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Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the cornerstone of atherosclerotic cardiovascular disease (ASCVD) in both primary and secondary prevention. Despite the statintherapy-mediated positive effects on cardiovascular events, patient compliance is often poor. Statinassociated muscle symptoms (SAMS) are the most common side effect associated with treatment discontinuation. SAMS, which range from mild-to-moderate muscle pain, weakness, or fatigue to potentially life-threatening rhabdomyolysis, are reported by 10% to 25% of patients receiving statin therapy. There are many risk factors associated with patient features and hypolipidemic agents that seem to increase the risk of developing SAMS. Due to the lack of a “gold standard”, the diagnostic test for SAMS is based on a clinical criteria score, which is independent of creatine kinase (CK) elevation. Mechanisms that underlie the pathogenesis of SAMS remain almost unclear, though a high number of risk factors may increase the probability of myotoxicity induced by statin therapy. Some of these, related to pharmacokinetic properties of statins and to concomitant therapies or patient characteristics, may affect statin bioavailability and increase vulnerability to high-dose statins. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

OBJECTIVE: The optimal protein intake for elderly individuals who exercise regularly has not yet been clearly defined. The aim of this study was to test the hypothesis that protein intake level is associated with muscle strength in elderly elite athletes. METHODS: We evaluated 50 elite senior athletes (38 men and 12 women) participating in the European Master Games 2011 in an observational cross-sectional study. Participants were divided into two groups-lower (LPI) or higher (HPI) protein intake-according to the median value of their ratio of urinary urea nitrogen to urinary creatinine (i.e., 8.8 g/L), as a marker of protein intake. A dietary interview confirmed differences in protein consumption between the LPI and HPI groups. We also evaluated body composition (bioimpedance), muscle strength, and hematochemical indices. RESULTS: LPI and HPI groups were homogeneous for age (72 [68-74] and 71 [68-74] y, respectively), fat-free mass index (18.4 [17-19.4] and 18.2 [17-19.1] kg/m2), body fat (18.3% [12.3-20.7%] and 16.6% [13.6-21.2%]), and glomerular filtration rate (57.7 [53.8-64.9] and 62.7 [56.1-69.3] mL/min/1.73 m2). The HPI group showed greater leg and trunk muscle strength (N) compared with the LPI group (left leg extension, 339 [238-369] versus 454 [273-561], respectively, P < 0.05; right leg extension, 319 [249-417] versus 432 [334-635], P ≤ 0.05; trunk extension, 435 [370-467] versus 464 [390-568], P ≤ 0.05). CONCLUSIONS: Higher protein intake in elite senior athletes is associated with a greater muscle strength.

Comment on Redox status alterations during the competitive season in élite soccer players: focus on peripheral leukocyte-derived ROS.

BACKGROUND & AIMS: Physical inactivity is associated with lean body mass wasting, oxidative stress and pro-inflammatory changes of cell membrane lipids. Alkalinization may potentially counteract these alterations. We evaluated the effects of potassium bicarbonate supplementation on protein kinetics, glutathione status and pro- and anti-inflammatory polyunsaturated fatty acids (PUFA) in erythrocyte membranes in humans, during experimental bed rest. METHODS: Healthy, young, male volunteers were investigated at the end of two 21-day bed rest periods, one with, and the other without, daily potassium bicarbonate supplementation (90 mmol × d-1), according to a cross-over design. Oxidative stress in erythrocytes was evaluated by determining the ratio between reduced (GSH) and oxidized glutathione (GSSG). Glutathione turnover and phenylalanine kinetics, a marker of whole body protein metabolism, were determined by stable isotope infusions. Erythrocyte membranes PUFA composition was analyzed by gas-chromatography. RESULTS: At the end of the two study periods, urinary pH was 10 ± 3% greater in subjects receiving potassium bicarbonate supplementation (7.23 ± 0.15 vs. 6.68 ± 0.11, p < 0.001). Alkalinization increased total glutathione concentrations by 5 ± 2% (p < 0.05) and decreased its rate of clearance by 38 ± 13% (p < 0.05), without significantly changing GSH-to-GSSG ratio. After alkalinization, net protein balance in the postabsorptive state improved significantly by 17 ± 5% (p < 0.05) as well as the sum of n-3 PUFA and the n-3-to-n-6 PUFA ratio in erythrocyte membranes (p < 0.05). CONCLUSIONS: Alkalinization during long-term inactivity is associated with improved glutathione status, anti-inflammatory lipid pattern in cell membranes and reduction in protein catabolism at whole body level. This study suggests that, in clinical conditions characterized by inactivity, oxidative stress and inflammation, alkalinization could be a useful adjuvant therapeutic strategy.

PURPOSE OF REVIEW: Cachexia is a disease-related multifactorial syndrome characterized by inflammation, massive muscle protein catabolism and carbohydrate and lipid metabolism disorder.Several studies tried to define the impact of either nutrition or physical exercise (single approach strategy) or their combination (multimodal approach strategy) on prevention and/or treatment of muscle wasting in cachectic patients. RECENT FINDINGS: Single approach strategies (i.e. nutrition or physical exercise) have the potential of preventing and improving features of the cachexia syndrome possibly with a differential impact according to the underlying disease. Limited information is available on the beneficial effect of multimodal approach strategies. SUMMARY: Multimodal approaches appear to be more effective than those based on single interventions in physiological condition and in cachectic patients with COPD or chronic kidney disease. Further studies, however, are required in cachexia induced by heart failure, cancer and critical illness.

Background: Acute myocardial infarction (AMI) survivors are at risk of major adverse cardiac events and their risk stratification is a prerequisite to tailored therapeutic approaches. Biomarkers could be of great utility in this setting. Methods: We sought to evaluate the utility of the combined assessment of Galectin 3 (Gal-3) and Galectin 3 binding protein (Gal-3bp) for post-AMI risk stratification in a large, consecutive population of AMI patients. The primary outcomes were: Recurrent angina/AMI and all-cause mortality at 12 months after the index event. Results: In total, 469 patients were included. The median Gal-3bp was 9.1 &mu, g/mL (IQR 5.8&ndash, 13.5 &mu, g/mL), while median Gal-3 was 9.8 ng/mL (IQR 7.8&ndash, 12.8 ng/mL). During the 12 month follow-up, 34 patients died and 41 had angina pectoris/reinfarction. Gal-3 was associated with all-cause mortality, while Gal-3bp correlated with the risk of angina/myocardial infarction even when corrected for other significant covariates. The final multivariable model for mortality prediction included patients&rsquo, age, left ventricular ejection fraction (LVEF), Gal-3, and renal function. The ROC curve estimated for this model has an area under the curve (AUC) of 0.84 (95%CI 0.78&ndash, 0.9), which was similar to the area under the ROC curve obtained using the GRACE score 1-year mortality. Conclusions: The integrated assessment of Gal-3 and Gal-3bp could be helpful in risk stratification after AMI.

OBJECTIVES: To derive and validate a predictive algorithm integrating a nomogram-based prediction of the pretest probability of infection with a panel of serum biomarkers, which could robustly differentiate sepsis/septic shock from noninfectious systemic inflammatory response syndrome. DESIGN:Multicenter prospective study. SETTING: At emergency department admission in five University hospitals. PATIENTS:Nine-hundred forty-seven adults in inception cohort and 185 adults in validation cohort. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A nomogram, including age, Sequential Organ Failure Assessment score, recent antimicrobial therapy, hyperthermia, leukocytosis, and high C-reactive protein values, was built in order to take data from 716 infected patients and 120 patients with noninfectious systemic inflammatory response syndrome to predict pretest probability of infection. Then, the best combination of procalcitonin, soluble phospholipase A2 group IIA, presepsin, soluble interleukin-2 receptor α, and soluble triggering receptor expressed on myeloid cell-1 was applied in order to categorize patients as "likely" or "unlikely" to be infected. The predictive algorithm required only procalcitonin backed up with soluble phospholipase A2 group IIA determined in 29% of the patients to rule out sepsis/septic shock with a negative predictive value of 93%. In a validation cohort of 158 patients, predictive algorithm reached 100% of negative predictive value requiring biomarker measurements in 18% of the population. CONCLUSIONS: We have developed and validated a high-performing, reproducible, and parsimonious algorithm to assist emergency department physicians in distinguishing sepsis/septic shock from noninfectious systemic inflammatory response syndrome

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

OBJECTIVE: The objective of this study was to assess whether functional genetic polymorphisms of matrix metalloproteinases (MMPs) 1, 3, 9, and 12 are associated with arterial enlargements or aneurysms of the thoracic aorta or popliteal arteries in patients with abdominal aortic aneurysm (AAA). METHODS: The associations between MMP1 (-1607 G in/del, rs1799750), MMP3 (-1171 A in/del rs35068180), MMP9 (13-26 CA repeats around -90, rs2234681, rs917576, rs917577), and MMP12 (G/T missense variation, rs652438) polymorphisms and enlargements or aneurysms of the thoracic aorta and popliteal arteries were tested in 169 consecutive AAA patients. RESULTS: Thoracic aorta enlargement or aneurysm (TE/A; maximum diameter, >35 mm) was detected in 34 patients (20.1% prevalence). MMP9 rs2234681 microsatellite was the only genetic determinant of TE/A in AAA patients (P = .003), followed by hypercholesterolemia and antiplatelet use. Carriers of both alleles with ≥22 CA repeats had a 5.9 (95% confidence interval, 1.9-18.6; P < .0001) increased odds of TE/A, and a score considering all three variables showed 98% negative predictive value and 30% positive predictive value for thoracic aortic aneurysm detection. Eighty-two popliteal artery enlargements or aneurysms (diameter >10 mm) occurred in 55 patients (33.1% prevalence). Carriers of MMP12 rs652438 C allele showed an 18% (P = .006) increased diameter in popliteal arteries and a 2.8 (95% confidence interval, 1.3-6; P = .008) increased odds of popliteal artery enlargement or aneurysm compared with TT genotype. CONCLUSIONS: Among patients with AAA, carriers of homozygous ≥22 CA repeats in MMP9 rs12234681 and of C allele in MMP12 rs652438 have a substantial risk of carrying thoracic and popliteal enlargements, respectively.

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.

Purpose of review In clinical management of acutely ill adults and children, continuous enteral feeding (CEF), being considered the most tolerable approach, in comparison to other temporal patterns of nutrient administration (i.e. intermittent, cyclic and bolus), is the most frequently applied method. However, uncertainties remain about the most efficient approach to counteract protein catabolism. Recent findings In critically ill adults, protein loss is mainly driven by increased protein breakdown whereas, in pediatric patients, acute illness is mainly characterized by blunted regulation of protein synthesis and stunted growth. Kinetic studies in fed adult volunteers indicate that protein synthesis can be stimulated for a limited period only. However, continuous feeding persistently improves protein balance through a sustained suppression of protein breakdown. This leads to the hypothesis that CEF could be more anticatabolic than intermittent enteral feeding (IEF) in these patients. Differently from adults, experimental models of acute disease in growing animals have consistently indicated that IEF can improve protein anabolism more efficiently than CEF, mainly through protein synthesis stimulation. The scarce number of clinical studies in acutely ill adults or pediatric patients, mostly performed with inadequate methodology, could not define the best approach to maintain protein balance. Summary There is a need for pragmatic studies to directly compare the protein anabolic action of CEF and IEF using accurate methodologies, such as stable isotopes of amino acids, in both adult and pediatric patients with acute illness.

The prevalence of atrial fibrillation (AF) is related to age and is projected to rise exponentially as the populationages and the prevalence of cardiovascular risk factors increases. The risk of ischemic stroke is significantly increasedin AF patients, and there is evidence of a graded increased risk of stroke associated with advancingage. Oral anticoagulation (OAC) is far more effective than antiplatelet agents at reducing stroke risk in patientswith AF. Therefore, increasing numbers of elderly patients are candidates for, and could benefit from, the use ofanticoagulants. However, elderly people with AF are less likely to receive OAC therapy. This is mainly due to concernsabout a higher risk of OAC-associated hemorrhage in the elderly population. Until recently, older patientswere under-represented in randomized controlled trials of OAC versus placebo or antiplatelet therapy, and thereforethe evidence base for the value of OAC in the elderly population was not known. However, analyses of theavailable trial data indicate that the expected net clinical benefit of warfarin therapy is highest among patientswith the highest untreated risk for stroke, which includes the oldest age category. An important caveat with warfarintreatment is maintenance of a therapeutic international normalized ratio, regardless of the age of the patient,where time in therapeutic range should be 65%. Therefore, age alone should not prevent prescription ofOAC in elderly patients, given an appropriate stroke and bleeding risk stratification. (J Am Coll Cardiol 2010;56:827–37) © 2010 by the American College of Cardiology Foundation

INTRODUCTION: A 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. METHODS: We 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 CONCLUSIONS: The 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.

Purpose: To assess if a polymorphism (PM) of the microsatellite (CA13–27) in the promoter region of Matrix Metalloproteinase 9 (MMP-9) was associated with the exudative form of age-related macular degeneration (AMD) and to its risk factors. Methods: In 107 patients with AMD (AMD Group) and 223 age- and gender-matched controls (Control Group) with cataract, demographic, clinical data, and MMP-9 PM have been compared. Results: The comparison of allelic frequencies showed a different pattern of CA repeats between AMD and Control Group (P < 0.00005), in particular the prevalence of longer microsatellites (≥ 22 CA repeats) was higher in AMD than in Control Group (O.R. 2.49, 95% CI 1.71 - 3.37, P < 0.001). Analyses of genetic frequencies gave similar results. Logistic regression confirmed that 22 or more CA repeats are associated to AMD. The only association between MMP-9 PM and other risk factors for AMD was with BMI (Spearman’s R = 0.298, P < 0.00005): all patients with both microsatellites ≥ 22 CA repeats were overweight or obese (χ2 test P < 0.0005, compared to other genotypes). Conclusions: Longer microsatellites in the promoter of MMP-9 are associated to the exudative form of AMD and to body mass index, a well-known risk factor for the disease.

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.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.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 (pIn 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.

The objective of the study was to determine the accuracy of phospholipase A2 group II (PLA2-II), interferon-gamma-inducible protein 10 (IP-10), angiopoietin-2 (Ang-2), and procalcitonin (PCT) plasma levels in early ruling in/out of sepsis among systemic inflammatory response syndrome (SIRS) patients. Biomarker levels were determined in 80 SIRS patients during the first 4 h of admission to the medical ward. The final diagnosis of sepsis or non-infective SIRS was issued according to good clinical practice. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for sepsis diagnosis were assessed. The optimal biomarker combinations with clinical variables were investigated by logistic regression and decision tree (CART). PLA2-II, IP-10 and PCT, but not Ang-2, were significantly higher in septic (n = 60) than in non-infective SIRS (n = 20) patients (P ≤ 0.001, 0.027, and 0.002, respectively). PLA2-II PPV and NPV were 88 and 86 %, respectively. The corresponding figures were 100 and 31 % for IP-10, and 93 and 35 % for PCT. Binary logistic regression model had 100 % PPV and NPV, while manual and software-generated CART reached an overall accuracy of 95 and 98 %, respectively, both with 100 % NPV. PLA2-II and IP-10 associated with clinical variables in regression or decision tree heterogeneous models may be valuable biomarkers for sepsis diagnosis in SIRS patients admitted to medical ward (MW). Further studies are needed to introduce them into clinical practice.

Sepsis is a leading healthcare problem, accounting for the vast majority of fatal events in critically ill patients. Beyond early diagnosis and appropriate treatment, this condition requires a multifaceted approach for monitoring the severity, the potential organ failure as well as the risk of death. Monitoring of the efficacy of treatment is also a major issue in the emergency department (ED). The assessment of critically ill conditions and the prognosis of patients with sepsis is currently based on some scoring systems, which are, however, inefficient to provide definite clues about organ failure and prognosis in general. The discretionary and appropriate use of some selected biomarkers such as procalcitonin, inducible protein 10 (IP10), Group IV phospholipase A2 type II (PLA2 II), neutrophil gelatinase-associated lipocalin (NGAL), natriuretic peptides, mature adrenomedullin (ADM), mid-regional pro-adrenomedullin (MR-proADM), copeptin, thrombopoietin, Mer receptor and even red blood cell distribution width (RDW) represent thereby an appealing perspective in the diagnosis and management of patients with sepsis. Nevertheless, at the moment, it is not still clear if it is better to use a multimarkers approach or if a single, most appropriate, biomarker exists. This collective opinion paper is aimed at providing an overview about the potential clinical usefulness of some innovative biomarkers of sepsis in its diagnosis and prognosis, but also in the treatment management of the disease. This manuscript represents a synopsis of the lectures of Third Italian GREAT Network Congress, that was hold in Rome, 15–19 October 2012.

The thickening of the vessel wall (intimal hyperplasia) is a pathological process which often follows re-vascularization approaches such as transluminal angioplasty and artery bypass graft, procedures used to re-vascularize stenotic artery. Despite the significant improvements in the treatment of intimal hyperplasia obtained in the last years, the problem has not completely solved. Nucleic acid based-drugs (NABDs) represent an emergent class of molecules with potential therapeutic value for the treatment of intimal hyperplasia. NABDs of interest in the field of intimal hyperplasia are: ribozymes, DNAzymes, antisense oligonucleotides, decoy oligonucleotides, small interfering RNAs and micro interfering RNAs. These molecules can recognize, in a sequence-specific fashion, a target which, depending on the different NABDs, can be represented by a nucleic acid or a protein. Upon binding, NABDs can down-modulate the functions of the target (mRNA/proteins) and thus they are used to impair the functions of disease-causing biological molecules. In spite of the great therapeutic potential demonstrated by NABDs in many experimental model of intima hyperplasia, their practical use is hindered by the necessity to identify optimal delivery systems to the vasculature. In the first part of this review a brief description of the clinical problem related to intima hyperplasia formation after revascularization procedures is reported. In the second part, the attention is focused on the experimental evidences of NABD therapeutic potential in the prevention of intimal hyperplasia. Finally, in the third part, we will describe the strategies developed to optimize NABD delivery to the diseased vessel.

Therapy with Vitamin K antagonists (VKA) effectively reduces the thrombosis risk in many clinical conditions. Genetic variants of vitamin K epoxide reductase (VKORC-1) are associated with increased VKA effect and bleeding risk. It is unknown whether these variants could also affect the long-term outcome in patients with high-dosage oral anticoagulation and/or more difficult adherence to the therapeutic INR range. Hundred and twenty-four patients with mechanical heart valve replacement assuming VKA were genotyped for VKORC-1 −1639G>A (Rs9923231) polymorphism. Hemorrhage, venous thrombosis and atherothrombotic events were retrospectively assessed for a 6-year period. Furthermore, stability of their INR in relationship with the VKORC-1 genotype was investigated day-by-day for 3 months. No differences were observed in hemorrhage and venous thrombosis events according to rs 9923231. GG genotype carriers (n = 41) had no atherothrombotic events, while 4 strokes, 4 TIA and 3 AMI were diagnosed in A carriers (n = 83; P = 0.0008). During the daily observation period, A allele carriers had lower VKA requirements (4.7, 3.7, 2.2 mg/day for GG/GA/AA genotype respectively; P = 0.00001), higher mean INR (2.7, 2.8, 2.9; P = 0.05) and a higher number of examinations above the therapeutic range than GG carriers (17 % vs. 0 % in GG genotype, P = 0.036). Conversely, patients with GG genotype had a more stable dosage of VKA (P = 0.006) and a higher percentage of examinations under the therapeutic range (51, 43 and 36 % in GG, GA and AA genotype, respectively, P = 0.040). In patients with high dosage VKA, VKORC-1 polymorphism is associated to a different warfarin dosage, anticoagulation level, time spent outside the therapeutic range and, in the long-term, a different incidence of atherothrombotic events.

Critically ill patients (CIP) are patients who, because of dysfunction or failure of one or more organs/systems, depend on advanced instruments for monitoring and therapy for their survival. Coagulation abnormalities are common in CIP. The most common (35–44%) is thrombocytopenia (platelet count less than 150,000/µl), due to sepsis, disseminated intravascular coagulation (DIC), thrombotic microangiopathy, or induced by drugs, such as heparin. Prolonged global coagulation times, beyond antithrombotic therapy, are also found, and are a result of quantitative defects of coagulation factors, caused by synthesis defects (liver insufficiency), excessive loss (massive hemorrhage), or consumption (DIC), low levels of one or more coagulation factors due to antibodies, antiphospholipid antibodies, or the presence of inhibitors. This chapter provides information on the principles, clinical significance, technology, and open problems in laboratory assessment of hemostasis in critically ill patients.

Genetic defects accounting for increased prothrombotic risk are related to antithrombin, prothrombin, protein C, protein S, and factor V. These defects can induce a wide array of clinical relevance and total a few hundred. Suspicion of the defect derives from clinical observation of spontaneous thrombosis either in the deep veins of the leg or in atypical sites (cerebral sinus, mesenteric hepatic veins) and/or at a young age ranging from intrauterine life (hence spontaneous abortion) until 50 years of age. The diagnosis can be frustrating because it requires combined techniques of hemostaseology and molecular biology and is therefore time- and resource-consuming, because only some of the above-mentioned events are associated with genetic defects, and not all identified carriers have the same risk. This reflects on their management, with recommendations for each condition at increased thrombotic risk, such as surgery, immobility, venous or arterial thromboembolism, and pregnancy.

Objective: To assess the association of matrix metalloproteinases (MMP) genetic polymorphism (PM) with plaques vulnerability and clinical outcome of acute vascular events. Methods: MMP-1 (-1607 G in/del), MMP-3 (-1171 A in/del), and MMP-9 microsatellite (13–26 CA repeats around -90) PMs have been determined (i) in 204 patients with cerebrovascular disease to assess the association with features of vulnerability in carotid plaques and prevalence of stroke, (ii) in 208 patients with UA/NSTEMI to assess the association with in-hospital clinical outcome. Results: Plaques from carriers of MMP-1 G insertion showed significantly smaller plaques and thicker fibrous cap. In CVD patients carrying such variant, Odds Ratio for previous stroke was 0.27 (95% C.I. 0.13–0.56, P = 0.0002) and, in UA/NSTEMI patients, the risk of Major Adverse Cardiac Events (MACE, persistent angina, NSTEMI, and vascular death) was 0.22 (95% C.I. 0.11–0.44, P < 0.0001).Novariants inMMP-3 PM were associated to differences in either plaque features or clinical outcome. Carriers of MMP-9≥22 repeats in the microsatellite had larger plaques and lipid core. In CVD patients with such variant, Odds Ratio for stroke was 2.2 (95% C.I. 1.1–4.4) and, in UA/NSTEMI patients, MACE risk was 4.1 (95% C.I. 2.3–7.4, P < 0.0001). Persistent angina and NSTEMI separately provided comparable results. Conclusions: Carriers of MMP-1 G insertion show smaller and more stable plaques, as well as better prognosis in acute vascular events, while patients with ≥22 repeats in MMP-9 have larger necrotic core and worse prognosis in UA/NSTEMI.

Background No effective therapy is available for hepatocellular carcinoma. To identify novel therapeutic strategies, we explored the effects of the depletion of E2F1, cyclin E1–E2 whose inter-relationships in hepatocellular carcinoma cell proliferation have never been defined. Methods siRNA-mediated depletion of the targets was studied in the hepatocellular carcinoma cells HepG2, HuH7 and JHH6 characterized by high, medium and low hepatocyte differentiation grade, respectively; a model of normal human hepatocytes was also considered. Results The depletion of each target mRNA reduced the levels of the other two mRNAs, thus demonstrating a close regulatory control, also confirmed by over-expression experiments. At the protein level, an exception to this trend was observed for cyclinE1 whose amount increased upon cyclin E2 (HepG2, HuH7, JHH6) and E2F1 (HepG2) depletion. In HepG2, reduced cyclinE1 proteolysis accounted for this observation. Additionally, cyclin E1–E2–E2F1 targeting decreased the levels of cyclin A2 mRNA and of the hyper-phosphorylated form of pRb thus leading to an S-phase cell decrease; migration was impaired as well. Finally, the model of human hepatocytes used was clearly less affected by target mRNAs depletion than hepatocellular carcinoma cells. Conclusion Our data provide novel mutual relationships amongst cyclin E1–E2–E2F1 and indicate their role in sustaining hepatocellular carcinoma cell proliferation/migration, validating the concept of an anti-cyclin E1–E2–E2F1 therapeutic approach for hepatocellular carcinoma.

To investigate the short term effects of Doxycycline on MMP-2 and MMP-9.Short term effects of Doxycycline (100 mg B.I.D.) on plasma levels of MMP-2 and MMP-9 were investigated in 20 healthy subjects; the effects of Doxy, Acetylsalicylic acid, Nitrates, and Enalapril on MMP-9 release from were assessed in isolated polymorphonuclear cells.In plasma, MMP-9 activity was reduced (-22\%, 95\% CI -32/-11; P = 0.002) starting at 12 h after doxy; in vitro, MMP-9 released from stimulated neutrophils was reduced by Doxy (-28\%, 95\% CI -43/-14; P = 0.001), inhibiting degranulation, and by nitrates (-52\%, 95\% CI -76/-28 P = 0.005), increasing three times both pro- and active-MMP-9 bound to neutrophils (P = 0.007 and 0.040, respectively).Doxy decreases MMP-9 plasma levels by around 20\%, within the first 12 h. The mechanism leading to such reduction seems due to the inhibition of PMN degranulation.

Alcoholic beverages are known to exert a protective effect on atherosclerotic disease. This study aimed to assess the in vivo and in vitro effects of alcohol on matrix metalloproteinase (MMP) -2 and -9, known to determine atherosclerosis progression. Eighteen healthy volunteers, regular drinkers (two standard alcohol servings/day, on average) at first examination (baseline) were asked to abstain from any alcoholic beverage for one week (abstention), and then to assume two standard alcohol servings of beer daily for 1 week (re-exposure). Activity of MMP-2 and -9, total antioxidant activity (AOA), glutathione (GSH) plasma levels were carried out at baseline, at the end of abstention, and after 1 week of re-exposure. To validate the in vivo results, MMP-2 activity and expression, AOA, and GSH, were determined in human smooth muscle cells treated for 96 h with increasing concentrations (12.5-100 mM) of ethanol. MMP-2, but not MMP-9 plasma activity was higher at abstention than at baseline or re-exposure (P

Introduction: Experimental models and ex-vivo studies suggest a crucial role of some matrix metalloproteinases (MMPs) in the development of acute coronary syndromes, but expression levels of MMP-2, MMP-9 and TIMP-1 in human coronary plaques causing stable angina or an acute coronary syndrome have not been reported, yet. Methods: MMP-2, -9 and TIMP-1 expressions were assessed by real-time PCR from the debris collected into distal protective vascular guards from patients with stable angina (SA-Group, n=16), acute coronary syndrome (ACS-Group, n=16) undergoing percutaneous coronary interventions (PCI). MMP-2 and -9 activities were also evaluated by gelatin-substrate zymography on plasma samples collected immediately before PCI, and compared to those of healthy subjects (Control-Group). Results: The expression of MMP-2 was similar in ACS and SA-Groups. MMP-9 (P=0.011), but not TIMP-1, expression was higher in debris samples from patients in the ACS-Group than in SA-Group. In both groups, the expression of MMP-2 and MMP-9 were inversely correlated (rho=−0.7; Pb0.004). Zymography data indicated that pro and active MMP-9 were higher in ACS than in SA-Group, while no difference in MMP-2 was found. Conclusions: MMP-9, but not TIMP-1 or MMP-2 expression is increased in plaques causing acute coronary syndrome.

OBJECTIVES AND METHODS The present study was designed to evaluate the role of some inflammation [interleukin (IL)-1beta, soluble IL-1 receptor, IL-1 receptor antagonist (IL-1RA), high-sensitivity C-reactive protein (hsCRP) and fibrinogen], and remodeling markers [matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2] in patients with acute coronary syndrome (ACS; 40 patients), or chronic stable angina (CSA; 40 patients) compared to age- and sex-matched healthy controls (20 subjects). RESULTS IL-1RA, hsCRP, fibrinogen, MMP-9, and TIMP-1 plasma levels were significantly higher in patients than in controls, whereas soluble IL-1 receptor had an opposite pattern. Among patients with ACS, hsCRP plasma levels were higher in patients with non-ST segment elevation myocardial infarction (NSTEMI) than in those with unstable angina (UA). TIMP-1 plasma levels were higher in those patients with ACS who did not respond to medical therapy (non-responsive unstable angina; NR-UA). A CRP plasma level higher than 0.86 mg/dl had a 91% positive predictive value (PPV) and 63% negative predictive value for NSTEMI (odds ratio = 6.4, 95% confidence interval = 1.5-27.4). TIMP-1 plasma level higher than 21.5 ng/ml had a 100% PPV for patients with NR-UA or NSTEMI. Binary logistic analysis confirmed TIMP-1 levels as being able to predict responsiveness to therapy. CONCLUSIONS In conclusion, a different biochemical pattern characterizes ACS patients: those with NR-UA show only an increase of remodeling markers, whereas ACS patients with NSTEMI have an increase of both remodeling and inflammation markers.

Chronic renal failure (CRF) is characterized by persistent systemic inflammatory response. We tested the hypothesis that the balance between synthetic capacity of pro-inflammatory, as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and anti-inflammatory cytokines, as IL-10, may become progressively impaired during decline of renal function. Cytokine mRNA transcript levels (fraction of GAPDH mRNA) were detected by real time RT-PCR technique in whole blood cells of patients with far-advanced or less-advanced CRF (glomerular filtration rate lower or greater than 15ml/min per 1.73m(2), respectively) undergoing conservative treatment and in healthy controls. TNF-alpha mRNA levels were greater (p

Objective— The aims of this study were to compare a microsatellite polymorphism (PM) of matrix metalloproteinase (MMP)-9 in patients with carotid atherosclerosis and control population, and to assess the relationship between this PM and plaque structure. Methods and Results— One hundred fifty patients referring to vascular diagnostic centers for suspected carotid atherosclerosis (at ultrasound examination: 110 positive, 40 negative) and controls (n=110) have been genotyped for MMP-9 PM. After controlling for risk factors, allelic and genotype frequencies were significantly different among the groups, with significant prevalence of long microsatellites in patients with carotid atherosclerosis. Long microsatellites (settled as 22 to 27 repeats) were associated with carotid atherosclerosis (odds ratio [OR], 5.2; 95% confidence interval [CI], 2.9 to 9.2), compared with controls; an independent case control study on patients with coronary atherosclerosis confirmed such result. Binary logistic regression showed that hypertension, long microsatellites in MMP-9 PM and smoking habits were variables accounting for the difference between ultrasound-positive patients and controls. Long microsatellites were also associated to plaques with thin fibrous cap and echolucent core (OR, 13.1; 95% CI, 1.6 to 100). These alleles were slightly more represented in female patients (χ 2 test=0.019; OR, 2.7; 95% CI, 1.2 to 6) but not associated with other risk factors. Plasma MMP-9 levels were related neither to MMP-9 PM nor to plaque type, and were related to gender and extension of atherosclerosis in carotid arteries. Conclusions— The number of repeats (≥22 CA) in the microsatellite of MMP-9 promoter, but not MMP-9 plasma levels, is associated to carotid atherosclerosis and particularly to plaques with a thin fibrous cap.

PURPOSE: To investigate the effects of photodynamic therapy (PDT) on subfoveal choroidal neovascularization (CNV) secondary to reticular pattern dystrophy (RPD) of the retinal pigment epithelium. DESIGN: Open-label, prospective, interventional case series. METHODS: Thirteen eyes diagnosed with subfoveal CNV associated with RPD were considered. Complete ophthalmic examinations were performed at baseline and thereafter at three-month intervals for three years. Primary outcome measure was the number of eyes with

Atherosclerosis is considered an ubiquitous pathological process. In patients symptomatic for coronary artery or carotid or peripheral arterial disease, other localizations – still asymptomatic – of atherosclerotic lesions are often found. Despite this consideration, the patterns of arteries developing atherosclerosis can be quite diverse: for example, lesions prevalently develop in regions where the flow is either low or turbulent such as where artery bifurcates, mammalian artery are nearly unaffected by atherosclerosis. 1

Background Matrix metalloproteinase (MMP)-12 levels are increased in the abdominal aortic aneurysm (AAA), implicating this protease in AAA pathogenesis. The purpose of this study was to assess the role of MMP-12 in aneurysm formation. Methods A murine aneurysm model was generated by periaortic application of 0.25 mol/L calcium chloride (CaCl 2 ) for 15 minutes. Aortic diameters were measured and compared before and 10 weeks after aneurysm induction. Aortic diameter changes for wild type (WT) and MMP-12 knockout (MMP-12 −/− ) mice were determined. MMP-12 production in mouse aorta was analyzed by casein zymography. MMP-2 and MMP-9 expressions were examined by gelatin zymography. Immunohistochemical study was used to measure macrophage infiltration into the aorta. Results There is an increase of 63 ± 5% (mean ± SEM) in aortic diameters of WT mice after CaCl 2 inductions, while MMP-12 −/− mice increased only 26 ± 14%. Connective tissue staining of aortic sections from WT mice showed disruption and fragmentation of medial elastic fibers, while MMP-12 −/− mice showed only focal elastic lamellae breakdown. MMP-12 levels in WT mice were significantly increased after CaCl 2 treatment, whereas no MMP-12 was detected in MMP-12 −/− mice. There was no difference in the MMP-2 and MMP-9 productions between WT and MMP-12 −/− mice. Immunohistochemical analysis demonstrated that infiltrating macrophages in the aorta of MMP-12 −/− mice were significantly less than WT controls. Conclusions MMP-12 deficiency attenuates aneurysm growth, possibly by decreasing macrophage recruitment.

Objective. To determine the fatal and non-fatal cardiovascular event rate in patients with intermittent claudication treated with antiplatelet agents.Methods and design. Patients with PAD-II stage Fontaine (n=223) and sex and age matched controls (n=446) were followed up from 1974 to 1998. All patients were treated with antiplatelet agents (aspirin, 325 mg once daily or ticlopidine, 250 mg twice daily) and for risk factors, if present. The end points were death for any cause (vascular event, cancer, and others) and non-fatal vascular events (myocardial infarction, ischemic/hemorrhagic stroke, and leg amputation).Results. PAD patients had a significantly higher mortality rate than controls (3.99 vs. 2.53 deaths for 100 patients per year, respectively), cancer (mostly lung, stomach and colon) and vascular mortality accounted for such difference. The incidence of non-fatal vascular events was three times higher in patients than in controls (1.7 vs. 0.56, 100 patients per year, respectively, p

In the present study, we evaluated plasma levels of the prototypical acute phase protein CRP, Interleukin-1 receptor antagonist (IL-1Ra) which is synthesized and released by activated monocyte-macrophages at sites of tissue damageyinflammation and Interleukin-2 soluble receptor (sIL-2R), a specific marker of T-lymphocyte activation, in patients with mild ischaemic LVD.

The aim of the study was to evaluate which pattern of coagulation indicators characterizes unstable angina and, particularly, its relationship with short-term prognosis. Forty patients with unstable angina (UA Group) at admission in the intensive care unit, 40 patients with chronic stable effort angina (SEA Group), and 20 age- and sex-matched healthy controls were studied. Blood coagulation indicators were fibrinogen, prothrombin fragment F1 + 2 (F1 + 2), thrombus precursor protein (TpP), and D-dimer. C reactive protein (CRP) and cardiac Troponin I (cTnI) have also been determined and compared. Patients in the UA Group were followed for in-hospital adverse events (sudden death, acute myocardial infarction and angina refractory to medical therapy). CRP, D-dimer and cTnI plasma levels were significantly lower in the SEA Group than in the UA Group; the same trend was found for fibrinogen and F1 + 2 plasma levels, although not statistically significant. The TpP was similar in all groups. The control group showed the lowest levels for all indicators. Within the UA Group, 17 patients developed adverse events during hospitalization; F1 + 2, D-dimer, cTnI and CRP plasma levels were higher in these patients than in those with good outcome. Relative risks for adverse events associated with the highest tertile of D-dimer, cTnI, and CRP plasma levels were 8.4 (95% confidence interval, 1.5-48.9), 6.7 (95% confidence interval, 1.1-38.6) and 5.2 (95% confidence interval, 1.1-25.2), respectively. D-Dimer is significantly increased in patients with unstable angina and, in particular, in those who develop an adverse event.

Background. Prominent inflammatory infiltrates of macrophages and T-lymphocytes are found in both aortic occlusive disease (AOD) and abdominal aortic aneurysms (AAA). These cells secrete different cytokines that might affect matrix turnover through modulation of matrix metalloproteinase expression. A different cytokine pattern might account for the evolution of AOD vs AAA. Materials and Methods. Six different cytokines were examined to determine whether AOD and AAA could be characterized by unique cytokine patterns. AOD (n = 8) and AAA (n = 8) tissues were collected and serially treated with salt, dimethyl sulfoxide, and urea buffers to extract the soluble matrix or cell-bound cytokines. Levels of IL-1β, TNF-α, IL-10, IL-12, and IFN-γ were measured by immunoenzymatic methods. Additionally, RNA levels of IL-12 and IFN-γ were measured. Results. AAA tissue contained higher levels of IL-10 compared to AOD tissue (P < 0.05). Higher levels of the proinflammatory cytokines IL-1β, TNF-α, and IL-6 were found in AOD (P < 0.05). mRNA levels of IL-12 and IFN-γ did not differ between the diseases. Aortic tissues contained large amounts of matrix or cell-bound cytokines. Conclusions. AAA is characterized by greater levels of IL-10 while IL-1β, TNF-α, and IL-6 are higher in AOD. Targeted deletion of these cytokines in animal models might help in identifying their role in the progression of AAA.

The aim of this study was to determine whether paroxysmal atrial fibrillation (PAF) and/or restoration to sinus rhythm with electric or pharmacologic cardioversion induce modifications to the coagulation system. Thirty-five patients with PAF undergoing either electric (n = 11) or pharmacologic (n = 24) cardioversion were studied. Fibrinopeptide A and D-dimer blood samples were taken immediately before and after cardioversion at different intervals. When compared with the control group (n = 70), the precardioversion fibrinopeptide A plasma values were significantly elevated (11.8 vs 2.5 ng/mL). Fibrinopeptide A plasma values were significantly reduced 5 minutes after cardioversion (11.8 vs 5.3 ng/mL) and remained stable throughout the follow-up sequential measurements. D-dimer plasma values were significantly increased (measured at 12 hours and at day 7) in patients who underwent electrical cardioversions only. A positive correlation (R(2) = 0.76) was found between the energy delivered for cardioversion to sinus rhythm and D-dimer plasma values on day 7. In patients with PAF, levels of fibrinopeptide A, an indicator of coagulation activation, are elevated and soon reduced by the restoration of sinus rhythm. Electric, but not pharmacologic, cardioversion induces an early activation of the fibrinolytic system.

Matrix metalloproteinases are involved in the development of acute coronary syndromes, but they are not reliable clinical markers of the occurrence or the outcome of this syndrome. Many limitations in their assessment account for such failure. Functional genetic polymorphisms, as alternatives to plasma levels, might be an interesting alternative.

Inflammatory phenomena at sites of atherosclerotic plaques are increasingly thought to be major determinants of the progression and clinical outcome of atherosclerotic disease. Therefore, attention is being paid to systemic markers/mediators which may reflect the inflammatory activity in the plaques. This study evaluates the pattern of the main proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6), their soluble receptors/antagonist, and a variety of inflammatory markers, in patients with peripheral arterial disease (PAD). Eight patients with PAD suffering from claudicatio intermittens (CI), eight with critical limb ischemia (CLI) and eight controls (C) were studied. Blood samples were collected at baseline in all groups and. for C and CI, immediately after and 4 h after a 30-min treadmill test. Baseline: no differences in cytokine plasma levels were detected among the three groups. In contrast, soluble receptors of TNF (type I and II) and of IL-6, and IL-1beta receptor antagonist (IL-1ra) were increased in CI and CLI patients, as compared to C. Of note, IL-Ira correlated with the occurrence and stage of the disease in a highly significant proportion of the patients, reaching a predictive value for the disease of P < 0.0001. The opposite trend was observed for the soluble receptor of IL-1beta. Notably, in the patients no alterations could be found in white blood cell counts, expression of CD11c adherence molecule by circulating monocytes or, in vitro. O2- release from zymosan-activated neutrophils. Moreover, plasma levels of platelet activating factor (PAF), of neutrophil elastase and of the acute phase reactants C-reactive protein (CRP) and alpha1-acid glycoprotein were not found to be significantly altered. In contrast, the acute-phase proteins alpha1-antitrypsin (alpha1AT) and haptoglobin (HG) were found to be increased. Effect of treadmill: IL-1beta and TNFalpha remained at baseline levels following exercise, and IL-6 dropped to undetectable levels. Among cytokine antagonists, again the most relevant changes concerned the IL-1ra, which was significantly increased immediately after the treadmill test, both in CI and C, and returned to baseline levels after 4 h. In contrast, soluble TNFalpha, IL-1beta and IL-6 receptors, PAF, and the other markers of leukocyte activation were not found to be altered. Soluble TNFalpha and IL-6 receptors were shown to inhibit the biological effects of their ligands. Similarly, IL-1ra and the acute phase proteins alpha1AT and HG have been reported to exert anti-inflammatory functions. The increased plasma levels of these agents, together with low levels of inflammatory cytokines and other pro-inflammatory mediators such as PAF and alpha1-acid glycoprotein, appear to draw an undescribed picture, so far, of upregulation of a composite systemic anti-inflammatory mechanism in atherosclerotic patients. IL-1ra appears to be a reliable marker of the state of activation of this mechanism. These results may provide a basis for developing new insights into the pathogenesis of the atherosclerotic disease.

Abstract The best anticoagulation level in patients with mechanical heart valve prostheses is still being debated. D-dimer, which detects the presence of cross-linked fibrin degradation products, has been demonstrated to be a useful marker of coagulation activation. This study was designed to verify whether heart valve prostheses in anticoagulated patients are associated with abnormalities in D-dimer plasma levels, and if so, whether such levels are related to the anticoagulation level and/or whether they could be predictive of acute vascular or hemorrhagic events. In 132 patients with single and 10 with double mechanical valve replacement, international normalized ratio (INR) and D-dimer plasma levels were determined. The INR levels of the previous 8 months were reviewed to assess the time that each patient spent in the therapeutic range. The D-dimer plasma levels were compared with those obtained from 102 matched control subjects. The patients were then followed up for 2 years to record acute vascular and hemorrhagic events. For the entire group, D-dimer plasma levels in patients were the same as those in the control group. Patients with double valve replacement had higher D-dimer plasma levels than either monovalvular implant patients or control subjects. Patients who had spent P =.02). The major determinants of D-dimer plasma levels were age ( R 2 =.07, P =.009) and the percentage of time spent below the predetermined INR level ( R 2 =.09, P =.001). During follow-up, 19 acute vascular and 16 hemorrhagic events occurred. High D-dimer tertile was the only parameter predicting the occurrence of thromboembolic events. In patients with mechanical heart valve prostheses, the D-dimer plasma level depended on the thoroughness of anticoagulation. Patients in the upper tertile of D-dimer values have an ≈5-fold risk of vascular thromboembolic events. D-dimer determination can therefore be useful in detecting patients who are at a higher risk of severe vascular events.

In a double-blind study, 296 patients with intermittent claudication (Fontaine stage II) were treated with 250 mg ticlopidine twice daily, 500 mg aspirin every third day plus 75 mg dipyridamole three times daily, or 300 mg xanthinol nicotinate three times daily for 6 months. Ticlopidine and aspirin/dipyridamole, but not xanthinol nicotinate, improved platelet aggregation, reduced β-thromboglobulin, platelet factor IV and fibrinopeptide A concentrations, and increased antithrombin III concentrations and red blood cell filterability. No changes in lipid profiles, platelet count or fibrinogen were recorded following any treatment. The doppler systolic blood pressure ratio was improved in patients treated with ticlopidine or aspirin/dipyridamole, but not with xanthinol nicotinate. It is concluded that antiplatelet treatment is useful for the treatment of limb arteriopathy.

BACKGROUND AND OBJECTIVE To compare the effects of panretinal photocoagulation (PRP) and photodynamic therapy (PDT) for anterior segment neovascularization secondary to ischemic central retinal vein occlusion (CRVO). PATIENTS AND METHODS Fifty-seven eyes were randomized to receive standard PRP (19 eyes), selective PRP (20 eyes), or PDT (17 eyes). Selective PRP was performed only when iris neovascularization and/or angle neovascularization showed progression on weekly follow-up. Primary outcome measures were the extension of anterior segment neovascularization and the rate of neovascular glaucoma development. Secondary outcome measures included visual acuity results. RESULTS After 12 months of follow-up, iris neovascularization extension was 0.52, 2.55, and 2.27 in the PRP, selective PRP, and PDT groups, respectively. Anterior segment neovascularization extension was 0.57, 1.50, and 1.27 in the PRP, selective PRP, and PDT groups, respectively. Both showed a statistically significant difference in the PRP group. The rate of neovascular glaucoma development was similar in the three groups. CONCLUSIONS Although PRP was better at determining iris neovascularization and anterior segment neovascularization regression, the similar rate of neovascular glaucoma development found in the three groups indicates that anterior segment neovascularization secondary to ischemic CRVO can also be safely managed using selective PRP or PDT. [Ophthalmic Surg Lasers Imaging 2007;38:94-99.] AUTHORS From the Eye Clinic (MBP, MP, GD, GR), Azienda Ospedaliero-Universitaria di Trieste, Trieste, Italy; the Department of Ophthalmology/Eye & Ear Institute (TRF), University of Pittsburgh, Pittsburgh, Pennsylvania; and the Dipartimento Scienze Ciniche Morfologiche e Tecnologiche (NF), Azienda Ospedaliero-Universitaria, Trieste, Italy. Accepted for publication January 8, 2007. Presented in part as a poster at the annual meeting of the American Academy of Ophthalmology, Chicago, Illinois, October 15-18, 2005. Address correspondence to Maurizio Battaglia Parodi, MD, Azienda Ospedaliero-Universitaria di Trieste, Ospedale Maggiore, Piazza Ospedale 1, 34129, Trieste, Italy.

Background: The prognostic value of quick sepsis-related organ failure assessment (qSOFA) outside intensive care units has been criticized. Therefore, we aimed to improve its ability in predicting 30-day all-cause mortality, and in ruling out the cases at high risk of death among patients with suspected or confirmed sepsis at emergency department (ED) admission. Methods: This study is a secondary analysis of a prospective multicenter study. We built three predictive models combining qSOFA with the clinical variables and serum biomarkers that resulted in an independent association with 30-day mortality, in both 848 undifferentiated patients (Group 1) and in 545 patients definitively diagnosed with sepsis (Group 2). The models reaching the highest negative predictive value (NPV) with the minimum expenditure of biomarkers in Group 1 and in Group 2 were validated in two cohorts of patients initially held out due to missing data. Results: In terms of the area under the receiver-operating characteristic curve, all six models significantly exceeded qSOFA in predicting prognosis. An &ldquo, extended&rdquo, qSOFA (eqSOFA1) in Group 1 and an eqSOFA2 integrated with C-reactive protein and mid-regional proadrenomedullin (eqSOFA2+CRP+MR-proADM) in Group 2 reached the best NPV (0.94 and 0.93, respectively) and ease of use. eqSOFA1 and eqSOFA2+CRP+MR-proADM performed equally well in both the inception and validation cohorts. Conclusions: We have derived and validated two prognostic models that outweigh qSOFA in predicting mortality and in identifying the low risk of death among patients with suspected or confirmed sepsis at ED admission.