SOC-V-11 New serum miRNA biomarkers to predict liver steatosis by valproic acid in paediatric epileptic patients

Depakine (Valproate, VPA) has been the first line, most-frequently prescribed, anti-epileptic drug in children for the past 50 years. Idiosyncratic hepatotoxicity (iDILI) by VPA has been demonstrated in several case reports, where microvesicular liver steatosis was the most frequent feature. Moreover, more than half of VPA-treated patients could have silent fatty liver as demonstrated by ultrasounds. Extensive experimental studies support that VPA has a high potential to induce steatosis in hepatocytes. However, there is an apparent lack of significant hepatic problems in the Neuropediatric Units, despite transaminitis is not uncommon. One of the reasons could be that iDILI and liver steatosis diagnosis lack specific biomarkers. Thus, it is likely that a relevant number of children under VPA treatment may have a significant, but sub-clinical, hepatosteatosis

Contribution of Efflux Pumps, Porins, and B-Lactamases to Multidrug Resistance in Clinical Isolates of Acinetobacter baumannii

Weinvestigated the mechanisms of resistance to carbapenems, aminoglycosides, glycylcyclines, tetracyclines, and quinolones in 90 multiresistant clinical strains of Acinetobacter baumannii isolated from two genetically unrelated A. baumannii clones: clone PFGEROC- 1 (53 strains producing the OXA-58B-lactamase enzyme and 18 strains with the OXA-24B-lactamase) and clone PFGE-HUI-1 (19 strains susceptible to carbapenems).Weused real-time reverse transcriptase PCR to correlate antimicrobial resistance (MICs) with expression of genes encoding chromosomalB-lactamases (AmpC and OXA-51), porins (OmpA, CarO, Omp33, Dcap-like, OprB, Omp25, OprC, OprD, and OmpW), and proteins integral to six efflux systems (AdeABC, AdeIJK, AdeFGH, CraA, AbeM, and AmvA). Overexpression of the AdeABC system (level of expression relative to that by A. baumannii ATCC 17978, 30- to 45-fold) was significantly associated with resistance to tigecycline, minocycline, and gentamicin and other biological functions. However, hyperexpression of the AdeIJK efflux pump (level of expression relative to that by A. baumannii ATCC 17978, 8- to 10-fold) was significantly associated only with resistance to tigecycline and minocycline (to which the TetB efflux system also contributed). TetB and TetA(39) efflux pumps were detected in clinical strains and were associated with resistance to tetracyclines and doxycycline. The absence of the AdeABC system and the lack of expression of other mechanisms suggest that tigecycline-resistant strains of the PFGE-HUI-1 clone may be associated with a novel resistance-nodulation-cell efflux pump (decreased MICs in the presence of the inhibitor Phe-ArgB-naphthylamide dihydrochloride) and the TetA(39) system

Epidemiologic and clinical impact of acinetobacter baumannii colonization and infection: A reappraisal

Abstract: Acinetobacter baumannii is one of the most important antibiotic-resistant nosocomial bacteria. We investigated changes in the clinical and molecular epidemiology of A. baumannii over a 10-year period. We compared the data from 2 prospective multicenter cohort studies in Spain, one performed in 2000 (183 patients) and one in 2010 (246 patients), which included consecutive patients infected or colonized by A. baumannii. Molecular typing was performed by repetitive extragenic palindromic polymerase chain reaction (REP-PCR), pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST). The incidence density of A. baumannii colonization or infection increased significantly from 0.14 in 2000 to 0.52 in 2010 in medical services (p<0.001). The number of non-nosocomial health careassociated cases increased from 1.2% to 14.2%, respectively (p<0.001). Previous exposure to carbapenems increased in 2010(16.9% in 2000 vs 27.3% in 2010, p¼0.03). The drugs most frequently used for definitive treatment of patients with infections were carbapenems in 2000 (45%) and colistin in 2010 (50.3%). There was molecular-typing evidence of an increase in the frequency of A. baumannii acquisition in non-intensive care unit wards in 2010 (7.6% in 2000 vs 19.2% in 2010, p¼0.01). By MSLT, the ST2 clonal group predominated and increased in 2010. This epidemic clonal group was more frequently resistant to imipenem and was associated with an increased risk of sepsis, although not with severe sepsis or mortality. Some significant changes were noted in the epidemiology of A. baumannii, which is increasingly affecting patients admitted to conventional wards and is also the cause of non-nosocomial health care-associated infections. Epidemic clones seem to combine antimicrobial resistance and the ability to spread, while maintaining their clinical virulence.ACKNOWLEDGMENTS: The authors thank the Platform for Genotyping of Pathogens and Public Health (Institut Pasteur, Paris, France) for coding MLST alleles and profiles as available at www. pasteur.fr/mlst. The authors are grateful for the support of the Spanish Group for Nosocomial Infections (GEIH) and the Spanish Group for Antimicrobial Mechanisms of Action and Resistance (GEMARA) from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) for their support in the development of the project

Genomic Evolution of Two Acinetobacter baumannii Clinical Strains from ST-2 Clones Isolated in 2000 and 2010 (ST-2_clon_2000 and ST-2_clon_2010)

Acinetobacter baumannii is a successful nosocomial pathogen due to its ability to persist in hospital environments by acquiring mobile elements such as transposons, plasmids, and phages. In this study, we compared two genomes of A. baumannii clinical strains isolated in 2000 (ST-2_clon_2000) and 2010 (ST-2_clon_2010) from GenBank project PRJNA308422

Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T&gt;C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity

Combined Use of the Ab105-2φΔCI Lytic Mutant Phage and Different Antibiotics in Clinical Isolates of Multi-Resistant Acinetobacter baumannii

Phage therapy is an abandoned antimicrobial therapy that has been resumed in recent years. In this study, we mutated a lysogenic phage from Acinetobacter baumannii into a lytic phage (Ab105-2phi∆CI) that displayed antimicrobial activity against A. baumannii clinical strain Ab177_GEIH-2000 (isolated in the GEIH-REIPI Spanish Multicenter A. baumannii Study II 2000/2010, Umbrella Genbank Bioproject PRJNA422585, and for which meropenem and imipenem MICs of respectively, 32 μg/mL, and 16 μg/mL were obtained). We observed an in vitro synergistic antimicrobial effect (reduction of 4 log–7 log CFU/mL) between meropenem and the lytic phage in all combinations analyzed (Ab105-2phi∆CI mutant at 0.1, 1 and 10 MOI and meropenem at 1/4 and 1/8 MIC). Moreover, bacterial growth was reduced by 8 log CFU/mL for the combination of imipenem at 1/4 MIC plus lytic phage (Ab105-2phi∆CI mutant) and by 4 log CFU/mL for the combination of imipenem at 1/8 MIC plus lytic phage (Ab105-2phi∆CI mutant) at both MOI 1 and 10. These results were confirmed in an in vivo model (G. mellonella), and the combination of imipenem and mutant Ab105-2phi∆CI was most effective (p < 0.05). This approach could help to reduce the emergence of phage resistant bacteria and restore sensitivity to antibiotics used to combat multi-resistant strains of Acinetobacter baumannii

El registro sedimentario del lago Sant Maurici (Pirineos Centrales)

[spa] El Lago de St. Maurici (1.004818 E, 42.580801 N, 1924 m s.n.m) se localiza en la zona oriental del 'Parc Nacional d'Aigüestortes i Estany de Sant Maurici', Pirineos Centrales, Catalunya. El lago ocupa una cuenca de sobre- excavación detrás de una morrena terminal. El objetivo de este trabajo es reconstruir la evolución de los ambientes de depósito y su relación con la variabilidad climática desde la deglaciación hasta la actualidad, basándose en un sondeo de 8,7 m de longitud de la zona profunda del lago y un modelo de edad preliminar con tres dataciones AMS 14C. Tras la retirada del glaciar, se sedimentó una secuencia de arenas carbonatadas muy finas y limos arcillosos sin materia orgánica, propios de un lago proglacial. El Holoceno temprano se caracteriza por facies de arenas finas masivas que pasan a facies de limos arenosos laminados con un aumento progresivo del contenido en materia orgánica y con algunas capas de arenas. La secuencia presenta un hiato sedimentario durante el Holoceno medio. Desde el re-inicio de la sedimentación en el Holoceno tardío (ca. 4 ka) se han depositado facies organógenas.[eng] The St. Maurici Lake (1.004818 E, 42.580801 N, 1924 m a.s.l.) is located in the eastern area of 'Parc Nacional d'Aigüestortes i Estany de Sant Maurici', Central Pyrenees, Catalonia. The lake occupies an overexcavated basin behind a terminal moraine. This paper aims to reconstruct the evolution of depositional environments and their relation to climate evolution since deglaciation to the present, based on a 8.7-m long sequence retrieved in the deepest part of the lake and a preliminary chronological model with three 14C AMS dates. After the glacial retreat carbonatic very fine sands and silts without organic matter were deposited in a proglacial environment. Early Holocene sediments are massive fine sands to laminated sandy silts with increasing organic content and some sand layers. A sedimentary hiatus occurred during the mid Holocene and the sedimentation re-started after ca. 4 ka with deposition of organic facies. Changes in clastic content reflect centennial scale run-off variability during the last millennia

SOLTI-1805 TOT-HER3 Study Concept: A Window-of-Opportunity Trial of Patritumab Deruxtecan, a HER3 Directed Antibody Drug Conjugate, in Patients With Early Breast Cancer

Background: Preclinical data support a key role for the human epidermal growth factor receptor 3 (HER3) pathway in hormone receptor (HR)-positive breast cancer. Recently, new HER3 directed antibody drug conjugates have shown activity in breast cancer. Given the need to better understand the molecular biology, tumor microenvironment, and mechanisms of drug resistance in breast cancer, we designed this window-of-opportunity study with the HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402). Trial Design: Based on these data, a prospective, multicenter, single-arm, window-of-opportunity study was designed to evaluate the biological effect of patritumab deruxtecan in the treatment of naïve patients with HR-positive/HER2-negative early breast cancer whose primary tumors are ≥1 cm by ultrasound evaluation. Patients will be enrolled in four cohorts according to the mRNA-based ERBB3 expression by central assessment. The primary endpoint is a CelTIL score after one single dose. A translational research plan is also included to provide biological information and to evaluate secondary and exploratory objectives of the study

Effect of fluid emissions in the acoustic response on the seabed of the Gulf of Cádiz

Advances in remotely-sensed techniques have revolutionized mapping methods and our understanding of the seabed environment. In particular, multibeam backscatter data nowadays allows developing quantitative studies on the composition of the seafloor, which represents an important baseline for habitat mapping. Usually, the acoustic response is considered as a direct proxy of sediment texture, but seepage could affect significantly this relationship. A multibeam data set from the Gulf of Cádiz, was grouped using an ISO-cluster analysis and results were compared with 80 ground-truthing stations taken inside and outside cold seepage areas. Results show significant differences between the acoustic response of sediments with the same texture depending on the presence/absence of fluid emissions. Understanding this relationship is necessary to make image-based backscatter classification that allows the production of sediment and habitat maps in areas with extensive fluid emissions such as the Gulf of Cádiz.Versión del edito

Anuario de estudios celianos 2014-15

La Universidad Camilo José Cela recoge en estos anuarios las investigaciones que se llevan a cabo cada año sobre la obra de quien fue su rector Honorario. Se compromete así, en colaboración con la Fundación que también lleva su nombre, con la herencia literaria y la memoria de CJC, y favorece la divulgación de las conclusiones de los estudios más importantes realizados cada año. El presente número doble (2014-2015) del Anuario de estudios celianos se articula excepcionalmente en dos apartados: ensayos y artículos y los anexos en los que se recogen los textos ganadores del VI y VII Premio de relatos Camilo José Cela para jóvenes. Una revista de vuelo universitario quiere estar también vinculada a la creación literaria que realizan las nuevas generacionesCátedra Camilo José Cela de Estudios Hispánico