/ml). The assessment of TPA blood plasma concentrations showed higher ones in the examined group of patients: 225.7 U/l on the 1st day; 96.1 U/l on the 7th day; 125.64 U/l on the 14th day after the stroke in relation to the control population. The analysis of obtained results showed significant increase of S-100B protein blood plasma concentrations in patients with severe stroke and TPA in patients with mild stroke. S-100 protein blood plasma concentration assessed on the 1st day after the ischemic stroke is the parameter presenting the highest diagnostic utility and its value above 0.6 ng/ml was obtained only in patients with severe stroke.
Cocaine-amphetamine regulated transcript peptides (CART) belong to a neuropeptide family expressed in the central nervous system, especially in the hypothalamus, and also in peripheral tissues. The physiological functions of CART include modulation of pituitary hormone release, regulation of body weight, and the control of feeding behavior and metabolic activity. The reciprocal relationships between CART and immune system function have to be established. Therefore, in the present study we aimed to investigate the influence of CART, administered intracerebroventricularly (icv), on selected immune parameters and pituitary-adrenal axis hormone secretion in the rat. In rats submitted to icv infusion of CART or artificial cerebrospinal fluid (aCSF, control) selected immune parameters: splenocyte proliferation (spontaneous and mitogen-stimulated) and peritoneal leukocyte (PTL) activity (spontaneous and phorbol myristate acetate (PMA)-stimulated) were examined 60 and 120 min after treatment. The direct effect of CART on splenocytes in culture in vitro was also examined. Concentration of adrenocorticotrophic hormone (ACTH) and corticosterone was also measured in serum of control and CART infused rats. Splenocytes isolated 60 min after CART infusion exhibited a decreased, albeit non-significant, ability to proliferate spontaneously and were unable to answering to the mitogenic stimulation. This effect was not seen 120 min after CART treatment, which restored splenocyte proliferation decreased by aCSF infusion. CART addition in vitro did not influence proliferation of splenocytes from control rats. Spontaneous activity of peritoneal leukocytes was not modified by CART infusion. PMA-stimulated PTL activity was significantly decreased in aCSF-infused rats 120 min after treatment and CART infusion antagonized this effect. Non-significant increase in serum cortisol after 60 min followed by a significant decrease after 120 min with no change in ACTH concentration was found. The immunomodulatory activity of icv-infused CART appears to consist in the creation of a short-lasting immunosuppressive internal milieu, followed by the immunostimulatory one. This first effect was most probably due to the activation of the HPA axis and/or other immunosuppressive peptides, but not through the direct action of CART on immune cells. Thus, CART appears to be short-lasting and indirect modulator of immunity.
Thyroid function and other biochemical data from parents and proband. 
Objective: We aimed to evaluate the prognostic value of thyroid fine needle aspiration biopsy (FNAB) in the diagnosis of pathologic lesions. Methods: Data from 1 078 consecutive patients (female : male ratio, 9:1) who underwent thyroidectomy were retrospectively analyzed. All patients had preoperative thyroid FNAB. Unilateral and bilateral FNAB were performed in 872 and 206 patients, respectively, resulting in 1 284 cytologic aspirates, which were compared to postoperative histology. Risk factors for malignancy (age, sex, single nodule, or nodule in multinodular goiter) were evaluated. Results: 203 (15.81%) aspirates were non-diagnostic. 768 (59.81%) were benign; 112 (8.72%) were atypical; 170 (13.24%) were follicular neoplasms, 5 (0.4%) had suspicion of malignancy; and 26 (2.02%) were malignant tumors on FNAB. The calculated risk of malignancy in each group was: 1.97%, 1.84%, 7.15%, 12.35%, 60%, and 100%. There were 2.02% false negative and 0.15% false positive results. Diagnostic discrepancies occurred in the follicular neoplasm group, of 86 biopsies (0.15%). Conclusion: FNAB is the primary method of preoperative diagnostics of thyroid tumors, as it allows many patients to avoid thyroidectomy. In addition, it helps the operating surgeon to decide the extent of surgical resection.
THE AIMS OF THE STUDY WERE: To evaluate range and median values of NT in a large, unselected Polish population; to determine the value of the 95th percentile and the median values for NT for given weeks of late 1st trimester pregnancy and to determine the level of chromosomal aberration risk corresponding to the values of the 95th percentile in the examined groups; to examine the possible correlation between CRL, NT width as well as the mother's age with the risk of the most frequent chromosomal aberrations. We have retrospective analyzed 7,866 pregnant women. All fetuses of this women had NT measurement performed, as well as CRL and assessed of the most frequent chromosomal abnormalities. The group of pregnant women was divided into 2 subgroups: until and above 35 years old. All population group was divided into 3 subgroups depending on gestational age (11, 12 and above 13th weeks of gestation). The median of NT in all population group was 1.5 mm and 95th percentile was 2.4 mm, whilst in group with low risk median of NT and 95th percentile were the same and in group with high risk of chromosomal abnormalities respectively 1.5 mm and 2.5 mm. There were strong correlations between maternal age and the risk of most frequent chromosomal abnormalities from NT. The obtained results of median values and the 95th percentiles of NT in the examined group and the age groups under 35 and 35 plus are similar to these quoted by FMF. The risk levels of trisomy of 21st chromosome were similar to the reference values used by FMF. With gestational age, NT value increases in a non-linear way, therefore it is incorrect to use the term "a normal value" for NT, therefore, only the risk level calculated with the dedicated software using NT and CRL measurements with maternal age should be stated.
Arch n. 2440: a patient who underwent surgery but not chemotherapy, treated with adjuvant DBM). The patient underwent mastectomy in 1997 due to "Infiltrating ductal G2". October 27, 2009 - Lymph node histological test "Infiltation due to ductal cancer, metastatic" December 11, 2009 - PET scan: "... High metabolic activity lesions at axillary lymph nodal and bone level (dorsolumbar rachis, right acromion, some ribs bilaterally, right and left iliac regions, right pubic symphysis, left intertrocanteric region). Doubts with respect to right lung." December 29, 2009 - start of DBM treatment June 3, 2010 - PET scan "disappearance of the tracing focal hyper accumulation in the right nodal axillary region and some uptake skeletal areas (III front right costal arch, IV back right arch, left iliac ala, right sacroiliac synchondrosis and left intertrochanteric region) uptake gradient reduction at a vertebral level, uptake gradient reduction in the right subareolar region" 
Objectives: To increase the efficacy and reduce the toxicity of cancer therapy. Method: The DBM with MLT (melatonin), Retinoids, vitamins E, D3, and C has a differentiating, cytostatic, antiangiogenic, immunomodulating, factorially synergic effect, at the same time reinforcing those functions that Physiology considers essential for life. With Somatostatin and/or its analogues, the DBM has an antiproliferative effect, negatively regulating the most powerful mitogenic molecule (GH), receptorially co-expressed and interactive with Prolactin, inhibited by Cabergoline and/or Bromocriptin. The negative regulation of GH extends directly to the GH-dependent growth factors. In breast cancer, the DBM entails the use of estrogen inhibitors and minimal apoptotic, non-cytotoxic and non-mutagenic doses of Cyclophosphamide or Oncocarbide, the tolerability of which is enhanced by MLT and the vitamins in the DBM. Results: Complete and stable cure of 4 cases, and rapid regression of the tumour in another 5 cases with just the DBM (first-line therapy), without surgical intervention. No disease recurrence with the use of the DBM as adjuvant therapy. Five-year survival of 50%, of stage IV cases, considerably higher than the data reported in the literature. A more or less generalised improvement in the quality of life, without any significant and/or prolonged toxicity. Conclusions: The acknowledgement of the still underestimated scientific evidence, such as the multiple antitumoral mechanisms of action of MLT, the negative regulation of the interactive mitogens GH-GF (GH-dependent growth factors), Prolactin and estrogens, together with the differentiating and homeostatic action of retinoids and Vitamins E, D3, and C and MLT, made it possible to achieve these results. An essential aspect of the mechanism of action on the clinical response is the factorial synergy of the DBM components.
The purpose of this study was the correlation of the combined type of ADHD in children and Taq IA polymorphism DRD2 gene. We hypothesized a positive correlation of DRD2 polymorphisms in the combined type of ADHD patients without co-morbidity. Our research sample included 586 unrelated boys of the Czech origin aged between 6 and 13 years. The ADHD group consisted of 269 boys and the control group consisted of 317 boys. PCR detection of the DRD2 polymorphism was carried out by using primers, described by Grandy (Grandy et al. 1989). The comparison of genotype frequencies showed statistically highly significant difference between the studied groups (p<0.0001). A statistically significant difference was also found when the allelic frequencies between the two groups were compared (p<0.0001), with the A1 allele having a 4.359 fold higher risk of ADHD (Risk Ratio=4.359, 95% CI of RR=3.5753 to 5.3144, Odds Ratio= 7.7824; 95% CI of OR=10.315 to 13.6719). Our results presented a highly positive correlation between the combined type of ADHD without co-morbidity and ANKK l (DRD2) polymorphism .
Ellipticine is a potent antineoplastic agent exhibiting multiple mechanisms of its action. Recently, we have found that 13-hydroxyellipticine, formed from ellipticine as the predominant metabolite in human livers, is bound to deoxyguanosine in DNA, generating the major DNA adduct in vivo and in vitro. The development of the methods suitable for the preparation of this adduct in the amounts sufficient for identification of its structure and those for its isolation and partial characterization is the aim of this study. High performance liquid chromatography (HPLC) was employed for separation of 13-hydroxyellipticine-mediated deoxyguanosine adduct. The 32P-postlabeling technique was utilized to detect this adduct in DNA. The formation of the 13-hydroxyellipticine-derived deoxyguanosine adduct in DNA in vitro was increased under the alkaline pH of the incubations and by the formation of the sulfate and acetate conjugates of 13-hydroxyellipticine generated by reactions with 3'-phosphoadenosine-5'-phosphosulfate (PAPS) or acetyl-coenzyme A (acetyl-CoA) catalyzed by human sulfotransferases (SULTs) 1A1 and 1A2 and N,O-acetyltransferases (NATs) 1 and 2. The HPLC method suitable for separation the 13-hydroxyellipticine-derived deoxyguanosine adduct from other reactants, deoxyguanosine and 13-hydroxyellipticine, was developed. The structure of this adduct is proposed to correspond to the product formed from ellipticine-13-ylium with the exocyclic 2-NH2 group of guanine in DNA. The data are the first report on HPLC isolation of the deoxyguanosine adduct formed by 13-hydroxyellipticine in DNA and its partial characterization.
Acromegaly is a rare disease with increased mortality rate. The aim was to present our centre experience in the diagnosis and treatment of a series of patients suffering from acromegaly. 130 patients (55 men, 75 women) aged 19-84 years presenting with clinical and hormonal features of acromegaly, attending Department of Endocrinology and Out-patient Clinic between 1990 and 2004 were studied. They were analyzed their GH and IGF-1 levels, CT and MRI scans, and they were administered medical therapy, neurosurgery and radiotherapy. We have observed 106 macro-, 16 microadenomas and 1 case of ectopic GHRH. 115 patients were operated, as cured were recognized 74 of them. Pituitary irradiation was applied to 11 patients, in 4 of them it did not cure the disease. Medical therapy was efficacious in 12% patients treated with bromocriptine, 73% with long-acting lanreotide and 58% with long-acting octreotide. In 7 patients other malignant neoplasm were detected. 11 patients died during the follow-up. There is possible underdiagnosis of acromegaly in our region, especially in males. We have observed better diagnostic opportunities in recent years when MRI was available. It was accompanied by better outcome of surgical and pharmacological treatment and better control of the complications of the disease.
Understanding the enzyme mechanism of P450 enzymes needs a detailed knowledge of substrate-enzyme interactions. Here, we examined the interaction of cytochrome P450 2B4 with a diamantanoid substrate. The interaction was followed using a photoactivable label, 3-azidiamantane. After photochemically driven reaction, the labeled enzyme was cleaved by trypsine and the labeled peptides separated by HPLC and identified with the help of radioactivity (for tritiated label) and mass spectrometry. The results were analysed on the basis of the known X-ray structures for mammalian cytochromes P450. Identification of labeled peptides has shown that the probe (binding as a substrate to the enzyme) was attached to fragments: 30-48 (the most likely positions of the label are Leu44, Gln45 and Asp47), 127-140 (with Arg133 labeled, as indicated by mass spectrometry), 359-373 and 434-443 (the exact position of the label unknown). The structural comparison indicates considerable differences in Arg133 interaction with heme propionates, connected with binding of the substrate. Labeling of this residue may thus reflect its involvement in modulation of cytochrome P450 activity. The results show existence of additional binding sites for substrate on cytochrome P450 2B4, located close to the surface of the enzyme.
In 1993-1998 and in 1999-2004 we have performed two surveys of pediatric bacterial meningitis in all 8 neurosurgery/pediatrics and infectious diseases departments in Slovakia. We have detected 101 and another 54 cases with attributable mortality of 15% and sequellae in 18%.
The human behavior is a fundamental phenomenon in contemporary sciences in the widest sense of the word. The wide range of world problems such as wars, criminality, social depravation, famine, different catastrophes as Tjernobyl up to the pandemic AIDS, etc. are transferable into one common denominator: the failure of man in his behavior. Adequate understanding of all behavioral mechanisms and their failures is condition sine qua non for the most important task-the prediction of actual behavior resulting from different bio-psycho-socio-cultural sources. The authors express presumption about the essential importance of three basic postulates (I-III) in every kind of behavioral research: (I) Human life is an indivisible continuum from its very beginning (especially vulnerable) over adulthood (inclusive reproduction) until death. The prenatal stages of life are integral and very sensitive periods of human ontogenesis. Every discontinuity in this development can lead to physical, mental and social disfunctions in both prenatal and postnatal life. (II) Motivation is a basic inner drive generating the actual human behavior. All its five components should be taken into consideration: 1. Qualitative (the kind of motivational state: alimentary, sexual, territorial, etc.) 2. Quantitative (the intensity of motivational state, "arousal"). 3. Inner structure of each motivational state (into partial motivational states with specific sensitivity to external stimulation). 4. Synthetic (causal and functional aspects of actual motivation). 5. Hierarchy of motivational states (self-preservation of the individual is probably on the top of such a hypothetical hierarchical structure). (III) Both previous postulates demand the integrative approach to the study of human behavior and refers to three basic sources of behavior: 1. Function of the CNS. 2. Function of the endocrine system. 3.Variability of external conditions (including all kinds of behavioral stimulation).
Wolfram syndrome (WS) is an autosomal recessive disorder characterized by the association of juvenile-onset diabetes mellitus and optic atrophy. It is also known by the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). We diagnosed Wolfram syndrome in 2 male siblings and determined a new mutation (c. 1522-1523delTA, Y508fsX421). Both affected siblings were homozygous, other family members were heterozygous. Dilated renal outflow tracts in the third decade, and neuropsychiatric disorders including bipolar disorder and neurosensorial deafness appear in the fourth decade in ordinary WS, whereas these features appeared in second decade in our patients. This mutation may be responsible for early appearance of dilated renal outflow tracts and multiple neurological abnormalities. Psychiatric disturbances such as suicide were reported at increased frequency in Wolfram patients and in heterozygous carriers. Suicidal behaviour occurred in our patients when they were yet 11 and 13 years old. Therefore, our findings may indicate that there may be a relationship between this WFS1 mutation and mood disorder such as suicidal behaviour. We determined a new mutation (c. 1522-1523delTA, Y508fsX421) in WS1 gene in 2 siblings with Wolfram syndrome. This mutation may be responsible for early appearance of clinical features of Wolfram syndrome, and there may be a relationship between this mutation and suicidal behaviour.
The endocannabinoid system (ECS) is a lipid signalling system, comprising of the endogenous cannabis-like ligands (endocannabinoids) anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which derive from arachidonic acid. These bind to a family of G-protein-coupled receptors, called CB1 and CB2. The cannabinoid receptor 1 (CB1R) is distributed in brain areas associated with motor control, emotional responses, motivated behaviour and energy homeostasis. In the periphery, the same receptor is expressed in the adipose tissue, pancreas, liver, GI tract, skeletal muscles, heart and the reproduction system. The CB2R is mainly expressed in the immune system regulating its functions. Endocannabinoids are synthesized and released upon demand in a receptor-dependent way. They act as retrograde signalling messengers in GABAergic and glutamatergic synapses and as modulators of postsynaptic transmission, interacting with other neurotransmitters. Endocannabinoids are transported into cells by a specific uptake system and degraded by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS is involved in various pathophysiological conditions in central and peripheral tissues. It is implicated in the hormonal regulation of food intake, cardiovascular, gastrointestinal, immune, behavioral, antiproliferative and mammalian reproduction functions. Recent advances have correlated the ECS with drug addiction and alcoholism. The growing number of preclinical and clinical data on ECS modulators is bound to result in novel therapeutic approaches for a number of diseases currently treated inadequately. The ECS dysregulation has been correlated to obesity and metabolic syndrome pathogenesis. Rimonabant is the first CB1 blocker launched to treat cardiometabolic risk factors in obese and overweight patients. Phase III clinical trials showed the drug's ability to regulate intra-abdominal fat tissue levels, lipidemic, glycemic and inflammatory parameters. However, safety conerns have led to its withrawal. The role of endocannabinoids in mammalian reproduction is an emerging research area given their implication in fertilization, preimplantation embryo and spermatogenesis. The relevant preclinical data on endocannabinoid signalling open up new perspectives as a target to improve infertility and reproductive health in humans.
Melatonin may influence directly tumor cells through the specific binding sites. The best known melatonin binding sites are membrane receptors. Recently, the participation of nuclear signalling via estrogen as well as RZR/ROR receptors in oncostatic action of melatonin on the breast cancer has been widely discussed. The aim of present study was to investigate effects of melatonin, the selective ligand for nuclear RZR/ROR receptors - CGP 52608, and methotrexate on growth of murine 16/C breast cancer cells. The experiment was performed in vitro. The breast cancer cells were incubated for 2 days in the presence of melatonin, CGP 52608 (at concentrations of 10(-5)M, 10(-7)M, 10(-9)M, 10-(11)M ) and methotrexate (at concentrations of 0.25 and 0.125 microg/ml). The growth of cells was measured using the modified Mossman method. All examined compounds significantly inhibited the growth of cancer cells. The effects of MLT and CGP 52 608 were comparable with suppression caused by methotrexate. The significant differences of efficacy between two examined concentrations of methotrexate were not observed. The obtained data together with our previous results indicate that nuclear receptors RZR/ROR play an important, although not sufficiently recognized role in the oncostatic action of melatonin.
Objective: To evaluate the objective clinical response and the safety of the combined administration of somatostatin, melatonin, retinoids, vitamin D3, dopamine subtype 2 receptor (D2R) agonists and low doses of cyclophosphamide, associated with androgen ablation, in patients with a histological diagnosis of prostate adenocarcinoma (Pac). Materials and methods: The clinical data of 30 patients with non-invasive and metastatic prostate cancer, who attended our institution over a period of more than 5 years, were retrospectively reviewed. Results: 16 patients satisfied the evaluation criteria. Median age: 64 years. Disease stages: 8 patients (50%) were in Stage II. For advanced stages (Stage IV), secondary lesions were located in the bones and lymph nodes. Taken together, an overall objective response (OR) [Complete response (CR) + Partial Response (PR)] was achieved in 69% of the patients, with 88% of objective clinical benefit [CR+PR+SD]. For local Prostate Cancer group, an OR was achieved in 87.5% of patients (7 cases; 53-98; 95% CI), with CR in 62.5% (5 cases, 31-86; 95% CI). In metastatic disease, the OR was 50% (4 cases; 21-78; 95% CI), with a 20% of CR (2 cases; 7-59; 95% CI) and 75% of clinical benefit. Conclusions: This preliminary study shows that patients with early and advanced forms of prostate cancer, not previously treated by surgery and/or chemo-radiotherapy, can achieve a more than positive clinical benefit with the protocol foreseen by the Di Bella Method. Further clinical investigations are strongly recommended.
Dear Colleagues, in front of you is a supplement of Neuroendocrinology Letters containing the full text of selected papers to be presented at the opening of the XVI Congress of Atherosclerosis for 2012. The dominant role in atherosclerosis and its clinical complications as a leading cause of death is evident. During the past two decades, the clinical complications of atherosclerosis is not only the top killer in the developed countries but also in many developing countries. This Supplement represents a new and groundbreaking step in the development of the Czech Society for Atherosclerosis. When we started to set up our society in 1995, our intention was to unite all our Czech colleagues working in the field of risk factors for atherosclerosis - from the experimental approach in preventive cardiology, to clinical treatment and epidemiology of cardiovascular diseases. Our aim was quite modest and we expected to organize relatively small conferences to give a chance for all specialists to meet and discuss issues of common research. In recent years, our Congress has become a conclave that promotes interaction between these groups and provides an exchange of basic research in the prevention and treatment of atherosclerosis in the Czech Republic. Not only has the size of our annual congresses increased steadily from our first conference in Podebrady 1996, but also the quality of the data presented is to gradually increase. It is clear from the list of full-text papers to be presented this year - that the broad research field of atherosclerosis and its risk factors is expanding. We will consider new information on such topics as the ongoing fight against smoking, the treatment of risk factors for cardiovascular disease through diet, statins, and hormones and the clinical data technologically advanced treatment of heart failure. There is a tradition of our congresses that several documents on molecular genetics of cardiovascular disease are also included. Personally, I am glad that this addition also contains several articles focusing on gradually increasing importance of adipose tissue in obesity and the risk of premature atherosclerosis development. The new scientific information in this Supplement of Neuroendocrinology Letters is a further step in the development of our society.
Human corticotrophin-releasing hormone (CRH) plays a pivotal role in the stress response. Its expression is under the control of various steroid hormones, such as estrogens. The transcriptional activity of the estrogen receptor (ER) may be modified by small-ubiquitin related modifier (SUMO1). In the present study, we aim to reveal the role of SUMO1 in the regulation of ER-mediated CRH promoter activation. CHO-K1 cells were transfected with human ER and SUMO1 expressing plasmids together with the CRH promoter reporter gene. CRH mRNA was detected in BE(2)C cells by real time PCR. We found that estradiol could elevate CRH promoter activity to a much higher level in cells co-transfected with ER and SUMO1 than that with ER alone, and that the enhancement was blocked by the ER inhibitor, ICI182,780. Furthermore, the endogenous CRH mRNA expression was also increased when the BE(2)C cell were transfected with ERalpha and SUMO1 in contrast to the transfection with ERalpha alone. Our results indicate that SUMO1 participates in the modulation of ER-mediated CRH mRNA expression which may be important for the regulation of the stress response.
OBJECTIVES: The aim of the study was to examine susceptibility of the pituitary gland to estrogenic impulse in old, noncycling rats by measurement of steady state level of mRNAs encoding LH subunits a and b and mRNA for PRL. METHODS: 22-month-old rats were ovariectomized and after one week they were subcutaneously implanted with silastic tubing filled with oil or with estradiol 17-beta. Pituitary alpha, LHbeta and PRL mRNAs content and serum LH and PRL concentration was determined. RESULTS: The effect of E (2)treatment was manifested by the significant increase in the weight of the uterus and pituitary gland as well as by elevation of total pituitary RNA (109%, 60% and 78%, respectively; p<0.001). No significant changes (p>0.05) in serum LH concentration were observed, while levels of mRNAs encoding alpha and LH-beta subunits were lowered by 54% (p<0.05) and 96% (p<0.01), respectively, in the rats subjected to E(2) stimuli. No direct correlation between synthesis and release of LH in E(2) treated old rats was observed. The blood PRL concentration and the pituitary level of PRL mRNA increased up to 2,000% and 1,300%, respectively (p<0.001). Spontaneous pituitary adenoma was observed in about 30% of the rats, irrespective of treatment. CONCLUSIONS: These data show that in old rats estrogenic stimulus can effectively diminish both pituitary LH subunits mRNAs as well as stimulate pituitary PRL mRNA level indicating that the E(2)-dependent processes involved in the regulation of corresponding genes are still functional.
In earlier studies, we demonstrate that 17-beta -estradiol and an estrogen cell surface receptor can be found on various human cells, i.e., vascular endothelial, monocytes, and granulocytes, where they are coupled to nitric oxide release. We further demonstrated this phenomenon in the marine mussel Mytilus edulis ganglionic tissues. In the present report we sought to determine if estrogen can be found in M. edulis reproductive tissues. We determined the presence of 17-beta -estradiol via high pressure liquid chromatography (HPLC) and radioimmunoassay (RIA) in the animals gonads. This substance was further identified via nanoelectro-spray ionization quadrupole time of flight mass spectrometry (Q-TOF-MS). 17-beta -estradiol was identified and quantified in Mytilus gonads. Interestingly, we also determined that estradiol isoforms also were present in this tissue. These data demonstrate that 17-beta-estradiol and an estradiol isoform is present in M. edulis gonadal tissues, suggesting that they have functions related to reproduction. This further suggests that estrogen's association with reproductive activities has a long evolutionary history and that this association began in invertebrates.
Growth hormone-releasing hormone (GHRH) plays a crucial role in the secretion of GH from the pituitary, acts as a growth factor in variety of cancer cells and possesses immunomodulatory activity. Interleukin(IL)-17 apart from its pro-inflammatory role has been also shown to play a role in carcinogenesis. The effect of GHRH on the IL-17 has not been studied so far. To evaluate the effect of GHRH on the secretion of IL-17 from human peripheral blood mononuclear cells (PBMC) in vitro. The concentrations of IL-17 in supernatants from PBMC cultured for 24 hrs were assessed using ELISA kit. We show for the first time that GHRH can stimulate the secretion of IL-17 from human PBMC in 24 hrs culture, and that GHRH antagonist counteracts this effect. Our study further elucidates the immunomodulatory role of GHRH.
Microglial exodus over a 24 hour period and its antagonism by varying concentrations of E 2 -BSA. The experiments were replicated 4–6 times. The mean value of these trials is represented along with the standard deviation. Statistical signifi cance (P<0.01) was determined by a one-tailed students t-test comparing migration numbers at 24 hours to 10 –8 to 10 –6 M E 2 -BSA exposed values.  
In earlier studies we have demonstrated that 17-beta-estradiol and an estrogen cell surface receptor can be found on various human cells where they are coupled to nitric oxide release. We also demonstrated the presence of estrogen signaling in Mytilus edulis ganglia. In the present report, we sought to determine a function for these ganglionic estrogen receptors, transcending a reproductive role for estrogen. Ganglionic microglial egress from excised pedal ganglia was examined microscopically following pharmacological treatments designed to determine a role for 17-beta-estradiol in microglial regulation via nitric oxide. Additionally, we examined the tissue by RT-PCR and sequence analysis for the estrogen receptor beta gene. In ganglia incubated with varying concentrations of 17-beta-estradiol-BSA there is a significant drop in microglial egress at the 24 hour observation period (58.7 +/- 7.4 vs. 17-beta-estradiol-BSA exposed = 14.7 +/- 1.5; P<0.01), which can be antagonized by tamoxifen and significantly diminished by L-NAME, a nitric oxide synthase inhibitor. By RT-PCR and sequence analysis Mytilus edulis pedal ganglia was found to express a 266 bp fragment of the estrogen receptor-beta gene, which exhibits 100% sequence identity with the human counterpart. These data suggest that 17-beta-estradiol-BSA is working on estrogen cell surface receptors since 17-beta-estradiol-BSA does not enter the cytoplasm and that these receptors are coupled to constitutive nitric oxide release. This study demonstrates that 17-beta-estradiol can down regulate microglial fMLP induced activation and activation following ganglionic excision.
Recurrent miscarriages (RM) are significant social and clinical problem. One of suggested reason of RM is hyperhomocysteinemia. Polymorphic genes involved in homocysteine and folate metabolism, including 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, are considered as an important risk factors for homocysteine accumulation and modulator of RM susceptibility. Therefore the aim of this study was to evaluate the frequency of MTHFR polymorphisms (677C>T, 1298A>C, and 1793G>A) in women with recurrent miscarriages. We have analyzed 104 Polish women with a history of 3 or more unexplained recurrent miscarriages in the first pregnancy trimester (6-13 gestation week). The control group consisted of 169 women without obstetrical complication, any history of miscarriage and with at least one live birth in anamnesis. The investigated polymorphisms were determined by PCR/RFLP methods. For MTHFR 1793G>A polymorphism we have observed significant overrepresentation of heterozygotic GA genotypes in RM group (15.38% vs. 4.14% in the controls, OR=4.21, p=0.003). For 677C>T and 1298A>C we have shown lack of significant association with RM. Nevertheless, such significant association was observed if more than one mutated MTHFR variant was present in one patient. Our research indicate the possible role of MTHFR 1793G>A polymorphism in pathogenesis of RM. The noticed tendency to more frequent occurrence of haplotypes of MTHFR gene including two or three mutated alleles showed the possibility of summarized amplification of these variants effect influencing RM susceptibility.
The aim of present work was to examine estrogen influence on neurogenesis in the model of predegenerated peripheral nerve grafts implantation into the rat hippocampal dentate gyrus. Experiment was carried out on female rats divided into three experimental groups: NO - non-ovariectomized, OV - ovariectomized and E - heterogeneous group with various 17-beta-estradiol substitution after ovariectomy. Proliferating cells were labeled with BrdU. Brains were subjected to immunohistochemical procedures to visualize nestin, GFAP and estrogen receptors (ERalpha and ERbeta). Proliferation rate was highest in E groups with estrogen levels resembling that in proestrus phase. Ovariectomy resulted in higher than in NO group number of new neurons, while high hyperestrogenemia worsened the results. The proportions of nestin-labeled cells correlated in similar way with different hormonal state. We found also distinct co-localization of nestin and GFAP in E group (proestrus). It may suggest the presence of radial glia, a potential source of new neurons in adult mammals. Nerve graft induced ERalpha expression at the site of injury in all groups. Distribution of ERbeta in hippocampus was estradiol-dose-dependent and correlated with cell proliferation. In our model, 17-beta-estradiol and predegenerated nerve graft implantation had synergistic effect on hippocampal neurogenesis.
Calcium transport pathways are key factors for understanding how changes in the cytoplasmic calcium concentration are associated with neuroprotection because calcium is involved in the onset of death signaling in neurons. This study characterized the effects of 17β-estradiol and IGF-1 on voltage-activated and stretch-activated calcium channels in rat cultured cortical neurons. The whole-cell patch-clamp technique, using a voltage steps protocol or by applying positive pressure into the micropipette, was used on 7-10 day cultured neurons from a Wistar rat cortex, and pharmacological characterization was performed on these neurons. Both 17β-estradiol and IGF-1 inhibited the currents mediated by L-type voltage-activated calcium channels, although the IGF-1 effects were lower than those of 17β-estradiol. The effect of both hormones together was greater than the sum of the effects of the individual agents. Unlike IGF-1, 17β-estradiol decreased the current mediated by stretch-activated channels. The inhibition of the classical receptors of these hormones did not affect the results. Both hormones regulate voltage-activated calcium channels in a synergistic way, but only 17β-estradiol has an inhibitory effect on stretch-activated calcium channels. These effects are not mediated by classical receptors and may be relevant to the neuroprotective effects of both hormones because they diminish calcium entry into the neuron and decrease the possibility for the onset of apoptotic signaling.
A strong positive coupling has been already documented between the adrenocortical axis and the gonadal axis at the time of the initiation of the preovulatory LH surge of the menstrual cycle in the human. The LH preovulatory surge starts in the morning at the time of the acrophase (maximal plasma cortisol values) of the cortisol circadian rhythm. Also, it was shown that morning maximal plasma cortisol values were higher during the follicular phase than during the luteal phase. The objective of the present study was designed to determine the exact day of the fall of morning maximal plasma cortisol values and the functional correlates which could exist between plasma 17beta-Estradiol, LH, ACTH and Cortisol at the time of the preovulatory LH surge. We performed a detailed analysis of variations of plasma ACTH and cortisol concentrations during the various phases of the LH surge: 1) the day before the ascending phase, 2) the day of the ascending phase, 3) the day of the LH peak, 4) the day of the descending phase, 5) the day after the descending phase. 17beta-Estradiol, LH and FSH were determined by microparticle enzyme immunoassays kits and Progesterone determination was made using a radioimmunoassay kit. ACTH determination was made using a RIA kit and Cortisol was assayed by a RIA method. Plasma ACTH concentrations were at their highest the day before the day of the ascending phase of the LH surge and significantly higher than the day of the descending phase and the day after the day of the descending phase (p < 0.02). Plasma cortisol concentrations were at their highest, with almost similar values, the day before the day of the ascending phase, the day of the ascending phase and the day of the LH peak; then, plasma cortisol concentrations were significantly lower than those of the preceding days, the day of the descending phase (p = 0.0001) and the day after the day of the descending phase (p = 0.02), when plasma 17beta-Estradiol starts to decrease. Overall, these results suggest that the positive ACTH-Cortisol-Estrogen dependency, well documented in the female rat, is also operating at midcycle during the menstrual cycle in the human.
Objectives: To compare the effect exerted by oral tibolone or intramuscular 17β-estradiol administration on the expression of ZO-1, occludin, GFAP and c-fos levels in the brain cortex and hippocampus of ovariectomized rats. Results: Immunostaining for ZO-1 and occludin revealed similar staining patterns between controls and tibolone rats and between controls and E2 rats. When staining in tibolone and E2 rats were compared both for ZO-1 and occludin, staining patterns were again identical. Positive staining for the GFAP was detected in the controls, tibolone rats and E2 rats. Staining was more intense in the tibolone rats than controls and in the E2 rats than controls. In sections from the controls, tibolone rats and E2 rats, number of reactive cells for c-fos were 1.75±0.25, 3.75±0.36 and 4.50±0.50, respectively. There was a statistically significant difference between the three groups (p=0.0001). Comparison of tibolone and E2 rats revealed no statistically significant difference (p=0.246). Conclusions: It is well known that natural hormones like E2 regulate brain development and function. Our results provide further information on the mechanism of action of tibolone in the brain cortex and hippocampus. These results will allow us to continue with further studies with different post-ovariectomy intervals, because tibolone can be proposed as an attractive alternative for hormone replacement therapy, acting as a neuroprotective agent for the prevention of neurodegenerative diseases in menopausal women.
A controlled laboratory study was carried out to quantify vitellogenin (VTG) concentrations in a common cyprinid freshwater fish, the chub (Leuciscus cephalus L.), exposed to steroid hormones. The effect of 17betaestradiol, testosterone and testosterone-estradiol mixture was investigated on vitellogenin induction. Gonad status was also determined. Oral exposure to estradiol and a testosterone-estradiol mixture increased (p < 0.01) blood plasma concentrations of VTG in blood plasma of both sexes. The testosterone-estradiol mixture had a negative effect on the investigated chub gonads. The effects were signified by histological changes when compared to control fish. Our results showed a significant VTG increase in blood plasma of both sexes, indicating that vitellogenic response in the chub is sensitive to steroid hormones.
Akathisia is a clinical important symptom, frequently induced by neuroleptic treatment. Despite its clinical importance, less is known about its pathophysiology. Using [18]-FDG-PET, imaging patterns of cortical metabolic activity were obtained in a patient during olanzapine-induced akathisia and after recovery. Akathisia was characterized by a reduced metabolic activity in thalamus and cerebellum. After discontinuing medication akathisia disappeared, reflected by a recovery of metabolic activity in these brain areas. [18]-FDG-PET may be useful to identify cortical regions mediating clinical aspects of drug-induced akathisia, thereby offering a deeper insight into the pathophysiology of this serious side effect.
The aim of this study is to assess the toxicity of PAX-18 in different developmental stages of common carp (Cyprinus carpio). The preparation PAX-18, with its active ingredient polyaluminium chloride (9% of Al), is a coagulation agent that is used mainly to precipitate phosphates, to prevent surface water eutrophication and incidences of cyanobacteria. It is applied to the water environment and thus could present a potential risk to fish. The toxicity tests were performed on common carp according to OECD (203, 210) methodologies. The acute toxic effect was evaluated for juveniles and the early development stage effect was observed in embryo-larval toxicity tests. The results of the toxicity tests (the number of dead individuals at particular test concentrations) were subjected to a probit analysis using an EKO-TOX 5.2 programme to determine the LC50 values of PAX-18. Acute toxicity value expressed as 96hLC50 was 753.1 +/- 24.3 mg.l-1 (67.8 mg.l-1 Al). Effect on early development stage expressed as the no observed effect concentration was 10 mg.l-1 (0.9 mg.l-1 Al), the lowest observed effect concentration was 50 mg.l-1 (4.5 mg.l-1 Al). No significant effects of the preparation PAX-18 in concentrations of 50 mg.l-1 of PAX-18 and lower were found on hatching, length and weight parameters, morphology and histopathology. The lethal concentration of PAX-18 found in acute toxicity tests on common carp was 7-14 times higher than the concentration which is usually applied to water (5-10 mg.l-1 Al). Moreover, fish in eutrophicated water sources are exposed to PAX-18 concentrations corresponding with the lowest observed effect concentration only for a short time, therefore the effect on them can be considered as minimal.
Nosocomial neuroinfections due to Enterobacteriaceae represented 9.5% in our cohort of 171 cases of paediatric meningitis within last 15 years. Commonest etiologic agents was E. coli - 9 (50%) followed by Klebsiella pneumoniae - 3 (16,7%) and Enterobacter cloacae. Citrobacter freundii, Proteus mirabilis and Salmonella enteritidis (1 each). Commonest risk factors were neonatal age 13 - (72.2%), very low birth weight 5 (27.8%), craniocerebral trauma - 4 (22.2%) and neurosurgery - 5 (27.8%). All but 1 case were treated with antibiotics: 8 with III-rd and 3 with IV-th generation cephalosporins (ceftazidim, cefotaxim and cefepim) 2 with meropenem and 4 with ciprofloxacin: Nosocomial meningitis due to enterobacteriaceae was associated with significantly high mortality (29.9% vs. 15.1% in all cohort of pediatric meningitis - p<0.02).
The aim of the study was to investigate effects of the triazine herbicide metribuzin on signal crayfish Pacifastacus leniusculus Dana by determining oxidative stress (thiobarbituric acid reactive substances) and antioxidant indices (total superoxide dismutase, catalase, glutathione reductase) in hepatopancreas, muscle, and gill as well as assessing their histopathology. Crayfish were exposed to metribuzin concentrations of 0.52 µg.l-1 (realistic environmental concentration) and 3.06 mg.l-1 (10% 96hLC50) for 10 and 30 days followed by a 30-day depuration period without exposure to metribuzin. In the thiobarbituric acid reactive substances, superoxide dismutase, and catalase were observed differences in all examined tissues compared to the control group. Differences from control were observed in glutathione reductase activity in hepatopancreas after 10 days for both exposure concentrations and after 30 days at 3.06 mg.l-1. Histological examination revealed extensive focal autolytic disintegration of tubular epithelium in hepatopancreas of crayfish exposed to metribuzin for 30 days. Chronic exposure of metribuzin resulted in oxidative damage to cell lipids, in changes of antioxidant activity in crayfish tissue, and pathological changes in hepatopancreas. The results suggest that selected oxidative stress biomarkers, antioxidant enzymes, and pathologies of hepatopancreas may have potential as biomarkers for monitoring residual triazine herbicides in the aquatic environment.
Antidepressants administered in pharmacotherapy group: 
Regions of decreased and increased 18 FDG-PET uptake in the group of patients treated with antidepressants or CBT.  
The goal of our study was to identify brain structures in patients with panic disorder (PD) that show changes in 18FDG PET during the treatment with cognitive behavioral therapy (CBT) or antidepressants. Twelve patients suffering from panic disorder were studied with [18F]-2-fluoro-deoxyglucose positron emission tomography (18FDG PET) scanning during resting state (condition of random episodic silent thinking, REST). After PET examination patients were randomly assigned to either cognitive behavioral treatment group (6 patients) or antidepressants treatment group (6 patients). After a 3 month period 18FDG PET examination was repeated in both groups. Psychopathology was assessed using the rating scales HAMA, CGI and Panic Disorder Severity Scale (PDSS). Data were analysed using software for statistical parametric mapping (SPM99). The scores of psychopathology rating scales (CGI, HAMA, PDSS) decreased in both groups. Changes of 18FDG uptake in the pharmacotherapy group: decreases were found in the a priori hypothesized regions in the right hemisphere, in the superior, middle, medial and inferior frontal gyrus, superior and middle temporal gyrus, and increases were detected in the a priori hypothesized regions, mainly in the left hemisphere in medial and middle frontal gyrus, superior, middle and transverse temporal gyrus. Changes of 18FDG uptake in the CBT group: decreases were found in the a priori hypothesized regions of the right hemisphere in the inferior temporal gyrus, superior and inferior frontal gyrus, and increases were detected in the a priori hypothesized region, mostly in the left hemisphere: inferior frontal gyrus, middle temporal gyrus and insula. We did not detect changes in 18FDG uptake in the limbic region (hippocampus, parahippocampal gyrus and amygdala). Changes in brain metabolism (18FDG uptake) after the treatment either with CBT or with antidepressants were similar in number of brain areas, with prominent right-left difference. This is in concordance with the asymmetry of brain activity noted in patients with PD according to previous PET (and SPECT) studies.
The positive correlation between 18 FDG uptake and abstinence duration after discharge from the inpatient treatment program. 
The acute and maintenance treatment of alcohol addiction represents the clinical challenge. The aims of our study were to evaluate the influence of alcohol consumption on regional brain metabolism and the predictive value of PET by means of the duration and quality of remission which followed the sub-acute treatment. PET investigation with 18fluoro-deoxyglucose (18FDG) were performed in detoxified patients with alcohol dependence at the end of short-term treatment. Abstinence was evaluated in patients during the one year follow-up period. We detected the positive correlation between 18FDG uptake in the cerebellar vermis (FWE, p<0.05) and duration of abstinence within one year. Our findings support the assumption that the cerebellum would be involved in the maintenance of abstinence in alcohol dependent subjects. Cerebellar connections with cortical areas critical for addiction such as frontal, parietal, temporal regions would mediate the influence of the cerebellum on emotional systems related to addiction. Our study is the first to document that the cerebellum and particularly the vermis is involved in the clinical outcome in terms of abstinence during one year. Our findings support the role of the cerebellum in addiction and the possibility to predict therapeutic outcome.
With the aim to indicate the functional anatomical substrate of cognitive dysfunction in schizophrenia we evaluated the relationship between resting brain metabolism and performance on the Trail Making Test (TMT). As the prerequisite analysis we compared the performance in Part A and B of the TMT between schizophrenic patients and controls. Resting brain metabolism was investigated by (18)FDG positron emission tomography (PET) as the probe for the relative regional synaptic strength and density. (18)FDG PET data were analyzed by SPM99 with TMT A and B as the covariate (p< or =0.001). Schizophrenic patients (N=42) had worse performance in both TMT A and B compared to controls (N=42). In schizophrenic subjects (18)FDG PET did not predict the performance on Part A (psychomotor speed) but predicted that for Part B (set-shifting and flexibility) of the TMT. The (18)FDG uptake in the superior, middle and inferior frontal gyruses bilaterally was associated with better performance in the TMT B. The negative covariation between 18FDG uptake and time spent in the TMT B was detected in the temporal and parietal cortices, pre- and postcentral gyruses, precuneus limbic regions (anterior cingulate, uncus) and the pons. Our data indicate that hypometabolism in the frontal lobes and hypermetabolism in the temporo-parieto-limbic regions is the neurobiological basis for deficient TMT B performance in schizophrenia.
The aim of the study was to detect whether the abnormal regional brain activity correlates with auditory verbal hallucination-proneness (AVH) in a group of patients with schizophrenia and schizophrenia-related psychoses. 15 patients with prominent AVH (score for hallucination intensity--item 3 in the PANSS > or =4) and 15 control patients without AVH (item 3 PANSS score < or =2) underwent 18FDG positron emission tomography at rest. SPM group analysis revealed an increased uptake of 18FDG in the right middle frontal gyrus (BA46) in subjects with high verbal hallucination score compared to non-hallucinating patients (p<0.001, uncorrected). Activation in BA46 positively correlated with the intensity of hallucinations (Spearman r=0.57; p<0.001). The observed functional recruitment of the right prefrontal cortex in subjects with high hallucination score may reflect impairment in the integration of intended actions and sensory feedback resulting in misattribution of internal events to an external source. This mechanism may form the cognitive basis for AVH.
The therapeutic effect of probiotics has been studied in many clinical and experimental studies but no data exist concerning the influence of probiotics on pharmacokinetics of contemporary administered drugs. In this paper, we describe the influence of indomethacin-induced gastrointestinal lesions and Escherichia Coli Nissle 1917 medication on absorption of 5-aminosalicylic acid and its metabolite N-acetyl-5-aminosalicylic acid in rat. 5-aminosalicylic acid (5-ASA) was given orally to rat using gastric probe as a suspension (25 mg/kg). The plasma time profiles of 5-ASA and its metabolite were compared between Group A (animals medicated with a suspension of Escherichia coli Nissle 1917 [EcN] in dose of 5 × 108 CFUs/day for 14 consecutive days), Group B (animals with indomethacin [IND]-induced gastrointestinal lesions; single dose of 25 mg/kg of IND), Group C (simultaneous administration of EcN and IND), and Group D (control animals without any medication). The blood samples for HPLC analysis has been taken from incannulated vena jugularis in time 30, 60, 90, 120, 180, 240, 360 min after 5-ASA administration to rat. The pharmacokinetics of 5-ASA was not significantly changed by EcN medication (Group A) in comparison to control animals (Group D). The significantly elevated absorption (AUC and cmax) of 5-ASA was found in animals with induced gastro-enteropathy with concurrently medicated with EcN (Group C) when compred to controls. In the case of metabolite N-acetyl-5-ASA, statistically no-significant differences were found between groups. Simultaneous probiotics (EcN) medication did not affect absorption 5-ASA from intestinal tract (the main site of ASAs action).
The aim of the study was to find whether probiotic Escherichia coli Nissle 1917 O6:K5:H1 (EcN) influences the expression of cytochromes P450 (CYP) in the rat intestine. Live bacterial suspension of EcN was administered to healthy male Wistar rats daily for 7 days. Control group of rats was stressed by oral application of the saline solution daily for 7 days as well. Sections of the duodenum, jejunum, ileum, caecum and colon have been taken from each experimental animal. With all individual samples, microsomal fraction has been prepared and expression of selected CYPs was determined by Western blotting. The levels of expression of CYPs were also evaluated by mRNA using real-time PCR. It was found that there are changes in expression of CYP enzymes studied along the intestine. CYP1A1, 2B1/2 and 2E1 are present mainly in the duodenum and jejunum; on the other hand, CYP2C6 is expressed mainly in the caecum and colon. CYP3A was found all over the rat intestine. The results show that there are no prominent differences between control samples and samples with EcN, only the expression of CYP3A protein in the duodenum appears to exhibit a clear tendency to decrease. In the case of the colon, a significant increase in the expression of CYP3A (most likely CYP3A1) after treatment of rats with EcN was found. This in vivo study revealed that the levels of colon CYP3A could be significantly increased in rats treated with probiotic EcN. On the contrary, the expression of CYP3A in the duodenum decreased. However, the changes in the expression of CYP enzymes are probably not as extensive to be clinically important in man; hence, most likely the probiotic EcN has little influence on the intestinal drug metabolism by CYP enzymes.
Franz often said he hoped he would leave the world a better place than he found it. He certainly did! On Sunday morning June 9, 2013, one of the greatest scientists of the 20th and 21st centuries left us. His close associates also lost a very staunch friend and a mentor who never ceased to inspire. Franz Halberg's passing shy of his 94th birthday leaves a void that cannot be filled. Franz Halberg (Figure 1) will be remembered for founding the fields of chronobiology (Halberg, 1969), chronomics (Halberg et al. 2001c) and chronobioethics (Halberg et al. 2012b). These new transdisciplinary scientific disciplines could not have flourished without Franz Halberg's unveiling of lawful variations as a function of TIME within the physiological range and his vision that they had far-reaching implications. Toward this goal, he not only gathered a critical mass of data, himself, but with a steadily increasing network of colleagues worldwide, he also developed inferential statistical methods for their analysis and interpretation. By adding TIME to the existing body of knowledge in all of biology and medicine, and by recognizing the crucial role this new element plays in all matters of life, Franz Halberg developed the new science of chronobiology. By insisting on an inferential statistical foundation, details of a rich time structure were revealed akin to the finer spatial resolution obtained with a microscope. His methodical scrutiny of periodicities shared between biological systems and their broad environment, seen (photic) and unseen (non-photic) influences from the Sun and the cosmos led to chronomics in a way reminiscent of discoveries enabled by the advent of the telescope.
Significance has been attached to the pineal gland in numerous different cultures and beliefs. One religion that has advanced the role of the pineal gland is Spiritism. The objective of the present study was to compile information on the pineal gland drawing on the books of Francisco Cândido Xavier written through psychography and to carry out a critical analysis of their scientific bases by comparing against evidence in the current scientific literature. A systematic search using the terms "pineal gland" and "epiphysis" was conducted of 12 works allegedly dictated by the spirit "André Luiz". All information on the pineal having potential correlation with the field of medicine and current studies was included. Specialists in the area were recruited to compile the information and draw parallels with the scientific literature. The themes related to the pineal gland were: mental health, reproductive function, endocrinology, relationship with physical activity, spiritual connection, criticism of the theory that the organ exerts no function, and description of a hormone secreted by the gland (reference alluding to melatonin, isolated 13 years later). The historical background for each theme was outlined, together with the theories present in the Spiritist books and in the relevant scientific literature. The present article provides an analysis of the knowledge the scientific community can acquire from the history of humanity and from science itself. The process of formulating hypotheses and scientific theories can benefit by drawing on the cultural aspects of civilization, taking into account so-called non-traditional reports and theories.
The composition of the DTaP vaccines under study in the Vaccine Adverse Event Reporting System database 
A summary of the neurodevelopmental disorder raw data evaluated in the Vaccine Adverse Event Reporting System broken down by vaccine type, vaccine manufacturer, year of vaccine administration, and adverse event type. 
Thimerosal is an ethylmercury-containing compound (49.6% mercury by weight) used as at the preservative level in vaccines (0.005% to 0.01%). Statistical modeling in a meta-analysis epidemiological assessment of the Vaccine Adverse Event Reporting System (VAERS) for neurodevelopment disorders (NDs) reported following Diphtheria-Tetanus-whole-cell-Pertussis (DTP) vaccines in comparison to Diphtheria-Tetanus-whole-cell-Pertussis-Haemophilus Influenzae Type b (DTPH) vaccines (administered: 1994-1997) and following Thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis (DTaP), vaccines in comparison to Thimerosal-free DTaP vaccines (administered: 1997-2000), was undertaken. Significantly increased adjusted (sex, age, vaccine type, vaccine manufacturer) risks of autism, speech disorders, mental retardation, personality disorders, thinking abnormalities, ataxia, and NDs in general, with minimal systematic error or confounding, were associated with TCV exposure. It is clear from the results of the present epidemiological study and other recently published data associating mercury exposure with childhood NDs, additional ND research should be undertaken in the context of evaluating mercury-associated exposures, especially from Thimerosal-containing vaccines.
In a group of 465 patients diagnosed as having chronic mercury toxicity (CMT), 32.3% had severe fatigue, 88.8% had memory loss, and 27.5% had depression. A significant correlation was found between CMT and the Apo-lipoprotein E4 genotype (p=0.001). An investigation into an additional 864 consecutively seen general practice patients, resulted in 30.3% having evidence consistent with CMT, and once again a significant correlation was found with the APO-E4 genotype (p=0.001). Removal of amalgam mercury fillings when combined with appropriate treatment resulted in a significant symptom reduction (p<0.001) to levels reported by healthy subjects.
Reason of intoxication due to drugs affecting central nervous system registered by the specialists of Toxicological Information Center from 2005 to 2012. 
Numbers of calls to the Toxicological Information Center concerning poisoning due to drugs affecting central nervous system in the years 1997 and 2012. Note: antidepres.-antidepressants, SSRIs (selective serotonin reuptake inhibitors), OA (other antidepressants). 
Number of calls yearly due to four most common benzodiazepines from 1997 to 2012. 
Dose severity evaluation in different types of central neural system affecting drugs (%). The severity did not differ significantly among the groups excepting the benzodiazepines where the largest proportion of exposures (p≤0.05) was classified as non-toxic/minor toxic (denoted by ). Note: TCAs (tricyclic antidepressants),SSRIs (selective serotonin reuptake inhibitors), OA (other antidepressants). The error bars correspond to the confidence intervals on significance level 0.05. 
Symptoms in different types of central neural system affecting drugs (%). Note: TCAs (tricyclic antidepressants), SSRIs (selective serotonin reuptake inhibitors), OA (other antidepressants). The error bars correspond to the confidence intervals on significance level 0.05. 
To analyze the number and trends in calls to the Toxicological Information Center (TIC) concerning pharmaceutical poisoning retrospectively during the past 15 years and to compare selected characteristics of the poisonings. Inquiries arising from drug poisonings in the years 1997-2012 were extracted and evaluated from the Czech database recording the consultations of TIC specialists. In addition, their cause, severity and dose evaluation (data electronically collected after 2005) were compared in the years 2005-2012 using standard statistical methods. During 15 years total 152,649 calls due to all types of potentially toxic agents were recorded in the TIC database. Central nervous system (CNS) affecting drugs represented 39.8% of calls due to all pharmaceutical poisonings. The proportion of adults was 72.2% and women comprised 64.4% of all patients. Whereas the number of calls caused by poisoning with tricyclic antidepressants (TCAs) and barbiturates decreased (by 366.7% and 340%, respectively), the calls due to selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines overdose increased (by 1347.4% and 359.8%). The dose of CNS affecting drugs in 2005-2012 was considered lethal in 14.6% of the inquiries due to barbiturates and 8.6% due to TCAs, but only in 1.6% calls due to SSRIs and 0.5% of benzodiazepines. The highest percentage of medications errors was found during the treatment with barbiturates (16.4%). The current drugs prescription with improved safety profiles brings the beneficial effect of lowering the severity of poisonings and better prognosis of intoxications as observed in the TIC statistics.
Top-cited authors
Michael Maes
  • King Chulalongkorn Memorial Hospital
Marta Kubera
  • Polish Academy of Sciences
George B Stefano
  • Charles University in Prague
Russel J Reiter
  • University of Texas Health Science Center at San Antonio
Tobias Esch
  • Universität Witten/Herdecke