Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

A preliminary account of the Cucurbitariaceae.

Fresh collections, type studies and molecular phylogenetic analyses of a multigene matrix of partial nuSSU-ITS-LSU rDNA, rpb2, tef1 and tub2 sequences were used to evaluate the boundaries of Cucurbitaria in a strict sense and of several related genera of the Cucurbitariaceae. Two species are recognised in Cucurbitaria and 19 in Neocucurbitaria. The monotypic genera Astragalicola, Cucitella, Parafenestella, Protofenestella, and Seltsamia are described as new. Fenestella is here included as its generic type F. fenestrata (= F. princeps), which is lecto- and epitypified. Fenestella mackenzei and F. ostryae are combined in Parafenestella. Asexual morphs of Cucurbitariaceae, where known, are all pyrenochaeta- or phoma-like. Comparison of the phylogenetic analyses of the ITS-LSU and combined matrices demonstrate that at least rpb2 sequences should be added whenever possible to improve phylogenetic resolution of the tree backbone; in addition, the tef1 introns should be added as well to improve delimitation of closely related species.

Self-assembly of bicomponent molecular monolayers: adsorption height changes and their consequences.

Codeposition of two molecular species [copper phtalocyanine (CuPc, donor) and perfluoropentacene (PFP, acceptor)] on noble metal (111) surfaces leads to the self-assembly of an ordered mixed layer with a maximized donor-acceptor contact area. The main driving force behind this arrangement is assumed to be the intermolecular C-H ⋯ F hydrogen-bond interactions. Such interactions would be maximized for a coplanar molecular arrangement. However, precise measurement of molecule-substrate distances in the molecular mixture reveals significantly larger adsorption heights for PFP than for CuPc. Most surprisingly, instead of leveling to increase hydrogen-bond interactions, the height difference is enhanced in the blends as compared to the heights found in single-component CuPc and PFP layers. The increased height of PFP in mixed layers points to an overall reduced interaction with the underlying substrate, and its influence on electronic properties like the interface dipole is investigated through work function measurements.

JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death.

Our aim was to better understand the mechanism and importance of sustained c-Jun N-terminal kinase (JNK) activation in endoplasmic reticulum (ER) stress and effects of ER stress on mitochondria by determining the role of mitochondrial JNK binding protein, Sab. Tunicamycin or brefeldin A induced a rapid and marked decline in basal mitochondrial respiration and reserve-capacity followed by delayed mitochondrial-mediated apoptosis. Knockdown of mitochondrial Sab prevented ER stress-induced sustained JNK activation, impaired respiration, and apoptosis, but did not alter the magnitude or time course of activation of ER stress pathways. P-JNK plus adenosine 5'-triphosphate (ATP) added to isolated liver mitochondria promoted superoxide production, which was amplified by addition of calcium and inhibited by a blocking peptide corresponding to the JNK binding site on Sab (KIM1). This peptide also blocked tunicamycin-induced inhibition of cellular respiration. In conclusion, ER stress triggers an interaction of JNK with mitochondrial Sab, which leads to impaired respiration and increased mitochondrial reactive oxygen species, sustaining JNK activation culminating in apoptosis.

Mitochondrial dysfunction in non-alcoholic fatty liver disease and insulin resistance: cause or consequence?

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome and refers to a spectrum of disorders ranging from steatosis to steatohepatitis, a disease stage characterized by inflammation, fibrosis, cell death and insulin resistance (IR). Due to its association with obesity and IR the impact of NAFLD is growing worldwide. Consistent with the role of mitochondria in fatty acid (FA) metabolism, impaired mitochondrial function is thought to contribute to NAFLD and IR. Indeed, mitochondrial dysfunction and impaired mitochondrial respiratory chain have been described in patients with non-alcoholic steatohepatitis and skeletal muscle of obese patients. However, recent data have provided evidence that pharmacological and genetic models of mitochondrial impairment with reduced electron transport stimulate insulin sensitivity and protect against diet-induced obesity, hepatosteatosis and IR. These beneficial metabolic effects of impaired mitochondrial oxidative phosphorylation may be related not only to the reduction of reactive oxygen species production that regulate insulin signaling but also to decreased mitochondrial FA overload that generate specific metabolites derived from incomplete FA oxidation (FAO) in the TCA cycle. In line with the Randle cycle, reduced mitochondrial FAO rates may alleviate the repression on glucose metabolism in obesity. In addition, the redox paradox in insulin signaling and the delicate mitochondrial antioxidant balance in steatohepatitis add another level of complexity to the role of mitochondria in NAFLD and IR. Thus, better understanding the role of mitochondria in FA metabolism and glucose homeostasis may provide novel strategies for the treatment of NAFLD and IR.

Oxidative stress and altered mitochondrial function in neurodegenerative diseases: lessons from mouse models.

Oxidative stress has been consistently linked to ageing-related neurodegenerative diseases leading to the generation of lipid peroxides, carbonyl proteins and oxidative DNA damage in tissue samples from affected brains. Studies from mouse models that express disease-specific mutant proteins associated to the major neurodegenerative processes have underscored a critical role of mitochondria in the pathogenesis of these diseases. There is strong evidence that mitochondrial dysfunction is an early event in neurodegeneration. Mitochondria are the main cellular source of reactive oxygen species and key regulators of cell death. Moreover, mitochondria are highly dynamic organelles that divide, fuse and move along axons and dendrites to supply cellular energetic demands; therefore, impairment of any of these processes would directly impact on neuronal viability. Most of the disease-specific pathogenic mutant proteins have been shown to target mitochondria, promoting oxidative stress and the mitochondrial apoptotic pathway. In addition, disease-specific mutant proteins may also impair mitochondrial dynamics and recycling of damaged mitochondria via autophagy. Collectively, these data suggest that ROS-mediated defective mitochondria may accumulate during and contribute to disease progression. Strategies aimed to improve mitochondrial function or ROS scavenging may thus be of potential clinical relevance.

Brain mitochondrial alterations after chronic alcohol consumption

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The aim of this study was to demonstrate the existence of alterations in glutathione and cholesterol homeostasis in brain mitochondria from alcoholic rats. Glutathione concentration decreased, whereas oxidized glutathione and cholesterol contents increased in these organelles, suggesting the ethanol-induced generation of reactive oxygen species, and the impairment of mitochondrial uptake of glutathione, possibly due to the increase in cholesterol deposition. The release of apoptogenic proteins was increased after stimulating mitochondria from the brain of alcoholic rats with atractyloside. As a conclusion, chronic alcohol consumption might sensitize brain mitochondria to apoptotic stimuli, and promote the subsequent release of apoptotic proteins (AU)

Nondegenerate metallic States on Bi(114): a one-dimensional topological metal.

The (114) surface of the semimetal Bi is found to support a quasi-one-dimensional, metallic surface state. As required by symmetry, the state is degenerate along the Gamma-Y line of the surface Brillouin zone with a highest binding energy of approximately 150 meV. In the Gamma-X direction the degeneracy is lifted by the strong spin-orbit splitting in Bi, as directly shown by spin-resolved photoemission. This results in a Fermi contour consisting of two closely separated, parallel lines of opposite spin direction. It is argued that similar states on related insulators would give rise to a one-dimensional quantum spin Hall effect.

Brain mitochondrial alterations after chronic alcohol consumption.

The aim of this study was to demonstrate the existence of alterations in glutathione and cholesterol homeostasis in brain mitochondria from alcoholic rats. Glutathione concentration decreased, whereas oxidized glutathione and cholesterol contents increased in these organelles, suggesting the ethanol-induced generation of reactive oxygen species, and the impairment of mitochondrial uptake of glutathione, possibly due to the increase in cholesterol deposition. The release of apoptogenic proteins was increased after stimulating mitochondria from the brain of alcoholic rats with atractyloside. As a conclusion, chronic alcohol consumption might sensitize brain mitochondria to apoptotic stimuli, and promote the subsequent release of apoptotic proteins.

Mitochondrial cholesterol in health and disease.

Cholesterol is a critical component of biological membranes, which not only plays an essential role in determining membrane physical properties, but also in the regulation of multiple signaling pathways. Cells satisfy their need for cholesterol either by uptake from nutrients and lipoproteins or de novo synthesis from acetyl-CoA. The latter process occurs in the endoplasmic reticulum, where transcription factors that regulate the expression of enzymes involved in the de novo cholesterol synthesis reside. Cholesterol is distributed to different membranes most prominently to plasma membrane, where it participates in the physical organization of specific membrane domains. Mitochondria, however, are considered cholesterol-poor organelles, and obtain their cholesterol load by the action of specialized proteins involved in its delivery from extramitochondrial sources and trafficking within mitochondrial membranes. Although mitochondrial cholesterol fulfills vital physiological functions, such as the synthesis of bile acids in the liver or the formation of steroid hormones in specialized tissues, recent evidence indicates that the accumulation of cholesterol in mitochondria may be a key step in disease progression, including steatohepatitis, carcinogenesis or Alzheimer disease.

Structural origin of the Sn 4d core level line shape in Sn/Ge(111)-(3x3).

High-resolution photoemission of the Sn 4d core level of Sn/Ge(111)-(3x3) resolves three main components in the line shape, which are assigned to each of the three Sn atoms that form the unit cell. The line shape found is in agreement with an initial state picture and supports that the two down atoms are inequivalent. In full agreement with these results, scanning tunnel microscopy images directly show that the two down atoms are at slightly different heights in most of the surface, giving rise to an inequivalent-down-atoms (3x3) structure. These results solve a long-standing controversy on the interpretation of the Sn 4d core-level line shape and the structure of Sn/Ge(111)-(3x3).

Some new hysteriaceous Fungi from Costa Rica.

Four new lignicolous species of the family Hysteriaceae (Gloniella gracilis, Graphyllium panduratum, Hysterium asymmetricum and Hysterographium pulchrum) are described from Costa Rica based in their macroscopic and microscopic characters.

Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo.

Ceramidases (CDases) play a key role in cancer therapy through enhanced conversion of ceramide into sphingosine 1-phosphate (S1P), but their involvement in hepatocarcinogenesis is unknown. Here, we report that daunorubicin (DNR) activated acid CDase post-transcriptionally in established human (HepG2 cells) or mouse (Hepa1c1c7) hepatoma cell lines as well as in primary cells from murine liver tumors, but not in cultured mouse hepatocytes. Acid CDase silencing by small interfering RNA (siRNA) or pharmacological inhibition with N-oleoylethanolamine (NOE) enhanced the ceramide to S1P balance compared to DNR alone, sensitizing hepatoma cells (HepG2, Hep-3B, SK-Hep and Hepa1c1c7) to DNR-induced cell death. DNR plus NOE or acid CDase siRNA-induced cell death was preceded by ultrastructural changes in mitochondria, stimulation of reactive oxygen species generation, release of Smac/DIABLO and cytochrome c and caspase-3 activation. In addition, in vivo siRNA treatment targeting acid CDase reduced tumor growth in liver tumor xenografts of HepG2 cells and enhanced DNR therapy. Thus, acid CDase promotes hepatocarcinogenesis and its antagonism may be a promising strategy in the treatment of liver cancer.

Mitochondrial dysfunction in COPD patients with low body mass index.

Patients with chronic obstructive pulmonary disease (COPD) show abnormal adaptations of skeletal muscle redox status after exercise training. Increased skeletal muscle oxidative stress in COPD patients may prompt mitochondrial dysfunction. The present study explores the association between body composition and mitochondrial respiration in seven COPD patients with low body mass index (BMI(L)), eight COPD patients with normal body mass index (BMI(N)) and seven healthy controls. All of them underwent a vastus lateralis biopsy in which muscle structure, in vitro mitochondrial respiratory function, uncoupling protein 3 (UCP3) mRNA expression and glutathione levels in both isolated mitochondria and the whole muscle were determined. Mitochondrial respiratory function (assessed by acceptor control ratio (ACR)) was impaired in BMI(L) (2.2+/-0.6) compared with both BMI(N) (5.3+/-1.3) and controls (8.2+/-1.3). ACR significantly correlated with arterial oxygen tension and with muscle endurance but it showed a negative association with exercise-induced increase in blood lactate levels. UCP3 mRNA expression was reduced in BMI(L) patients. In conclusion, chronic obstructive pulmonary disease patients with low body mass index show electron transport chain dysfunction, which may contribute to low muscle endurance in the current subgroup of patients.

Direct patient treatment costs in the Allergology Service of a University Hospital.

Health resources are limited and consequently real cost generators must be identified to optimize resources. In the present article, we describe the structure of the Allergy Unit of the University Hospital Virgen de la Arrixaca in Murcia (Spain), the health area in which allergic patients are attended, and the final healthcare products generated. Based on the 2004-2005 budget, variable costing was used to calculate the costs of the healthcare products generated (first visits, subsequent visits, and diverse laboratory tests) by two of the three homogeneous functional groups (HFG), i.e., HFG of the ambulatory service and HFG of complementary tests. The following conclusions can be drawn: 1) the current system of variable costing provides information, which should be useful to health professionals; 2) the real cost generators in the microcosm of daily clinical practice should be identified to allow resource reallocation; 3) the costing system used enables modifications to be made that allow decision making on optimal use of the budget; 4) clinical management and complementary tests should go hand in hand with a view to optimizing resources.

Direct patient treatment costs in the Allergology Service of a University Hospital / Costes directos del tratmiento de los pacientres en el servicio de alergología de un hospital universitario

Health resources are limited and consequently real cost generators must be identified to optimize resources. In the present article, we describe the structure of the Allergy Unit of the University Hospital Virgen de la Arrixaca in Murcia (Spain), the health area in which allergic patients are attended, and the final healthcare products generated. Based on the 2004-2005 budget, variable costing was used to calculate the costs of the healthcare products generated (first visits, subsequent visits, and diverse laboratory tests) by two of the three homogeneous functional groups (HFG), i.e., HFG of the ambulatory service and HFG of complementary tests. The following conclusions can be drawn: 1) the current system of variable costing provides information, which should be useful to health professionals; 2) the real cost generators in the microcosm of daily clinical practice should be identified to allow resource reallocation; 3) the costing system used enables modifications to be made that allow decision making on optimal use of the budget; 4) clinical management and complementary tests should go hand in hand with a view to optimizing resources

Los recursos sanitarios son limitados, por lo que es preciso identificar los auténticos generadores del gasto, con el fin de poder optimizar los recursos. En la presente publicación se describe la estructura de la Unidad de Alergología del Hospital Universitario “Virgen de la Arrixaca” de Murcia (España), el área sanitaria en la que son atendidos los pacientes alérgicos, y los productos sanitarios finalistas que genera. Partiendo del presupuesto ejecutado durante los años 2004 y 2005, y utilizando la contabilidad analítica, se calculan los costes de los productos sanitarios generados (primeras visitas, sucesivas y diversas determinaciones analíticas), por dos de los Grupos Funcionales Homogéneos (GFH) de los tres que la componen, a saber, el GFH de Consultas Externas y el GFH de Exploraciones Complementarias. Como conclusiones cabe destacar que el actual sistema de gestión analítica: 1) Proporciona información y ésta debe de tener validez para el clínico. 2) Es necesario identificar verdaderos generadores de gastos en el microcosmos de la clínica diaria que permitan la reasignación de recursos. 3) Hace posible correcciones que permitan tomar decisiones para ejecutar de forma óptima el presupuesto. 4) La gestión clínica y la analítica deben de caminar al unísono, con el fin de poder tomar las medidas necesarias tendentes a optimizar los recursos

Los costes de un paciente ingresado en la Unidad de Hospitalización de Alergología de un hospital universitario / The costs of a patient admitted to the Allergy Hospitalisation Unit in a University Hospital

Los recursos sanitarios son limitados, por lo que es preciso identificar los auténticos generadores del gasto, con el fin de poder optimizar los recursos. En la presente publicación se describe la estructura de la Unidad de Alergología del Hospital Universitario "Virgen de la Arrixaca" de Murcia (España), el área sanitaria en la que son atendidos los pacientes alérgicos, y los productos sanitarios finalistas que genera. Partiendo del presupuesto ejecutado durante el año 2004, y utilizando la contabilidad analítica, se calculan los costes de los productos sanitarios generados en el Grupo Funcional Homogéneo (GFH) de hospitalización de Alergología y la de los GRD comunes con la Unidad de Corta Estancia. En ambos casos se analiza el coste económico de la estancia del mismo grupo de diagnósticos (GRD), diferenciando el lugar donde ingresan. En nuestro trabajo hemos encontrado que el coste económico es muy similar en las dos unidades, 481,77 euros por estancia para la hospitalización tradicional frente a 474,04 euros para la corta estancia. Con independencia del coste, la corta estancia aporta otras ventajas para el paciente que deben ser tenidas en cuenta, como comentaremos en otros apartados de este estudio. Como conclusiones cabe destacar: a) la necesidad de que los clínicos tengan siempre in mente la importancia del diagnóstico principal en el Informe Clínico de alta del paciente; b) que el actual sistema de gestión analítica: 1) Proporciona información y ésta debe de tener validez para el clínico. 2) Es necesario identificar verdaderos generadores de gastos en el microcosmos de la clínica diaria que permitan la reasignación de recursos. 3) Hace posible correcciones que permitan tomar decisiones para ejecutar de forma óptima el presupuesto. 4) La gestión clínica y la analítica deben de caminar al unísono, con el fin de poder tomar las medidas necesarias tendentes a optimizar los recursos

Health care resources are limited, leading to a need to identify the true expense generators so as to be able to optimise resources use. We here describe the structure of the Allergology Unit of the “Virgen de la Arrixaca” University Hospital (Murcia, Spain), the area where the allergic patients are cared for, and the generated health-care end results. Based on the budget for the year 2004 and using analytical accounting, the costs were calculated for the generated health-care products for the Homogeneous Functional Group (HFG) of Allergy Hospitalisation and for the common diagnostic groups (GDR) at the Short Admission Unit. In both cases the economic costs of admission were analysed for the same group of the actual economic costs are quite similar for the two units, 481.77 € per admission for traditional admissions vs. 474.04 € for “short” admissions. Regardless of the actual costs, the Short Admission Unit provides further advantages for the patient that are considered in this paper. Our conclusions are the following: a) clinicians should always keep in mind the importance of stating the main dianosis in the patient’s discharge report. b) The current analytical management system 1) provides information, and this information should be of value for the clinician; 2) there is a need to identify the true cost generators within the microcosmos of everyday clinical practise that will allow reassignation of resources; 3) renders possible corrections that allow decision-making for the optimal execution of the budget, and 4) clinical and analytical management should work hand in hand so as to be able to implement the necessary measures for resource optimisation

Desinfección de superficies en el hospital / Disinfection of surface in the Hospital

Este artículo, revis el uso de desinfectantes para la desinfcción de suelos y otras superficies de amterial no crítico en el hospital. Basados en la bilbografia, hemos evaluado la necesidad de la desinfección de las superficies ambientales hospitalaias. De acuerdo con los conocimientos científicos actuaes y teniendo en cuenta la compleja naturaleza de los factores de riesgo de la infección nosocomial, los smilares porcntajes de nfección cuando se realiza limpieza o desinfección del suelo y la peligrosidad de los desnfectantes para el personal sanitario, concluimos que la desinfeccin es razonable para desinfectar el suelo y conveniente para otras superficies ambientaes (mesitas de noche, cuñas, aparatos de tensión…) (AU)

Review of the use of disifectants on the floor and other surfaces of non-critical material in the hospital (AU)

Infección quirúrgica en cirugía maxilofacial / Cross Infection in maxillofacial surgery

Objetivos. Determinar la incidencia de infección del lecho quirúrgico en un Servicio de Cirugía Maxilofacial que atiende a una población de 818.959 habitantes y analizar los factores de riesgo implicados en la misma. Método. Estudio de cohorte prospectivo (septiembre 1999noviembre 2000). Se incluyeron a todos los pacientes intervenidos quirúrgicamente por patología maxilofacial en este Servicio excepto aquellos ingresados por cuadros de celulitis odontógena y los sometidos a extracciones dentarias. Población total de estudio = 382. Seguimiento hasta treinta días posteriores a la intervención o un año si se requirió osteosíntesis.Diagnóstico de infección según criterios CDC. Análisis estadístico. bivariante, (Chi cuadrado, t-Student y regresión logística simple) y análisis multivariante (regresión logística múltiple). Paquete estadístico SPSS 10.0.Resultados. La incidencia total de infección quirúrgica fue del 9,4 por ciento. En cirugía traumatológica fue del 1.8 por ciento, en no traumatológica del 15,5 por ciento. Dentro de esta última, en procesos benignos, la incidencia de infección fue del 2,9 por ciento y en procesos malignos 20,9 por ciento. En el análisis multivariable resultaron como factores predictores de infección el tiempo de intervención superior a dos horas (OR=7, IC95 por ciento: 3,01-16,25), el grado de contaminación de la herida (OR=7,20, IC95 por ciento:1,25-26,52) y la reintervención quirúrgica (OR=6,29, IC95 por ciento:2,64-14,94). La incidencia de infección aumenta escalonadamente para cada unidad de incremento del índice NISS (Nacional Nosocomial Infection Surveillance) (OR=3,61, IC95 por ciento:2,38-5,60). Conclusiones. La incidencia de infección del sitio quirúrgico en cirugía traumatológica maxilofacial es baja, mientras que en cirugía no traumatológica es similar a la aportada por otros estudios. Los factores que de manera independiente se asocian a la infección son el tiempo de intervención, el grado de contaminación de la herida y la reintervención quirúrgica.La incidencia de infección aumenta a mayor puntuación del índice NISS. (AU)