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Renata de Melo Felipe da Silva,1 Andre Russowsky Brunoni,2 Eurípedes Constantino Miguel,1 Roseli Gedanke Shavitt3 1Department and Institute of Psychiatry, Obsessive-Compulsive Spectrum Disorders Program and Service of Interdisciplinary Neuromodulation (SIN), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil; 2Department and Institute of Psychiatry, Department of Internal Medicine, Laboratory of Neurosciences (LIM-27), Service of Interdisciplinary Neuromodulation (SIN), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil; 3Department and Institute of Psychiatry and Director of the Obsessive-Compulsive Spectrum Disorders Program, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BrazilCorrespondence: Roseli Gedanke ShavittInstituto de Psiquiatria – HC-FMUSP, R. Dr Ovidio Pires de Campos 785 3o Andar Ala Norte, São Paulo, SP CEP 05403-000, BrazilEmail roseligshavitt@gmail.comAbstract: Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that has been increasingly examined as an alternative treatment modality for Obsessive-Compulsive Disorder (OCD), due to its low costs, ease of use, and portability. Previous studies have suggested that tDCS may achieve a reasonably good response and present a safe tolerability profile. However, at this point there is not strong evidence for the use of this modality of treatment. Considering that OCD is very heterogeneous with regard to clinical presentation, clinical severity and comorbidities, we have conducted a systematic review of studies on tDCS for OCD aiming to evaluate the clinical characteristics of the selected patients and to discuss perspectives for future studies. A literature search was conducted from inception until March 2019 at PubMed/MedLine and Scielo using the following keywords: “tdcs” or “transcranial direct current stimulation” and “obsessive compulsive disorder”. Out of 45 manuscripts, twelve were included. Most of the included studies are uncontrolled. A few controlled studies reported improvement of OCD, but some limitations need to be considered. Our main findings were that the selected patients were adults with severe OCD and psychiatric comorbidities, medicated at the time of assessment and resistant to at least one previous conventional treatment. We could not find any studies including specific populations such as adolescents, elderly, pregnant and breastfeeding participants. Similarly, the potential use of tDCS has not been tested in patients with less severe OCD, as a first treatment option, or for those who do not tolerate pharmacological treatments. These opportunities should be explored in future controlled trials.Keywords: obsessive-compulsive disorder, transcranial direct current stimulation, neuromodulation

Abstract During bone regeneration, the periosteum acts as a carrier for key regenerative cues, delivering osteochondroprogenitor cells and crucial growth factors to the injured bone. We developed a biocompatible, 3D polycaprolactone (PCL) melt electro-written membrane to act as a mimetic periosteum. Poly (ethyl acrylate) coating of the PCL membrane allowed functionalization, mediated by fibronectin and low dose recombinant human BMP-2 (rhBMP-2) (10-25 μg/ml), resulting in efficient, sustained osteoinduction in vitro. In vivo, rhBMP-2 functionalized mimetic periosteum demonstrated regenerative potential in the treatment of rat critical-size femoral defects with highly efficient healing and functional recovery (80%-93%). Mimetic periosteum has also proven to be efficient for cell delivery, as observed through the migration of transplanted periosteum-derived mesenchymal cells to the bone defect and their survival. Ultimately, mimetic periosteum demonstrated its ability to deliver key stem cells and morphogens to an injured site, exposing a therapeutic and translational potential in vivo when combined with unprecedentedly low rhBMP-2 doses.

Background: Transarterial radioembolization (TARE) is increasingly used in patients with hepatocellular carcinoma (HCC). This treatment can induce or impair portal hypertension, leading to hepatic decompensation. TARE also promotes changes in liver and spleen volumes that may modify therapeutic decisions and outcomes after therapy. Objectives: We aimed to investigate the impact of TARE on the incidence of decompensation events and its predictive factors. Design: In all, 63 consecutive patients treated with TARE between February 2012 and December 2018 were retrospectively included. Methods: We assessed clinical (including Barcelona Clinic Liver Cancer stage, portal hypertension assessment, and liver decompensation), laboratory parameters, and liver and spleen volumes before and 6 and 12 weeks after treatment. A multivariate analysis was performed. Results: In total, 18 out of 63 (28.6%) patients had liver decompensation (ascites, variceal bleeding, jaundice, or encephalopathy) within the first 3 months after therapy, not associated with tumor progression. Clinically significant portal hypertension (CSPH) and bilobar treatment independently predicted the development of liver decompensation after TARE. A significant volume increase in the non-treated hemi-liver was observed only in patients with unilobar treatment (median volume increase of 20.2% in patients with right lobe TARE; p = 0.007), especially in those without CSPH. Spleen volume also increased after TARE (median volume increase of 16.1%; p = 0.0001) and was associated with worsening liver function scores and decreased platelet count. Conclusion: Bilobar TARE and CSPH may be associated with an increased risk of liver decompensation in patients with intermediate or advanced HCC. A careful assessment considering these variables before therapy may optimize candidate selection and improve treatment planning.

Abstract Objective Advances in hepatic radioembolization are based on a selective approach with radical intent and the use of multicompartment dosimetric analysis. The objective of this study is to assess the utility of voxel-based dosimetry in the quantification of actual absorbed doses in radiation segmentectomy procedures and to establish cutoff values predictive of response. Methods Ambispective study in hepatocarcinoma patients treated with radiation segmentectomy. Calculated dosimetric parameters were mean tumor-absorbed dose, maximum tumor AD, minimal tumor AD in 30, 50, and 70% of tumor volume and mean AD in non-tumor liver. The actual absorbed dose (aAD) was calculated on the Y-90-PET/CT image using 3D voxel-based dosimetry software. To assess radiological response, localized mRECIST criteria were used. The objective response rate (ORR) was defined as CR or PR. Results Twenty-four HCC patients, BCLC 0 (5), A (17) and B (2) were included. The mean yttrium-90 administered activity was 1.38 GBq in a mean angiosome volume of 206.9 cc and tumor volume 56.01 cc. The mean theoretical AD was 306.3 Gy and aAD 352 Gy. A very low concordance was observed between both parameters (rho_c 0.027). ORR at 3 and 6 m was 84.21% and 92.31%, respectively. Statistically significant relationship was observed between the maximum tumor-absorbed dose and complete radiological response at 3 m (p 0.022). Conclusion A segmental approach with radical intention leads to response rates greater than 90%, being the tumor maximum absorbed dose the dosimetric parameter that best predicts radiological response in voxel-based dosimetry.

La tuberculosis es uno de los mayores problemas que enfrenta la salud mundial en la actualidad. La única vacuna disponible contra esta enfermedad es la BCG, esta protege solo contra la tuberculosis grave de la infancia, lo cual plantea un reto en la búsqueda de nuevos candidatos vacunales. Teniendo en cuenta el antecedente protector de Mycobacterium ´habana´ contra la tuberculosis experimental, nos propusimos aportar elementos que avalen el empleo de M. ´habana´ TMC 5135 como candidato vacunal contra la tuberculosis, mediante estudios de infección en cultivos celulares de macrófagos murinos. Se caracterizó el proceso de fagocitosis de esta micobacteria por cultivos primarios de macrófagos peritoneales murinos y por la línea celular RAW 264.7, para lo cual se determinó el porcentaje de fagocitosis y el número fagocítico. El presente trabajo demostró que el proceso de fagocitosis de M. ´habana´ TMC 5135 está influenciado por la fuente celular empleada como célula hospedadora, así como por la carga bacteriana infectante y el tiempo de exposición a la misma. La presente investigación contribuye a la caracterización de la infección por esta micobacteria en sus principales células blanco de la inmunidad innata y traza el camino de futuras investigaciones para evaluar la activación de mecanismos efectores de la inmunidad innata frente a este candidato.

Background: Tuberculosis (TB) is one of the biggest problems of global health, at present. Bacillus–Calmette–Guérin is the only vaccine available against this disease. It protects only against the severe forms of TB in the childhood, which is a challenge in the search of new vaccine candidates. Taking into account the protective history of Mycobacterium “habana” against experimental TB, we proposed to provide the elements that support the use of M. “habana” TMC 5135 as a vaccine candidate against TB by infection studies in murine macrophages cell cultures. Methods: The production of microbicidal compounds dependent on oxygen metabolism as nitric oxide and hydrogen peroxide by murine peritoneal macrophages was detected. The invasive and toxigenic capacity of M. “habana” to infect this cell type was also evaluated through the quantification of intracellular alive bacillus and 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay, respectively. Results: The results suggest that M. “habana” TMC 5135 is able to persist into peritoneal macrophages, to resist the effectors mechanisms of respiratory burst, and to keep the viability of the target cell. The demonstration of these effector mechanisms and the survival capacity of M. “habana” in this niche are relevant aspects of this research assuring the continuity of this candidate to next phases of preclinical development. Conclusion: The present investigation contributes to the characterization of the infection by this mycobacteria in its main target cells of innate immunity and it suggest future investigations to evaluate the activation of effector mechanisms of the innate immunity against this candidate.

Background: Since the publication of the DSM-IV in 1994, research on obsessive-compulsive disorder (OCD) has continued to expand. It is timely to reconsider the nosology of this disorder, assessing whether changes to diagnostic criteria as well as subtypes and specifiers may improve diagnostic validity and clinical utility.Methods: The existing criteria were evaluated. Key issues were identified. Electronic databases of PubMed, ScienceDirect, and PsycINFO were searched for relevant studies.Results: This review presents a number of options and preliminary recommendations to be considered for DSM-V. These include: (1) clarifying and simplifying the definition of obsessions and compulsions (criterion A); (2) possibly deleting the requirement that people recognize that their obsessions or compulsions are excessive or unreasonable (criterion B); (3) rethinking the clinical significance criterion (criterion C) and, in the interim, possibly adjusting what is considered "time-consuming" for OCD; (4) listing additional disorders to help with the differential diagnosis (criterion D); (5) rethinking the medical exclusion criterion (criterion E) and clarifying what is meant by a "general medical condition"; (6) revising the specifiers (i.e., clarifying that OCD can involve a range of insight, in addition to "poor insight," and adding "tic-related OCD"); and (7) highlighting in the DSM-V text important clinical features of OCD that are not currently mentioned in the criteria (e.g., the major symptom dimensions).Conclusions: A number of changes to the existing diagnostic criteria for OCD are proposed. These proposed criteria may change as the DSM-V process progresses. [ABSTRACT FROM AUTHOR]

Introducción. La vigilancia de la resistencia a medicamentos antituberculosos permite alertar sobre el hallazgo de aislamientos de Mycobacterium tuberculosis multirresistentes y extremadamente resistentes. Objetivo. Determinar los patrones de resistencia de los aislamientos de M. tuberculosis recuperados en Cuba entre los años 2010 y 2011 y demostrar el desempeño del Laboratorio Nacional de Referencia en la ejecución de las pruebas de sensibilidad. Materiales y métodos. Se realizó un estudio prospectivo longitudinal en el que se incluyeron 657 aislamientos de M. tuberculosis recibidos de todo el país. Se empleó el método de la nitrato reductasa para detectar resistencia a isoniacida y rifampicina, y el método de las proporciones para corroborar la resistencia a dichos medicamentos e investigar la sensibilidad a estreptomicina, etambutol, ofloxacina, kanamicina y capreomicina en aislamientos multirresistentes. Como parte del control de calidad externo de las pruebas de sensibilidad, se evaluaron dos paneles de cepas de M. tuberculosis. Resultados. En 95,69 % de los aislamientos recuperados de casos nuevos de tuberculosis y en 72,64 % de los recuperados de casos previamente tratados, se encontró sensibilidad a isoniacida y rifampicina, siendo la multirresistencia de 1,03 y 10,38 %, respectivamente. Se encontraron dos aislamientos extremadamente resistentes. Con la excepción del etambutol y la capreomicina, para todos los medicamentos la eficiencia fue de 100% en el control de calidad externo. Conclusiones. Se confirmó la baja prevalencia de aislamientos de M. tuberculosis multirresistentes en Cuba, resultado avalado por el excelente desempeño demostrado en el control de calidad externo de las pruebas de sensibilidad.

Este artículo tiene como objetivo fundamental analizar algunas de las contribuciones más importantes de la escuela de Chicago. Nos centramos sobre todo en la teoría cuantitativa del dinero que relaciona la oferta monetaria con el nivel general de precios. El supuesto implícito en esta teoría es que el dinero es neutral y que, por tanto, la política monetaria no tiene efectos a largo plazo sobre el desempleo y la estructura productiva. El artículo pretende demostrar que este supuesto no es cierto y que la inyección monetaria siempre tiene efectos sobre la estructura de la producción, tanto a corto como a largo plazo. Analizaremos los aportes de los teóricos más importantes de la escuela de Chicago (Frank Knight, Milton Friedman, etc) en temas macroeconómicos y veremos las principales diferencias de esta escuela con la escuela austríaca y la Nueva macroeconomía clásica de Robert Lucas. Finalmente se estudiará la interpretación de los economistas de Chicago y de la escuela austríaca sobre la gran depresión de 1929. Palabras Clave: Expansión crediticia, Apriorístico-deductivo, Ideas positivistas

When engaged in a repetitive task our performance fluctuates from trial-to-trial. In particular, inter-trial reaction time variability has been the subject of considerable research. It has been claimed to be a strong biomarker of attention deficits, increases with frontal dysfunction, and predicts age-related cognitive decline. Thus, rather than being just a consequence of noise in the system, it appears to be under the control of a mechanism that breaks down under certain pathological conditions. Although the underlying mechanism is still an open question, consensual hypotheses are emerging regarding the neural correlates of reaction time inter-trial intra-individual variability. Sensory processing, in particular, has been shown to covary with reaction time, yet the spatio-temporal profile of the moment-to-moment variability in sensory processing is still poorly characterized. The goal of this study was to characterize the intra-individual variability in the time course of single-trial visual evoked potentials and its relationship with inter-trial reaction time variability. For this, we chose to take advantage of the high temporal resolution of the electroencephalogram (EEG) acquired while participants were engaged in a 2-choice reaction time task. We studied the link between single trial event-related potentials (ERPs) and reaction time using two different analyses: 1) time point by time point correlation analyses thereby identifying time windows of interest, and 2) correlation analyses between single trial measures of peak latency and amplitude and reaction time. To improve extraction of single trial ERP measures related with activation of the visual cortex, we used an independent component analysis procedure.Our ERP analysis revealed a relationship between the N1 visual evoked potential and reaction time. The earliest time point presenting a significant correlation of its respective amplitude with reaction time occurred 175 ms after stimulus onset, just after the onset of the N1 peak. Interestingly, single trial N1 latency correlated significantly with reaction time, while N1 amplitude did not.In conclusion, our findings suggest that inter-trial variability in the timing of extrastriate visual processing contributes to reaction time variability.

There is limited information available concerning the treatment of daytime somnolence associated with Parkinson’s disease (PD); the most frequently applied therapeutic strategies include decreasing the dose of dopamine agonists or adding potential wake-promoting agents. There is recent data from a placebo-controlled trial concluding on a non-significant trend in favor of caffeine. We aimed to evaluate the efficacy of espresso-coffee in the treatment of daytime somnolence in PD. To evaluate the efficacy of espresso-coffee in the treatment of daytime somnolence in PD, we have conducted multiple single-patient (n-of-1) clinical trials comparing regular espresso coffee to decaffeinated coffee in PD patients presenting moderate to severe daytime somnolence defined as an Epworth Sleepiness Scale (ESS) score >9. Each single-patient (n-of-1) trial included a sequence of three crossovers (two treatment periods separated by two days of washout). Four patients were included in the studies and three completed the three pairs of treatment periods. In two of the four patients, espresso coffee was considered beneficial. This study concludes that multiple single patient trials are feasible in PD and suggests that espresso-coffee may have a beneficial effect on daytime somnolence in some patients. These results cannot be generalized beyond the patients included in these trials.

Chronic brain ischemia is a prominent risk factor for neurological dysfunction and progression for dementias, including Alzheimer’s disease (AD). In rats, permanent bilateral common carotid artery occlusion (2VO) causes a progressive neurodegeneration in the hippocampus, learning deficits and memory loss as it occurs in AD. Kyotorphin (KTP) is an endogenous antinociceptive dipeptide whose role as neuromodulator/neuroprotector has been suggested. Recently, we designed two analgesic KTP-derivatives, KTP-amide (KTP-NH2) and KTP-NH2 linked to ibuprofen (IbKTP-NH2) to improve KTP brain targeting. This study investigated the effects of KTP-derivatives on cognitive/behavioral functions (motor/spatial memory/nociception) and hippocampal pathology of female rats in chronic cerebral hypoperfusion (2VO-rat model). 2VO-animals were treated with KTP-NH2 or IbKTP-NH2 for 7 days at weeks 2 and 5 post-surgery. After behavioral testing (week 6), coronal sections of hippocampus were H&E-stained or immunolabeled for the cellular markers GFAP (astrocytes) and NFL (neurons). Our findings show that KTP-derivatives, mainly IbKTP-NH2, enhanced cognitive impairment of 2VO-animals and prevented neuronal damage in hippocampal CA1 subfield, suggesting their potential usefulness for the treatment of dementia.

Estrogen-receptor-positive (ER+) tumors employ complex signaling that engages in crosstalk with multiple pathways through genomic and non-genomic regulation. A greater understanding of these pathways is important for developing improved biomarkers that can better determine treatment choices, risk of recurrence and cancer progression. Deficiencies in DNA repair capacity (DRC) is a hallmark of breast cancer (BC); therefore, in this work we tested whether ER signaling influences DRC. We analyzed the association between ER positivity (% receptor activation) and DRC in 270 BC patients, then further stratified our analysis by HER2 receptor status. Our results show that among HER2 negative, the likelihood of having low DRC values among ER- women is 1.92 (95% CI: 1.03, 3.57) times the likelihood of having low DRC values among ER+ women, even adjusting for different potential confounders (p

La eficacia protectora de la actual vacuna (BCG) contra la tuberculosis, para contrarrestar las formas pulmonares de esta enfermedad y su reactivación, resulta variable o poco eficiente, lo cual impone la búsqueda urgente de nuevas alternativas profilácticas contra esta enfermedad. Basados en las ventajas inmunogénicas que ofrece el uso de vacunas vivas, se han encaminado diferentes estrategias de este tipo empleando mutantes auxotróficos de Mycobacterium tuberculosis , BCG recombinante o micobacterias no tuberculosas. Existen evidencias experimentales acerca de la protección conferida tras la vacunación con cepas vivas, inactivadas o fracciones proteicas de Mycobacterium'habana' TMC-5135 contra la infección por Mycobacterium tuberculosis. Esta respuesta protectora parece ir aparejada de escasos signos de virulencia en los modelos animales ensayados, lo cual coloca a M.´habana´ dentro de los posibles candidatos vacunales contra la tuberculosis al ajustarse a la condición que impone una vacuna clásica de reproducir la infección y los eventos inmunes que le suceden lo más fielmente posible a como ocurren de manera natural, sin causar extensos daños en el receptor.

El poblado ibérico de Begastri es la base de los 2500 años de Historia de Cehegín. A través de todo tipo de documentos como “los Falsos Cronicones” se ha intentado encontrar, sin éxito, el destino de esta antigua villa romana-visigótica. No fue si no gracias al descubrimiento epigráfico del ARA Begastrense dedicada a Júpiter en el “Cabecico Roenas” o “cabezo de la Muela”, que es descubierto finalmente el lugar exacto de Begastri en 1878 por Don Aureliano. Habría que esperar un siglo para poder presenciar la excavación de numerosas estructuras que nos han permitido establecer una historia más fidedigna: desde su nacimiento como poblado íbero, pasando por su pasado romano, su incipiente cristianización, las invasiones bárbaras que dieron lugar al dominio visigodo y la oficialización de la religión de Cristo (época en la que fue Sede del Obispado de Cartagena) hasta su destrucción por Almanzor y reconversión en poblado musulmán.

En la actualidad, los antígenos lipídicos de las micobacterias constituyen blancos atractivos para el desarrollo de nuevas formulaciones vacunales contra la tuberculosis. En nuestro trabajo se realizó la caracterización parcial de un extracto lipídico de pared celular de Mycobacterium smegmatis mediante cromatografía de capa delgada y Dot blot frente a gammaglobulina humana. Se identificó, fundamentalmente, la presencia de fosfolípidos y ácidos micólicos en el extracto lipídico y se observó un elevado reconocimiento de los mismos por la gammaglobulina humana, lo cual indica la importancia de continuar los estudios de inmunoprotección empleando antígenos lipídicos de micobacterias.

Introduction. Alzheimer’s disease (AD) is a major threat for the well-being of an increasingly aged world population. The physiopathological mechanisms of late-onset AD are multiple, possibly heterogeneous, and not well understood. Different combinations of variables from several domains (i.e., clinical, neuropsychological, structural, and biochemical markers) may predict dementia conversion, according to distinct physiopathological pathways, in different groups of subjects. Methods. We launched the Vallecas Project (VP), a cohort study of non-demented people aged 70 to 85, to characterize the social, clinical, neuropsychological, structural, and biochemical underpinnings of AD inception. Given the exploratory nature of the VP, multidimensional and machine learning techniques will be applied, in addition to the traditional multivariate statistical methods. Results. A total of 1,169 subjects were recruited between October 2011 and December 2013. Mean age was 74.4 years (SD 3.9), 63.5% of the subjects were women, and 17.9% of the subjects were carriers of at least one ε4 allele of the apolipoprotein E (APOE) gene. Cognitive diagnoses at inclusion were as follows: normal cognition 93.0% and mild cognitive impairment (MCI) 7.0% (3.1% amnestic MCI, 0.1% non-amnestic MCI, 3.8% mixed MCI). Blood samples were obtained and stored for future determinations in 99.9% of the subjects and 3T magnetic resonance imaging (MRI) study was conducted in 89.9% of the volunteers. The cohort is being followed up annually for four years after the baseline. Conclusion. We have established a valuable homogeneous single-center cohort which, by identifying groups of variables associated with high risk of MCI or dementia conversion, should help to clarify the early physiopathological mechanisms of AD and should provide avenues for prompt diagnosis and AD prevention.

The International Pseudomonas aeruginosa Consortium is sequencing over 1000 genomes and building an analysis pipeline for the study of Pseudomonas genome evolution, antibiotic resistance and virulence genes. Metadata, including genomic and phenotypic data for each isolate of the collection, are available through the International Pseudomonas Consortium Database (http://ipcd.ibis.ulaval.ca/). Here, we present our strategy and the results that emerged from the analysis of the first 389 genomes. With as yet unmatched resolution, our results confirm that P. aeruginosa strains can be divided into three major groups that are further divided into subgroups, some not previously reported in the literature. We also provide the first snapshot of P. aeruginosa strain diversity with respect to antibiotic resistance. Our approach will allow us to draw potential links between environmental strains and those implicated in human and animal infections, understand how patients become infected and how the infection evolves over time as well as identify prognostic markers for better evidence-based decisions on patient care.

Resistance to powdery mildew has been studied in a number of plant species, yet the molecular mechanisms remain largely unknown. Transcription factors (TFs) play a critical role in the plant defense response by regulating the transcriptional machinery which coordinates the expression of a large group of genes involved in plant defense. Using high-throughput quantitative real-time PCR (qPCR) technology more than 1,000 Medicago truncatula TFs were screened in a pair of susceptible and resistant genotypes of M. truncatula after 4 h of Erysiphe pisi infection. Seventy nine TF genes, belonging to 33 families showed a significant transcriptional change in response to E. pisi infection. Forty eight TF genes were differentially expressed in the resistant genotypes compared to the susceptible one in response to E. pisi infection, including pathogenesis-related transcriptional factors, AP2/EREBP (APETALA2/ETHYLENE-RESPONSIVE ELEMENT BINDING FACTORS), WRKY (highly conserved WRKYGQK amino-acid sequence), MYB (Myeloblastoma), homeodomain (HD) and zinc finger C2C2 (CYS2-CYS2), C2H2, (CYS2-HIS2), LIM (Lin-11, Isl-1, Mec-3) gene families, which are involved in known defense responses. Our results suggest that these TF genes are among the E. pisi responsive genes in resistant M. truncatula that may constitute a regulatory network which controls the transcriptional changes in defense genes involved in resistance to E. pisi.

Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment, from diet to the new nanomaterials as putative risk factors has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ) peptide and the phosphorylation of Tau protein (P-Tau), causing senile/amyloid plaques and neurofibrillary tangles characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies, a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzymes such as neprilysin or insulin degrading enzyme. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action.

Familial Alzheimer's disease (AD), mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1 and PSEN2) involved in the production of the amyloid  peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies (GWAS) there is a mounting list of genetic risk factors associated to common genetic variants that have been associated to sporadic AD. Besides APOE, that presents a strong association with the disease (OR~4), the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated to AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways and networks rather than the contribution of specific genes.

In this work, we used the eel (Anguilla anguilla) as an animal model to test the hypothesis of Barr et al. about the putative role of the epidermal mucosa as a phage enrichment layer. To this end, we analyzed the microbial content of the skin mucus of wild and farmed eels by using a metagenomic approach. We found a great abundance of replicating phages (concatemers) in all the samples. They were assembled in four complete genomes of three Myovirus and one Podovirus. We also found evidences that ΦKZ and Podovirus phages could be part of the resident microbiota associated to the eel mucosal surface and persist on them over the time. Moreover, the viral abundance estimated by epiflorescent counts and by metagenomic recruitment from eel mucosa was higher than that of the surrounding water. Taken together, our results support the hypothesis that claims a possible role of phages in the animal mucus as agents controlling bacterial populations, including pathogenic species, providing a kind of innate immunity.

La vigilancia de la resistencia a fármacos a través del cultivo y de las pruebas de susceptibilidad in vitro permite conocer la magnitud regional y mundial de la resistencia en tuberculosis. En el presente trabajo se determinó la prevalencia de la resistencia a fármacos antituberculosos en Cuba, durante el periodo 1995-1998 en casos nuevos y en aquéllos que han recibido tratamiento previo. Los resultados incluidos en este estudio forman parte de los dos proyectos mundiales organizados por la OMS/UICTER. La resistencia a los medicamentos se evaluó usando el método de las proporciones en 1.379 cepas de Mycobacterium tuberculosis a los fármacos de primera línea (isoniacida, rifampicina, estreptomicina y etambutol). La resistencia en casos nuevos fue del 8,3% y 6,5% y la resistencia múltiple a fármacos (multidrug-resistance, MDR) fue del 0,7% y 0% en el primer y segundo estudio, respectivamente. Estos resultados permitieron demostrar la escasa circulación de cepas MDR en Cuba; se reconoció a nivel mundial el buen funcionamiento del Programa Nacional de Control y el éxito de la aplicación en nuestro país de la estrategia del tratamiento estrictamente supervisado desde 1971.

The direct detection of pyrazinamide resistance in Mycobacterium tuberculosis is not routinely performed in many laboratories in the world because the drug is active only at acid pH, which also affects the growth of M. tuberculosis. The pyrazinamidase enzyme, encoded by pncA gene, is necessary to convert prodrug pyrazinamide to its active form. Taking into account that nicotinamide, a structural analogue of pyrazinamide, converted in its active forms by the pyrazinamidase enzyme at a physiological pH does not affect bacterial growth, the aim of this research was to evaluate two colorimetric methods: Nitrate reductase and malachite green microtube assays, using nicotinamide to perform susceptibility testing in 102 M. tuberculosis strains. The results were compared with those obtained by the classic Wayne assay. Mutations in the pncA gene were identified by sequencing the pncA gene from all isolates in which pyrazinamide resistance was detected by any of the three methods. Both the nitrate reductase and malachite green microtube assays showed sensitivities of 93.75% and specificities of 97.67%. Mutations in the pncA gene were found in 14 of 16 strains (87.5%) that were pyrazinamide resistant.

Disruption of the high-affinity nitrate transporter NRT2.1 activates the priming defence against Pseudomonas syringae, resulting in enhanced resistance. In this study, it is demonstrated that the high-affinity ammonium transporter AMT1.1 is a negative regulator of Arabidopsis defence responses. The T-DNA knockout mutant amt1.1 displays enhanced resistance against Plectosphaerella cucumerina and reduced susceptibility to P. syringae. The impairment of AMT1.1 induces significant metabolic changes in the absence of challenge, suggesting that amt1.1 retains constitutive defence responses. Interestingly, amt1.1 combats pathogens differently depending on the lifestyle of the pathogen. In addition, N starvation enhances the susceptibility of wild type plants and the mutant amt1.1 to P. syringae whereas it has no effect on P. cucumerina resistance. The metabolic changes of amt1.1 against P. syringae are subtler and are restricted to the phenylpropanoid pathway, which correlates with its reduced susceptibility. By contrast, the amt1.1 mutant responds by activating higher levels of camalexin and callose against P. cucumerina. In addition, amt1.1 shows altered levels of aliphatic and indolic glucosinolates and other Trp-related compounds following infection by the necrotroph. These observations indicate that AMT1.1 may play additional roles that affect N uptake and plant immune responses.

La virgen de las Maravilla de Cehegín a dado nombre a multitud de sus devotos. Así pues, nos encontramos que en la villa Cehegín son muchas las personas con nombres y apellidos relacionados con su patrona. Ostentaros estos apellidos, miembros emparentados con la Realeza y Grandeza de España, ministros del Gobierno de la Nación, Diputados, Senadores vitalicios y Embajadores internacionales.

El convento de Cehegín ha tenido una larga historia que será analizada en este artículo. El convento es un edifico centenario y no siempre estuvo dedicado y ocupado para lo que se fundó y edificó. Es por ello, que tras la expulsión de los frailes, fue utilizado para múltiples funciones, siendo alguna de ellas como alojamiento para soldados franceses durante la ocupación o como prisión. También se hace un repaso de como era la vida en las prisión.

Una familia de escultores originarios de Francia esculpió una cruz que se veneró en la iglesia del convento de los franciscanos de Cehegín desde 1802 hasta que en 1936 se perdió durante la Guerra Civil Española. La cruz fue trasladada desde su emplazamiento original hasta un altar donde hoy se venera el Corazón de Jesús. Se conocía como “La Cruz de Jerusalén”.

La historia de Cehegín se inicia con la ciudad romana de Begastri, pasando en manos diferentes asentamientos y civilizaciones, hasta llegas a mano cristiana de los templarios, quienes introdujeron el culto a María Magdalena, cuya iglesia fue edificada a partir del siglo XVI por la Orden de Santiago y se prolongó hasta el siglo XVIII. La iglesia contaba con numerosos elementos ornamentales como un retablo polícromo.

Dihydropyrimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome associated with life-threatening toxicity following exposure to the fluoropyrimidine drugs 5-fluorouracil (5-FU) and capecitabine (CAP), widely used for the treatment of colorectal cancer and other solid tumors. The most prominent loss-of-function allele of the DPYD gene is the splice-site mutation c.1905+1G>A. In this study we report the case of a 73-year old woman with metastatic colorectal cancer who died from drug-induced toxicity after the first cycle of 5-FU-containing chemotherapy. Her symptoms included severe neutropenia, thrombocytopenia, mucositis and diarrhea; and she died 16 days later despite intensive care measures. Post-mortem genetic analysis revealed that the patient was homozygous for the c.1905+1G>A deleterious allele and several family members consented to being screened for this mutation. This is the first report in Spain of a case of 5-FU-induced lethal toxicity associated with a genetic defect that results in the complete loss of the DPD enzyme. Although the frequency of c.1905+1G>A carriers in the white population ranges between 1-2%, the few data available for the Spanish population and the severity of this case prompted us to design a genotyping procedure to prevent future toxic effects of 5-FU/CAP. Since our group had previously developed a high-resolution melting (HRM) assay for the simultaneous detection of KRAS, BRAF and/or EGFR somatic mutations in colorectal and lung cancer patients considered for EGFR-targeted therapies, we included the DPYD c.1905+1G>A mutation in the screening test that we describe herein. HRM provides a rapid, sensitive and inexpensive method that can be easily implemented in diagnostic settings for the routine pre-therapeutic testing of a gene mutation panel with implications in the pharmacologic treatment.

El presente articulo tiene como objetivo el repaso de la historia de una de las imágenes escultóricas más representativas de la localidad ceheginera, la virgen de las Angustias, desde su controvertida fecha de encargo (y autoría) por finales del siglo XVIII a los sucesos acaecidos durante la guerra civil. Asimismo, se realiza un examen artístico de la obra, lo que permitirá conocer más en detalle diferentes procesos de restauración, así como los aspectos formales de la preciada talla.

En los pueblos poblacionalmente menores, como la Cehegín del siglo XX, el convento se convierte en una institución esencial para el desarrollo de la vida pública, sirviendo desde escuela primaria a lugar de auxilio a los necesitados. Así, además de un recorrido por la historia del convento, se nos ofrece la narración de cómo era la vida diaria de la institución, así como una descripción exhaustiva del lugar, incluyendo la Iglesia anexa, lo que hace que al extenso relato histórico se acompañe una exhaustiva descripción artística de los diferentes elementos y espacios. A todo ello hay que sumar la narración de diversos relatos acaecidos en este lugar, especialmente durante la guerra civil.

The development of clinical practice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance with regard to adverse drug reactions. The potential of pharmacogenomic biomarkers has been extensively investigated in recent years. However, several barriers to implementing the use of pharmacogenomics testing exist. We conducted a survey among members of the Spanish Societies of Pharmacology and Clinical Pharmacology to obtain information about the perception of such barriers and to compare the perceptions of participants about the relative importance of major gene/drug pairs.Of 11 potential barriers, the highest importance was attributed to lack of institutional support for pharmacogenomics testing, and to the issues related to the lack of guidelines. Of the proposed gene/drug pairs the highest importance was assigned to HLA-B/abacavir, UGT1A1/irinotecan and CYP2D6/tamoxifen. In this perspective article we compare the relative importance of 29 gene/drug pairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology & Therapeutics study, and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testing.

Mammalian cell membranes regulate homeostasis, protein activity and cell signaling. The charge at the membrane surface has been correlated with these key events.Although mammalian cells are known to be slightly anionic, quantitative information on the membrane charge and the importance of electrostatic interactions in pharmacokinetics and pharmacodynamics remain elusive. Recently, we reported for the first time that brain endothelial cells are more negatively charged than human umbilical cord cells, using zeta-potential dynamic light scattering. Here, we hypothesize that anionicity is a key feature of the blood-brain barrier and contributes to select which compounds cross into the brain. For the sake of comparison, we also studied the membrane surface charge of blood components – red blood cells, platelets and peripheral blood mononuclear cells. To further quantitatively correlate the negative zeta-potential values with membrane charge density, model membranes with different percentages of anionic lipids were also evaluated.From all the cells tested, brain cell membranes are the most anionic and the ones having their lipids mostly exposed, which explains why lipophilic cationic compounds are more prone to cross the blood-brain barrier.

Model checking is a well-established technique for automaticallyverifying complex systems. Recently, model checkers have appearedin computer tools for the analysis of biochemical (and generegulatory) networks. We survey several such tools to assess thepotential of model checking in computational biology. Next, our overviewfocuses on direct applications of existing model checkers, as well ason algorithms for biochemical network analysis influenced by modelchecking, such as those using binary decision diagrams or Booleansatisfiability solvers. We conclude with advantages and drawbacks ofmodel checking for the analysis of biochemical networks.

Previous studies in patients with amygdala lesions suggested that deficits in emotion recognition might be mediated by impaired scanning patterns of faces. Here we investigated whether scanning patterns also contribute to the selective impairment in recognition of disgust in Huntington disease (HD). To achieve this goal, we recorded eye movements during a two-alternative forced choice emotion recognition task. HD patients in presymptomatic (n=16) and symptomatic (n=9) disease stages were tested and their performance was compared to a control group (n=22). In our emotion recognition task, participants had to indicate whether a face reflected one of six basic emotions. In addition, and in order to define whether emotion recognition was altered when the participants were forced to look at a specific component of the face, we used a second task where only limited facial information was provided (eyes/mouth in partially masked faces). Behavioural results showed no differences in the ability to recognize emotions between presymptomatic gene carriers and controls. However, an emotion recognition deficit was found for all 6 basic emotion categories in early stage HD. Analysis of eye movement patterns showed that patient and controls used similar scanning strategies. Patterns of deficits were similar regardless of whether parts of the faces were masked or not, thereby confirming that selective attention to particular face parts is not underlying the deficits. These results suggest that the emotion recognition deficits in symptomatic HD patients cannot be explained by impaired scanning patterns of faces. Furthermore, no selective deficit for recognition of disgust was found in presymptomatic HD patients.