What we know: the inflammatory basis of hepatic encephalopathy.

Central Nervous System (CNS) degeneration appearing in patients with cirrhosis is responsible for cognitive and persistent motor impairments that lead to an important impact on life quality. Brain injury affects certain areas of the CNS that might affect two types of cells: neurons and astrocytes. The process leading to brain injury could be induced by portosystemic shunting accompanied by hyperammonemia and by the activation of peripheral inflammation, manifested as episodic encephalopathy. Hyperammonemia combined with a decrease on the BCA/AAA ratio induces alterations of energetic metabolism and the formation of free radicals in the CNS. This process would be stimulated by the activation of peripheral inflammatory mediators that could act on receptors of the blood brain barrier such as TLR4, activating inflammatory responses in the CNS. As a result, a persistent activation of microglia and an irreversible neuronal and astrocytic injury would be induced. A new knowledge of the mechanisms leading to brain injury in cirrhosis would develop protective strategies to correct changes of nitrogen metabolism and inflammation.

Eptifibatide infusion versus placebo in high risk patients with non-st segment elevation acute coronary syndromes managed with urgent coronary artery bypass graft surgery. a prospective multicenter randomized placebo-controlled clinical trial.

AIM: This randomized prospective clinical trial aimed to evaluate safety and efficacy of preoperative use of eptifibatide in high risk patients with non--ST--segment elevation acute coronary syndrome (NSTE--ACS), requiring urgent coronary artery bypass graft surgery (CABG). METHODS: A total of 140 patients with NSTE--ACS eligible for urgent surgical revascularization received either eptifibatide (bolus plus infusion) 12--48 hours prior to surgery (n=72 patients) or placebo (normal saline; n=68 patients) followed by routinely administered enoxaparin and aspirin. Patients were regarded as unsuitable for percutaneous coronary intervention by the heart team. CABG was performed 4 hours after discontinuation of eptifibatide or placebo infusion. The primary end point was major adverse cardiac and cerebrovascular events (MACCE) defined as death, nonfatal myocardial infarction (MI), stroke and the need for re--hospitalization due to recurrent ischaemia at 12 months follow--up. Secondary endpoints included MACCE rate at 1 month, bleeding complications, platelet inhibition efficacy and correlation of platelet activity with MACCE rate. RESULTS: Cumulative one year MACCE rate was 35% vs 14% in the control and treated group respectively (p=0.012). Mortality rate at 30 days follow--up was 10% vs 3% (p=0.021) and was not changed at 12 months follow--up. There was a significant difference between both groups regarding perioperative MI (22% vs. 8%, p=0.03). The rates of stroke, blood loss and blood transfusion were similar in both groups. CONCLUSION: Preoperative use of eptifibatide vs. placebo is linked to significantly reduced 12--month MACCE rate in patients with NSTE--ACS requiring urgent CABG, while it simultaneously seems not to confer a greater risk of postoperative bleeding.

Gene set enrichment analysis identifies key innate immune pathways in primary graft dysfunction after lung transplantation.

We hypothesized alterations in gene expression could identify important pathways involved in transplant lung injury. Broncho alveolar lavage fluid (BALF) was sampled from donors prior to procurement and in recipients within an hour of reperfusion as part of the NIAID Clinical Trials in Organ Transplantation Study. Twenty-three patients with Grade 3 primary graft dysfunction (PGD) were frequency matched with controls based on donor age and recipient diagnosis. RNA was analyzed using the Human Gene 1.0 ST array. Normalized mRNA expression was transformed and differences between donor and postreperfusion values were ranked then tested using Gene Set Enrichment Analysis. Three-hundred sixty-two gene sets were upregulated, with eight meeting significance (familywise-error rate, FWER p-value <0.05), including the NOD-like receptor inflammasome (NLR; p < 0.001), toll-like receptors (TLR; p < 0.001), IL-1 receptor (p = 0.001), myeloid differentiation primary response gene 88 (p = 0.001), NFkB activation by nontypeable Haemophilus influenzae (p = 0.001), TLR4 (p = 0.008) and TLR 9 (p = 0.018). The top five ranked individual transcripts from these pathways based on rank metric score are predominantly present in the NLR and TLR pathways, including IL1ß (1.162), NLRP3 (1.135), IL1α (0.952), IL6 (0.931) and CCL4 (0.842). Gene set enrichment analyses implicate inflammasome-mediated and innate immune signaling pathways as key mediators of the development of PGD in lung transplant patients.

Circulating endothelial progenitor cells are inversely correlated with in-stent restenosis in patients with non-ST-segment elevation acute coronary syndromes treated with EPC-capture stents (JACK-EPC trial).

AIM: Aim of the study was to evaluate the association between circulating endothelial progenitor cells (EPCs) and angiographic outcomes after implantation of GenousTM stent in patients with non-ST-segment elevation acute coronary syndromes (ACS) (NSTE-ACS) undergoing urgent percutaneous coronary intervention (PCI). METHODS: Sixty patients treated with EPC-capture stent (N.=30) or bare metal stents (BMS) (N.=30) receiving 80 mg atorvastatin and dual antiplatelet therapy (DAT) for 12 months. Restenosis was assessed after 6 months by quantitative coronary angiography (QCA) and major acute coronary events (MACE) evaluated after 6 and 12 months. INCLUSION CRITERIA: de novo lesion >70% in native vessel, diameter 2.5-4 mm, lesion length <30 mm. EXCLUSION CRITERIA: diabetes, previous revascularization, significant left main stenosis, chronic total occlusions (CTO) and multivessel disease. RESULTS: Majority of patients in EPC-capture stent and BMS groups presented with NSTEMI (73.3% and 70%, respectively). Mean stent length was 20.1±8 and 19.9±10 mm, diameter 3±0.97 and 3.1±0.88 mm in respective groups. The binary restenosis was significantly lower in GenousTM (13 vs. 26.6%, P=0.04). Risk of MACE after 6 and 12 months were comparable in both groups. There was no stent thrombosis. Numbers of circulating EPCs were significantly approximately 2-fold higher during the ACS than after 6 months. Mobilization of EPCs during acute ischemia was significantly lower in patients who developed restenosis after 6 months (3 vs. 4.5 cells/µL, P=0.002) and it was negatively correlated with late-loss after 6 months (R=-0.42; P<0.03). CONCLUSION: Use of GenousTM stents in NSTE-ACS is associated with lower restenosis rate than BMS at 6 months. There was no ST through 1 year. The number of circulating EPCs is inversely correlated with in-stent late loss (LL).

Immunological measurement of transferrin compared with chemical measurement of total iron-binding capacity.

Because of uncertainty as to the molecular weight of transferrin, a previous comparison [Von der Heul et al., Clin. Chim. Acta 38, 347 (1972)] between transferrin content of serum and total iron-binding capacity cannot be definitive. We found a conversion factor for expressing the maximum amount of iron bound by 1 mg of transferrin. We compared the resulting calculated value with values obtained by three other methods for measuring total iron-binding capacity. We agree with the previous observation that the latter, as measured radioisotopically, give higher results than would be judged from the transferrin content but the same as those for two chemical methods. The diffusion rate of transferrin in agar was the same irrespective of the degree of iron saturation. Serum transferrin concentrations were low in patients with anemia resulting from malignancy, chronic disorders, and cirrhosis of the liver, and high or normal in patients with iron deficiency anemia and in pregnant women or women who were taking birth-control pills. Measurement of transferrin concentration can be used to distinguish iron deficiency anemia from anemia resulting from chronic disorders, but offers no advantages over existing methods for estimating total iron-binding capacity.