Etiologies and outcomes of acute liver failure in a spanish community

Previous retrospective study (1992 to 2000) performed in Spain showed that drug toxicity, viral hepatitis, and indeterminate etiology were the most prevalent causes of acute liver failure (ALF). In the last decade, there is no information about ALF in our country. For these reasons we analyze retrospectively, in a ten-year period (2000 to 2010), the presumed causes, clinical characteristics, course, and outcome of ALF in a Spanish community. Causes of ALF were indeterminate in 4 patients (24%), acute hepatitis B infection in 4 patients (24%), drug or toxic reactions in 4 patients (24%), including one case of acetaminophen overdose, followed by miscellaneous causes. The overall short-term survival (6 weeks after admission) was 65%. Liver transplantation was performed in 11 patients with a survival of 82%. Despite fulfilling criteria, 2 patients were not transplanted because of contraindications; they both died. In summary, acute hepatitis B and indeterminate cause are still being the most frequent causes of ALF in our region, and patients with ALF have an excellent chance of survival after emergency liver transplantation. Acetaminophen overdose still represents a very rare cause of ALF in our community

Nucleolar disruption and cajal body disassembly are nuclear hallmarks of DNA damage-induced neurodegeneration in purkinje cells

The Purkinje cell (PC) degeneration (pcd) phenotype results from mutation in nna1 gene and is associated with the degeneration and death of PCs during the postnatal life. Although the pcd mutation is a model of the ataxic mouse, it shares clinical and pathological characteristics of inherited human spinocerebellar ataxias. PC degeneration in pcd mice provides a useful neuronal system to study nuclear mechanisms involved in DNA damage-dependent neurodegeneration, particularly the contribution of nucleoli and Cajal bodies (CBs). Both nuclear structures are engaged in housekeeping functions for neuronal survival, the biogenesis of ribosomes and the maturation of snRNPs and snoRNPs required for pre-mRNA and pre-rRNA processing, respectively. In this study, we use ultrastructural analysis, in situ transcription assay and molecular markers for DNA damage, nucleoli and CB components to demonstrate that PC degeneration involves the progressive accumulation of nuclear DNA damage associated with disruption of nucleoli and CBs, disassembly of polyribosomes into monoribosomes, ribophagy and shut down of nucleolar and extranucleolar transcription. Microarray analysis reveals that four genes encoding repressors of nucleolar rRNA synthesis (p53, Rb, PTEN and SNF2) are upregulated in the cerebellum of pcd mice. Collectively, these data support that nucleolar and CB alterations are hallmarks of DNA damage-induced neurodegeneration.ACKNOWLEDGMENTS: The authors wish to thank Raquel García-Ceballos and Saray Pereda for technical assistance. This work was supported by the following grants: Dirección General de Investigación (BFU2008- 00175); Instituto de Salud Carlos III (CIBERNED, CB06/05/ 0037), Ministerio de Ciencia y Tecnología (BFU2010-18284), Ministerio de Sanidad, Política Social e Igualdad (Plan Nacional Sobre Drogas), Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV, FMV/UC09-02), Junta de Castilla y León, Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León and Fundación Memoria D. Samuel Solórzano-Barruso, all of them from Spain

Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders

Producción CientíficaWe reported previously that the expression of Wnt-related genes is lower in osteoporotic hip fractures than in 26 osteoarthritis. We aimed to confirm those results by analyzing β-catenin levels and explored potential genetic 27 and epigenetic mechanisms involved. 28 β-Catenin gene expression and nuclear levelswere analyzed by real time PCR and confocal immunofluorescence. 29 Increased nuclear β-catenin was found in osteoblasts isolated from patients with osteoarthritis (99 ± 4 30 units vs. 76 ± 12, p = 0.01, n = 10), without differences in gene transcription, which is consistent with 31 a post-translational down-regulation of β-catenin and decreased Wnt pathway activity. 32 Twenty four single nucleotide polymorphisms (SNPs) of genes showing differential expression between fractures 33 and osteoarthritis (WNT4, WNT10A, WNT16 and SFRP1) were analyzed in DNA isolated from blood of 853 pa- 34 tients. The genotypic frequencies were similar in both groups of patients, with no significant differences. 35 Methylation ofWnt pathway genes was analyzed in bone tissue samples (15 with fractures and 15 with osteo- 36 arthritis) by interrogating a CpG-based methylation array. Six genes showed significant methylation differences 37 between both groups of patients: FZD10, TBL1X, CSNK1E, WNT8A, CSNK1A1L and SFRP4. The DNA demethylating 38 agent 5-deoxycytidine up-regulated 8 genes, including FZD10, in an osteoblast-like cell line, whereas it down- 39 regulated other 16 genes. 40 In conclusion,Wnt activity is reduced in patientswith hip fractures, in comparisonwith thosewith osteoarthritis. 41 It does not appear to be related to differences in the allele frequencies of the Wnt genes studied. On the other 42 hand, methylation differences between both groups could contribute to explain the differences inWnt activit

Is Routine Prophylaxis Against Pneumocystis jirovecii Needed in Liver Transplantation? A Retrospective Single-Centre Experience and Current Prophylaxis Strategies in Spain

In liver transplant (LT) recipients, Pneumocystis jirovecii pneumonia (PJP) is most frequently reported before 1992 when immunosuppressive regimens were more intense. It is uncertain whether universal PJP prophylaxis is still applicable in the contemporary LT setting. We aimed to examine the incidence of PJP in LT recipients followed at our institution where routine prophylaxis has never been practiced and to define the prophylaxis strategies currently employed among LT units in Spain. All LT performed from 1990 to October 2019 were retrospectively reviewed and Spanish LT units were queried via email to specify their current prophylaxis strategy. During the study period, 662 LT procedures were carried out on 610 patients. Five cases of PJP were identified, with only one occurring within the first 6 months. The cumulative incidence and incidence rate were 0.82% and 0.99 cases per 1000 person transplant years. All LT units responded, the majority of which provide prophylaxis (80%). Duration of prophylaxis, however, varied significantly. The low incidence of PJP in our unprophylaxed cohort, with most cases occurring beyond the usual recommended period of prophylaxis, questions a one-size-fits-all approach to PJP prophylaxis. A significant heterogeneity in prophylaxis strategies exists among Spanish LT centres.Funding: This study was supported by the Health Research Institute Marqués de Valdecilla. IDIVAL. Santander. NEXT VAL17/07 grant to José Ignacio Fortea Ormaechea

A collaboratively derived environmental research agenda for Galapagos

Galápagos is one of the most pristine archipelagos in the world and its conservation relies upon research and sensible management. In recent decades both the interest in, and the needs of, the islands have increased, yet the funds and capacity for necessary research have remained limited. It has become, therefore, increasingly important to identify areas of priority research to assist decision-making in Galápagos conservation. This study identified 50 questions considered priorities for future research and management. The exercise involved the collaboration of policy makers, practitioners and researchers from more than 30 different organisations. Initially, 360 people were consulted to generate 781 questions. An established process of preworkshop voting and three rounds to reduce and reword the questions, followed by a two-day workshop, was used to produce the final 50 questions. The most common issues raised by this list of questions were human population growth, climate change and the impact of invasive alien species. These results have already been used by a range of organisations and politicians and are expected to provide the basis for future research on the islands so that its sustainability may be enhanced. </jats:p

Beneficios de las presas en España

La característica esencinl del regimen de los ríos españoles es su gran irregularidad. Irregularidad en el tiempo, con pronunciadas variaciones in­teranuales, que dan lugar a largos períodos de sequía, y también marcadas va­riaciones estaciónales, que producen fuertes estiajes durante los meses de verano. Irregularidad en el espacio, que da lugar a un profundo desequibrio de los re­cursos renovables, con la mitad norte del país con abundantes recursos hídricos, frente a la escasez de gran parte de las cuencas de la vertiente mediterránea. Todo ello significa una falta de recursos de agua adecuadamente regulados, ya que la regulación natural sólo alcanza a unas 9.200 Hm3/año, alrededor de un 9% de los recursos renovables, y por otra parte en numerosas áreas del arco me­diterráneo los recursos naturales son muy inferiores a los 1.000 mJ por habitante y año, que es el nivel que se considera básico para poder cubrir las necesidades de agua. En esta Comunicación se presenta la necesidad que a lo largo de la historia ha tenido el país de construir presas y regular el agua en sus embalses, describiendo do la evolución del número de presas, y su situación actual, que ha hecho posible alcanzar una regulación real de alrededor del 40% de los recursos renovables. La parte troncal de la comunicación se dedica a describir los objetivos de las pre­sas en España, y a presentar una evaluación cuantitativa de los beneficios eco­nómicos que las presas y embalses representan para la economía nacional. Así, se analiza el valor económico del agua regulada por los embalses en el sector agrícola, en el sector industrial, en el sector energético, en los abastecimientos de agua a las poblaciones, en la refrigeración y en otros usos. En total se estima que este valor económico representa unos 4.2 billones de pesetas al año, lo que su­pone alrededor de un 6% del Valor Añadido Bruto Nacional a precio de mercado. Ello significa un valor medio del agua regulada para diferentes usos de unas 90 pts/m3.Postprint (published version

The PML-nuclear inclusion of human supraoptic neurons: A new compartment with SUMO-1- and ubiquitin-proteasome-associated domains

It is well known that the cell nucleus is organized in structural and functional compartments involved in transcription, RNA processing and protein modifications such as conjugation with SUMO-1 and proteolysis. Promyelocytic leukaemia (PML) bodies are dynamic nuclear structures that concentrate PML protein, SUMO-1 and several sumoylated and non-sumoylated protein regulators of nuclear functions. PML bodies and their associated CBP has been involved in neuronal survival. By light and electron microscopy immunocytochemistry and in situ hybridization we reported the presence, in non-pathological conditions, of a large PML-nuclear inclusion (PML-NI) in human supraoptic neurons. This inclusion appears as a single nuclear structure composed of a capsule enriched in PML, SUMO-1 and CBP proteins and a central lattice of filaments immunoreactive for class III β-tubulin, ubiquitinated proteins and proteasomes. Furthermore, the PML-NI concentrates the SUMO-conjugating enzyme E2 (UBC9). The PML-NI may be considered a nuclear factory involved in sumoylation and proteolysis via ubiquitin-proteasome system, two nuclear pathways engaged in the control of the nucleoplasmic concentration of active transcriptional regulators. Interestingly, the structural and molecular organization of the PML-NI is related to the Marinesco bodies, age-associated ubiquitinated intranuclear inclusions, and to the intranuclear rodlets enriched in class III β-tubulin, which are nuclear structures markedly decreased in Alzheimer's disease. © 2005 Elsevier Inc. All rights reserved.This study was supported by “Dirección General de Investigación Científica” from Spain (BFI2002-0454; BFU2005-01030), “Fondo de Investigación Sanitaria” from Spain (Red CIEN C03-C06) and Fundación Marqués de Valdecilla from Santander (API/05/04).Peer Reviewe

Purkinje cell degeneration in pcd mice reveals large scale chromatin reorganization and gene silencing linked to defective DNA repair.

DNA repair protects neurons against spontaneous or disease-associated DNA damage. Dysfunctions of this mechanism underlie a growing list of neurodegenerative disorders. The Purkinje cell (PC) degeneration mutation causes the loss of nna1 expression and is associated with the postnatal degeneration of PCs. This PC degeneration dramatically affects nuclear architecture and provides an excellent model to elucidate the nuclear mechanisms involved in a whole array of neurodegenerative disorders. We used immunocytochemistry for histone variants and components of the DNA damage response, an in situ transcription assay, and in situ hybridization for telomeres to analyze changes in chromatin architecture and function. We demonstrate that the phosphorylation of H2AX, a DNA damage signal, and the trimethylation of the histone H4K20, a repressive mark, in extensive domains of genome are epigenetic hallmarks of chromatin in degenerating PCs. These histone modifications are associated with a large scale reorganization of chromatin, telomere clustering, and heterochromatin-induced gene silencing, all of them key factors in PC degeneration. Furthermore, ataxia telangiectasia mutated and 53BP1, two components of the DNA repair pathway, fail to be concentrated in the damaged chromatin compartments, even though the expression levels of their coding genes were slightly up-regulated. Although the mechanism by which Nna1 loss of function leads to PC neurodegeneration is undefined, the progressive accumulation of DNA damage in chromosome territories irreversibly compromises global gene transcription and seems to trigger PC degeneration and death.This work was supported by Dirección General de Investigación Grant BFU2008-00175, Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas Grant CB06/05/0037 from Instituto de Salud Carlos III, Ministerio de Ciencia y Tecnología Grant BFU2010-18284, Ministerio de Sanidad, Política Social e Igualdad (Plan Nacional Sobre Drogas), Instituto de Formación e Investigación Marqués de Valdecilla Grant FMV/UC09-02, Junta de Castilla y León, and Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León.Peer reviewe

Cajal body number and nucleolar size correlate with the cell body mass in human sensory ganglia neurons

This paper studies the cell size-dependent organization of the nucleolus and Cajal bodies (CBs) in dissociated human dorsal root ganglia (DRG) neurons from autopsy tissue samples of patients without neurological disease. The quantitative analysis of nucleoli with an anti-fibrillarin antibody showed that all neurons have only one nucleolus. However, the nucleolar volume and the number of fibrillar centers per nucleolus significantly increase as a function of cell body size. Immunostaining for coilin demonstrated the presence of numerous CBs in DRG neurons (up to 20 in large size neurons). The number of CBs per neuron correlated positively with the cell body volume. Light and electron microscopy immunocytochemical analysis revealed the concentration of coilin, snRNPs, SMN and fibrillarin in CBs of DRG neurons. CBs were frequently associated with the nucleolus, active chromatin domains and PML bodies, but not with telomeres. Our results support the view that the nucleolar volume and number of both fibrillar centers and CBs depend on the cell body mass, a parameter closely related to transcriptional and synaptic activity in mammalian neurons. Moreover, the unusual large number of CBs could facilitate the transfer of RNA processing components from CBs to nucleolar and nucleoplasmic sites of RNA processing. © 2007 Elsevier Inc. All rights reserved.This study was supported by the “Direccion General de Investigacion Cientifica” (Spain; BFU2005-01030), the “Instituto de Salud Carlos III (Spain; CIBERNED), and “Fundación Marqués de Valdecilla” in Santander (Spain; API05/04).Peer Reviewe