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Background: Matrix metalloproteinases (MMPs) are a heterogeneous family of endopeptidases that play a role in many physiological functions, including the immune response. An imbalance between the activity of MMPs and their physiological tissue inhibitors (TIMPs) has been proposed in the pathophysiology of different autoimmune disorders. We aimed to assess the plasmatic levels of MMP-2, MMP-9, and their inhibitors TIMP-1 and -2 in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Subjects and methods: Twenty patients with CIDP and 20 age- and sex-matched healthy controls were enrolled. Plasma concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined by the enzyme-linked immunosorbent assay. Results: CIDP subjects had higher MMP-9 concentrations along with TIMP-1 downregulation when compared to controls, with the consequent increase in the MMP-9/TIMP-1 ratio (p

Protein carbonylation is a marker of oxidative protein damage, that is likely involved in the pathogenesis of several diseases. The aim of this study was to evaluate the protein carbonyl (PC) groups in different clinical conditions. It included different groups of subjects: 81 trained subjects; 23 subjects with mild essential hypertension; 31 middle-aged subjects with metabolic syndrome (MS); 106 subjects with MS not selected for age (subdivided into two subgroups, with and without diabetes mellitus); 91 obese adults subdivided in two subgroups (BMI 30-35 Kg/m2 and BMI > 35 kg/m2); 48 subjects with obstructive sleep apnea syndrome (OSAS) subdivided in accordance with the apnea/hypopnea index (AHI); 27 subjects with chronic kidney disease (CKD) on conservative therapy; 31 subjects with CKD on haemodialysis treatment; and 50 subjects with juvenile myocardial infarction. PC groups were reduced in trained subjects in comparison with sedentary controls, while no variation was observed in mild essential hypertension. PC groups were increased in MS subjects and in adult obese subjects. In MS subjects the PC groups were not influenced by the presence of diabetes mellitus and in adult obese subjects were not influenced by the obesity degree. In OSAS subjects only those with AHI > 30 showed an increase of PC groups. PC groups increased in CKD subjects undergoing conservative treatment and haemodialysis therapy. In dialyzed subjects, after a standard dialysis session, there was a marked increase in PC groups. In juvenile myocardial infarction PC groups were higher than in controls; there was no difference between STEMI and NSTEMI and their concentration was unaffected by the number of cardiovascular risk factors or stenosed coronary vessels.

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.

BACKGROUND: in this study, with a re-evaluation of the hemorheological determinants previously described in MGUS subjects and in MM patients, we have detected the calculated whole blood viscosity, according whether to the hematocrit and total plasma protein concentration (de Simone formula) or to the haematocrit and plasma fibrinogen level (Merrill formula), and a marker of the erythrocyte aggregation (albumin/fibrinogen level). METHODS: data were expressed as means±standard deviation. Student’s t test for unpaired data was used to compare MGUS subjects and MM patients. The correlation coefficient between mean erythrocyte aggregation (MEA) and hematocrit (Ht) was evaluated in MGUS, MM and MGUS + MM groups using the Spearman test. RESULTS: the comparison between MGUS and MM shows that the measured blood viscosity and calculated blood viscosity based on hematocrit and total plasma protein, but not which estimated in relation to the hematocrit and plasma fibrinogen, differentiate the two groups. A difference between the two groups also regards the measured erythrocyte aggregation and its surrogate marker. In addition, the measured plasma viscosity at low shear rate (0.51 s–1) and, in particular, the ratio between plasma viscosity at low (0.51 s–1) and high (450 s–1) shear rates distinguish MGUS and MM. CONCLUSIONS: calculated blood viscosity (de Simone formula and other formulas) and the surrogate marker of erythrocyte aggregation disclose an alike trend with the corresponding hemorheological determinants obtained by using their direct measurement.

The association between obesity and cardiovascular diseases has a multifactorial pathogenesis, including the synthesis of inflammatory molecules, the increase in oxidative stress and the dysregulation of the matrix metalloprotease (MMP) concentration and activity. In a group of adults with obesity, divided in 2 subgroups according to the body mass index (BMI), we examined lipid peroxidation, expressed as thiobarbituric acid-reactive substances (TBARS), protein oxidation, expressed as protein carbonyl groups (PCs), plasma gelatinases (MMP-2 and MMP-9), and their tissue inhibitors (TIMP-1 and TIMP-2). In the whole group, as well as in the 2 subgroups (with BMI 30–35 or BMI>35) of obese subjects, we observed an increase in TBARS, PCs, MMP-2, and MMP-9, and also TIMP-1 and TIMP-2 in comparison with the control group. A positive correlation between TBARS and PCs emerged in obese subjects and persisted after dividing obese subjects according to BMI. The correlation between MMP-2 and TIMP-2 was not statistically significant, while a significant correlation was present between MMP-9 and TIMP-1. The correlations between the markers of oxidative stress (TBARS and PCs) and those of the MMP/TIMP profile indicated a more marked influence of protein oxidation on MMPs and TIMPs in comparison with TBARS. The innovative aspect of our study was the simultaneous evaluation of oxidative stress markers and MMP/TIMP profile in adult obese subjects. We observed significant alterations and correlations that may negatively influence the clinical course of the disease.

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.

The goal of this research was to evaluate the plasma concentration of MMP-9 and its tissue inhibitor (TIMP-1) in different clinical conditions. It included several groups of subjects: 31 overweight subjects; 91 obese adults divided into two subgroups according to the BMI value (BMI 30–35 Kg/m2 and BMI > 35 Kg/m2); 90 subjects with metabolic syndrome (MS) divided into two subgroups (with and without diabetes mellitus); 100 subjects with preclinical carotid atherosclerosis (PCA) divided according to the number of cardiovascular risk factors and to the insulin resistance degree; 48 subjects with obstructive sleep apnoea syndrome (OSAS) divided according to the apnoea/hypopnea index (AHI); 27 subjects with chronic kidney disease (CKD) on conservative management; 31 subjects with CKD on regular haemodialysis treatment. We have found a significant increase of MMP-9 and TIMP-1 in overweight subjects, in obese adult and in MS subjects. In obese adults, the behaviour of these two parameters was not influenced by the degree of obesity, while in the group of MS subjects both these parameters were clearly influenced by the presence of diabetes mellitus. In subjects with PCA, we observed an increase of MMP-9 associated with a significant decrease of TIMP-1; the same trend was found by subdividing the entire group in accordance with the number of cardiovascular risk factors and with the insulin resistance degree. In subjects with OSAS, we noted an increase in MMP-9 and TIMP-1; this increase was more evident in subjects with OSAS having AHI > 30. In individuals with CKD on conservative and haemodialysis treatment we have found, at baseline, a marked increase in MMP-9 and a significant decrease of TIMP-1. In dialyzed subjects, after a standard dialysis session was noted, a significant increase in MMP-9 was associated with a further decrease in TIMP-1.

Hyperviscosity syndrome is a clinical condition characterized by the slowing of blood flow through the vessels and it may be associated with several diseases. The nosographic classification of primary hyperviscosity conditions (Wells classification 1970) divided the primary hyperviscosity syndromes in polycythaemic, sclerocytemic and sieric. Recent and personal laboratory observations have highlighted an unexpected behaviour of the erythrocyte deformability observed in some haematological disorders such as polycythemia vera, multiple myeloma and monoclonal gammopathy of undetermined significance. The interest of this observation depends on the fact that up to now, according to the Wells classification, the hemorheological alteration present in PV was related to the increase of RBC mass while that present in MM and MGUS was attributable to the abnormality of plasma or serum viscosity only. Through an extensive research among the literature, using MEDLINE/PubMed to identify all published reports on the hyperviscosity syndromes, issues that until now have been dealt with separately will therefore be analyzed in a unique paper, allowing a global view. The aim of this paper is to provide some suggestions for reflection and emphasizing the need of a nosographic framework of hyperviscosity that, probably, deserves to be reviewed.

The spreading of Coronavirus (SARS-CoV-2) pandemic, known as COVID-19, has caused a great number of fatalities all around the World. Up to date (2020 May 6) in Italy we had more than 28,000 deaths, while there were more than 205.000 infected. The majority of patients affected by COVID-19 complained only slight symptoms: fatigue, myalgia or cough, but more than 15% of Chinese patients progressed into severe complications, with acute respiratory distress syndrome (ARDS), needing intensive treatment. We tried to summarize data reported in the last months from several Countries, highlighting that COVID-19 was characterized by cytokine storm (CS) and endothelial dysfunction in severely ill patients, where the progression of the disease was fast and fatal. Endothelial dysfunction was the fundamental mechanism triggering a pro-coagulant state, finally evolving into intravascular disseminated coagulation, causing embolization of several organs and consequent multiorgan failure (MOF). The Italian Society of Clinical Hemorheology and Microcirculation was aimed to highlight the role of microcirculatory dysfunction in the pathogenetic mechanisms of COVID-19 during the spreading of the biggest challenges to the World Health.

In this case report, we examine the behavior of plasma viscosity, explored at high and low shear rates, and erythrocyte aggregation in two patients with congenital afibrinogenemia, a clinical disorder firstly described in 1920 and that has an estimated incidence of 1 : 1-200 0000. The two hemorheological parameters examined by us showed a marked decrease in both patients, in one of whom erythrocyte aggregation was even undetectable. Keeping in mind that spontaneous thrombosis (venous and arterial) has been often described in congenital afibrinogenemia, it can be hypothesized that the decrease in plasma viscosity and erythrocyte aggregation might cause a reduction of the endothelial synthesis and release of nitric oxide through the fall of the wall shear stress.

The complement system is an essential component of the innate immune defence that, if overly activated, may damage organs and tissues. For this reason, there is a fine complement regulatory system. The complement modulation system includes two proteins with important regulatory activity, CD55 or decay accelerating factor (DAF) and CD59 or membrane inhibitor of reactive lysis (MIRL). The paroxysmal nocturnal hemoglobinuria (PNH) is a clonal and non-neoplastic disease characterized by intravascular haemolysis, occurrence of thrombosis and bone marrow failure. In clinical practice, in opposition to PNH, a variety of pathological conditions have been observed with an acquired and non-genetic deficiency of the regulatory proteins CD55 and CD59. This abnormal, non-clonal, reduced expression of complement regulatory proteins configures what we may define as PNH-like phenotype. Similarly to PNH, even in the PNH-like phenotype diseases there has been a greater exposure to the mediated complement cellular lysis and, a likely increased risk of thromboembolic events. Therefore, the knowledge of the potential roles of the complement system becomes necessary for a deeper understanding of several pathological conditions and for an improved clinical management of the patients.

Considering the role of hemorheology in coronary circulation, we studied blood viscosity in patients with juvenile myocardial infarction. We examined whole blood viscosity at high shear rate using the cone-on-plate viscosimeter Wells-Brookfield ½ LVT and at low shear rate employing a viscometer Contraves LS30 in 120 patients (aged

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.

Fasting from dawn to sunset during Ramadan is one of the five pillars of Islam. A significant number of diabetic patients insist on fasting during Ramadan against the recommendations of their physicians. Fasting in diabetic subjects may be associated with increased risk of hypoglycemia and hyperglycemia, diabetic ketoacidosis, dehydration and thrombosis. Patients with uncontrolled diabetes mellitus are predisposed to major metabolic risks. Another problem is the reluctance of diabetic patients in taking their medications during the fast; therefore the timing and the dosage of anti-diabetic drugs must be adapted for each patient. It is important for diabetic patients who wish to fast during Ramadan to effect the necessary preparation to approach the fasting as safely as possible. Up to now, the management of these patients is a challenge for healthcare professionals. The aim of this minireview is that to offer a simple guide for management of Muslim diabetic patient during Ramadan.

In this brief review, we have examined some clinical disorders which are associated to an altered hemorheological profile and at times accompanied by skin ulcers. This skin condition may be, in fact, observed in patients with primary plasma hyperviscosity such as multiple myeloma, Waldenstrom macroglobulinemia, cryoglobulinemia, cryofibrinogenemia, dysfibrinogenemia and connective tissue diseases. It must be underlined that the altered hemorheological pattern is not the only responsible for this skin complication but, as it worsens the microcirculatory flow, it contributes to determine the occurrence of the skin ulcers.

Background/Aims: Arterial hypertension is characterized by vascular remodelling, atherosclerosis and cardiovascular complications. Matrix metalloproteases (MPPs) are endopeptidases produced by all the cells present in the vascular wall and are involved in the regulation of the extracellular matrix protein turnover. MMPs contribute to blood vessel formation, remodelling, angiogenesis; whereas an altered expression or activity of MMPs or their tissue inhibitors (TIMPs) results correlated with the development and progression of cardiovascular complications. Methods: We examined the literature data regarding the role of MMPs in human hypertension, including their involvement in vascular remodelling, and the effects of some antihypertensive molecules on these MMP/TIMP profile. Results: The expression and the activity of some MMPs and TIMPs are impaired in human hypertension. An altered MMPs/TIMPs balance plays an important role in the vascular wall rearrangement, in response to hemodynamic changes which may induce myocardial hypertrophy and fibrosis leading to ventricular remodelling. Several studies have examined the effects of some antihypertensive molecules, such as ACE inhibitors, angiotensin receptor blockers, calcium-channel blockers, and aldosterone antagonists, on the MMPs/TIMPs profile by obtaining positive results. Conclusion: Considering the data taken into consideration, the authors believe that in clinical practice a strategic antihypertensive therapy directed to the MMPs profile, may be useful to decrease the risk of cardiovascular complications.

Considering that obstructive sleep apnea syndrome (OSAS) is usually associated with endothelial dysfunction, atherosclerosis and cardiovascular disorders, our aim was to examine the erythrocyte deformability and the oxidative status in a group of OSAS subjects. We consecutively enrolled 48 subjects with OSAS defined after a 1-night cardiorespiratory sleep study, subsequently subdivided according to the apnea/hypopnea index (AHI) value in two subgroups: Low (L = 21 subjects with AHI30) and High (H = 27 subjects with AHI30). We evaluated the erythrocyte deformability, expressed as elongation index (EI) and the parameters of the oxidative status, such as lipid peroxidation (expressed as thiobarbituric acid-reactive substances - TBARS) and protein oxidation (measured as carbonyl groups - PC). In the entire group and in the two subgroups of OSAS subjects we found a decreased erytrocyte deformability at all shear stresses, not correlated with the plasmatic oxidative stress nor with the polysomnographic parameters. Lipid peroxidation was increased in the whole group and in the H subgroup of OSAS while protein oxidation showed a different trend. As in OSAS the osmotic fragility and the metabolism of the red cells seem to be not impaired, the oxidative damage to the red cell membrane proteins might be responsible for the reduced erythrocyte deformability. This rheological alteration, in addition to the increase in whole blood and plasma viscosity and to the erythrocyte hyperaggregation, could influence the microcircolatory profile in OSAS subjects.

Background: Malnutrition in elderly inpatients hospitalized on medical wards is a significant public health concern. The aim of this study was to investigate nutritional markers as mortality predictors following discharge in hospitalized medical elderly patients. Materials and methods: This is a prospective observational cohort study with follow-up of 48 months. Two hundred and twenty-five individuals aged 60 and older admitted from the hospital emergency room in the past 48 h were investigated at the medical ward in the University hospital in Palermo (Italy). Anthropometric and clinical measurements, Mini-nutritional Assessment (MNA) questionnaire, bioelectrical (BIA) phase angle (PA), grip strength were obtained all within 48 h of admission. Mortality data were verified by means of mortality registry and analysed using Cox-proportional hazard models. Results: Ninety (40%) participants died at the end of follow-up. There were significant relationships between PA, MNA score, age and gender on mortality. Patients in the lowest tertile of PA (< 4·6°) had higher mortality estimates [I vs II tertile: hazard ratio (HR) = 3·40; 95% confidence interval (CI): 2·01–5·77; II vs III tertile: HR = 3·83; 95% CI: 2·21–6·64; log-rank test: χ2 = 43·6; P < 0·001]. Similarly, the survival curves demonstrated low MNA scores (< 22) were associated with higher mortality estimates (HR = 1·85; 95% CI: 1·22–2·81 χ2 = 8·2; P = 0·004). Conclusions: The MNA and BIA-derived phase angle are reasonable tools to identify malnourished patients at high mortality risk and may represent useful markers in intervention trials in this high-risk subgroup.

In the last years the neutrophil to lymphocyte ratio (NLR) has been examined in cardiovascular disorders and in particular in coronary artery disease and acute myocardial infarction (AMI). Now we examined this parameter in subjects with juvenile myocardial infarction at the initial stage and after 3 and 12 months. We enrolled 123 young subjects (112 men and 11 women, mean age 39.4 ± 5.8 yrs) with AMI. The time interval between the AMI onset and the investigation was 13 ± 7 days. The mean value of NLR observed in young AMI subjects was significantly increased compared to normal controls (N = 1.817 ± 0.711; young AMI subjects = 2.376 ± 0.873, p < 0.0001). NLR does not discriminate STEMI (2.427 ± 0.878) and non STEMI (2.392 ± 0.868) or diabetics (2.604 ± 1.000) and non diabetics (2.324 ± 0.853), but it differentiates smokers (2.276 ± 0.853) and non smokers (2.837 ± 1.072). NLR at the initial stage is not correlated with the number of cardiovascular risk factors or with the extent of the coronary disease. In this study we found a significant decrease of neutrophil count at 3 and 12 months later AMI without any significant variation of lymphocyte and consequently we observed a decrease in NLR at these two intervals of time in comparison with the initial stage. Despite some limitations present in this study, it is interesting to underline that also in juvenile myocardial infarction this low-cost haematological marker may be considered together with other inflammatory indicators.

The aim of this study was the evaluation of the erythrocyte deformability in multiple myeloma (MM). We enrolled 29 MM patients and we evaluated, on fasting venous blood, the erythrocyte deformability, expressed as elongation index, and examined using the diffractometric method. By comparing normal controls and MM patients, a significant decrease in erythrocyte deformability, especially at low shear stresses, was found. In this research paper we evaluated all the hypothesis for a possible explanation of the behaviour of red blood cell deformability in MM, even considering how the alteration of erythrocyte deformability worsens the microcirculatory flow in these patients in association with the marked increase in plasma viscosity.

Summary 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.

Physical exercise influences the body's oxidative status. The modifications can involve lipids, proteins and nucleic acids, and different effects seem to be induced by regular and acute exercise respectively. We examined protein oxidation, expressed as concentration of protein carbonyl groups (PC), in trained subjects before (time 0), 10 min (time 1) and 24 hours (time 2) after a cardiopulmonary test performed on a cycloergometer. We enrolled 38 trained subjects (26 men and 12 women), subdivided in two groups (A1 and B1) of 19 subjects each, according to the median value of VO2max, and in two groups (A2 and B2) of 19 subjects each, according to the median value of PC at baseline. PC concentration was measured by an enzyme-linked immunosorbent assay (ELISA). The groups A1 and B1 did not differ from each other as regards the basal PC level and groups A2 and B2 were not different as regards the VO2max. At time 1 PC showed a significant increase in comparison with baseline in trained subjects as a whole group, as well as in each subgroup. At time 2, PC were decreased in comparison with both times 0 and 1 in the whole group and in subgroups A1 and B2, whereas in subgroups A2 and B1 the PC value at time 2 was not different compared to time 0. The percentage increase of PC at time 1 vs time 0, as well as the percentage decrease at time 2 vs time 1 and time 0 respectively, were not different between subgroups A1 and B1. On the contrary, the percentage variations observed at each interval were significantly different between subgroups A2 and B2. The results suggest a reaction of antioxidant systems to acute exercise in trained subjects, influenced by basal PC levels more than by aerobic fitness.

In our early research regarding the hemorheological pattern in patients with acute myocardial infarction (AMI) with a mean age of 61.45 + 10.99 years, we showed that the major hemorheological parameters were almost normalized 2 weeks after the acute event. In the last decade, we focused on hemorheological parameters in juvenile myocardial infarction (JMI), defined as AMI in patients aged 45 years, in the ‘‘Sicilian study on juvenile myocardial infarction’’. Juvenile myocardial infarction is responsible for 2% to 10% of all cases with AMI in different surveys. Juvenile myocardial infarction presents a typical pattern of risk factors and shows clinical, angiographic, and prognostic characteristics. Regarding risk factors, cigarette smoking is by far the most common, followed by family history of coronary artery disease and hypercholesterolemia, while arterial hypertension and diabetes mellitus are less frequent. Juvenile myocardial infarction may be associated with the use of oral contraceptives, pregnancy, or cocaine abuse as well as with congenital coronary artery abnormalities. Concerning the clinical picture, patients with JMI reach hospital earlier than older patients, enhancing the effectiveness of revascularization procedures and treatment of complications. In JMI, the absence of coronary stenosis is often demonstrated or just 1 coronary vessel is affected; 2or 3vessel disease is infrequent. Generally, patients with JMI have a lower incidence of complications, such as early and late heart failure, angina, reinfarction, and atrioventricular block; mortality during hospitalization and after 6 months is significantly reduced. In the Sicilian study, we observed a pattern of inflammatory polymorphisms in patients with JMI. A higher prevalence of proinflammatory polymorphisms (SNP A2080G of pyrin gene, SNP Gly670Arg of PECAM gene, C1019T of Cx 37 gene, and SNP G1059C of PCR gene) and a lower prevalence of antiinflammatory polymorphisms (Asp299Gly of TLR4 gene, SNP – 1082 G/A of IL10 gene, CCR5D32) were present. We revisited plasma viscosity (PV) in our survey of patients with JMI and considered 2 aspects in particular. The first is the potential role played by PV in the dynamics of myocardial microcirculation (namely, in the phenomenon of coronary slow flow) that may be secondary to AMI; the second aspect was life expectancy. Plasma viscosity is dependent on the plasma protein concentration, although the contribution of different proteins (fibrinogen, a2-macroglobulin, immunoglobulins, haptoglobin, and ceruloplasmin) differs in relation to their molecular size and shape; the plasma protein composition can also change due to pathophysiological processes. The PV plays a pivotal role, together with erythrocyte deformability and platelets, in microcirculatory blood flow. In this editorial, we describe the behavior of PV in 120 patients with JMI (109 men; mean age 39.4 + 5.8 years); the time interval between AMI onset and the first hemorheological evaluation was 13 + 7 days. Using fasting venous blood, we measured PV at the shear rate of 450 s 1 using the cone-andplate viscometer Wells-Brookfield mod 1⁄2 LVT (Middleboro, Massachusetts). We reexamined this parameter 3 (n 1⁄4 83) and 12 (n 1⁄4 70) months after AMI. At the initial stage, PV was increased compared to controls (CS 1.259 + 0.125 vs JMI 1.519 + 0.108 mPas, P < .001). The PV did not differ between ST-segment elevation myocardial infarction (STEMI) and non-STEMI as well as in 3 subgroups of the patients with JMI subdivided according to the number of cardiovascular risk factors (39 had 0 or 1 risk factor, 39 had 2 risk factors, and 42 had 3). Coronary angiography was performed in 103 patients; no significant coronary stenosis was demonstrated in 23, 46 had a single vessel disease, and 34 had multi-vessel disease. The PV did not differ between the 3 subgroups. At 3 and 12 months after AMI, PV was persistently increased compared to controls (at 3 months 1.466 + 0.119 mPas and at 12 months 1.475 + 0.009 mPa-s, respectively). Although the literature has described a low incidence of cardiovascular complications in JMI, in our survey, followup carried out for as long as 18 months showed that 5 patients developed heart failure, 15 a new ischemic event (angina in 12

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.

Background Matrix metalloproteinases (MMPs), particularly gelatinase A (MMP-2) and gelatinase B (MMP-9), as well as their tissue inhibitors (TIMP-1 and TIMP-2), are involved in the development of skeletal muscle tissue, in the repair process after muscle injury and in the adaptive modifications induced by physical exercise in skeletal muscle. This paper aims at reviewing results from human studies that investigated the role of gelatinases and their inhibitors in skeletal muscle response to acute physical exercise or training. Methods Electronic databases PubMed/MEDLINE, Scopus and Web of Science were searched for papers published between January 2000 and February 2017. The papers were eligible when reporting human studies in which MMP-2 and/or MMP-9 and/or the inhibitors TIMP-1/TIMP-2 were evaluated, in blood or muscular tissue, before and after acute physical exercise or before and after a period of structured physical training. We included studies on healthy subjects and patients with chronic metabolic diseases (obesity, diabetes mellitus, metabolic syndrome-MS) or asymptomatic coronary artery disease. We excluded studies on patients with neurological, rheumatologic or neoplastic diseases. Results Studies conducted on muscle biopsies showed an early stimulation of MMP-9 gene transcription as a result of acute exercise, whereas MMP-2 and TIMP transcription resulted from regular repetition of exercise over time. Studies on serum or plasma level of gelatinases and their inhibitors showed an early release of MMP-9 after acute exercise of sufficient intensity, while data on MMP-2 and TIMP were more contrasting. Most of the studies dealing with the effect of training indicated a trend toward reduction in blood gelatinase levels, once again more clear for MMP-9. This result was related to an anti-inflammatory effect of regular exercise and was more evident when training consisted of aerobic activities. This study has limitations: as the initial selection was done through titles and abstracts, incomplete retrieval cannot be excluded, as well as we cannot exclude bias due to selective reporting within studies. Conclusion A better knowledge of the molecular events activated by different types of acute exercise and regular training could be of great relevance in order to maximize the benefits of physical activity in healthy subjects and patients.

In this brief review, we have examined some clinical conditions that result to be associated to an altered hemorheological profile and at times accompanied by skin ulcers. This skin condition may be observed in patients with the following condtions, such as primary polycythemic hyperviscosity (polycythemia, thrombocytemia) treated with hydroxyurea, primary plasma hyperviscosity (multiple myeloma, cryoglobulinemia, cryofibrinogenemia, dysfibrinogenemia, and connective tissue diseases), primary sclerocythemic hyperviscosity (hereditary spherocytosis, thalassemia, and sickle cell disease). In addition, it may be present in patients with secondary hyperviscosity conditions such as diabetes mellitus, arterial hypertension, critical limb ischemia and chronic venous insufficiency.

Blood rheology is impaired in hypertensive patients. The alteration involves blood and plasma viscosity, and the erythrocyte behaviour is often abnormal. The hemorheological pattern appears to be related to some pathophysiological mechanisms of hypertension and to organ damage, in particular left ventricular hypertrophy and myocardial ischemia. Abnormalities have been observed in erythrocyte membrane fluidity, explored by fluorescence spectroscopy and electron spin resonance. This may be relevant for red cell flow in microvessels and oxygen delivery to tissues. Although blood viscosity is not a direct target of antihypertensive therapy, the rheological properties of blood play a role in the pathophysiology of arterial hypertension and its vascular complications.

Our aim was to evaluate lipid peroxidation, expressed as thiobarbituric acid-reactive substances (TBARS), nitric oxide metabolites (nitrite + nitrate) expressed asNOx, and TBARS/NOxratio in a group of subjects with metabolic syndrome (MS). In this regard we enrolled 106 subjects with MS defined according to the IDF criteria, subsequently subdivided into diabetic (DMS) and nondiabetic (NDMS) and also into subjects with a low triglycerides/HDL-cholesterol (TG/HDL-C) index or with a high TG/HDL-C index. In the entire group and in the four subgroups of MS subjects we found an increase in TBARS andNOxlevels and a decrease in TBARS/NOxratio in comparison with normal controls. Regarding all these parameters no statistical difference between DMS and NDMS was evident, but a significant increase inNOxwas present in subjects with a high TG/HDL-C index in comparison with those with a low index. In MS subjects we also found a negative correlation between TBARS/NOxratio and TG/HDL-C index. Considering the hyperactivity of the inducible NO synthase in MS, these data confirm the altered redox and inflammatory status that characterizes the MS and suggest a link between lipid peroxidation, inflammation, and insulin resistance, evaluated as TG/HDL-C index.

In the “Sicilian study on juvenile myocardial infarction,” we had evaluated plasma viscosity (PV) and neutrophil/lymphocyte ratio (NLR) in patients with acute myocardial infarction (AMI) at the age of ⩽45 years. Now, we examined the relationship between these 2 parameters in 120 subjects (109 men and 11 women) aged ⩽45 years with recent AMI. The patients were classified according to the number of cardiovascular risk factors, the electrocardiographic criteria (ST-segment elevation myocardial infarction [STEMI] or non-ST-segment elevation myocardial infarction [NSTEMI]), and the extent of coronary stenosis, evaluated with coronary angiography. On fasting venous blood, we measured PV at the shear rate of 450 s −1 and NLR. The control group included 50 healthy subjects (mean age = 35.1 ± 7.8 years). At the initial stage, PV and NLR were significantly increased in comparison with controls. Subdividing AMI patients according to the median value of NLR, in the group with high NLR PV was significantly higher, whereas subdividing the patients according to the PV median value, NLR was not different between the 2 groups; 3 and 12 months after AMI, we observed only a significant decrease in NLR. Only PV was discriminant regarding the cardiovascular complications registered during an 18-month follow-up. The evaluation of PV may be of prognostic value in juvenile AMI.

Objective: In this mini-review we describe the behavior of polymorphonuclear leukocyte (PMN) membrane fluidity and of PMN cytosolic Ca2+ concentration in some chronic and acute clinical conditions. Methods: PMN membrane fluidity was evaluated employing the fluorescent probe Fura-2AM, and PMN cytosolic Ca2+ concentration was evaluated using the fluorescent probe TMA-DPH. Results: From the determination of these two parameters investigated on resting PMNs, an almost constant increase in PMN cytosolic Ca2+ concentration in chronic clinical conditions, such as vascular atherosclerotic disease with and without diabetes mellitus, essential hypertension, chronic kidney disease, and diabetes mellitus of both types, and a decrease in PMN membrane fluidity in acute clinical conditions, such as juvenile acute myocardial infarction and acute ischemic stroke, are evident. Conclusion: The possible reasons for this different behavior are analyzed on the basis of pathophysiological considerations.

Endothelial dysfunction and plasma markers of inflammation are significantly increased in type 2 diabetics. Several proinflammatory cytokines, acute-phase proteins, and cell adhesion molecules, such as C-reactive protein (CRP), interleukines (IL), and tumor necrosis factor alpha (TNF-α), seem to play a role in the low-grade systemic inflammation observed in these subjects. Lifestyle changes are necessary to prevent atherosclerosis and cardiovascular events. Physical exercise is known to reduce markers of inflammation by decreasing adipocytokine production and cytokine release from skeletal muscles, endothelial cells, and immune system and also improving antioxidant status. In type 2 diabetics, aerobic and resistance training have different effects on cytokine levels, and the differences in the modalities of exercise (type, duration, and intensity) and especially in the examined population could produce different results. Recent research showed that combined exercise has greater anti-inflammatory effects than aerobic or resistance exercise alone causing a deepest decrease in CRP, IL-6, IL-1β, TNF-α, leptin, and resistin and a higher increase in anti-inflammatory cytokines such as IL-4, IL-10, and adiponectin.

Aerobic capacity, as indicated by maximal oxygen uptake (VO(2) max) has an important role in contrasting the traditional cardiovascular risk factors and preventing cardiovascular morbidity and mortality. It is known that endothelial function, measured as flow-mediated dilation (FMD) of the brachial artery, is strictly linked to atherogenesis and cardiovascular risk. However, the relationship between VO(2) max and FMD has not been fully investigated especially in healthy non-obese subjects. This preliminary study cross-sectionally investigated the relationship between VO(2) max and FMD in 22 non-obese, healthy sedentary male subjects. Dividing the cohort in two subgroups of 11 subjects each according to the median value of VO(2) max, the FMD was significantly lower in the subgroup with lower VO(2) max (mean ± sem: 7.1 ± 0.7 vs. 9.5 ± 0.8 %; P = 0.035). Absolute VO(2) max (mL min(-1)) was significantly and independently correlated with body fat mass (r = -0.50; P = 0.018) and with FMD (r = 0.44; P = 0.039). This preliminary study suggests that maximal oxygen uptake is independently correlated with endothelial function in healthy non-obese adults. These results are also in agreement with the possibility that improving maximal oxygen uptake may have a favorable effect on endothelial function and vice versa.

Acute myocardial infarction (AMI) in young adult presents a typical pattern of risk factors, clinical, angiographic and prognostic characteristics. In the last years we demonstrated that hemorheological profile is altered in these patients in a persistent way and independently of the number of risk factors and of the extent of coronary lesions. Thus, the hyperviscosity syndrome following AMI could be considered an intrinsic characteristic of these patients. Consequently it is possible to hypothesise the presence of a genetic background at the origin of this predisposition. If this background is able to influence the risk of ischemic heart disease, this should be particularly evident in young subjects. Since inflammatory mechanisms play a central role in mediating all phases of atherosclerosis, genes encoding for inflammatory or anti-inflammatory molecules are candidates for the risk of developing atherosclerosis. As atherosclerosis is the first cause of mortality in Western countries and if pro-inflammatory genotypes contribute to risk of coronary heart disease, alleles associated to disease susceptibility should not be included in the genetic background favouring longevity: People genetically predisposed to a weak inflammatory activity have fewer chances to develop cardiovascular disease and, therefore, have better chance for a long-life. According to this hypothesis, we studied in our population of young patients with AMI, the distribution of some polymorphisms influencing a inflammation and found an higher prevalence of pro-inflammatory polymorphisms (SNP A2080G of pyrin gene, SNP Gly670Arg of PECAM gene, C1019T of Cx 37 gene, SNP G1059C of PCR gene) and a lower prevalence of anti-inflammatory polymorphisms (Asp299Gly of TLR4 gene, SNP -1082 G/A of IL10 gene, CCR5Δ32). Results of these studies show that early myocardial infarction could be associated with a genetic predisposition to an intense inflammatory response, associated also to an hyperviscosity syndrome.

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.

Many papers have showed non univocal data about oxidative stress status and nitric oxide metabolites in essential hypertension. Considering this preamble we examined the total antioxidant status (TAS), the lipid peroxidation (LP), expressed as thiobarbituric acid-reactive substances (TBARS), the stable end products of nitric oxide (NOx) and LP/NOx ratio in 25 subjects with untreated mild essential hypertension. The obtained data show a significant increase in TBARS (p < 0.001) and NOx (p < 0.001) in hypertensives and no variation in TAS and in TBARS/NOx ratio. None of these parameters was statistically related to the metabolic parameters or to the blood pressure values. The high level of lipid peroxidation observed in this group of hypertensives suggests the timely and specific employment of antihypertensive and antioxidant agents while the NOx increase seems to confirm the inflammatory status accompanying this clinical condition.

This review shows how polymorphonuclear leukocytes (PMNs) play a pivotal role in the development of the organ injury that is associated with arterial hypertension. Elevated white blood cell count and higher levels of PMNs activation are risk factors for arterial hypertension and cardiovascular disease. Spontaneously activated PMNs release proinflammatory factors and reactive oxygen species, which have negative effects on vascular tone and on their adhesion to the endothelium. The oxidative stress in hypertensive PMNs is revealed by increased NADPH-oxidase production and lipid peroxidation and by decreased cytosolic and mitochondrial superoxide dismutase concentrations. The overexpression of adhesion molecules, such as beta2-integrin, promotes PMNs rolling and leukocyte-endothelium interactions too. All these events underline how polymorphonuclear leukocytes may contribute to the vascular damage accompanying arterial hypertension.

Nitric oxide (NO) has a role in the pathophysiology of acute and chronic cardiovascular events. We studied the plasma concentration of NO stable end products (nitrite and nitrate - NO x ) in 43 patients aged

In a group of young subjects with acute myocardial infarction (AMI) (68 men and 7 women; mean age 39.6 ± 5.7 years) we examined the plasma concentration of elastase, the thiobarbituric acid-reactive substances (TBARS) and the total antioxidant status (TAS) at the initial stage of AMI. In this group we found an increase of elastase (p

Background & aims: The metabolic syndrome is associated with central accumulation of fat. Previous studies showed that some obese subjects are characterized by a sparing energy metabolism. The aim of this study was to investigate whether obese subjects with metabolic syndrome have a lower resting metabolic rate than obese subjects without metabolic syndrome. Methods: Forty obese subjects were divided into three groups according to the presence of metabolic syndrome and type 2 diabetes; 15 non-obese healthy control subjects were also enrolled. Body composition (bio-impedance analysis) and resting metabolic rate (indirect calorimetry) were performed. Results: The group with metabolic syndrome exhibited a significantly lower resting metabolic rate adjusted for fat-free mass with respect to the control group and the obese group without metabolic syndrome (respectively: 10873 vs. 11873, po0.01 and 12373kJ/kg fat-free mass 24h, po0.01; mean7sem). The obese group with metabolic syndrome and type 2 diabetes (T2D) had a not different adjusted resting metabolic rate (11476 kJ/kg fat-free mass 24 h) with respect to other groups. Conclusions: An energy sparing condition seems to characterize non-diabetic obese subjects with metabolic syndrome.

Hypertension is one of the leading causes of death in developed countries, and the number of prehypertensive patients is increasing. The beneficial effects of moderate wine consumption on cardiovascular diseases have been demonstrated, along with the healthy influence of a Mediterranean dietary pattern. The association of these 2 factors on hypertension and its complications is considered here. As wine polyphenols exert a vasorelaxing action, they might positively influence the hemodynamic situation of these patients. These effects could be enhanced by dietary constituents, such as garlic, onions, and olive oil, which are widely employed in Mediterranean cooking. By evaluating many studies performed in animal models and in humans, the authors conclude that moderate wine consumption, if associated with a healthy dietary pattern, such as the Mediterranean one, could help hypertensive patients to ameliorate their arterial pressure and quality of life by reducing cardiovascular morbidity and mortality rates.

It is known that in OSAS the plasma lipid peroxidation has an opposite behavior in comparison with nitric oxide metabolites. In the re-examination of our survey of OSAS subjects we calculated the ratio between thiobarbituric acid reactive substances (TBARS) and nitric oxide metabolites (NOx) in relation to OSAS severity. The study has regarded 48 OSAS subjects subdivided in two subgroups according to the apnea/hypopnea index - AHI- (Low = 21 subjects with AHI30 and High = 27 subjects with AHI30). From the obtained data it is evident that the TBARS/NOx ratio is significantly higher in the H subgroup compared to L subgroup as well as this ratio is reduced in L subgroup in comparison with the whole group of OSAS subjects. In the entire group of OSAS subjects the TBARS/NOx ratio results positively correlated with AHI and ODI and inversely correlated with mSO2.

Obstructive sleep apnea syndrome (OSAS) is associated with an elevated risk of cardiovascular events and stroke. Matrix metalloproteinases (MMPs) are endopeptidases involved in extracellular matrix degradation and then in the development and progression of cardiovascular diseases. Our aim was to evaluate plasma levels of gelatinases (MMP-2 and MMP-9) and their tissue inhibitors (TIMP-1 and TIMP-2) in a group of subjects with OSAS. We enrolled 48 subjects (36 men and 12 women; mean age 49.7 ± 14.68 yrs) with OSAS diagnosed with a 1-night cardiorespiratory study and then we subdivided these subjects into two subgroups according to the apnea/hypopnea index (AHI): Low (L = 21 subjects with AHI 30). We measured plasma concentration of the gelatinases and their inhibitors using ELISA kits. We observed a significant increase in plasma concentration of MMP-9, MMP-2, TIMP-1 and TIMP-2 in the entire group of OSAS subjects and in the two subgroups, with higher levels in the H in comparison with the L subgroup. In the whole group of OSAS subjects we also noted a significant decrease in MMP-9/TIMP-1 ratio in comparison with normal controls. Only MMP-9 was significantly correlated with the severity of the disease, expressed as AHI, with the oxygen desaturation index and also with the mean oxygen saturation. MMPs pattern is altered in OSAS and significantly influenced by the severity of the disease; it probably contributes to the vascular remodeling that leads to the atherosclerotic disease and cardiovascular complications.

Venous leg ulcers are common in subjects with chronic venous insufficiency. The increased intraluminal pressure causes alteration of the skin microcirculation, leukocyte activation and release of proteolytic enzymes leading to ulceration. An impaired expression and activity of matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) might influence extracellular matrix degradation and deposition in chronic venous ulcers with the failure of the healing process. Our aim was to evaluate plasma concentration of gelatinases (MMP-2 and MMP-9) and their inhibitors (TIMP-1 and TIMP-2) in subjects with venous leg ulcers before and after the compression therapy. We enrolled 36 subjects (12 men and 24 women, mean age 67.38 ± 12.7 yrs) with non-infected venous leg ulcers (CEAP C6), which underwent a color Duplex scan examination of the veins and arteries of the inferior limbs and were treated with a multi-layer bandaging system. The ulcer healing was obtained in 23 subjects only (9 men and 14 women). We evaluated, on fasting venous blood, the plasma levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 using ELISA kit, before and after the treatment. We observed a significant increase in plasma concentration of gelatinases and their inhibitors and in MMP-2/TIMP-2 ratio in subjects with leg ulcers in comparison with normal controls. In subjects with healed ulcers we found a decrease in MMP-9 and TIMP-1 levels and in MMP-2/TIMP-2 ratio compared to the baseline values, although higher levels of all the examined parameters in comparison with normal controls. In conclusion, plasma MMPs profile is impaired in subjects with venous leg ulcers and it improves after the healing, persisting anyway altered in respect to healthy controls.

The major trait characterizing offspring in centenarians is a reduction in the prevalence of cardiovascular disease. Because a pro-inflammatory genotype seems to contribute significantly to the risk of coronary heart disease, alleles associated with disease susceptibility would not be included in the genetic background favoring longevity, as suggested by our previous studies on inflammatory cytokines. To confirm whether genotypes of inflammatory molecules play an opposite role in atherosclerosis and longevity, we are studying the role of other proinflammatory alleles, such as pyrin and CCR5, in acute myocardial infarction and longevity. The results support the hypothesis that the genetic background favoring cardiovascular diseases is detrimental to longevity. In addition, they suggest that the centenarian genetic background may be useful for investigating genetic key components of age-associated diseases that are characterized by a multifactorial etiology.