Employment of vasopressin receptor antagonists in management of hyponatraemia and volume overload in some clinical conditions.

WHAT IS KNOWN AND OBJECTIVE: Hyponatraemia, the most common electrolyte imbalance occurring in hospitalized subjects, is usually classified as hypovolaemic, euvolaemic or hypervolaemic. Hyponatraemia is a predictor of death among subjects with chronic heart failure and cirrhosis. The inappropriate secretion of the antidiuretic hormone (AVP) seems to be of pivotal importance in the decline of serum sodium concentration in these clinical conditions. The objective of this review was to summarize recent progress in management of hyponatraemia in SIADH, cirrhosis and heart failure. METHODS: Literature searches were conducted on the topics of hyponatraemia and vasopressin receptor antagonists, using PubMed, pharmaceutical company websites and news reports. The information was evaluated for relevance and quality, critically assessed and summarized. RESULTS AND DISCUSSION: The initial treatment of severe hyponatraemia is directed towards the prevention or management of neurological manifestations and consists of an intravenous infusion of hypertonic saline. Fluid restriction is indicated in oedematous states. Diuretics alone or in combination with other specific drugs remain the main strategy in the management of volume overload in heart failure. In resistant cases, ultrafiltration can lead to effective removal of isotonic fluid preventing new episodes of decompensation; however, aquapheresis is associated with increased costs and other limits. In several trials, the efficacy of vasopressin receptor antagonists in euvolaemic patients (inappropriate antidiuretic hormone secretion) or in hypervolaemic hyponatraemia (chronic heart failure, cirrhosis) has been evaluated. It was found that vaptans, which promote aquaresis, were superior to a placebo in raising and maintaining serum sodium concentrations in these subjects. WHAT IS NEW AND CONCLUSIONS: Combined with conventional therapy, vasopressin receptor antagonists (AVP-R antagonists) are able to increase the excretion of electrolyte-free water and the sodium concentration. Further studies are needed to assess efficacious outcomes of aquaresis compared with aquapheresis and with conventional therapy.

Study of the correlations among some parameters of the oxidative status, gelatinases, and their inhibitors in a group of subjects with metabolic syndrome.

Our aim was to examine some parameters of oxidative status, gelatinases, and their inhibitors and to evaluate their interrelationships in subjects with metabolic syndrome (MS). We enrolled 65 MS subjects, subdivided according to the presence or not of diabetes mellitus. We examined lipid peroxidation (expressed as thiobarbituric acid reacting substances, TBARS), protein oxidation (expressed as carbonyl groups), nitric oxide metabolites (NO x ), total antioxidant status (TAS), MMP-2, MMP-9, TIMP-1, and TIMP-2. We found that MS subjects, diabetics and nondiabetics, showed an increase in TBARS, PC, and NO x . A significant decrease in TAS was observed only in nondiabetic MS subjects in comparison with diabetic MS subjects. We observed increased concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2, higher in diabetic subjects. Our data showed a positive correlation between TAS and MMP-2, TAS and MMP-9, and TAS and MMP-9/TIMP-1 and a negative correlation between TBARS and MMP-2 in diabetic MS subjects in the entire group. In MS subjects a prooxidant status and increased levels of gelatinases and their inhibitors are evident although the correlations between oxidative stress and MMPs or TIMPs are controversial and need further investigation.

Calculated whole blood viscosity in non-diabetic subjects with asymptomatic carotid atherosclerosis: How insulin resistance may affect blood viscosity.

BACKGROUND AND OBJECTIVE: Asymptomatic atherosclerosis is an important early marker of vascular damage and, among its risk factors, hemorheological alterations play an important role. PATIENTS AND METHODS: In a cohort of 85 non-diabetic subjects with asymptomatic carotid atherosclerosis (ACA), we have measured whole blood viscosity (cWBV) according to the haematocrit and plasma fibrinogen level. The cWBV distinguish the subgroup of ACA subjects with 3-5 cardiovascular risk factors (CRFs) from that with 1-2 CRFs and the same behavior is present for haematocrit and plasma fibrinogen level. Therefore, we divided the whole group of ACA subjects according to the medians of the four surrogate indexes with an insulin resistance degree of TG/HDL-C, TyG, VAI and LAP. RESULTS: The analysis of the correlation between cWBV and each index of insulin resistance has shown that no correlation is present in the whole group and in the group of ACA subjects with 1-2 CRFs, while in the subgroup with 3-5 CRFs there is a positive correlation between cWBV with TG/HDL-C and TyG at a low degree of statistical significance. CONCLUSIONS: The date underline that subjects with this clinical condition have an unaltered evaluation of the cWBV compared to the other indices.

Changes in RDW according to prognostic predictors in newly diagnosed multiple myeloma.

RDW is an erythrocyte index that increase in multiple myeloma, in which it appears to have an important role in predicting outcome. For this reason, we performed a retrospective analysis to evaluate the relationships of RDW with some important prognostic predictors. Specifically, in a cohort of 190 newly diagnosed multiple myeloma patients, we have examined the behaviour of RDW and its trend in relation to the ISS stage and other prognostic factors, such as albumin, beta-2 microglobulin, LDH and bone marrow plasma cell infiltration. We performed the analysis in the entire cohort of patients and in the three different disease isotypes (Light chain, IgA, and IgG multiple myeloma). The evaluation of RDW in the different isotypes was made with the Kruskal-Wallis test, integrated by the Dunn test. The comparison between the subgroups allocated above and below the median value of each prognostic factor, was made with the Mann-Whitney test. From our analysis, we observed that RDW is higher in the IgA multiple myeloma, and it increases significantly from ISS I to III. Moreover, RDW increases in the presence of lower albumin values, higher levels of beta2-microglobulin and LDH and in the presence of a greater bone marrow plasma cell infiltrate.

Leukocyte activation markers and oxidative status in chronic kidney disease.

AIM: In chronic kidney disease (CKD) cardiovascular risk is increased. Oxidative stress is strictly involved in the pathophysiology of this enhanced risk as well as leukocytes' activation. To better elucidate these phaenomena we evaluated some parameters of leukocyte activation and oxidative state on fasting blood samples obtained from CKD patients on conservative or hemodialysis (HD) treatment, compared to those obtained from control subjects. METHODS: We enrolled 41 patients (25 men and 16 women, mean age 64.7 ± 11.1 years) with CKD and 42 patients (21 men and 21 women, mean age 66.83 ± 14.8 years) with CKD on hemodialysis (HD) treatment. Hemodialyzed patients were evaluated before and after a standard HD session. Leukocyte activation was evaluated by determining plasma elastase and myeloperoxidase level employing ELISA methods. Lipid peroxidation was evaluated as thiobarbituric acid-reactive substances (TBARS), total antioxidant status using spectrophotometry. RESULTS: Elastase was higher in CKD on conservative and on HD treatment and its value increased after the HD session. Myeloperoxidase did not show any variation in CKD on conservative and HD treatment while after HD its value was increased. Lipid peroxidation was increased in CKD on conservative and on HD therapy and its value after dialysis showed no significant variation. Total antioxidant status was increased in CKD on HD treatment and significantly decreased after the HD session; no variation between normal controls and CKD subjects on conservative therapy was observed. CONCLUSION: Several aspects derive from these data considering the role of oxidative stress in the cardiovascular events that accompany CKD.

The unpredictable erythrocyte deformability alteration in some hematological disorders: How the classification of primary hyperviscosity syndromes could change.

According to Wells classification, it is possible to distinguish the primary hyperviscosity syndromes in polycythemic, sclerocythemic and sieric and/or plasmatic. In polycythemia vera, multiple myeloma, Waldenström's macroglobulinemia, and monoclonal gammopathy of undetermined significance, we have observed an unexpected behaviour of the erythrocyte deformability. This data highlights that the hemorheological alteration present in polycythemia vera has not been related to the increase of RBC mass only, as well as that present in plasmacellular dyscrasias has not been attributable to the increase of plasma viscosity only.The aim of this paper is to suggest some starting points for an accurate reflection, emphasizing the need of a revision of the current classification of primary hyperviscosity syndromes.

[Oxidative stress and endothelial dysfunction]. / Stress ossidativo e disfunzione endoteliale.

Endothelial dysfunction and oxidative stress are the main pathophysiological mechanisms of several diseases such as hypertension, atherosclerosis, dyslipidemia, diabetes mellitus, cardiovascular disease, renal failure and ischemia-reperfusion injury. Reactive oxygen species (ROS) can modulate cellular function, receptor signals and immune responses in physiological conditions, but when present in excess, they mediate progressive endothelial damage through growth and migration of vascular smooth muscle and inflammatory cells, alteration of extracellular matrix, apoptosis of endothelial cells, activation of transcription factors (NFkB, AP-1), over-expression of inflammatory cytokines and adhesion molecules (ICAM-1, VCAM-1 , E-selectin). Recent evidences suggest that the major source of ROS is the NADPH-oxidase, especially activated by angiotensin II, shear stress and hyperglycemia. The unbalance between production of free radicals and the ability to neutralize them by antioxidant systems causes a condition of "oxidative stress". ROS alter vascular tone by increasing concentration of cytosolic calcium and especially causing a decreased availability of nitric oxide, the principal agent of endothelial function with vasodilating action. The data emerged from experimental and clinical studies confirm that endothelium-dependent vasodilation is altered in many diseases.

Exercise in obesity management.

Obesity is considered a global epidemic by the World Health Organization in both developed and developing countries. It is associated with a higher risk of cardiovascular disease, diabetes mellitus, cancer and other clinical conditions. Visceral fat is the major responsible for metabolic complications, such as insulin-resistance, and it acts as an endocrine organ producing adipokines involved in lipidic and glycaemic metabolism. TNF-α and IL-6, produced by adipose tissue, increase NADPH oxidase activity activating protein kinase C and NFκB leading to an higher oxidative stress. The obesity management includes physical activity: aerobic training improves lipid profile and insulin sensitivity while resistance training increases lean body mass and basal metabolism and has beneficial effects on bone mineral density and glucose tolerance. An exercise program should include 30 to 45 minutes of moderate intensity activity performed 3 to 5 days a week. Weight loss is also associated with lower blood pressure and improved oxidative status, confirmed by reduced oxidative stress markers and increased antioxidant protection. An inverse association between indicators of systemic inflammation and physical activity has been demonstrated, so exercise training may reduce endothelial damage and cardiovascular risk.

An assessment of the hemorheological profile in patients with subclinical carotid atherosclerosis divided in relation to the number of cardiovascular risk factors and different degrees of insulin resistance.

We present a cohort of 100 subjects [43 men and 57 women; median age 66.00(25)] who were tested using carotid ultrasound to identify subclinical carotid atherosclerosis (SCA). We have evaluated the behaviour of whole blood viscosity (WBV) at high (450 s-1) and low (0.51 s-1) shear rates, plasma viscosity (450-1), hematocrit and mean erythrocyte aggregation. When compared to normal control subjects, using the Mann-Whitney test, we observed in SCA patients a significant increase in WBV only. The results were substantial after having divided the SCA subjects according to the cardiovascular risk factors (CRFs) and the degree of insulin resistance; the research was performed using two surrogate indexes such as TG/HDL-C and TyG. With the division carried out according to CRFs, employing the Kruskal-Wallis test, results show a significant increase in WBV (at high and low shear rates), in plasma viscosity, in erythrocyte aggregation and plasma fibrinogen level. Whereas by dividing them into the median of TG/HDL-C and TyG, we noticed a significant increase in WBV (at high and low shear rates) and in erythrocyte aggregation in the two groups with high TG/HDL-C ratio and with high TyG; having found an increased level of plasma fibrinogen in the latter. The data underlines the role of the main hemorheologic aspects in subclinical carotid atherosclerosis being closely correlated to the CRFs and different degrees of insulin resistance.

A novel component of the metabolic syndrome: the oxidative stress.

The metabolic syndrome (MS) represents a cluster of cardiovascular (CV) risk factors associated to CV disease and type 2 diabetes. It is still under debate whether MS is a mere aggregation of risk factors or it represents a clinical entity with visceral obesity as underlying pathophysiological trigger. The publication of several diagnostic criteria of MS by scientific associations or experts panels reflects this uncertainty in understanding the real nature of MS. Besides the metabolic disturbances of MS, as visceral obesity, hypertriglyceridemia, low HDL cholesterol, hypertension and hyperglycemia, novel mechanisms of arterial damage have been identified. This paper reviews the evidence showing that MS and MS factors are characterized by increased oxidative stress, a relevant factor contributing to the development of metabolic and cardiovascular complications. In the next future, the measure of plasma oxidative stress may contribute to identify a subset of MS patients at increased CV risk, candidates to more intensive therapies.

Nitric oxide metabolites, leukocyte activation markers and oxidative status in dialyzed subjects.

AIMS: Our purpose was to evaluate, in a group of 42 end-stage renal disease patients who regularly undergo hemodialysis, some indexes of leukocyte activation, nitric oxide metabolites (NOx) and other parameters that reflect the oxidative stress before and after a standard hemodialysis session. METHODS: Elastase and myeloperoxidase (MPO) were determined by means of ELISA. The NO production was evaluated by a micromethod which measures the concentration of NOx. The oxidation of polyunsaturated fatty acids was evaluated in plasma by detection of thiobarbituric acid-reactive substances (TBARS). Total antioxidant status (TAS) was obtained using spectrophotometry. RESULTS: At baseline, we observed an increase of elastase, NOx, TBARS and TAS, without any variation of MPO. After the dialysis session, we found an increase in elastase and MPO, a decrease in NOx and TAS and no variation in TBARS. No modification occurred after subdividing the patients in two subgroups. CONCLUSIONS: Our data confirm the involvement of leukocytes and oxidative stress in hemodialysis patients.

Haemorheological profile in congenital afibrinogenemia and in congenital dysfibrinogenemia: A clinical case report.

Although the inherited quantitative and qualitative disorders of fibrinogen are rare, in the course of time patients may develop complications including episodes of arterial and venous thrombosis. It can be useful to complete the laboratory assessment of these clinical conditions with the evaluation of the haemorheological profile. The data obtained from this study showed that congenital afibrinogenemia was characterized by a primary plasma hypoviscosity, whereas congenital dysfibrinogenemia by a primary plasma hyperviscosity. Both these haemorheological alterations may concur, with different mechanisms, to the pathogenesis of thrombotic vascular complications.

[Metabolic syndrome: from insulin resistance to adipose tissue dysfunction]. / Sindrome metabolica: dall'insulino-resistenza alla disfunzione del tessuto adiposo.

Recently the definition, the pathophysiology and even the clinical utility of metabolic syndrome (MS) have been discussed. The risk induced by each component of the metabolic syndrome is higher than the risk induced by MS alone. MS alone is, in fact, a weaker predictor of cardiovascular disease than diabetes. New criteria to define the metabolic syndrome have been proposed, as adipokines, CRP and PAI-1. IGFBP-1 is related to hyperinsulinemia/insulin resistance and to the risk of diabetes and fatal ischemic heart disease development. IGF/IGFBP system could be a link between insulin resistance and cardiovascular disease. RBP-4 can attenuate insulin signalling in skeletal muscle and induce hepatic gluconeogenesis. The belief that insulin-resistance is the main cause of MS could change in favour of the adipose tissue dysfunction. The most common cause of a reduced capacity of the adipose tissue to store fats is the increased dietary intake, also present in lipodistrophy, type 1 diabetes mellitus and polycystic ovarian syndrome. The adipose tissue production of adipokines and cytokines (such as IL-6, TNF-alpha and TGF-beta) and the excessive lipid flux towards muscles, heart and liver (Ectopic fat storage syndrome) contribute to the MS genesis and to an increased cardiovascular risk. The comprehension of adipose tissue dysfunction mechanisms offers new possibilities of prevention and therapy.

[Polimorphonuclear leukocytes and diabetes mellitus]. / Polimorfonucleati e malattia diabetica.

Diabetic subjects have a higher infective risk than healthy people, with more frequent and severe infections. This predisposition to infections is determined by hyperglycemia, microangiopathy and altered immune system. In particular, there is a polymorphonuclear leukocytes disfunction including chemotaxis, phagocytosis, bacterial killing and cellular activation by infective stimulus. These alterations are due to abnormal properties of polymorphonuclear leukocytes (PMN) in diabetic patients. Several parameters like phagocytosis of bacterial cells, chemiluminescence during oxidative burst and cell membrane deformability are related to glycaemia and glycated hemoglobin. Recent acquisitions show an altered integrin pattern on diabetics PMN, at baseline and after in vitro stimulation with soluble stimulus like fMLP or PMA. This could influence the interactions between PMN and endothelial cells and the diapedesis. Receptorial alterations on PMN surface may be ascribed to the abnormalities of the cytoscheleton, of the endocytosis and of the transduction mechanism, due to hyperglycemia.

Erythrocyte deformability and hemorheological profile in multiple myeloma.

The hemorheological profile in multiple myeloma (MM) has been extensively studied. Our investigation regarded the behavior of whole-blood viscosity, plasma viscosity and erythrocyte deformability in MM. We enrolled 24 MM patients; 13 of them had been recently diagnosed and were at the initial stage of therapy, 6 were on consolidation/conservation therapy and 5 had achieved a complete remission. On fasting venous blood we evaluated whole-blood and plasma viscosity at high and low shear rates, haematocrit, the ratios between whole-blood viscosity (at high and low shear rate) and haematocrit×100, the ratio between plasma viscosity at low and high shear rate and the erythrocyte deformability examined by using laser diffractometry and expressed as elongation index. A significant increase in plasma viscosity at low shear rate and a marked decrease in haematocrit were observed in MM patients compared with normal controls. Also the ratio between the high shear rate whole-blood viscosity and haematocrit ×100 and the ratio between the low and high shear rate plasma viscosity were significantly increased in MM patients. A significant decrease in erythrocyte deformability, especially at low shear stresses, was found. We discuss some hypotheses that might explain the behavior of red blood cell deformability in MM, considering that its impairment, in addition to the increase of plasma viscosity, can alter the microcirculatory flow in these patients.

Hemorheological parameters in Monoclonal Gammopathy of Undetermined Significance (MGUS).

There is scarcity of information about the hemorheological pattern in subjects with Monoclonal Gammopathy of Undetermined Significance (MGUS). This preliminary research is focused on the behaviour of whole-blood and plasma viscosity, haematocrit and erythrocyte deformability in the above clinical condition. We enrolled 21 MGUS subjects (10 women and 11 men; mean age 66.4 ± 11.6 years). In fasting venous blood we examined whole-blood and plasma viscosity at high and low shear rates, haematocrit, the ratios between whole-blood viscosity (at high and low shear rate) and haematocrit × 100, the ratio between plasma viscosity at low and high shear rate, and the erythrocyte deformability expressed as elongation index. By comparing normal controls to MGUS subjects a significant increase in whole-blood viscosity at high shear rate and in plasma viscosity at low shear rate were observed. In MGUS subjects the ratios between the high and low shear rate blood viscosity and haematocrit × 100, as well as the ratio between the low and high shear rate plasma viscosity were significantly higher. In MGUS subjects a marked decrease in erythrocyte deformability was also observed. The alteration of the hemorheological profile found in these subjects might be involved in the pathogenesis of thromboembolic events, which occur with a high frequency in MGUS.

Diabetic microangiopathy: physiopathological, clinical and therapeutic aspects.

New evidence about diabetic microangiopathy has enabled us to identify an integrated pathogenesis of diabetic complications, including classic metabolic pathways induced by hyperglycaemia, insulin-resistance, hyperinsulinaemia, hormonal alterations and growth factors. Oxidative stress is the most important cause of endothelial damage inducing leukocyte adhesion, altered coagulation and inflammation. Adhesion molecules are a marker of endothelial damage and a potential therapeutic target. Changes in the extracellular matrix induced by TGFbeta1 and lower levels of eparan-sulfate, increased thickness of basement membranes and loss of pericytes are early events of diabetic retinopathy and diabetic nephropathy. Capillary rarefaction produced by genetic factors or by fetal undernourishment contributes to the beginning of insulin-resistance and hypertension. Psychophysical tests, electroretinogram and evoked potentials show retinal functional alterations; fundoscopy and retinal fluorescein angiography show retinal anatomic alterations. The diagnosis of diabetic neuropathy is based not only on traditional neurological examination and electroneurograms, but also on neurothesiometry for sensory testing. Medical treatment of diabetic microangiopathy is based on control of glycaemia, lipemia and blood pressure using glytazones, ACE-inhibitors, angiotensin II receptor antagonists and statins. New knowledgeabout microangiopathy pathogenesis suggests potential drugs for its therapy (ruboxistaurin, AGE-inhibitors, angiopoietin-1 and anti-VEGF, etc.), not yet on sale.

Phonon analysis of the S = 1 quantum spin systems Ni(5)Te(4)O(12)X(2) (X = Cl and Br).

We report our investigations of the electrodynamic response of the S = 1 quantum spin systems Ni(5)Te(4)O(12)X(2) (X = Cl and Br), which develop a magnetic ordered state below 30 K. We measure the optical reflectivity over a broad spectral range extending from the far infrared up to the ultraviolet. Besides identifying the electronic interband transitions, we primarily focus our attention on the lattice dynamics, emphasizing the phonon modes spectrum and its temperature dependence. Our findings do not reveal any direct link between possible structural anomalies and the transition into the magnetically ordered state at low temperatures.

Impairment of plasma nitric oxide availability in senescent healthy individuals: apparent involvement of extracellular superoxide dismutase activity.

To verify the potential involvement of the age-dependent modifications of EC-SOD activity in the impairment of plasma NO availability with advancing age, 40 healthy men divided into 4 age groups for the purpose of comparison (young: 27.4 +/- 1.5 years; middle: 50.8 +/- 2.2, years; old: 70.0 +/- 1.8 years; very old: 86.1 +/- 1.1 years) were enrolled in this study. Plasma samples were used for measurements of the stable end-product nitrite/nitrate (NOx), as an expression of NO availability, EC-SOD activity, thiobarbituric acid reactive substances (TBARS) as a marker of lipid peroxidation, low density lipoprotein (LDL) copper-mediated oxidation in vitro and total antioxidant capacity (TEAC). Our results indicated a significant age-related progressive decrease of plasma NOx content and EC-SOD activity and their values were positively correlated (r = 0.713, p < 0.001). Increased TBARS amount together with reduced lag time for in vitro oxidation of LDL and decreased content of TEAC were observed with advancing age. Finally, EC-SOD values were negatively correlated with plasma TBARS values (r = -0.855, p < 0.001). Findings of the present study suggest that the decrease of antioxidant defence strategies play a primary role by compromising NO availability in normally aged individuals, particularly through a progressive decrease of EC-SOD activity.