Oak tree-rings record spatial-temporal pollution trends from different sources in Terni (Central Italy).

Monitoring atmospheric pollution in industrial areas near urban center is essential to infer past levels of contamination and to evaluate the impact for environmental health and safety. The main aim of this study was to understand if the chemical composition of tree-ring wood can be used for monitoring spatial-temporal variability of pollutants in Terni, Central Italy, one of the most polluted towns in Italy. Tree cores were taken from 32 downy oaks (Quercus pubescens) located at different distances from several pollutant sources, including a large steel factory. Trace element (Cr, Co, Cu, Pb, Hg, Mo, Ni, Tl, W, U, V, and Zn) index in tree-ring wood was determined using high-resolution laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). We hypothesized that the presence of contaminants detected in tree-rings reflected industrial activities over time. The accumulation of contaminants in tree-rings was affected by anthropogenic activities in the period 1958-2009, though signals varied in intensity with the distance of trees from the industrial plant. A stronger limitation of tree growth was observed in the proximity of the industrial plant in comparison with other pollutant sources. Levels of Cr, Ni, Mo, V, U and W increased in tree-ring profiles of trees close to the steel factory, especially during the 80's and 90's, in correspondence to a peak of pollution in this period, as recorded by air quality monitoring stations. Uranium contents in our tree-rings were difficult to explain, while the higher contents of Cu, Hg, Pb, and Tl could be related to the contaminants released from an incinerator located close to the industrial plant. The accumulation of contaminants in tree-rings reflected the historical variation of environmental pollution in the considered urban context.

The influence of slope on Spartium junceum root system: morphological, anatomical and biomechanical adaptation.

Root systems have a pivotal role in plant anchorage and their mechanical interactions with the soil may contribute to soil reinforcement and stabilization of slide-prone slopes. In order to understand the responses of root system to mechanical stress induced by slope, samples of Spartium junceum L., growing in slope and in plane natural conditions, were compared in their morphology, biomechanical properties and anatomical features. Soils sampled in slope and plane revealed similar characteristics, with the exception of organic matter content and penetrometer resistance, both higher in slope. Slope significantly influenced root morphology and in particular the distribution of lateral roots along the soil depth. Indeed, first-order lateral roots of plants growing on slope condition showed an asymmetric distribution between up- and down-slope. Contrarily, this asymmetric distribution was not observed in plants growing in plane. The tensile strength was higher in lateral roots growing up-slope and in plane conditions than in those growing down-slope. Anatomical investigations revealed that, while roots grown up-slope had higher area covered by xylem fibers, the ratio of xylem and phloem fibers to root diameter did not differ among the three conditions, as also, no differences were found for xylem fiber cell wall thickness. Roots growing up-slope were the main contributors to anchorage properties, which included higher strength and higher number of fibers in the xylematic tissues. Results suggested that a combination of root-specific morphological, anatomical and biomechanical traits, determines anchorage functions in slope conditions.

Effects of nicotine on thromboxane/prostacyclin balance in myocardial ischemia.

It has been proven that nicotine contributes to cardiovascular diseases, although its precise mechanism of action is still unclear. The purpose of this study is to find how nicotine may complicate myocardial ischemia by affecting the thromboxane/prostacyclin (TXA(2)/PGI(2)) balance. We used four groups (n=7 each) of isolated and perfused rabbit hearts according to Langendorff method: (i) control group; (ii) group submitted to 1 microM nicotine perfusion during 60 min; (iii) group submitted to a regional ischemia by ligation of the left descending coronary artery during 60 min and (iv) group submitted to nicotine perfusion during ischemia. Levels of TXB(2) and 6-keto PGF(1alpha), the stable metabolites of TXA(2) and PGI(2) were then determined in the microsomes of the hearts by radioimmunoassay. The results showed that (1) a TXA(2) synthetase activity is present in the myocardium, and this activity, as well as that of PGI(2) synthetase, is decreased by a 60min ischemia; (2) TXA(2) and PGI(2) activities are not affected by nicotine in the normal myocardium and (3) nicotine infusion during ischemia contributes to the increase of TXA(2)/PGI(2) ratio further by decreasing PGI(2). Therefore, these results provide one explanation on how nicotine might worsen myocardial ischemia.

Moderate alcohol consumption and urinary excretion of magnesium and calcium.

The aim of this study was to evaluate the magnesium (Mg) status of male subjects consuming moderate amounts of alcohol (n = 14) in comparison with that of a group of non-consumers of alcohol (n = 10). Plasma ionized Mg levels and total erythrocyte Mg content were determined as well as the excretion of Mg in urine before and after an oral loading test. Intake of Mg via food and water was estimated using a one-week dietary records. The results showed a significantly higher, alcohol dose-related excretion of Mg and Ca (calcium) in the urine after the oral Mg load among consumers of alcohol. Although the study is based on a small number of subjects with differences in smoking habits, it is suggested that alcohol consumption even in moderate amounts could contribute to Mg deficiency.

Insulin and glucagon impairments in relation with islet cells morphological modifications following long term pancreatic duct ligation in the rabbit--a model of non-insulin-dependent diabetes.

Plasma levels of glucose, insulin and glucagon were measured at various time intervals after pancreatic duct ligation (PDL) in rabbits. Two hyperglycemic periods were observed: one between 15-90 days (peak at 30 days of 15.1 +/- 1.2 mmol/l, p < 0.01), and the other at 450 days (11.2 +/- 0.5 mmol/l, p < 0.02). The first hyperglycemic episode was significantly correlated with both hypoinsulinemia (41.8 +/- 8 pmol/l, r = -0.94, p < 0.01) and hyperglucagonemia (232 +/- 21 ng/l, r = 0.95, p < 0.01). However, the late hyperglycemic phase (450 days), which was not accompanied by hypoinsulinemia, was observed after the hyperglucagonemia (390 days) produced by abundant immunostained A-cells giving rise to a 3-fold increase in pancreatic glucagon stores. The insulin and glucagon responses to glucose loading at 180, 270 and 450 days reflected the insensitivity of B- and A-cells to glucose. The PDL rabbit model with chronic and severe glycemic disorders due to the predominant role of glucagon mimicked key features of the NIDDM syndrome secondary to exocrine disease.

Modifications in the TXA(2) and PGI(2) plasma levels and some other biochemical parameters during the initiation and development of non-insulin-dependent diabetes mellitus (NIDDM) syndrome in the rabbit.

Having developed a non-insulin-dependent diabetes mellitus (NIDDM) syndrome model in the rabbit using Wirsung duct ligation, it appeared interesting to use it to study the relationship between glycemia and the plasma levels of TXA(2)and PGI(2), and of some other biochemical parameters such as cholesterol, triglycerides, alkaline phosphatase and transaminases. A comparative study was carried out in the sham-operated rabbits (controls, C) and those having their pancreatic duct ligatured (NIDDM, D) at 15, 30, 40, 50 and 60 days post-ligation. On the 40th days, whereas in the controls, glycemia was 1.17 +/- 0.04 g.l(-1), it reached a maximum of 4.62 +/- 0.76 g.l(-1)(25.40 mM) in the NIDDMs. No significant modification was observed either in cholesterolemia or in triglyceridemia in either group. The GOT and GPT were highly increased, from 11.50 +/- 4.00 IU. l(-1)and 27.00 +/- 1.50 IU.l(-1)(C) to 37.50 +/- 5.64 IU.l(-1)(P<0. 001) and 58.50 +/- 7.50 IU.l(-1)(D) (P<0.001) in the NIDDM group, suggesting that hyperglycemia occurred simultaneously with the degeneration of the pancreatic tissue. In parallel, in D rabbits, the plasma levels of TXB(2)and 6 keto PGF(1alpha)were augmented to 68.22 +/- 6.20 pg.ml(-1)versus 22.49 +/- 5.74 pg.ml(-1)(C) (P<0.001), and 127.11 +/- 14.39 pg.ml(-1)versus 48.65 +/- 4.51 pg.ml(-1)(C) (P<0. 001) respectively. Statistical studies showed a significant correlation (P<0.05 and <0.02) between glycemia and the biosynthesis of eicosanoids under study. Moreover, 25 mM was found to be the threshold level of glucose excess essential to increase the TXA(2)and PGI(2)biosynthesis significantly. This supports the results obtained by other authors studying the action of glucose on phospholipase activity and consequent eicosanoid production.

The anti-thromboxane A2 synthetase activity of myocardial tissue and its variation during ischemia and reperfusion in isolated rabbit heart.

In this investigation, an anti-thromboxane A2 (TXA2) synthetase activity in the myocardial tissue, which can be modulated by ischemia and reperfusion, was observed. Regional ischemia was induced by 60 min occlusion of the left anterior descending coronary artery in isolated Langendorff rabbit hearts. Biosynthesis of TXA2 was carried out by using arachidonic acid (AA) as substrate, horse platelet microsomes (HPM) as the source of TXA2 synthetase and left ventricle microsomes (LVM) from ischemic and non-ischemic areas as effectors TXB2, the stable metabolite of TXA2, was determined by radioimmunoassay. Experiments carried out under the adopted conditions showed that LVM from control hearts were able to inhibit by up to 50% the biosynthesis of TXA2 from HPM. This anti-TXA2 synthetase activity was more pronounced when LVM from the non-ischemic area were used, rather then LVM from the ischemic one. A 60 min reperfusion decreased the anti-TXA2 activity. A superfused rabbit aorta strip was also used as a cascade bioassay to study the effect of LVM on the TX2-synthetase activity of HPM, and this confirmed our findings. These results suggest that the left ventricle possesses a self-defense mechanism against acute myocardial ischemia, independently from the circulation. The postulated mechanism may be initiated in the non-ischemic area.

Pharmacophore requirements in new series of pyridazinyl alkanoic acids, N-[(pyridazin-2-yl) alkyl] succinyl and glutaryl amides, inhibitors of thromboxane A2 biosynthesis.

New series of 5-benzyl-6-methyl-4-oxo pyridazin-2-yl alkanoic acids, N-[(pyridazin-2-yl)alkyl] succinyl and glutaryl amides have been synthesized and evaluated in vitro as TXA2 biosynthesis inhibitors. The experiments were carried out using arachidonic acid (32.8 microM) as a substrate and horse platelet microsomes as sources of TXA2 synthase. The presence of TXB2, a stable metabolite of TXA2, was determined by RIA. The potency of active compounds (1.10(-4) < IC 50 < 1.10(-6) M) greatly depends on the length of the chain at the N-2 position on the pyridazine ring. Furthermore, enzyme inhibition in vitro is increased with the presence of a halogen atom on the aromatic moiety of the benzyl group at C-5. Compound 4f having a pentanoic side chain and a 4-fluoro benzyl moiety was the most active derivative with an IC50 value of 6.69 x 10(-6) M. Molecular modelling studies were done on all the synthesized pyridazinones and on prostaglandin H2 (PGH2) suggesting spatial features and volumes of TXA2 synthase pharmacophore mode in these series of derivatives.

Thromboxane A2 biosynthesis inhibitors: synthesis and evaluation of pyrazolotriazinyl alkanoic acids.

A novel series of (6-aryl-4-oxo-pyrazolo 2,3-d] [1,2,5] triazin-3-yl) alkanoic acids was synthesized and evaluated in vitro as thromboxane A2 (TXA2) biosynthesis inhibitors. The experiments were carried out using arachidonic acid (32.8 microM) as a substrate and horse platelet microsomes (HPM) as sources of TXA synthetase. TXB2, a stable breakdown product of TXA2, was determined by radioimmunoassays (RIA). The substances under study, at concentrations ranging from 1.10(-6) M to 1.10(-4) M, significantly inhibited the biosynthesis of TXA2 in vitro. This activity was found to be dose-dependent, the potency of which could be related to structural features of the molecules. Compound 3b, bearing a butanoic side chain in the 3-position and a 4-chloro phenyl ring in the 6-position of the bicyclic system, was the most active derivative in in vitro enzyme inhibition (ID50 = 2.81 x 10(-5) M). Comparison of the spatial configurations of prostaglandin H2 (PGH2 and 3b displayed a good correlation between essential structural moieties of both molecules. In addition, conceptual model for the PGH2 and TX synthetase interactions was applied to compound 3b.

Should magnesium therapy be considered for the treatment of coronary heart disease? I. A critical appraisal of current facts and hypotheses.

When given at physiological doses, therapy with magnesium corrects the alterations in cellular function resulting from magnesium deficiency, whereas at higher dosages, which induce hypermagnesaemic levels, magnesium possesses pharmacological effects, such as the inhibition of the calcium influx: this may alter the electrophysiological properties of heart cells, decrease catecholamine secretion, influence the synthesis of prostacyclin and/or alter platelet function. The evidence that magnesium deficiency has untoward effects in patients with ischaemic heart disease is only circumstantial and direct proof that magnesium deficiency causes cardiac disorders is at present lacking. A ubiquitous calcium-channel blockade mechanism is the main and well-established way of action whereby magnesium acts at pharmacological levels; other mechanisms may be involved as well but at present remain questionable or unsettled. On the basis of the present knowledge, beneficial effects may thus be expected from high dose intravenous magnesium therapy in the setting of acute myocardial infarction with respect to mortality rates, even when there is concurrent thrombolytic therapy, as recently demonstrated by the large LIMIT-2 study, although this could not be confirmed from the ISIS-4 trial. High dose intravenous magnesium is also a first choice therapy for terminating torsade de pointes ventricular tachycardia but cannot be considered an established therapy for other cardiac rhythm disturbances nor for settings other than acute myocardial infarction in the case of ischaemic heart disease. The preliminary evidence that magnesium deficiency has a high prevalence in patients with ischaemic heart disease and that it may have a detrimental influence on the course of ischaemic heart disease needs to be validated by larger prospective and controlled clinical studies. Magnesium therapy in ischaemic heart disease thus proves a promising approach which, however, requires that the respective pharmacological and physiological effects be distinguished and further delineated and that the type and stage of ischaemic heart disease be characterized.

Should magnesium therapy be considered for the treatment of coronary heart disease? II. Epidemiological evidence in outpatients with and without coronary heart disease.

In an epidemiological and follow-up survey on 712 patients, 52 subjects with proven ischaemic heart disease were matched with and compared to 52 coronary-prone subjects with similar major cardiovascular risk factors (high-risk controls, HR) as well as to 52 patients at low cardiovascular risk (low-risk controls, LR). HR and LR patients were all free of overt ischaemic heart disease. Both the average daily dietary magnesium intake and the 24 h renal magnesium output were slightly higher in HR as compared to LR and ischaemic heart disease patients. No difference could be observed between the three groups with respect to serum magnesium levels, whereas erythrocyte magnesium levels were lower in ischaemic heart disease patients than in LR (P = 0.089) and to HR (P = 0.042). Ischaemic heart disease patients below 60 years had significantly lower erythrocyte magnesium levels than older (> 60 years) ischaemic heart disease patients. Lower erythrocyte magnesium levels in ischaemic heart disease patients were also associated with an increased incidence of cardiac events in the follow-up period and with a more unfavourable outcome. A pilot phase 6 month open trial of oral magnesium supplementation in nine ischaemic heart disease patients with low erythrocyte magnesium levels led to significant increases of erythrocyte magnesium in these patients, and to an impressive decrease of anginal attacks and nitrate consumption, as well as to a lesser degree of ST segment depression on surface ECG obtained at exercise testing in seven patients.

Inhibition of thromboxane A2 biosynthesis in vitro by the main components of Crataegus oxyacantha (Hawthorn) flower heads.

A hydro-alcoholic extract from Crataegus o. (Co) flower heads inhibited thromboxane A2 (TXA2) biosynthesis in vitro. This present study aims to find out which are the active principles. The main components, as revealed by chromatography, were tested. We also took into consideration catechin and epicatechin: although they do not appear as such with chromatography because of their polymerisation or-and condensed structure, these two proanthocyanidins seem to play a major role in the mentioned activity of the plant.

The tris formulation of Fluorouracil is more cardiotoxic than the sodium-salt formulations.

The cardiotoxicity of 5-fluorouracil (FU) was attributed to degradation compounds present in the injected vials, fluoroacetaldehyde (Facet) and fluoromalonaldehydic acid (FMald). FU-NaOH vials were much less cardiotoxic than FU-Tris vials on the isolated perfused rabbit heart model since Facet and FMald are stored in stable depot forms in FU-Tris vials whereas, in FU-NaOH vials, they are extensively transformed. Cardiotoxic fluoroacetate (FAG), coming from Facet metabolization, was found in urine of patients, with a ratio FAC /FU catabolites 10-30 fold lower in patients treated with FU-NaOH than in those treated with FU-Tris.

Binding of a thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) receptor antagonist to rabbit and pig heart membrane protein.

This study aimed at testing the hypothesis that the binding sites for TXA2/PGH2 are present and different in the heart as compared to platelets and blood vessels. Kinetic studies on the thromboxane binding to protein of membrane preparations from rabbit and pig hearts were carried out using [125I]-PTA-OH, a potent specific thromboxane receptor antagonist. The following points are stressed: 1. the binding sites to 125I-PTA-OH were shown to be present in the heart membrane whatever the adopted experimental conditions were i.e. the temperature (4 or 30 degrees C) used for incubation the protein fractions under study: either the 105,000 g supernatant or the 200,000 g supernatant of the solubilized pellet (105,000 g) the animal species: rabbit and pig 2. the radioligand binding was rapid, saturable and reversible 3. the kinetically determined Kd's were in the picomolar range--11 and 14 pM for the rabbit and pig heart membrane preparation respectively--instead of the nanomolar range found in other tissues of the nanomolar range found in other tissues--27-39 nM and 2 nM for human platelets and bovine artery endothelial cells respectively- using the same thromboxane receptor antagonist.

Cardiotoxicity of commercial 5-fluorouracil vials stems from the alkaline hydrolysis of this drug.

The cardiotoxicity of 5-fluorouracil (FU) was attributed to impurities present in the injected vials. One of these impurities was identified as fluoroacetaldehyde which is metabolised by isolated perfused rabbit hearts into fluoroacetate (FAC), a highly cardiotoxic compound. FAC was also detected in the urine of patients treated with FU. These impurities were found to be degradation products of FU that are formed in the basic medium employed to dissolve this compound. To avoid chemical degradation of this antineoplastic drug, the solution of FU that will be injected should be prepared immediately before use.

Myocardial prostacyclin and thromboxane A2 synthetase activities during ischemia and reperfusion in isolated rabbit heart.

The aim of the study was to determine the prostacyclin (PGI2) and thromboxane A2 (TXA2) synthetase activities of myocardial tissue and their variation during ischemia and reperfusion. Regional ischemia was induced by 10 min occlusion of the left anterior descending coronary artery in isolated Langendorff rabbit hearts. Biosynthesis of PGI2 and TXA2 were carried out by using arachidonic acid as substrate and left ventricle microsomes (LVM) from ischemic and non-ischemic areas as sources of PGI2 and TXA2 synthetase. 6-keto-PGF1 alpha and TXB2, stable metabolites of PGI2 and TXA2 respectively, were determined by radioimmunoassay. Experiments carried out under the adopted conditions showed that LVM were able to synthetise PGI2 as well as TXA2 from arachidonic acid. On the other hand, ischemia depressed both PGI2 and TXA2 synthetase activities of cardiac tissue: the depression was more pronounced on TXA2 synthetase than on PGI2 synthetase with no significant difference between ischemic and non-ischemic regions. Moreover, ischemia increased the ratio 6-keto-PGF1 alpha/TXB2 indicating therefore that it can facilitate the formation of PGI2. The post ischemic reperfusion of the heart counteracted the decrease in PGI2 synthetase induced by ischemia which returned to the normal level: reperfusion also slightly reversed the decrease in TXA2 the decrease in TXA2 synthetase. However, the diminution in TXA2 synthetase of non-ischemic myocardium was attenuated but it remained lower than the normal level. These results suggested that the whole left ventricle is affected by regional ischemia. Furthermore it appears that myocardial TXA2 synthetase is more vulnerable than PGI2 synthetase to a lack of oxygen and nutrients.

Aminopyridazine derivatives and TXA2-PGI2 balance.

Experiments carried out under the conditions adopted showed the strong affinity of aminopyridazine derivatives for the eicosanoids TXA2 and PGI2. But this affinity depended on the chemical structure of the molecule: a small change in the radical grafted onto the pyridazine ring could completely modify the pharmacological activity of the molecule. Consequently it should be possible to control the properties of pyridazine derivatives according to pharmacological needs. Thus: --pyridazin-3-one derivatives were mainly active on TXA2 biosynthesis: 2-aminoalkyl 5-arylidene 6-methyl (4H) pyridazin-3-ones inhibited the TXA2-synthesizing activity of cardiac tissue whereas 3-amino 4,6-diaryl pyridazin-3-ones were specific inhibitors of the TXA2 synthetase in vitro, but these effects were weak. --pyridazine derivatives were devoid of any effect on the TXA2-synthesizing activity of cardiac tissue: they acted on either TXA2 synthetase or PGI2 synthetase according to the radicals grafted onto the pyridazine ring. --none of the compounds under study was active on the PGI2-synthesizing activity of cardiac tissue.