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Lesions arising in or around the pineal gland comprise a heterogeneous group of pathologies ranging from benign non-neoplastic cysts to highly malignant neoplasms. Pineal cysts are frequently encountered as an incidental finding in daily radiology practice but there is no universal agreement on the criteria for, frequency of, and duration of follow-up imaging. Solid pineal neoplasms pose a diagnostic challenge owing to considerable overlap in their imaging characteristics, although a combination of radiological appearances, clinical findings, and tumour markers allows for narrowing of the differential diagnosis. In this review, we describe the radiological anatomy of the pineal region, clinical symptoms, imaging appearances, and differential diagnosis of lesions arising in this area, and highlight the clinical management of these conditions.

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INTRODUCTION: The aim of this study was to assess the relationship between polymorphisms of genes encoding enzymes involved in arsenic metabolism and urinary arsenic concentration in people occupationally exposed to arsenic. MATERIALS AND METHODS: The data from 113 employers directly exposed to lead, cadmium, and arsenic in copper smelter in Legnica and Glogow were collected. Urinary arsenic concentration was measured. In addition, blood level of cadmium, lead, and zinc protoporphyrins was assayed. Genetic analyses included polymorphism of PNP (rs 1130650), GSTO-1 (rs 4925), AS3MT (rs 11191439), and ADRB3 (rs4994) genes. RESULTS: Individuals occupationally exposed to arsenic compounds, who have allele T in homozygous constellation in locus rs 1130650 of PNP gene, are predisposed to lower urinary arsenic concentration, while AA homozygosity in locus rs 4925 of GSTO-1 gene may result in statistically significant higher urinary arsenic concentration. Polymorphisms of AS3MT and ADRB3 genes showed no statistically significant correlation with urinary arsenic, however, there was a tendency to higher arsenic concentration in allele A carriers in locus rs4994 of ADRB3 gene and in allele T carriers in rs 11191439 of AS3MT gene. CONCLUSION: This study indicates that arsenic absorption and metabolism depend on polymorphisms of genes encoding PNP and GSTO-1. Individuals with disadvantageous constellation of polymorphisms are more susceptible to harmful effects of arsenic exposure.

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The bed nucleus of stria terminalis is a basal forebrain region involved in regulation of hormonal and behavioral responses to stress. In this report we demonstrate that bed nucleus of stria terminalis has a high and localized expression of tissue plasminogen activator, a serine protease with neuromodulatory properties and implicated in neuronal plasticity. Tissue plasminogen activator activity in the bed nucleus of stria terminalis is transiently increased in response to acute restraint stress or i.c.v. administration of a major stress mediator, corticotropin-releasing factor. We show that tissue plasminogen activator is important in bed nucleus of stria terminalis function using two criteria: 1, Neuronal activation in this region as measured by c-fos induction is reduced in tissue plasminogen activator-deficient mice; and 2, a bed nucleus of stria terminalis-dependent behavior, potentiation of acoustic startle by corticotropin-releasing factor, is attenuated in tissue plasminogen activator-deficient mice. These studies identify a novel site of tissue plasminogen activator expression in the mouse brain and demonstrate a functional role for this protease in the bed nucleus of stria terminalis.

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We investigated L-kynurenine distribution and metabolism in rats with experimental chronic renal failure of various severity, induced by unilateral nephrectomy and partial removal of contralateral kidney cortex. In animals with renal insufficiency the plasma concentration and the content of L-tryptophan in homogenates of kidney, liver, lung, intestine and spleen were significantly decreased. These changes were accompanied by increase activity of liver tryptophan 2,3-dioxygenase, the rate-limiting enzyme of kynurenine pathway in rats, while indoleamine 2,3-dioxygenase activity was unchanged. Conversely, the plasma concentration and tissue content of L-kynurenine, 3-hydroxykynurenine, and anthranilic, kynurenic, xanthurenic and quinolinic acids in the kidney, liver, lung, intestine, spleen and muscles were increased. The accumulation of L-kynurenine and the products of its degradation was proportional to the severity of renal failure and correlated with the concentration of renal insufficiency marker, creatinine. Kynurenine aminotransferase, kynureninase and 3-hydroxyanthranilate-3,4-dioxygenase activity was diminished or unchanged, while the activity of kynurenine 3-hydroxylase was significantly increased. We conclude that chronic renal failure is associated with the accumulation of L-kynurenine metabolites, which may be involved in the pathogenesis of certain uremic syndromes.

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Though the mechanisms for the vascular actions of vasodilatory beta-blockers are mostly determined, some of their interactions with monoaminergic systems are not elucidated. Because there are evidences supporting a possible involvement of serotonin (5-HT) in the actions of beta-blockers, we studied the effect of propranolol on peripheral serotonergic mechanisms in normotensive and Goldblatt two-kidney - one clip (2K1C) hypertensive rats. In both groups of animals propranolol decreased systolic blood pressure, significantly increased whole blood serotonin concentration and at the same time it decreased platelet serotonin level. The uptake of the amine by platelets from hypertensive animals was lower than that of normotensive animals and it was decreased by propranolol only in the latter. In both groups propranolol inhibited potentiation of ADP-induced platelet aggregation by serotonin. In conclusion, this study provides evidence that propranolol modifies platelet serotonergic mechanisms in normotensive and renal hypertensive rats.

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Angiotensin-(1-7) [Ang-(1-7)] is an active member of renin-angiotensin system (RAS). It counterbalances vasoconstriction, mitogenic, arrhythmogenic and prothrombotic actions of Ang II. Inducing natiuresis and diuresis opposes also the water and sodium retention produced by Ang II. Till now the specific receptor side for Ang-(1-7) has been not cloned, but the current data strongly suggest that an interaction (cross-talk) between angiotensin receptors may play a role in the effects of Ang-(1-7).

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BACKGROUND: In our previous experiments we showed that the prototype member of the AT1 receptor antagonists (AT1-As) family, losartan, prevented the development of arterial and venous thrombosis in rats. Recent studies have demonstrated that apart from blocking AT1 receptor, losartan is also a competitive antagonist to thromboxane A2/prostaglandin H2 receptor (TP receptor). Thus, we decided to assess if this feature could contribute to the antithrombotic action of losartan. MATERIAL AND METHODS: We compared the influence losartan, its active metabolite EXP3174 and valsartan on rat platelet adhesion to fibrillar collagen and platelet aggregation in response to thromboxane A2 analogue, U46619. We also assessed the efficacy of these drugs in platelet-dependent pulmonary thrombosis in mice as well as preventive and therapeutic models of venous thrombosis in rats. RESULTS: All the three compounds, given in a single dose, inhibited rat platelet adhesion to fibrillar collagen and platelet aggregation induced with U46619 in vitro and ex vivo, with the action of losartan being much more pronounced than that of EXP3174 or valsartan. Losartan also more effectively protected mice from death in response to the intravenous injection of collagen / epinephrine and it was the only compound which reduced mice mortality after the intravenous injection of U46619. In contrast, all the three AT1 receptor antagonists exerted a similar thrombolytic action and comparably decreased the thrombus weight in the therapeutic and preventive model of venous thrombosis, although in the latter case a high dose of losartan was slightly more effective than a corresponding dose of EXP3174 and valsartan. CONCLUSIONS: Since losartan is endowed with a relatively low affinity towards the AT1 receptor, we conclude that its superiority over EXP 3174 and valsartan in inhibiting thrombocyte function and platelet-dependent thrombosis could result from its stronger action on the TP receptor. This feature seems to be less important in the thrombolytic effect of AT1-As and in the inhibition of the venous thrombosis development, in which platelets play only a minor role.

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BACKGROUND: It has been demonstrated that the products of tryptophan degradation, kynurenamines, play an important role in senile cataract formation. However, the involvement of these compounds in the development of diabetic cataract has not been studied. The aim of the present study was to compare the concentration of tryptophan and kynurenamines in the aqueous humor and lenses obtained from non-diabetic and diabetic patients with cataract. MATERIAL AND METHODS: The concentration of tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid and anthranilic acid was measured using high-performance liquid chromatography (HPLC) with appropriate detection in aqueous humor and lenses obtained from 38 non-diabetic subjects and 20 patients with type II diabetes in course of surgical cataract extraction. RESULTS: In diabetic patients the concentration of kynurenine, 3-hydroxykynurenine and anthranilic acid in the aqueous humor was increased in comparison with non - diabetic subjects, while the concentration of tryptophan and kynurenic acid was similar in both groups. In the lenses obtained from patients with diabetes accumulation of tryptophan and all of its assayed metabolites was observed. CONCLUSIONS: Concentrations of the products of kynurenine pathway of tryptophan degradation in the aqueous humor and the lenses of diabetic patients are increased. We suggest that these compounds could play an important role in the development of diabetic cataract.

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Clinical and experimental data have recently accumulated for antithrombotic action of angiotensin-converting enzyme inhibitors (ACE-1s). We have shown previously that captopril (which contains a thiol group in the moiety) exerts more pronounced antithrombotic activity than does an equipotent dose of enalapril (the drug devoid of the thiol group). To clarify the relative importance of the presence of the thiol group in the molecule versus angiotensin-converting enzyme (ACE) inhibitory properties in the antithrombotic action of captopril, rats were treated with captopril (5 mg/kg twice daily; CAP), epicaptopril (stereoisomer of captopril devoid of ACE-inhibitory properties; 5 mg/kg twice daily; EPI), N-acetylcysteine (3.75 mg/kg twice daily; ACC), enalapril (3 mg/kg once daily; ENA), or distilled water (VEH) for 10 days, per os. After ligation of the vena cava, the incidence of the venous thrombosis and/or the thrombus weight decreased significantly in all but the ENA-treated groups when compared with control rats. The effect of CAP, EPI, and ACC was accompanied by a marked reduction of euglobulin clot lysis time and, with the exception of ACC, by an increase in prothrombin time in the blood collected from the site of the thrombus formation. Antithrombotic activity of EPI was completely abolished by nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) or indomethacin, with the parallel reversal of fibrinolytic and coagulation parameters toward normal. Activated partial thromboplastin time, mean blood pressure, and bleeding time were not altered by either of the administered drugs. Thus, we demonstrated that thiol compounds exert antithrombotic activity by increasing fibrinolysis and/or suppression of the extrinsic pathway of the coagulation cascade in a nitric oxide/prostacyclin-dependent manner.

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Recent data suggest that hypotensive effect of losartan may not be attributed solely to AT1-receptor blockade, but also to excessive AT2 or other receptors stimulation by elevated angiotensin II and its derivative peptides. Therefore in the present study we examined the effect of angiotensin II on mean blood pressure after AT -receptor blockade with losartan. Male Wistar rats were anaesthetised and received injection of either losartan (30 mg/kg, 1 ml/kg, i.v.) or saline (the same volume and route) followed by bolus injection of angiotensin II (100, 300 or 1,000 ng/kg; 1 ml/kg, i.v.) or 1-hour infusion of angiotensin II (200 ng/kg/min; 2.5 ml/kg/h, i.v.). Control animals received saline instead. Angiotensin II, given either as the injection or the infusion, caused an evident increase in mean blood pressure (p ranged from 0.05 to 0.001 depending on the experimental group). Losartan caused a rapid drop in mean blood pressure and blunted the hypertensive effect of angiotensin II (p < 0.01). Moreover, in the losartan-pretreated animals the hypotensive phase was enhanced by the infusion, but not single injection of angiotensin II, which was most evident from the 30 th minute of observation (p < 0.05 vs control). In conclusion, hypotensive effect of losartan may be amplified by simultaneous increase in angiotensin II level, the situation observed during chronic AT1-receptor blockade.

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The aim of the study was to evaluate the effect of losartan on rat platelet adhesion to fibrillar collagen. Washed platelets were counted before and after 15 minutes incubation with collagen (50 microg/ml) and the percentage of adhering platelets was calculated as the index of their adhesion. When the platelets were incubated with collagen 40.8 +/- 0.3% of the platelets adhered. Losartan produced a dose dependent decrease in a number of adhering platelets both when the drug was administered to the animals ex vivo at doses of 3, 10 and 30 mg/kg (p < 0.01-0.001) or was added to the preparation of washed platelets in vitro in concentrations of 10(-8)-10(-5) M (p < 0.01-0.001). In the next step of the study we assessed the influence of L-NAME (10 mg/kg ex vivo, 30 microM in vitro) and indomethacin (2.5 mg/kg ex vivo, 30 microM in vitro) on the antiadhesive effect of losartan (10 mg/kg ex vivo, 10(-6) M in vitro). Blockade of nitric oxide synthase with L-NAME partially reversed the antiadhesive effect of losartan both ex vivo and in vitro. Indomethacin diminished the inhibitory effect of losartan on platelet adhesion when administered ex vivo, but it failed to modify this parameter when added to the suspension of platelets in vitro. In conclusion, losartan reduces platelet adhesion to fibrillar collagen in a dose-dependent manner. The observed action of losartan seems to be mediated mainly by endothelium- and platelet-derived nitric oxide.

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In previous studies, we have shown that losartan possesses nitric oxide-dependent antithrombotic properties in various models of hypertension in rats. It was demonstrated that stimulation of AT2-receptors plays an important role in the pharmacological effects of AT1-receptor antagonists. Thus, in this study, we examine the participation of AT2-receptors in the antithrombotic action of losartan in renal hypertensive rats on venous thrombosis induced by a two-hour ligation of the vena cava. Losartan administration(30 mg/kg, p.o.) resulted in a marked decrease in thrombus weight (by 85%, p<0.001). PD123319, an AT2-receptor antagonist (10 mg/kg, i.v.), administered concomitantly with losartan, abolished its antithrombotic effect, whilst it had no influence on thrombus weight when given alone. A significant decrease in systolic blood pressure was observed in animals given losartan. PD123319 administration didnot abolish this action of losartan and did not alter blood pressure when given alone. No changes in prothrombin time, activated partial thromboplastin time, or euglobulin clot lysis time were observed in animals administered losartan and/or PD123319.Similarly, primary haemostatics evaluated by bleeding time and platelet count did not change in any group of rats. In conclusion, we have shown that AT2-receptor stimulation is involved in the antithrombotic action of losartan in renal hypertensive rats.

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Angiotensin-(1-7) [Ang-(1-7)] is the bioactive peptide which may be responsible for some of the pharmacological effects of losartan. Our previous study has demonstrated the antithrombotic action of losartan in a model of experimental thrombosis. In the present study, we compared the antithrombotic action of losartan and Ang-(1-7). Acute (10 mg/kg, p.o.) and chronic (10 mg/kg, p.o., three weeks) losartan administration to spontaneously hypertensive rats (SHR) induced a decrease in thrombus weight (1.6 +/- 0.6 mg and 1.2 +/- 0.3 mg respectively vs. control 2.9 +/- 0.8 mg; p<0.05, p<0.05). A similar reduction was observed in two-kidney, one-clip hypertensive rats (2K-IC)receiving acute losartan administration (1.39 +/- 0.29 mg vs. 3.25 +/- 0.62 mg; p<0.01). Infusion of Ang-(1-7) to2K-lC rats also reduced the thrombus weight(1.01 +/- 0.34 mg, 1.23 +/- 0.38 mg and 2.17 +/- 0.36 mg for 1, 10, 100 pmol/kg/min, respectively vs. 3.58 +/- 0.6 mg control; p<0.01, p<0.01, p<0.05). Losartan produced a decrease in systolic blood pressure (BP) in SHR as well as in 2K-1C rats, while Ang-(1-7) infusion had no effect on BP. Acute losartan dosing to 2K-1C rats decreased platelet adhesion to fibrillar collagen(24.9 +/- 1.0% vs. control 31.5 +/- 1.1%, p<0.001). The incubation of platelet samples with Ang-(1-7) (10-6 and 10 5 M) also reduced adhesion to fibrillar collagen(38.4 +/- 0.1% and 33.8 +/- 0.8% respectively vs. control 40.0 +/- 0.6%; p<0.05, p<0.001). There were no apparent changes in prothrombin time, activated partial thromboplastin time and euglobulin clot lysis time in losartan and Ang-(1-7)-treated groups. We conclude that, like losartan, Ang-(1-7) is able to act as an antithrombotic agent.

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Drugs blocking the renin - angiotensin system, angiotensin converting enzyme inhibitors and AT1 receptor antagonists, among many pharmacological effects may exert an antithrombotic action. The mechanisms, which mediate their antithrombotic activity are associated with enhanced nitric oxide and prostacyclin release or with attenuation of angiotensin II action (Fig. 1, 2). Nevertheless, endothelium plays an important role in this process linking the renin-angiotensin and fibrinolysis / coagulation systems.

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