Filippo Mearelli

Omega-3 Polyunsaturated Fatty Acids: Structural and Functional Effects on the Vascular Wall.

Omega-3 polyunsaturated fatty acids (n-3 PUFA) consumption is associated with reduced cardiovascular disease risk. Increasing evidence demonstrating a beneficial effect of n-3 PUFA on arterial wall properties is progressively emerging. We reviewed the recent available evidence for the cardiovascular effects of n-3 PUFA focusing on structural and functional properties of the vascular wall. In experimental studies and clinical trials n-3 PUFA have shown the ability to improve arterial hemodynamics by reducing arterial stiffness, thus explaining some of its cardioprotective properties. Recent studies suggest beneficial effects of n-3 PUFA on endothelial activation, which are likely to improve vascular function. Several molecular, cellular, and physiological pathways influenced by n-3 PUFA can affect arterial wall properties and therefore interfere with the atherosclerotic process. Although the relative weight of different physiological and molecular mechanisms and the dose-response on arterial wall properties have yet to be determined, n-3 PUFA have the potential to beneficially impact arterial wall remodeling and cardiovascular outcomes by targeting arterial wall stiffening and endothelial dysfunction.

Sepsis outside intensive care unit: the other side of the coin

IntroductionA growing body of evidence points out that a large amount of patients with sepsis are admitted and treated in medical ward (MW). With most of the sepsis studies conducted in intensive care unit (ICU), these patients, older and with more comorbidities have received poor attention. Provided the differences between the two groups of patients, results of diagnostic and therapeutic trials from ICU should not be routinely transferred to MW, where sepsis seems to be at least as common as in ICU.MethodsWe analyzed clinical trials on novel tools for an early diagnosis of sepsis published in the last two year adopting strict research criteria. Moreover we conducted a target review of the literature on non-invasive monitoring of severe sepsis and septic shock.Results and ConclusionsThe combination of innovative and non-invasive tools for sepsis rule in/out, as quick alternatives to blood cultures (gold standard) with bedside integrated ultrasonography could impact triage, diagnosis and prognosis of septic patients managed in MW, preventing ICU admissions, poor outcomes and costly complications, especially in elderly that are usually highly vulnerable to invasive procedures.

HELP LDL apheresis reduces plasma pentraxin 3 in familial hypercholesterolemia.

Background Pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, is secreted by vascular cells in response to injury, possibly aiming at tuning arterial activation associated with vascular damage. Severe hypercholesterolemia as in familial hypercholesterolemia (FH) promotes vascular inflammation and atherosclerosis; low-density lipoprotein (LDL) apheresis is currently the treatment of choice to reduce plasma lipids in FH. HELP LDL apheresis affects pro- and antiinflammatory biomarkers, however its effects on PTX3 levels are unknown. We assessed the impact of FH and of LDL removal by HELP apheresis on PTX3. Methods Plasma lipids, PTX3, and CRP were measured in 19 patients with FH undergoing chronic HELP LDL apheresis before and after treatment and in 20 control subjects. In the patients assessment of inflammation and oxidative stress markers included also plasma TNFα, fibrinogen and TBARS. Results At baseline, FH patients had higher (p = 0.0002) plasma PTX3 than matched control subjects. In FH PTX3 correlated positively (p≤0.05) with age, gender and CRP and negatively (p = 0.01) with HELP LDL apheresis vintage. The latter association was confirmed after correction for age, gender and CRP. HELP LDL apheresis acutely reduced (p≤0.04) plasma PTX3, CRP, fibrinogen, TBARS and lipids, but not TNFα. No association was observed between mean decrease in PTX3 and in LDL cholesterol. PTX3 paralleled lipids, oxidative stress and inflammation markers in time-course study. Conclusion FH is associated with increased plasma PTX3, which is acutely reduced by HELP LDL apheresis independently of LDL cholesterol, as reflected by the lack of association between change in PTX3 and in LDL levels. These results, together with the finding of a negative relationship between PTX3 and duration of treatment suggest that HELP LDL apheresis may influence both acutely and chronically cardiovascular outcomes in FH by modulating PTX3.

Disseminated tuberculosis in an immunocompetent patient

Miliary tuberculosis refers to the clinical disease resulting from the hematogenous dissemination of Mycobacterium tuberculosis. A tuberculous aneurysm of the aorta is exceedingly rare. Contiguous tuberculosis in the form of lymphadenitis is generally responsible for the aortic involvement. We report a case of tuberculous mycotic aneurysm in patient with miliary disease, not affected by a cellular immunodeficiency and with no other common risk factor for infection. He received anti-tubercular therapy and endovascular stenting before the identification of Mycobacterium tuberculosis in lung, lymph nodes, and gastric lavage. The clinician should be aware that a mycotic abdominal aortic aneurysm could be caused by M. tuberculosis, even if microbiological confirmation is lacking or is negative, especially if a contiguous focus of tubercular infection is detected.

Procalcitonin in early rule-in/rule-out of sepsis in SIRS patients admitted to a medical ward.

Abstract Background: A relevant amount of patients with clinical suspect of sepsis is admitted and treated in medical wards (MW). These patients have a better prognosis but are older and with more comorbidities compared to those admitted to intensive care units (ICU). Procalcitonin (PCT) is extensively used in emergency departments for the diagnosis of sepsis, but its accuracy in the setting of a MW has not been thoroughly investigated. Predicted low PCT levels also call for the comparison of immunomagnetic-chemiluminescent (L-PCT) and time-resolved amplified cryptate emission (TRACE, K-PCT) technologies, in PCT determination. Methods: In 80 patients with systemic inflammatory response syndrome (SIRS) diagnostic criteria and suspect of sepsis newly admitted to a MW, PCT was determined with L- and K-PCT method. Results: Sixty patients were diagnosed as sepsis (20 microbiologically and 40 clinically proven) and 20 with non-infective SIRS. The sepsis group had significantly higher levels of both PCTs, with no differences between the clinically and microbiologically proven subgroups. The areas under ROC curves for L- and K-PCT were 0.72 and 0.78 (p<0.001 for each), respectively. Based on MW customized cut-off values of 0.150 (L-PCT) and 0.143 ng/mL (K-PCT), overall accuracies were 66.8 (95% CI 58.7–78.9) and 78.2% (69.8–87.2), respectively, compared to the 55% (44.2–66) of 0.5 ng/mL canonical cut-off. Neither PCT-L nor -K held prognostic value on survival. Conclusions: In MW patients, customized PCT cut-off levels provide better accuracy than customary levels adopted from ICU, and TRACE technology seems to offer a wider analysis range.

Intensive insulin therapy increases glutathione synthesis rate in surgical ICU patients with stress hyperglycemia

Objective The glutathione system plays an essential role in antioxidant defense after surgery. We assessed the effects of intensive insulin treatment (IIT) on glutathione synthesis rate and redox balance in cancer patients, who had developed stress hyperglycemia after major surgery. Methods We evaluated 10 non-diabetic cancer patients the day after radical abdominal surgery combined with intra-operative radiation therapy. In each patient, a 24-hr period of IIT, aimed at tight euglycemic control, was preceded, or followed, by a 24-hr period of conventional insulin treatment (CIT) (control regimen). Insulin was administered for 24 hours, during total parenteral nutrition, at a dosage to maintain a moderate hyperglycemia in CIT, and normoglycemic blood glucose levels in IIT (9.3±0.5 vs 6.5±0.3 mmol/L respectively, P<0.001; coefficient of variation, 9.7±1.4 and 10.5±1.1%, P = 0.43). No hypoglycemia (i.e., blood glucose < 3.9 mmol/L) was observed in any of the patients. Insulin treatments were performed on the first and second day after surgery, in randomized order, according to a crossover experimental design. Plasma concentrations of thiobarbituric acid reactive substances (TBARS) and erythrocyte glutathione synthesis rates (EGSR), measured by primed-constant infusion of L-[2H2]cysteine, were assessed at the end of each 24-hr period of either IIT or CIT. Results Compared to CIT, IIT was associated with higher EGSR (2.70±0.51 versus 1.18±0.29 mmol/L/day, p = 0.01) and lower (p = 0.04) plasma TBARS concentrations (2.2±0.2 versus 2.9±0.4 nmol/L). Conclusions In patients developing stress hyperglycemia after major surgery, IIT, in absence of hypoglycemia, stimulates erythrocyte glutathione synthesis, while decreasing oxidative stress.

Growth Rate of Small Abdominal Aortic Aneurysms and Genetic Polymorphisms of Matrix MetalloProteases-1, -3, and -9

Genetic variants of matrix metalloproteases (MMPs)-1, -3, and 9, together with clinical variables, might predict the growth rate (GR) of abdominal aortic aneurysm (AAA). Genotyping of MMP-1 (-1,607 G+/G-), MMP-3 (- 1,171 6A/5A), and MMP-9 microsatellite (13-26 cytosine-adenosine repeats around -90) from peripheral blood was performed in 137 AAA patients with two AAA diameter measurements (at least 3 months to 1 year apart). When the same technique (either ultrasound or computed tomography) was used for the two measurements, yearly GR was estimated and compared with MMP genotype and clinical features by linear and binary logistic regression. Collectively, 36 patients provided 94 observations, with a median GR of 3 mm/year (interquartile range, 0-5.8); GRs in carriers of MMP-1 polymorphism G-/G-, G-/G+, and G+/G+ genotype were 0.3, 3.5, and 4.7mm/year, respectively (p = 0.008). In linear logistic regression, the main determinant of GR was growth arrest (GA, i.e., GR = 0, occurring in 32 observations, 34%). In turn, GA occurred mainly in G-/G- MMP-1 genotype (odds ratio, 3.9; 95% confidence interval, 1.6-9.7; p = 0.002), while variables accounting for GR > 0 were MMP-1 G + /G+ genotype, intake of any antihypertensive drug, and MMP-3 6A/6A genotype. Carriers of none, one, or two/three of these conditions accounted for a GR of 3, 4, and 9 mm/year, respectively (p = 0.001). MMP-1 (-1,607 G+/-) variant is associated to differential GR in AAA: homozygous G deletion variant shows higher GA prevalence and lower GR, while carriers of G + /G+ MMP-1 genotype, together with intake of antihypertensive drugs, and 6A/6A in MMP-3 present cumulative GR increase.

Invasive filamentous fungus infection with secondary cerebral vasculitis in a patient with no obvious immune suppression.

Invasive mold infections represent an emerging and important diagnostic challenge, especially in immunocompetent patients when microscopy and cultures of the biological fluids remain negative. A central nervous system localization is not common and the clinical presentation is aspecific.

Effects of Hypoxia and Bed Rest on Markers of Cardiometabolic Risk: Compensatory Changes in Circulating TRAIL and Glutathione Redox Capacity

In chronic diseases, hypoxia and physical inactivity are associated with atherosclerosis progression. In contrast, a lower mortality from coronary artery disease and stroke is observed in healthy humans residing at high altitude in hypoxic environments. Eleven young, male volunteers completed the following 10-day campaigns in a randomized order: hypoxic ambulatory, hypoxic bed rest and normoxic bed rest. Before intervention, subjects were evaluated in normoxic ambulatory condition. Normobaric hypoxia was achieved in a hypoxic facility simulating 4000 m of altitude. Following hypoxia, either in bed rest or ambulatory condition, markers of cardiometabolic risk shifted toward a more atherogenic pattern consisting of: (a) lower levels of total HDL cholesterol and HDL2 sub-fraction and decreased hepatic lipase; (b) activation of systemic inflammation, as determined by C-reactive protein and serum amyloid A; (c) increased plasma homocysteine; (d) decreased delta-5 desaturase index in cell membrane fatty acids, a marker of insulin sensitivity. Bed rest and hypoxia additively decreased total HDL and delta-5 desaturase index. In parallel to the pro-atherogenic effects, hypoxia activated selected anti-atherogenic pathways, consisting of increased circulating TNF-related apoptosis-inducing ligand (TRAIL), a protective factor against atherosclerosis, membrane omega-3 index and erythrocyte glutathione availability. Hypoxia mediated changes in TRAIL concentrations and redox glutathione capacity (i.e., GSH/GSSG ratio) were greater in ambulatory conditions (+34 ± 6% and +87 ± 31%, respectively) than in bed rest (+17 ± 7% and +2 ± 27% respectively). Hypoxia-induced cardiometabolic risk is blunted by moderate level of physical activity as compared to bed rest. TRAIL and glutathione redox capacity may contribute to the positive interaction between physical activity and hypoxia. Highlights: – Hypoxia and bed rest activate metabolic and inflammatory markers of atherogenesis. – Hypoxia and physical activity activate selected anti-atherogenic pathways. – Hypoxia and physical activity positive interaction involves TRAIL and glutathione.

Exercise-mediated reactive oxygen species generation in athletes and in patients with chronic disease

Reactive oxygen species (ROS) form a group of biological molecules that are generated through the process of electron transfer, especially in the mitochondria. In cellular systems, ROS are essential signaling molecules, while excess ROS production is normally counteracted by antioxidant systems. Increased ROS production or decreased antioxidant capacity may result in protein, lipid or DNA oxidative damage, activation of inflammatory pathways, as well as direct alteration of cellular structures (Table 1). Redox unbalance contributes to progression of several chronic diseases, such as coronary artery disease, heart failure, type 2 diabetes mellitus, chronic obstructive pulmonary disease (COPD) and chronic kidney disease. It is well known that muscle contraction is associated with an increased flux of energy in mitochondria, determining ROS generation. However, while moderate levels of ROS are necessary for normal muscle contraction, strenuous exercise results in increased ROS production causing muscle fatigue, contractile dysfunction and muscle damage [1]. Such increased ROS production in skeletal muscle can activate the immune system and the inflammatory response. While muscle contraction increases ROS generation, it simultaneously stimulates antioxidant defense systems. Antioxidant molecules are particularly elevated following regular exercise training, thereby preventing the potentially negative effects of ROS overproduction. Beneficial effects of regular exercise training are largely based on this mechanism. In primary prevention, there is a graded inverse relationship between exercise training and the development of common chronic diseases [2]. In addition, strong evidence indicates that exercise training can slow progression and control symptoms of several chronic diseases, such as diabetes mellitus, chronic kidney disease, heart failure and COPD [3–7]. Exercise training is particularly effective in delaying progression of those chronic diseases (e.g., heart failure with preserved ejection fraction and smoking-related COPD) that are more strongly associated with redox unbalance [7–9]. As for pharmacological therapies, the beneficial effects of exercise depend on quality and quantity of the training programs. Thus, the optimal exercise schedule needs to be defined in each pathological condition and individually prescribed to each patient. Inappropriate exercise prescription or demanding training schedule may be associated with excess ROS production or blunted antioxidant defenses, which may have negative effects in both healthy subjects and individuals with chronic diseases [10]. Elite athletes are exposed to high training loads and busy competition calendars leading to increased risk for the so-called ‘‘overtraining syndrome.’’ This is a maladaptive response to exercise training, characterized by decreased muscle efficiency, impaired immune response and increased rates of both traumatic injuries and respiratory infections. A number of biomarkers of muscle damage, oxidative stress, antioxidant capacity and systemic inflammatory response have been developed to monitor the risk of overtraining in athletes. In particular, ROS generation from circulating white blood cells accurately reflects systemic redox unbalance in different conditions (Table 1). & Gianni Biolo biolo@units.it