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BACKGROUND: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome of increased ammonia-mediated brain dysfunction caused by impaired hepatic detoxification or when the blood bypasses the liver. Ammonia-activated signal transduction pathways of hyperactivated NMDA receptors (NMDAR) are shown to trigger a cascade of pathological reactions in the brain, leading to oxidative stress. NMDARs outside the brain are widely distributed in peripheral tissues, including the liver, heart, pancreas, and erythrocytes. To determine the contribution of these receptors to ammonia-induced oxidative stress in peripheral tissues, it is relevant to investigate if there are any ammonia-related changes in antioxidant enzymes and free radical formation and whether blockade of NMDARs prevents these changes.; METHODS: Hyperammonemia was induced in rats by ammonium acetate injection. Oxidative stress was measured as changes in antioxidant enzyme activities and O2- and H2O2 production by mitochondria isolated from the tissues and cells mentioned above. The effects of the NMDAR antagonist MK-801 on oxidative stress markers and on tissue ammonia levels were evaluated.; RESULTS: Increased ammonia levels in erythrocytes and mitochondria isolated from the liver, pancreas, and heart of hyperammonemic rats are shown to cause tissue-specific oxidative stress, which is prevented completely (or partially in erythrocyte) by MK-801.; CONCLUSIONS: These results support the view that the pathogenesis of HE is multifactorial and that ammonia-induced multiorgan oxidative stress-mediated by activation of NMDAR is an integral part of the disease and, therefore, the toxic effects of ammonia in HE may be more global than initially expected.

Meningioma (MN) is an important cause of disability, and predictive tools for estimating the risk of recurrence are still scarce. The need for objective and cost-effective techniques addressed to this purpose is well known. In this study, we present methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a friendly method for deepening the understanding of the mechanisms underlying meningioma progression. A large follow-up allowed us to obtain 50 samples, which included the primary tumor of 20 patients in which half of them are suffering one recurrence and the other half are suffering more than one. We histologically characterized the samples and performed MS-MLPA assays validated by FISH to assess their copy number alterations (CNA) and epigenetic status. Interestingly, we determined the increase in tumor instability with higher values of CNA during the progression accompanied by an increase in epigenetic damage. We also found a loss of HIC1 and the hypermethylation of CDKN2B and PTEN as independent prognostic markers. Comparison between grade 1 and higher primary MN's self-evolution pointed to a central role of GSTP1 in the first stages of the disease. Finally, a high rate of alterations in genes that are related to apoptosis and autophagy, such as DAPK1, PARK2, BCL2, FHIT, or VHL, underlines an important influence on cell-death programs through different pathways.

Minimal hepatic encephalopathy (MHE) is associated with changes in the immune system including an increased pro-inflammatory environment and altered differentiation of CD4+ T lymphocytes. The mechanisms remain unknown. Changes in extracellular vesicle (EV) cargo including proteins and miRNAs could play a main role as mediators of immune system changes associated with MHE. The aim was to assess whether plasma EVs from MHE patients played a role in inducing the pro-inflammatory environment and altered differentiation of CD4+ T lymphocyte subtypes in MHE patients. We characterized the miRNA and protein cargo of plasma EVs from 50 cirrhotic patients (27 without and 23 with MHE) and 24 controls. CD4+ T cells from the controls were cultured with plasma EVs from the three groups of study, and the cytokine release and differentiation to CD4+ T-cell subtypes were assessed. Plasma EVs from MHE patients had altered miRNA and protein contents, and were enriched in inflammatory factors compared to the controls and patients without MHE. EVs from MHE patients modulated the expression of pro-inflammatory IL-17, IL-21, and TNF-a and anti-inflammatory TGF-ß in cultured CD4+ T lymphocytes, and increased the proportion of Th follicular and Treg cells and the activation of Th17 cells. In conclusion, plasma EVs could play an important role in the induction of immune changes observed in MHE.

BACKGROUND AND AIMS: Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy, but also has pleiotropic deleterious effects on several organ systems, impacting on immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis.; METHODS: We collected data from 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analysis and fast unified random forest were performed to predict complications and mortality. External validation was carried out using prospective data from 130 cirrhotic patients in an independent tertiary liver centre.; RESULTS: Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (HR=2.13; 95%CI=1.89-2.40; p

BACKGROUND: The relationship between liver disease and neuropathology in hepatic encephalopathy is well known, but the genesis of encephalopathy in liver failure is yet to be elucidated. Conceptually, the main cause of hepatic encephalopathy is the accumulation of brain ammonia due to impaired liver detoxification function or occurrence of portosystemic shunt. Yet, as well as taking up toxic ammonia, the liver also produces vital metabolites that ensure normal cerebral function. Given this, for insight into how perturbations in the metabolic capacity of the liver may be related to brain pathology, it is crucial to understand the extent of ammonia-related changes in the hepatic metabolism that provides respiratory fuel for the brain, a deficiency of which can give rise to encephalopathy.; METHODS: Hepatic encephalopathy was induced in starved rats by injection of ammonium acetate. Ammonia-induced toxicity was evaluated by plasma and freeze-clamped liver and brain energy metabolites, and mitochondrial, cytoplasmic, and microsomal gluconeogenic enzymes, including mitochondrial ketogenic enzymes. Parameters of oxidative phosphorylation were recorded polarographically with a Clark-type electrode, while other measures were determined with standard fluorometric enzymatic methods.; RESULTS: Progressive impairment of liver mitochondrial respiration in the initial stage of ammonia-induced hepatotoxicity and the subsequent energy crisis due to decreased ATP synthesis lead to cessation of gluconeogenesis and ketogenesis. Reduction in glucose and ketone body supply to the brain is a terminal event in liver toxicity, preceding the development of coma.; CONCLUSIONS: Our study provides a framework to further explore the relationship between hepatic dysfunction and progression of brain energy crisis in hepatic encephalopathy.

Patients with liver cirrhosis may develop hepatic encephalopathy. Rats with chronic hyperammonemia exhibit neurological alterations mediated by peripheral inflammation and neuroinflammation. Motor incoordination is due to increased TNF-a levels and activation of its receptor TNFR1 in the cerebellum. The aims were to assess (a) whether peripheral inflammation is responsible for TNF-a induction in hyperammonemic rats, (b) the cell type(s) in which TNF-a is increased, (c) whether this increase is associated with increased nuclear NF-?B and TNFR1 activation, (d) the time course of TNF-a induction, and (e) if TNF-a is induced in the Purkinje neurons of patients who die with liver cirrhosis.

Several million patients with liver cirrhosis suffer minimal hepatic encephalopathy (MHE), with mild cognitive and coordination impairments that reduce their quality of life and life span. Hyperammonaemia and peripheral inflammation act synergistically to induce these neurological alterations. We propose that MHE appearance is because of the changes in peripheral immune system, which are transmitted to brain, leading to neuroinflammation that alters neurotransmission leading to cognitive and motor alterations. We summarize studies showing that MHE in cirrhotic patients is associated with alterations in the immune system and that patients died with HE show neuroinflammation in cerebellum, with microglial and astrocytic activation and Purkinje cell loss. We also summarize studies in animal models of MHE on the role of peripheral inflammation in neuroinflammation induction, how neuroinflammation alters neurotransmission and how this leads to cognitive and motor alterations. These studies identify therapeutic targets and treatments that improve cognitive and motor function. Rats with MHE show neuroinflammation in hippocampus and altered NMDA and AMPA receptor membrane expression, which impairs spatial learning and memory. Neuroinflammation in cerebellum is associated with altered GABA transporters and extracellular GABA, which impair motor coordination and learning in a Y maze. These alterations are reversed by treatments that reduce peripheral inflammation (anti-TNF, ibuprofen), neuroinflammation (sulphoraphane, p38 inhibitors), GABAergic tone (bicuculline, pregnenolone sulphate) or increase extracellular cGMP (sildenafil or cGMP). The mechanisms identified would also occur in other chronic diseases associated with inflammation, aging and some mental and neurodegenerative diseases. Treatments that improve MHE may also be beneficial to treat these pathologies.

Background & Aims Learning ability may be impaired in patients with a history of overt hepatic encephalopathy (OHE). The aim of this study was to compare performance on the first/second attempt at a series of tests. Methods Two hundred and fourteen patients with cirrhosis were enrolled. On the day of study, 41% were classed as unimpaired, 38% as having minimal HE and 21% as having mild OHE; 58% had a history of OHE. Performance was compared between two versions of the trail-making test A (TMT-A), and between the first/second half of a simple/choice reaction time (sRT and cRT), and a working memory test (ScanRT). Results Both patients with and without OHE history improved in TMT-A, sRT and ScanRT. Only patients with no OHE history improved in cRT. All patients, regardless of their HE status on the day of study, improved in TMT-A and sRT. Only patients with mild OHE on the day of study improved in cRT. Only unimpaired patients improved in ScanRT. When OHE history and HE status on the day of study were tested together, only HE status had an effect. The same held true when age, the Model for End Stage Liver Disease (MELD) and educational attainment were adjusted for. Conclusions HE status on the day of study and the type of neuropsychological test had an effect on learning ability in a well-characterized group of patients with cirrhosis.

Trafficking of glutamate, glutamine and GABA between astrocytes and neurons is essential to maintain proper neurotransmission. Chronic hyperammonemia alters neurotransmission and cognitive function. The aims of this work were to analyze in cerebellum of rats the effects of chronic hyperammonemia on: a) extracellular glutamate, glutamine and GABA concentrations; b) membrane expression of glutamate, glutamine and GABA transporters; c) how they are modulated by extracellular cGMP. Hyperammonemic rats show increased levels of extracellular glutamate, glutamine, GABA and citrulline in cerebellum in vivo. Hyperammonemic rats show: a) increased membrane expression of the astrocytic glutamine transporter SNAT3 and reduced membrane expression of the neuronal transporter SNAT1; b) reduced membrane expression of the neuronal GABA transporter GAT1 and increased membrane expression of the astrocytic GAT3 transporter; c) reduced membrane expression of the astrocytic glutamate transporters GLAST and GLT-1 and of the neuronal transporter EAAC1. Increasing extracellular cGMP normalizes membrane expression of SNAT3, GAT3, GAT1 and GLAST and extracellular glutamate, glutamine, GABA and citrulline hyperammonemic rats. Extracellular cGMP also modulates membrane expression of most transporters in control rats, reducing membrane expression of SNAT1, GLT-1 and EAAC1 and increasing that of GAT1 and GAT3. Modulation of SNAT3, SNAT1, GLT-1 and EAAC1 by extracellular cGMP would be mediated by inhibition of glycine receptors. These data suggest that, in pathological situations such as hyperammonemia, hepatic encephalopathy or Alzheimer's disease, reduced levels of extracellular cGMP contribute to alterations in membrane expression of glutamine, glutamate and GABA transporters, in the extracellular levels of glutamine, glutamate and GABA and in neurotransmission. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.

Background and AimMinimal hepatic encephalopathy (MHE) predicts poor prognosis and could reflect an advanced liver disease. We aimed to assess whether MHE could be a surrogate marker of a further liver disease. MethodsProspective multicenter study including 320 cirrhotic patients, followed for up to 5years, which were classified at baseline in compensated cirrhosis without (stage 1) and with varices (stage 2), one decompensating event (stage 3), and any second decompensating event (stage 4). Cirrhosis progression was defined by a transition towards a different stage (competing events: liver transplant due to hepatocellular carcinoma and non-liver-related death). MHE was detected by critical flicker frequency and psychometric tests. ResultsMinimal hepatic encephalopathy was diagnosed in 18.2% (57/314) of patients. Cirrhosis progression occurred in 38.1% (122/320) of patients, while liver transplant was required in 10.9% (35/320), and 19.1% (61/320) died. In competing risk regression, MHE was associated with disease progression: model 1 {subhazard ratio [sHR] 2.34 [95%confidence interval (CI) 1.58-3.46]; P=0.0001}; model 2 [sHR 2.18 (95%CI 1.43-3.33); P=0.0001]; model 3 [sHR 2.48 (95%CI 1.63-3.76); P=0.0001]. The annual incidence rate of progression was higher in MHE patients: stage 1 (19.4 vs 5.6cases per 100person-years); stage 2 (26.8 vs 15.6); stage 3 (45.7 vs 16.5); and stage 4 (40.7 vs 12.8). MHE showed a higher cumulative incidence of disease progression from the first year in decompensated and the third year in compensated cirrhosis. ConclusionMinimal hepatic encephalopathy was associated with cirrhosis progression and showed a higher cumulative and annual incidence rate of disease progression. MHE could be a surrogate marker of disease progression, irrespective of cirrhosis status, identifying patients at risk of suffering a more aggressive cirrhosis form.

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) affect 29 million people in the European Union. Patients with ASH and NASH may exhibit cognitive impairment, reducing their quality of life. Steatohepatitis induces cerebral alterations. It is not known if histological analysis could allow distinguishing ASH, NASH, and/or cirrhosis neuropathology and other entities. The aim of this work was to analyze a set of histopathological features characterizing the brain lesions due to ASH, NASH, and cirrhosis. We performed a histological study using hematoxylin and eosin staining and immunohistochemical techniques in cerebellum of 31 subjects who died with healthy liver (n = 6), NASH (n = 14), ASH (n = 3), nonalcoholic cirrhosis (n = 4), and alcoholic cirrhosis (n =4). We analyzed in cerebellum, as an early marker for brain injury: I) vascular damage; 2) cerebellar atrophy and neurodegeneration in Purkinje layer; and 3) microglia and astrocytes activation in white matter and molecular layer. Patients with steatohepatitis have increased number of microtrombi in cerebellar parenchyma, neuronal loss in Purkinje layer and microglial and astrocyte activation in white matter and molecular layer. These alterations are stronger in patients with ASH than in those with NASH. These results provide a set of histopathological features in brain that may allow differentiation of steatohepatitis from other conditions.

Acute kidney injury (AKI) is a common complication after coronary angiography. Early biomarkers of this disease are needed since increase in serum creatinine levels is a late marker. To assess the usefulness of urinary kidney injury molecule-1 (uKIM-1), neutrophil gelatinase-associated lipocalin (uNGAL) and liver-type fatty acid-binding protein (uL-FABP) for early detection of AKI in these patients, comparing their performance with another group of cardiac surgery patients. Biomarkers were measured in 193 patients, 12 h after intervention. In the ROC analysis, AUC for KIM-1, NGAL and L-FABP was 0.713, 0.958 and 0.642, respectively, in the coronary angiography group, and 0.716, 0.916 and 0.743 in the cardiac surgery group. Urinary KIM-1 12 h after intervention is predictive of AKI in adult patients undergoing coronary angiography, but NGAL shows higher sensitivity and specificity. L-FABP provides inferior discrimination for AKI than KIM-1 or NGAL in contrast to its performance after cardiac surgery. This is the first study showing the predictive capacity of KIM-1 for AKI after coronary angiography. Further studies are still needed to answer relevant questions about the clinical utility of biomarkers for AKI in different clinical settings.

Introduction and objectives: Acute kidney injury (AKI) is a common complication after cardiac surgery and percutaneous coronary interventions that markedly worsens prognosis. In the last years new early biomarkers for AKI have been identified, but many important aspects still remain to be solved. Klotho is a pleiotropic protein that acts as a paracrine and endocrine hormonal factor in multiple organs. Renal Klotho deficiency has been shown in several AKI animal models. No study has been published in which Klotho was tested in humans as an early biomarker of AKI. The aim of this study was to assess the usefulness of urinary determination of Klotho for the early detection of AKI in patients with acute coronary syndrome or heart failure undergoing cardiac surgery or coronary angiography. Methods: Urinary Klotho was measured 12 hours after intervention in 60 patients admitted to the Intensive Care Unit with acute coronary syndrome or heart failure due to coronary or valvular pathologies, who underwent coronary angiography (30 patients), or cardiac bypass surgery or heart valve replacement (30 patients). The endpoint used for evaluating our patients was the appearance of AKI, in keeping with the RIFLE classification system. Human Klotho levels were measured using an ELISA assay. Results: We found no differences in urinary Klotho levels between patients with AKI and those who did not develop AKI. Moreover, there was no significant correlation between urinary Klotho levels and AKI development. Conclusions: Urinary Klotho measured by ELISA does not seem to be a good candidate to be used as an early biomarker of AKI. (C) 2015 Sociedad Espanola de Nefrologia. Published by ELSEVIER ESPANA, SLU. Published under the terms of the CC BY-NC-ND Licence(http://creativecommons.org/licenses/by-nc-nd/4.0).

Acute kidney injury (AKI) is a common complication after cardiac surgery and percutaneous coronary interventions which markedly worsens prognosis. In recent years, new early biomarkers of AKI have been identified, but many important aspects still remain to be solved. Klotho is a pleiotropic protein that acts as a paracrine and endocrine factor in multiple organs. Reduced renal Klotho levels have been show in several animal models of AKI. No study has been published in which Klotho was tested in humans as an early marker of AKI. The aim of this work is to assess the usefulness of measuring urinary Klotho for the early diagnosis of AKI in patients with acute coronary syndrome or heart failure undergoing cardiac surgery or coronary angiography.

BACKGROUND & AIMS: Minimal hepatic encephalopathy (MHE) is associated with falls, traffic accidents, and overt HE. However, the association with survival is controversial. We assessed the effects of MHE on the long-term survival of patients with cirrhosis. METHODS: We performed a prospective study of 117 consecutive patients with cirrhosis seen at a tertiary hospital in Seville, Spain (estimation cohort), followed by a validation study of 114 consecutive patients with cirrhosis seen at 4 hospitals in Spain from January 2004 through December 2007. Patients were examined every 6 months at outpatient clinics through December 2013 (follow-up periods of 5 +/- 2.8 y and 4.4 +/- 3.9 y for each group, respectively). Cirrhosis was identified by liver biopsy, ultrasound, endoscopic analysis, and biochemical parameters. Liver dysfunction was determined based on model for end-stage liver disease (MELD) and ChildPugh scores. All patients were administered the critical flicker frequency (CFF) test and psychometric hepatic encephalopathy scores were used to detect MHE. Survival curves were compared using the log-rank test and multivariable analysis was performed using Cox proportional hazards models. RESULTS: The distributions of Child-Pugh scores were as follows: 66% class A, 31% class B, and 3% class C in the estimation cohort, and 50% class A, 32% class B, and 18% class C in the validation cohort. In the estimation cohort, 24 of 35 patients (68.6%) with a CFF score less than 39 Hz survived for 5 years, whereas 50 of 61 patients (82%) with a CFF score of 39 Hz or higher survived during the follow-up period (log-rank score, 5.07; P = .024). Psychometric hepatic encephalopathy scores did not correlate with survival. In multivariable analysis, older age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.02-1.12; P = .009), CFF score less than 39 Hz (HR, 4.36; 95% CI, 1.67-11.37; P = .003), and MELD score (HR, 1.40; 95% CI, 1.21-1.63; P = .0001) were associated independently with survival during the follow-up period. In the validation cohort, CFF score less than 39 Hz and MELD score also were associated with patient survival during the follow-up period. MHE had no effect on the survival of patients with MELD scores less than 10 (among patients with CFF scores >= 39 Hz, 94.5% survived for 5 years vs 91.9% of patients with CFF scores < 39 Hz; log-rank score, 0.64; P = .423). Fewer patients with MELD scores of 10-15 and MHE survived for 5 years (44.4%; 12 of 27) than those with MELD scores greater than 15 without MHE (61.5%; 8 of 13) (P < .05). Only 2 of 12 patients (16.7%) with MELD scores of 15 or higher and MHE survived for 5 years (log-rank score, 90.56; P = .0001). CONCLUSIONS: MHE is associated with a reduced 5-year survival rate of patients with cirrhosis. Evaluation of MHE could help predict survival times and outcomes of patients with specific MELD scores. The CFF could help physicians determine prognoses of patients with cirrhosis.

Antecedentes: El fracaso renal agudo (FRA) es una complicación frecuente tras la cirugía cardíaca y la angiografía coronaria que ensombrece el pronóstico de estos pacientes. El diagnóstico se basa en el ascenso de la creatinina sérica, que es tardío. Es necesaria la identificación y validación de nuevos biomarcadores precoces que permitan intervenciones más tempranas y eficaces. Objetivos: Evaluar la sensibilidad y especificidad de interleuquina-18 (IL-18) en orina, neutrophil gelatinase-associated lipocalin en orina (uNGAL) y cistatina C en suero para la detección precoz del FRA en una población de pacientes con síndrome coronario agudo o fallo cardíaco y sometidos a cirugía cardíaca o cateterismo. Métodos: Se incluyeron en el estudio 135 pacientes ingresados en una unidad de cuidados intensivos por síndrome coronario agudo o fallo cardíaco por patología coronaria o valvular y a los que se realizaron una angiografía cardíaca o una cirugía cardíaca de revascularización o recambio valvular. Se determinaron los biomarcadores a las 12 horas de la intervención y se monitorizó la creatinina sérica durante los siguientes seis días para el diagnóstico del FRA. Resultados: Para NGAL se obtuvo un área bajo la curva ROC (AUC) de 0,983 y para cistatina C e IL-18 de 0,869 y 0,727, respectivamente. Para un punto de corte de NGAL en orina de 31,9 ng/ml la sensibilidad fue del 100% y la especificidad del 91%. Conclusiones: uNGAL es un marcador precoz de FRA en pacientes con síndrome coronario o fallo cardíaco agudo y sometidos a cirugía cardíaca y angiografía cardíaca, con una capacidad predictiva superior a cistatina o a IL-18. Background: Acute kidney injury (AKI) is a common complication in cardiac surgery and coronary angiography, which worsens patients' prognosis. The diagnosis is based on the increase in serum creatinine, which is delayed. It is necessary to identify and validate new biomarkers that allow for early and effective interventions. Aims: To assess the sensitivity and specificity of neutrophil gelatinase-associated lipocalin in urine (uNGAL), interleukin-18 (IL-18) in urine and cystatin C in serum for the early detection of AKI in patients with acute coronary syndrome or heart failure, and who underwent cardiac surgery or catheterization. Methods: The study included 135 patients admitted to the intensive care unit for acute coronary syndrome or heart failure due to coronary or valvular pathology and who underwent coronary angiography or cardiac bypass surgery or valvular replacement. The biomarkers were determined 12 hours after surgery and serum creatinine was monitored during the next six days for the diagnosis of AKI. Results: The area under the ROC curve (AUC) for NGAL was 0.983, and for cystatin C and IL-18 the AUCs were 0.869 and 0.727, respectively. At a cut-off of 31.9ng/ml for uNGAL the sensitivity was 100% and the specificity was 91%. Conclusions: uNGAL is an early marker of AKI in patients with acute coronary syndrome or heart failure and undergoing cardiac surgery and coronary angiography, with a higher predictive value than cystatin C or IL-18.

Antecedentes: El fracaso renal agudo (FRA) es una complicación frecuente tras la cirugía cardíaca y la angiografía coronaria que ensombrece el pronóstico de estos pacientes. El diagnóstico se basa en el ascenso de la creatinina sérica, que es tardío. Es necesaria la identificación y validación de nuevos biomarcadores precoces que permitan intervenciones más tempranas y eficaces. Objetivos: Evaluar la sensibilidad y especificidad de interleuquina-18 (IL-18) en orina, neutrophil gelatinase-associated lipocalin en orina (uNGAL) y cistatina C en suero para la detección precoz del FRA en una población de pacientes con síndrome coronario agudo o fallo cardíaco y sometidos a cirugía cardíaca o cateterismo. Métodos: Se incluyeron en el estudio 135 pacientes ingresados en una unidad de cuidados intensivos por síndrome coronario agudo o fallo cardíaco por patología coronaria o valvular y a los que se realizaron una angiografía cardíaca o una cirugía cardíaca de revascularización o recambio valvular. Se determinaron los biomarcadores a las 12 horas de la intervención y se monitorizó la creatinina sérica durante los siguientes seis días para el diagnóstico del FRA. Resultados: Para NGAL se obtuvo un área bajo la curva ROC (AUC) de 0,983 y para cistatina C e IL-18 de 0,869 y 0,727, respectivamente. Para un punto de corte de NGAL en orina de 31,9 ng/ml la sensibilidad fue del 100% y la especificidad del 91%. Conclusiones: uNGAL es un marcador precoz de FRA en pacientes con síndrome coronario o fallo cardíaco agudo y sometidos a cirugía cardíaca y angiografía cardíaca, con una capacidad predictiva superior a cistatina o a IL-18.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants present in human blood and milk. Exposure to PCBs during pregnancy and lactation leads to cognitive impairment in children. Perinatal exposure to PCB 153 or PCB 126 impairs the glutamate-nitric oxide-cGMP pathway in cerebellum in vivo and learning ability in adult rats. The aims of this work were: (1) to assess whether long-term exposure of primary cultures of cerebellar neurons to PCB 153 or PCB 126 reproduces the impairment in the function of the glutamate-nitric oxide-cGMP pathway found in rat cerebellum in vivo; (2) to provide some insight on the steps of the pathway affected by these PCBs; (3) to assess whether the mechanisms of interference of the pathway are different for PCB 126 and PCB 153. Both PCB 153 and PCB 126 increase basal levels of cGMP by different mechanisms. PCB 126 increases the amount of soluble guanylate cyclase while PCB 153 does not. PCB 153 reduces the amount of calmodulin while PCB 126 does not. Also both PCBs impair the function of the glutamate-nitric oxide-cGMP pathway by different mechanisms, PCB 153 impairs nitric oxide-induced activation of soluble guanylate cyclase and increase in cGMP while PCB 126 does not. PCB 126 reduces NMDA-induced increase in calcium while PCB 153 does not. When PCB 153 and PCB 126 exhibit the same effect, PCB 126 was more potent than PCB 153, as occurs in vivo.