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The recent investigations point out the significant role of oxidative stress in the development of thyroid gland disease. The present study was designed to investigate the variation of oxidative stae in women with non-autoimmunological subclinical hyperthyroidism.The study was conducted on 20 females with non-autoimmunological subclinical hyperthyroidism and 15 healthy women. Manganase-containing superoxide dismutase (Mn-SOD) and extracellular superoxide dismutase (EC-SOD) plasma activity, and malondialdehyde (MDA) plasma concentration were measured.EC-SOD plasma activity was significantly higher in women with subclinical hyperthyroidism when compared with the control group (13.3 +/- 2.1 vs. 10.9 +/- 1.4 NU/ml; p0.05), unlike Mn-SOD (4.2 +/- 0.5 vs. 4.0 +/- 1.0 NU/ml). MDA plasma concentration increased significantly in women with subclinical hyperthyroidism (3.5 +/- 1.2 vs. 2.0 +/- 0.6 micromol/l; p0.05).The increased EC-SOD plasma activity may reflect disturbances of oxidative state in subclinical hyperthyroidism. Parallel increase of MDA plasma concentration may indicate enhancement of lipid peroxidationin in patients with subclinical hyperthyroidism.

UNLABELLED INTRODUCTION. Hyperthyroidism in the course of Graves-Basedow disease leads to intensification of oxidative processes and increased production of free oxygen radicals. It results in abnormal oxidative status of the organism. OBJECTIVES Aim of this work was to assess the dynamics of oxidative status changes in women with Graves-Basedow disease before and after treatment with thiamazole. PATIENTS AND METHODS Studies were carried out in 20 women with newly diagnosed hyperthyroidism in the course of Graves-Basedow disease and in 15 healthy women. Measurements of activity of antioxidant enzymes--superoxide dismutase (cytosolic copper/zinc isoform--Cu/ZnSOD, mitochondrial manganese isoform--MnSOD and extracellular copper/zinc isoform--EC-SOD) and glutathione peroxidase (GPx), as well as of malondialdehyde (MDA) concentration were performed twice, i.e. before the treatment and after 3-7 months of thiamazole therapy (euthyroidism). RESULTS Before the treatment, higher MnSOD plasma activity and lower EC-SOD activity were observed in women with hyperthyroidism in comparison with the control group, whereas the erythrocyte Cu/ZnSOD activity did not differ between the groups. Besides, women with hyperthyroidism had higher GPx activity in red blood cells. In this group studies have demonstrated higher plasma MDA levels, without any differences between the groups in MDA levels in red blood cells. After thiamazole therapy no differences could be demonstrated in MnSOD, EC-SOD, Cu/ZnSOD and GPx activities and MDA level between the groups. CONCLUSIONS Women with hyperthyroidism in the course of Graves-Basedow disease experience abnormal oxidative status of the organism, and induction of euthyroidism after therapy with thiamazole results in resolution of these abnormalities.

1 Department of Basic Medical Sciences, Faculty of Public Health, Medical University of Silesia, Piekarska 18, 41-902 Bytom, Poland 2 Department of Physiology, Faculty of Medicine and Dentistry, Medical University of Silesia, H. Jordana 19, 41-808 Zabrze, Poland, Fax: ++48 32 2722362, e-mail: jjochem@poczta.onet.pl 3 Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia

The central neuronal systems associated with cardiovascular regulation in haemorrhagic shock can be functionally divided into two groups. The first one includes opioid peptides, which inhibit the activity of cardiovascular centre neurones and initiate the sympathoinhibitory phase of regulation in hypovolaemia. The second group consists of non-opioid systems demonstrating anti-shock properties, such as the melanocortinergic. cholecystokininergic, thyreoliberinergic, cholinergic and histaminergic systems. In the present paper, we review recent data concerning the role of the melanocortins in cardiovascular regulation in haemorrhagic shock. Melanocortin peptides, proopiomelanocortin (POMC)-derived peptides which have His-Phe-Arg-Trp sequence, are secreted in large amounts in the sympathoinhibitory phase of cardiovascular regulation in shock. Exogenous melanocortins. such as melanocyte-stimulating hormones (MSHs). adrenocorticotropic hormone (ACTH) and many ACTH fragments induce a long-lasting pressor effect with an increase in the survival rate in haemorrhage-shocked rats. The mechanisms of their action include centrally mediated activation of the sympathetic nervous system and the "cholinergic anti-inflammatory pathway". which leads to an increase in the peripheral resistance and suppression of the transcription nuclear factor appaB-dependent systemic inflammatory response. respectively. Moreover, acting peripherally, the melanocortins stimulate secretion of glucocorticoids, normalise the blood levels of nitric oxide and inhibit free radical generation in haemorrhagic shock. Further clinical studies are needed to confirm the usefulness of the melanocortins in the treatment of haemorrhagic shock in humans.

In inflamed bowel there is sustained local secretion of histamine not only from activated mast cells but also from some infiltrating cells. Released histamine acting through different receptors may exert variety of effects. H1 receptors mediate inflammatory effects i.e. smooth muscle and endothelial cell contractions, increased vascular permeability, but also antibody production; H2 and H4 receptors are involved in modulation of cytokine production and various immunomodulatory effects including eosinophil and mast cell chemotaxis and calcium influx in these cells, neutrophil chemotaxis, which affect inflammatory responses. Thus many, if not all events that are triggered by histamine could in consequence contribute to the severity of disease. Accordingly, elicited by histamine shift of Thl/Th2 towards Th2 potentiates inflammatory changes and makes the tissue more prone to some infections and tumors, normally eliminated by Thl dependent mechanisms. Preferential H4 receptor location on immune cells and recently reported anti-inflammatory effect of its highly specific antagonist administered in vivo in mouse model of peritonitis, suggest that the question of whether H4 antagonists will be used as anti-inflammatory drugs in human clinic will soon get an answer.

Respiratory and thermoregulatory responses to hyperthermia during isosmotic dehydration/hypovolemia were studied in 17 anaesthetized adult rabbits divided into two groups: normovolemic group (NV; n=10) and hypovolemic group (HV; n=7). Hypovolemia/isosmotic dehydration (a decrease in plasma volume by 16.1+/-1.2%) was induced by furosemide (5 mg kg(-1) i.v.). During hyperthermia (the rise in body temperature to 42 degrees C by a gradual body surface heating), the HV rabbits had lower (P0.05) respiratory frequency and higher (P0.05) tidal volume than the NV animals. The panting was absent in the HV rabbits at the BT of 42 degrees C, unlike the NV animals. The lower respiratory frequency and the absence of panting during exogenous hyperthermia in dehydrated animals are present not only during hyperosmotic dehydration induced by water deprivation [Doris, P.A., Baker, M.A., 1981. Hypothalamic control of thermoregulation during dehydration. Brain Res. 206 (1), 219-222], but they also occur in the furosemide-induced isosmotic dehydration/hypovolemia.

Objective and design:Histamine is a potent stimulator of arginine vasopressin (AVP) release and therefore, the role of AVP was studied in the reversal of critical haemorrhagic hypotension induced by endogenous central histamine after inhibition of histamine N-methyltransferase (HNMT) activity in rats. Material:In 48 ethylurethane-anaesthetised male Wistar rats cardiovascular parameters and plasma hormone concentrations were measured. Treatment:Haemorrhage-shocked rats with mean arterial pressure (MAP) 20–25 mmHg were injected intracerebroventricularly (icv) with HNMT inhibitor metoprine (20 μg) after pre-treatment with V1a, V1b and V2 receptor antagonists – [β-mercapto-β,βcyclopentamethylenepropionyl1, O-me-Tyr2,Arg8]AVP (10 μg/kg; iv), SSR149415 (10 mg/kg; ip) and [adamantaneacetyl1,O-Et-D-Tyr2,Val4, aminobutyryl6,Arg8,9]AVP (10 μg/kg; iv), respectively, or saline. Methods:MAP, heart rate (HR) and regional haemodynamics were monitored within 2 h after treatment or to death if it occurred earlier. Plasma hormone concentrations were measured using enzyme immunoassays. ANOVA followed by Neuman-Keules test, and Fisher’s exact test were used to compare the results. Results:Metoprine produced a long-lasting increase in MAP, HR, renal, hindquarters and mesenteric blood flows, and a 100% survival at 2 h (P < 0.05 vs. the control group). The action was associated with increased plasma AVP concentration (587.5 ± 98.9 vs. 387.3 ± 125.2 pg/ml; P < 0.05) in comparison to the control group as measured at 20 min after treatment. V1a, but not V1b and V2, receptor antagonist inhibited metoprine-induced haemodynamic effects, with no influence on survival at 2 h. SSR149415 did not influence ACTH and adrenaline plasma concentrations in the metoprine-treated group. Conclusion:AVP, acting via V1a receptors, is involved in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats.

We investigated the effect of leptin on systemic nitric oxide (NO) production, arterial pressure, renal hemodynamics and renal excretory function in the rat. Leptin (1 mg/kg) was injected intravenously and mean arterial pressure (MAP), heart rate (HR), renal blood flow (RBF) and renal cortical blood flow (RCBF), were measured for 210 min after injection. Urine was collected for seven consecutive 30-min periods and blood samples were withdrawn at 15, 45, 75, 105, 135, 165 and 195 min after leptin administration. Leptin had no effect on MAP, HR, RBF, RCBF and creatinine clearance, but increased urine output by 37.8% (0–30 min), 32.4% (31–60 min) and 27.0% (61–90 min), as well as urinary sodium excretion by 175.8% (0–30 min), 136.4% (31–60 min) and 124.2% (61–90 min). In contrast, leptin had no effect on potassium and phosphate excretion. Plasma concentration of NO metabolites, nitrites+nitrates (NOx), increased following leptin injection at 15, 45, 75 and 105 min by 27.7%, 178.1%, 156.4% and 58.7%, respectively. Leptin increased urinary NOx excretion by 241.6% (0–30 min), 552.6% (31–60 min), 430.7% (61–90 min) and 88.9% (91–120 min). This was accompanied by increase in plasma and urinary cyclic GMP. These data indicate that leptin stimulates systemic NO production but has no effect on arterial pressure and renal hemodynamics.

The increase in central histamine concentrations after inhibition of histamine N-methyltransferase (HNMT) activity is associated with the reversal of critical haemorrhagic hypotension, therefore the present study examines cardiac and regional haemodynamic effects of HNMT inhibitor metoprine in haemorrhage-shocked rats.Cardiovascular parameters were measured in 72 and central histamine concentrations in 12 male Wistar rats anaesthetised with ketamine/xylazine.Metoprine (5, 15 mg/kg) was administered intraperitoneally to normotensive and critically-hypotensive rats with mean arterial pressure (MAP) 20-25 mmHg. Haemorrhage-shocked rats were pre-treated intracerebroventricularly with histamine H(3) receptor agonist R(-)-alpha-methylhistamine (10 microg) or saline.MAP, heart rate (HR) and cardiac and regional haemodynamics were monitored within 2 h after treatment, or to death if it occurred earlier. Histamine concentrations were measured using enzyme immunoassay. ANOVA followed by Neuman-Keules test, and Fisher's exact test were used to compare the results.Bleeding resulted in an extreme decrease in cardiac index (CI), an increase in total peripheral resistance index (TPRI) and the death of control animals within 30 min. Metoprine induced increases in MAP and HR which were significantly higher in hypotensive than in normotensive animals. The resuscitating effect of metoprine (15 mg/kg) was associated with a rise in CI, a decrease in TPRI, and a 100% survival at 2 h. TPRI changes resulted from decreased renal, hindquarters and mesenteric vascular resistance. R(-)-alpha-methylhistamine inhibited metoprine-induced increases in endogenous histamine concentrations in the cerebral cortex (0.89 +/- 0.12 vs. 1.25 +/- 0.29 nmol/g of wet tissue; P0.05), hypothalamus (4.37 +/- 0.42 vs. 5.74 +/- 0.47 nmol/g of wet tissue; P0.01) and medulla oblongata (0.39 +/- 0.07 vs. 0.65 +/- 0.28 nmol/g of wet tissue; P0.05), diminished haemodynamic effects and decreased the survival rate at 2 h to 33% (P0.05 vs. the saline-pre-treated group).The results support the hypothesis that histaminergic system activation leads to mobilisation of compensatory mechanisms in haemorrhagic hypotension.

Background Hepatocyte growth factor (HGF) is a member of growth factor with a variety of known activities, including angiogenesis promotion and antiapoptotic action. It prevents acute graft-versus-host disease after bone marrow transplantation and prolongs allogenic graft survival in rats. The aim of the study was to investigate the relationship between serum HGF concentration and the grade of acute cellular rejection of heart transplant. Methods We studied 68 male heart recipients. All of them received triple-drug immunosuppression: cyclosporine A, prednisone, and azathioprine or mycofenolate mofetil. All patients were without signs of heart failure. Blood samples were taken before elective ambulatory endomyocardial biopsy. Biopsy specimens were graded with the International Society for Heart and Lung Transplantation scale. Acute cellular rejection grade 3A and higher were considered as significant. Measurement of serum HGF was made by enzyme-linked immunosorbent assay. Results We found a positive relationship between serum HGF levels and grade of cellular rejection. As an indicator for the detection of cell rejection processes, HGF with cutoff 2000 pg/ml seems to be useful. Conclusions The results of this study demonstrate that HGF can be useful as an indicator for heart graft cell rejection.

An increase in endogenous central histamine concentration after inhibition of histamine N-methyltransferase (HNMT) activity reverses critical hypotension and improves the survival of rats in haemorrhagic shock. The purpose of the study was to examine the involvement of the sympathetic nervous system in this endogenous central histamine-induced resuscitation. Experiments were carried out in ethylurethane-anaesthetised male Wistar rats subjected to haemorrhagic hypotension (mean arterial pressure MAP 20-25 mmHg), which led to the death of all control animals within 30 min. The HNMT inhibitor metoprine (20 micro g; i.c.v.) administered 5 min after establishing the critical hypotension increased the endogenous histamine concentration, measured 20 min after treatment, in the hypothalamus (534.33+/-67.52 vs. 423.98+/-54.17 ng/g wet tissue; P0.05) and medulla oblongata (53.12+/-9.78 vs. 39.58+/-11.16 ng/g wet tissue; P0.05). These responses were accompanied by plasma levels of noradrenaline and adrenaline 2.7 and 1.7 times higher respectively than in the control group ( P0.01). Metoprine evoked dose-dependent (5, 10, 20 micro g; i.c.v.) rises in MAP and heart rate (HR) that were significantly higher than those in normotensive animals, and resulted in a 100% survival rate at 2 h after treatment (20 micro g; i.c.v.). The resuscitative effect was associated with rises in renal, hindquarters and mesenteric blood flows. The nicotinic cholinoceptor antagonist hexamethonium (3 mg/kg; i.v.) attenuated the MAP and HR changes, whereas the muscarinic cholinoceptor blocker methylatropine (2 mg/kg; i.v.) attenuated only the pressor effect. Metoprine-induced MAP and regional haemodynamic effects were also reduced by alpha(1)- and alpha(2)-adrenoceptor antagonists prazosin (0.5 mg/kg; i.v.) and yohimbine (1 mg/kg; i.v.), while the beta-adrenoceptor blocker propranolol (1 mg/kg; i.v.) diminished only HR changes. Ganglionic transmission inhibitors and adrenoceptor antagonists did not influence the survival rate at 2 h in the metoprine-treated groups. Bilateral adrenal demedullation diminished the pressor effect of metoprine, however, without influence on HR and survival at 2 h after treatment. In conclusion, the study demonstrates the activation of the sympathetic nervous system elicited by endogenous central histamine in haemorrhage-shocked rats and confirms its involvement in histamine-induced resuscitation.

The aim of this study was to explore the relationship between local ischaemic preconditioning and the effectiveness of fractionated radiotherapy. The rat serum, bone marrow, and small intestine were examined for oxidative changes induced by total body irradiation with gamma rays with applied local ischaemic preconditioning immediately before irradiation. Serum concentrations of TBA-RS examined 12 hours after the last irradiation did not reveal any differences among the groups of animals analyzed. Twenty-four hours after the last dose of irradiation, the serum concentrations of TBA-RS varied in particular groups (P

Morbid obesity (BMIor = 40 kg/m2) is accompanied by lipid disturbances which may be involved in the increased incidence of arterial hypertension and non-insulin dependent diabetes mellitus. The aim of the study was to assess plasma concentrations of total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, triglycerides (TG) and two parameters of oxidation stress--vitamin E and oxysterols, in morbidly obese patients with coexisting arterial hypertension and non-insulin dependent diabetes mellitus. Studies were performed in 37 morbidly obese patients divided into three groups: group I--without coexisting diseases, group II--with arterial hypertension, and group III--with arterial hypertension and non-insulin dependent diabetes mellitus. In all groups there was an increase in TG concentration, a decrease in HDL-cholesterol level, and normal values of TC and LDL-cholesterol. The concentrations of 7-hydroxycholesterols (7-OH) in group II (602.65 +/- 264.46 ng/ml) and group III (570.94 +/- 210.59 ng/ml) were significantly higher compared to that in group I (336.09 +/- 220.74 ng/ml). There were no differences between groups in concentrations of 7-ketocholesterols (7-K), TC, HDL-cholesterol, LDL-cholesterol, TG, vitamin E and vitamin E/(TC + TG) ratio. In all groups TC concentration correlated positively with TG concentration, and negatively with vitamin E/(TC + TG) ratio. Moreover, the positive correlation between TG and HDL-cholesterol concentrations, and negative correlation between plasma vitamin E and 7-K concentrations were demonstrated. In conclusion, although the study demonstrates similar disturbances in lipid profile and oxidation stress parameters in all groups, with significant differences in 7-OH only, the role of cholesterol oxidation products in pathogenesis of arterial hypertension and non-insulin dependent diabetes mellitus in morbidly obese patients cannot be excluded.

Background Chronic spontaneous urticaria (CSU) is an immune-inflammatory disease, characterized by acute phase response (APR) and immune activation. There has been increasing evidence showing that vitamin D deficiency/insufficiency is associated with increased incidence and/or severity of immune-inflammatory disorders. Aim To assess relationship between vitamin D status and C-reactive protein (CRP), a nonspecific inflammatory marker of CSU activity. Methods Concentrations of CRP and 25-hydroxyvitamin D [25(OH)D], a biomarker of vitamin D status were measured in serum of CSU patients and compared with the healthy controls. Results Serum 25(OH)D concentration was significantly lower in CSU group as compared with the normal subjects. The prevalence of vitamin D deficiency (< 20 ng/ml) was significantly higher in patients with CSU than among normal population. There were no significant differences in prevalence of 25(OH)D insufficiency between the groups. Serum CRP concentrations were significantly higher in CSU patients as compared with the healthy subjects. There were no significant correlations between CRP and 25(OH)D concentrations in CSU patients. Conclusions CSU is associated with lower serum 25(OH)D concentration and higher prevalence of its deficiency. The results failed to show any effect of vitamin D status on circulating CRP concentrations in CSU. A potential role of vitamin D in pathogenesis and/or additive therapy of CSU needs to be examined in other cohorts of CSU patients as well as in larger studies.

Chronic spontaneous urticaria (CU) is associated with activation of the acute phase response (APR). Nevertheless, APR-associated proteins have not been well characterized as potential biomarkers of the disease severity. To assess the pattern of complement proteins C3 and C4 - the acute phase reactants in patients with CU. C3, C4 and CRP concentrations were measured in serum of 70 patients showing different degrees of urticarial severity as well as in 33 healthy subjects. Serum C3 and C4 concentrations were significantly increased in CU patients as compared with the healthy subjects and exceed the normal lab range by about 5% and 10%, respectively. Significant differences were found between patients with mild and increased CU severity. In addition, significant correlations were observed between C3, C4 and CRP concentrations. More severe CU is characterized by higher production of C3 and C4 complements accompanied by parallel changes in CRP concentration.

Background Overproduction of vascular endothelial growth factor (VEGF) in atopic dermatitis (AD) lesions has previously been observed. It is also known that platelet is an important source of VEGF and platelet factor 4 (PF-4), a potential marker of AD severity. Aim To evaluate concentrations of VEGF and its soluble receptors (sVEGF-R1 and sVEGF-R2) in the plasma of AD patients and to examine its possible correlation with disease severity and plasma concentrations of PF-4, a platelet activation marker. Methods Plasma concentrations of VEGF and its receptors and levels of PF-4 were measured by an immunoenzymatic assay in 51 AD patients and in 35 healthy non-atopic controls. The severity of the disease was evaluated using the eczema area and severity index. Results AD patients showed significantly increased VEGF and PF-4 plasma concentrations as compared with the controls. Plasma concentrations of sVEGF-R1 and sVEGF-R2 did not differ between the groups. There were no remarkable correlations between plasma VEGF concentration and disease severity or between VEGF and PF-4 concentration. Conclusions This study shows that plasma concentration of VEGF may be increased in patients suffering from AD. It seems that plasma VEGF concentration is not a useful marker of disease severity and, apart from platelets, other cells might also release the cytokine.