Regulatory polymorphisms in extracellular matrix protease genes and susceptibility to rheumatoid arthritis: a case-control study

Many extracellular matrix (ECM) proteases seem to be important in rheumatoid arthritis (RA) and regulation of their transcription levels is a critical mechanism for controlling their activity. We have investigated, therefore, whether the best-characterized single nucleotide polymorphisms (SNPs) affecting transcription of the ECM proteases that have been related with joint pathology are associated with RA susceptibility. Nine SNPs in eight genes were selected by bibliographic search, including SNPs in the genes encoding matrix metalloproteinase (MMP)1, MMP2, MMP3, MMP7, MMP9, MMP13, plasminogen activator, tissue type (PLAT) and PAI-1. They were studied in a case-control setting that included 550 RA patients and 652 controls of Spanish ancestry from a single center. Genotyping was performed by single-base extension. Only two of the nine SNPs showed significant association with RA susceptibility. RA patients showed increased frequencies of the -7351 T allele of the gene encoding PLAT (36.4% versus 32.1% in controls, p = 0.026) and the -1306 T allele of the gene encoding MMP2 (24.5% versus 20.3% in controls, p = 0.013). These two alleles seemed to cooperate according to an additive model with respect to increased RA susceptibility (p = 0.004), and they were the low-expression alleles of the respective SNPs in a PLAT enhancer and the MMP2 promoter. These findings are in agreement with previous data suggesting that these two ECM proteases have a protective role in RA pathology. Confirmation of these associations will be needed to support these hypotheses. The remaining SNPs did not show association, either individually or collectively. Therefore, although regulatory SNPs in ECM proteases did not show any major effect on RA susceptibility, it was possible to find modest associations that, if replicated, will have interesting implications in the understanding of RA pathology

Spanish version of the Dundee Ready Education Environment Measure (DREEM) applied to undergraduate physical therapy students in Spain using Google Form

[Intro] The educational climate (EC) is an important factor in determining the effectiveness and success of the curriculum in a school of medical sciences. The Dundee Ready Education Environment Measure (DREEM) questionnaire was used to assess EC in a competency-based curriculum in the physical therapy program analyzing the mean total, subscale, and item scores, as well as response rates. To carry out a psychometric evaluation of the Spanish-language version of the DREEM applied to undergraduate physical therapy students, a total of 671 students enrolled on Degrees in Physiotherapy at 22 faculties across public and private universities in Spainresponded to the DREEM questionnaire using Google Form. (...

Changes in metabolites in the brain of patients with fibromyalgia after treatment with an NMDA receptor antagonist

The aims of this work were to evaluate whether the treatment of patients with fibromyalgia with memantine is associated with significant changes in metabolite concentrations in the brain, and to explore any changes in clinical outcome measures. Magnetic resonance spectroscopy was performed of the right anterior and posterior insula, both hippocampi and the posterior cingulate cortex. Questionnaires on pain, anxiety, depression, global function, quality of life and cognitive impairment were used. Ten patients were studied at baseline and after three months of treatment with memantine. Significant increases were observed in the following areas: N-acetylaspartate (4.47 at baseline vs. 4.71 at three months, p¿=¿0.02) and N-acetylaspartate+N-acetylaspartate glutamate in the left hippocampus (5.89 vs. 5.98; p¿=¿0.007); N-acetylaspartate+N-acetylaspartate glutamate in the right hippocampus (5.31 vs 5.79; p¿=¿0.01) and the anterior insula (7.56 vs. 7.70; p¿=¿0.033); glutamate+glutamine/creatine ratio in the anterior insula (2.03 vs. 2.17; p¿=¿0.022) and the posterior insula (1.77 vs. 2.00; p¿=¿0.004); choline/creatine ratio in the posterior cingulate (0.18 vs. 0.19; p¿=¿0.023); and creatine in the right hippocampus (3.60 vs. 3.85; p¿=¿0.007). At the three-month follow-up, memantine improved cognitive function assessed by the Cognition Mini-Exam (31.50, SD¿=¿2.95 vs. 34.40, SD¿=¿0.6; p¿=¿0.005), depression measured by the Hamilton Depression Scale (7.70, SD¿=¿0.81 vs. 7.56, SD¿=¿0.68; p¿=¿0.042) and severity of illness measured by the Clinical Global Impression severity scale (5.79, SD¿=¿0.96 vs. 5.31, SD¿=¿1.12; p¿=¿0.007). Depression, clinical global impression and cognitive function showed improvement with memantine. Magnetic resonance spectroscopy could be useful in monitoring response to the pharmacological treatment of fibromyalgia

Survey of molecular methods for the typing of wine yeast strains

A survey of the genetic polymorphisms produced by distinct methods was performed in 23 commercial winery yeast strains. The microsatellite typing, using 6 different loci, an optimized interdelta sequence analysis and RFLP of mitochondrial DNA generated by the enzyme Hinf I had the same discriminatory power: among the 23 commercial yeast strains, 21 distinct patterns were obtained. Karyotype analysis originated 22 patterns, thereby allowing the discrimination of one of the three strains that were not distinguished by the other methods. Due to the equivalence of the results obtained in this survey, any of the methods can be applied at the industrial scale.Fundação para a Ciência e a Tecnologia (FCT) - POCTI/BIO/38106/2001 (Eixo 2, Medida 2.3, QCAIII - FEDER).Instituto de Cooperação Científica e Tecnológica Internacional (ICCTI) - grant nº 657 C2.Comunidade Europeia (UE) - contract number QLK4-CT-2001-51873

A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

The major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anticitrullinated protein antibodies (ACPA) and RA development. Nevertheless, some research findings do not fit this model. Therefore, we obtained six independent cohorts with 2253 RA patients for a detailed analysis of the association between smoking and RA autoantibodies. Our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs. 0 Ab: OR = 1.99, p = 2.5 × 10?8). Meta-analysis with previous data (4491 patients) confirmed the predominant association with the concurrent presence of the three antibodies (3 Ab vs. 0 Ab: OR = 2.00, p = 4.4 ×10?16) and revealed that smoking was exclusively associated with the presence of RF in patients with one or two antibodies (RF+ 1+2 vs. RF? 0+1+2: OR = 1.32, p = 0.0002). In contrast, no specific association with ACPA or ACarPA was found. Therefore, these results showed the need to understand how smoking favors the concordance of RA specific antibodies and RF triggering, perhaps involving smoking-induced epitope spreading and other hypothesized mechanisms

Risk of breast cancer and residential proximity to industrial installations: New findings from a multicase-control study (MCC-Spain)

Breast cancer is the most frequent tumor in women worldwide, although well-established risk factors account for 53%-55% of cases. Therefore, other risk factors, including environmental exposures, may explain the remaining variation. Our objective was to assess the relationship between risk of breast cancer and residential proximity to industries, according to categories of industrial groups and specific pollutants released, in the context of a population-based multicase-control study of incident cancer carried out in Spain (MCC-Spain). Using the current residence of cases and controls, this study was restricted to small administrative divisions, including both breast cancer cases (452) and controls (1511) in the 10 geographical areas recruiting breast cancer cases. Distances were calculated from the respective woman's residences to the 116 industries located in the study area. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (between 1 km and 3 km) to industrial plants, adjusting for matching variables and other confounders. Excess risk (OR; 95%CI) of breast cancer was found near industries overall (1.30; 1.00-1.69 at 3 km), particularly organic chemical industry (2.12; 1.20-3.76 at 2.5 km), food/beverage sector (1.87; 1.26-2.78 at 3 km), ceramic (4.71; 1.62-13.66 at 1.5 km), surface treatment with organic solvents (2.00; 1.23-3.24 at 3 km), and surface treatment of plastic and metals (1.51; 1.06-2.14 at 3 km). By pollutants, the excess risk (OR; 95%CI) was detected near industries releasing pesticides (2.09; 1.14-3.82 at 2 km), and dichloromethane (2.09; 1.28-3.40 at 3 km). Our results suggest a possible increased risk of breast cancer in women living near specific industrial plants and support the need for more detailed exposure assessment of certain agents released by these plants.The authors thank all those who took part in this study providing questionnaire data. The study was partially funded by the “Acción Transversal del Cáncer", approved on the Spanish Ministry Council on the 11th October 2007, by the Scientific Foundation of the Spanish Association Against Cancer (Fundación Científica de la Asociación Española Contra el Cáncer (AECC) – EVP-1178/14), by the Spain's Health Research Fund (Fondo de Investigación Sanitaria - FIS 12/01416), by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359 PS09/01286-León, PS09/00773-Cantabria, PS09/02078-Huelva, PS09/01903-Valencia, PS09/01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/00613, PI15/00069, PI15/00914, PI15/01032), by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII (RD12/0036/0036)), by the Fundación Marqués de Valdecilla (API 10/09), by the Consejería de Salud of the Junta de Andalucía (PI-0571-2009, PI-0306-2011, salud201200057018tra), by the Junta de Castilla y León (LE22A10-2), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the Regional Government of the Basque Country, by the Recercaixa (2010ACUP 00310), by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation, by the Catalan Government DURSI grant 2017SGR723, by the University of Oviedo, and by the Fundación Caja de Ahorros de Asturias. ISGlobal is a member of the CERCA Program, Generalitat de Catalunya.S

Engineered LINE-1 retrotransposition in nondividing human neurons

Half the human genome is made of transposable elements (TEs), whose ongoing activity continues to impact our genome. LINE-1 (or L1) is an autonomous non-LTR retrotransposon in the human genome, comprising 17% of its genomic mass and containing an average of 80-100 active L1s per average genome that provide a source of inter-individual variation. New LINE-1 insertions are thought to accumulate mostly during human embryogenesis. Surprisingly, the activity of L1s can further impact the somatic human brain genome. However, it is currently unknown whether L1 can retrotranspose in other somatic healthy tissues or if L1 mobilization is restricted to neuronal precursor cells (NPCs) in the human brain. Here, we took advantage of an engineered L1 retrotransposition assay to analyze L1 mobilization rates in human mesenchymal (MSCs) and hematopoietic (HSCs) somatic stem cells. Notably, we have observed that L1 expression and engineered retrotransposition is much lower in both MSCs and HSCs when compared to NPCs. Remarkably, we have further demonstrated for the first time that engineered L1s can retrotranspose efficiently in mature nondividing neuronal cells. Thus, these findings suggest that the degree of somatic mosaicism and the impact of L1 retrotransposition in the human brain is likely much higher than previously thought.We thank current members of the J.L.G.-P. laboratory for helpful discussions. We also thank Drs. Geoffrey Faulkner (Mater Research, Australia) and John V. Moran (University of Michigan) for sharing unpublished data and for critical input during the project; Ms. Raquel Marrero (Microscopy Unit, Genyo) for technical support; Simon Mendez-Ferrer (CNIC, Spain) for providing total RNA isolated from human mesenspheres; Dr. Oliver Weichenrieder (Max-Planck, Tubingen, Germany) for providing a polyclonal L1-ORF1p antibody; and Dr. Aurelien Doucet (IRCAN, Nice, France) for providing a plasmid containing an UBC-driven EGFP retrotransposition indicator cassette. J.L.G. was funded by the US Department of Defense, Breast Cancer Research Program (award #BC051386), the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (1R03NS087290-01), and the ALS Therapy Alliance (2013-F-067). A.M. has been partially funded by a Marie Curie IRG project (FP7-PEOPLE-2007-4-3-IRG: SOMATIC LINE-1). J.L.G.-P's laboratory is supported by CICE-FEDER-P09-CTS-4980, CICE-FEDER-P12-CTS-2256, Plan Nacional de I+D+I 2008–2011 and 2013–2016 (FIS-FEDER-PI11/01489 and FIS-FEDER-PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European Research Council (ERC-Consolidator ERC-STG-2012-233764), by an International Early Career Scientist grant from the Howard Hughes Medical Institute (IECS-55007420), and by The Wellcome Trust–University of Edinburgh Institutional Strategic Support Fund (ISFF2).S

Lymphangioleiomyomatosis: Searching for potential biomarkers

Biomarkers; Lymphangioleiomyomatosis; MetalloproteinasesBiomarcadores; Linfangioleiomiomatosis; MetaloproteinasasBiomarcadors; Limfangioleiomiomatosi; MetaloproteinasesBackground: Vascular endothelial growth factor-D (VEGF-D) is the most commonly used biomarker for diagnosing lymphangioleiomyomatosis (LAM). However, lung biopsy is often necessary as well; therefore, defining new biomarkers for LAM is crucial. The aim of this study was to describe the diagnostic accuracy of a variety of biomarkers. Methods: We assessed 13 analytes in serum related to extracellular matrix remodeling, lymphatic involvement and angiogenesis in a cohort of patients with LAM, comparing them with patients with other cystic lung diseases (OCLD) and healthy women. A scoring method based on the cut-point of each VEGF-D and metalloproteinase-2 (MMP-2) was used to evaluate the diagnostic performance of the marker combination. Results: A total of 97 subjects were recruited: 59 (61%) LAM patients, 18 (19%) OCLD patients, and 20 (20%) healthy female controls. MMP-2 was the only extracellular matrix remodeling biomarker able to differentiate LAM patients from OCLD and healthy patients. Serum MMP-2 was higher in LAM patients [median 578 (465–832) ng/ml] than in patients with OCLD and healthy controls [medians 360 (314–546) and 427 (365–513) ng/ml, respectively (p < 0.0001)]. The area under ROC curve (AUC) of MMP-2 was 0.785 and that of VEGF-D 0.815 (p = 0.6214). The sensitivity/specificity profiles of each biomarker (54/92% for MMP-2, 59/95% for VEGF-D) yielded a composite score (−6.36 + 0.0059 × VEGF-D + 0.0069 × MMP-2) with higher accuracy than each component alone (AUC 0.88 and sensitivity/specificity 79/87%). Conclusion: Combining MMP-2 and VEGF-D may increase diagnostic accuracy for LAM.This project was supported by the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), grant number: PI 638/2018. The funders have no role in study design, data and analysis collection, decision to publish, or preparation of the manuscript

SEAWINES: Use of macroalgae as biostimulants against fungal diseases in grapevines

The outlook for climate change foresees major impacts on vineyards worldwide, shifting pathogens distribution and dynamics demanding more intense plant protection measures in certain regions, increasing viticulture's dependence on phytochemicals and pesticides. However, the European Commission is applying restrictions on their use, encouraging the development of more sustainable strategies efficient for disease control. Seaweeds represent an ecological alternative for a more sustainable production. Previous studies have shown that algae extracts contain compounds capable of reducing the abundance of plant fungal pathogens. Despite it, little is known about the molecular mechanism underlying this response. SEAWINES project is evaluating the efficacy of the foliar application of Ulva ohnoi and Rugulopteryx okamurae extracts to control powdery and downy mildew, in addition to testing their effect on grape and wine quality. To our knowledge, this is the first study evaluating R. okamurae biostimulant capacity and fungicidal effect in viticulture. This macroalgae is relevant since it is an invasive species in our coasts, causing incalculable economic and environmental burdens. We aim to 1- Reduce the usage of chemicals in grapevines; 2- Reduce fungal diseases in viticulture; 3- Valorize polysaccharides from seaweeds; 4- Increase the added-value to wines (ecological and quality); and 5- Provide an alternative use to seaweed biomass, contributing to bio-circular economy and reducing its accumulation in our coasts