Efecto antiinflamatorio de la izalpinina derivada de Chromolaena leivensis: edema de la pata inducido por λ-carragenina y modelo in silico

El flavonoide izalpinina se aisló de las partes aéreas de Chromolaena leivensis. Su determinación estructural se llevó a cabo mediante técnicas espectroscópicas de EM y RMN (1H, 13C). Se evaluó el efecto antiinflamatorio de este compuesto en un modelo de edema plantar inducido por carragenina en ratas. La inflamación de la pata se midió a intervalos de una hora durante siete horas tras la administración de -carragenano. Se evaluaron los niveles séricos de creatina quinasa (CK), obteniéndose resultados estadísticamente significativos con los tratamientos a dosis de 10 mg/kg (* p < 0,01) y 20 mg/kg (** p < 0,005). El efecto antiinflamatorio del compuesto se evaluó mediante pletismografía, y los resultados mostraron diferencias significativas en las tres concentraciones (10 mg/kg, 20 mg/kg, 40 mg/kg) en la primera y tercera hora tras el tratamiento. * p < 0,05; ** p < 0,001; **** p < 0,0001 frente al grupo de control negativo tratado con vehículo (DMSO). Por último, los análisis de acoplamiento molecular revelan que la izalpinina tiene una fuerte afinidad de unión con cinco proteínas diana implicadas en el proceso inflamatorio. El análisis mediante dinámica molecular permitió demostrar que los complejos ligando-proteína presentan una estabilidad aceptable, con valores de RMSD dentro del rango permitido.The flavonoid izalpinin was isolated from the aerial parts of Chromolaena leivensis. Its structural determination was carried out using MS and NMR spectroscopic techniques (1H, 13C). This compound was evaluated for its anti-inflammatory effect in a rat model on -carrageenan-induced plantar edema. Paw inflammation was measured at one-hour intervals for seven hours following the administration of -carrageenan. Serum creatine kinase (CK) levels were evaluated, obtaining statistically significant results with the treatments at doses of 10 mg/kg (* p < 0.01) and 20 mg/kg (** p < 0.005). The anti-inflammatory effect of the compound was evaluated by using plethysmography, and the results showed significant differences at the three concentrations (10 mg/kg, 20 mg/kg, 40 mg/kg) in the first and third hours after treatment. * p < 0.05; ** p < 0.001; **** p < 0.0001 vs. the negative control group treated with vehicle (DMSO). Lastly, molecular docking analyses reveal that izalpinin has a strong binding affinity with five target proteins involved in the inflammatory process. The analysis using molecular dynamics allowed demonstrating that the ligand–protein complexes present acceptable stability, with RMSD values within the allowed range

Metric analysis of the information visibility and diffusion about the European Higher Education Area on Spanish university websites.

The purpose of the study proposed in this paper is to evaluate the Spanish public university websites dedicated to the European Higher Education Area (EHEA). To do so, the quality of these resources has been analysed in the light of data provided by a series of indicators grouped in seven criteria, most of which were used to determine what information is made available and in what way. The criteria used in our analysis are: visibility, authority, updatedness, accesibility, correctness and completeness, quality assessment and navigability. All in all, the results allow us to carry out an overall diagnosis of the situation and also provide us with information about the situation at each university, thus revealing their main strengths, namely authority and navegability, and also their chief shortcomings: updatedness, accessibility and quality assessment. In this way it is possible to detect the best practices in each of the aspects evaluated so that they can serve as an example and guide for universities with greater deficiencies and thus help them to improve their EHEA websites

Factores clínicos y epidemiológicos asociados con nefritis lúpica en pacientes del noroccidente colombiano

A cross-sectional and multicenter study was undertaken to analyze the clinical and immunological characteristics at diagnosis associated with nephritis in northwestern Colombian patients with systemic lupus erythematosus (SLE). Thirty-nine patients with lupus nephritis were included and were compared to 100 SLE patients without nephritis. A multivariate analysis was performed. The patients who developed nephritis had a higher frequency of oral ulcers (41% vs. 21%, OR = 3.1, 95% CI: 1.3-7.5 p = 0.01) and malar erythema (77% vs. 45%, OR = 4.4, 95% CI: 1.8-10.8 p = 0.001). Lupus nephritis was observed in 77% of cases during the first year of the disease. The frequency of anti-DNA antibodies was higher in patients with nephritis, however, differences were not statistically significant (83% vs 64%, OR = 2.6, 95% CI: 1.03-6.41, p = 0.06). The presence of other autoantibodies (anti-Ro, anti-La, anti-RNP, anti-Sm and anticardiolipin) at diagnosis was similar in both groups. This autoantibody profile remained unchanged throughout the evolution of the disease. Patients with lupus nephritis had a higher prevalence of arterial hypertension (60% vs 10%, OR = 13.7, 95% IC: 5-37, p = 0.00001) and hyperlipidemia (30% vs 7%, OR = 8.1, 95% IC: 2.5-27, p = 0.0006) at onset. Finally, patients with lupus nephritis required more hospitalizations (> 1) over the course of disease (89% vs 60%, OR = 7.8, 95% CI: 2.1-29, p = 0.002). In conclusion, lupus nephritis appears early during the course of SLE. Malar erythema, oral ulcers, hypertension and hyperlipidemia at onset of disease are associated factors. Lupus nephritis is a major risk factor leading to repeated hospitalizations. This study may help to assist in public health policies in our population in order to improve patient outcomes while simultaneously reducing disease costs.Este estudio transversal y multicéntrico investigó las características clínicas e inmunológicas asociadas con la nefritis lúpica en pacientes colombianos de Medellín. Se incluyeron treinta y nueve pacientes con nefritis lúpica y se compararon sus características con las de 100 pacientes con lupus eritematoso sistémico (LES) sin compromiso renal. Se realizó un análisis multivariado para evaluar los factores asociados con la nefritis lúpica. Los pacientes que desarrollaron nefritis presentaron, al inicio, más úlceras orales (41% vs. 21%, OR=3,1, IC95%: 1,3-7,5, p=0,01) y eritema malar (77% vs. 45%, OR=4,4, IC95%: 1,8-10,8, p=0,001) que aquellos pacientes sin nefropatía. La nefritis lúpica se observó en 77% de los casos durante el primer año de evolución del LES. La frecuencia de anticuerpos anti-ADN fue mayor en los pacientes con nefritis; sin embargo, las diferencias no fueron significativas (83% vs. 64%, OR=2,57, IC95%:1,03-6,41, p=0,06). La presencia de otros anticuerpos (anti-Ro, anti-La, anti-RNP, anti-Sm y anticardiolipina) en el momento del diagnóstico fue similar en ambos grupos. El perfil de los autoanticuerpos permaneció sin modificación significativa durante el curso del LES. Los pacientes con nefritis lúpica presentaron una mayor prevalencia de hipertensión arterial (60% vs 10%, OR=13,7, IC95%: 5-37, p=0,00001) y dislipidemia (30% vs 7%, OR=8,1, IC95%: 2,5-27, p=0,0006) al inicio de la enfermedad que aquellos pacientes sin nefropatía. Los pacientes con nefritis lúpica requirieron más hospitalizaciones (>1) durante el curso de la enfermedad (89% vs 60%, OR=7,8, IC95%: 2,1-29, p=0,002). En conclusión, la nefritis lúpica se presenta tempranamente en el LES. El eritema malar, las úlceras orales, la hipertensión arterial y la dislipidemia son factores asociados. A su vez, la nefritis lúpica es un factor de riesgo de hospitalizaciones repetidas. Este estudio puede ser útil en la toma de decisiones de políticas de salud para beneficio de los pacientes y reducción de costos

Tissue Localization and Extracellular Matrix Degradation by PI, PII and PIII Snake Venom Metalloproteinases: Clues on the Mechanisms of Venom-Induced Hemorrhage

20 páginas, 4 figuras, 3 tablas y 7 tablas en material suplementario.Snake venom hemorrhagic metalloproteinases (SVMPs) of the PI, PII and PIII classes were compared in terms of tissue localization and their ability to hydrolyze basement membrane components in vivo, as well as by a proteomics analysis of exudates collected in tissue injected with these enzymes. Immunohistochemical analyses of co-localization of these SVMPs with type IV collagen revealed that PII and PIII enzymes co-localized with type IV collagen in capillaries, arterioles and post-capillary venules to a higher extent than PI SVMP, which showed a more widespread distribution in the tissue. The patterns of hydrolysis by these three SVMPs of laminin, type VI collagen and nidogen in vivo greatly differ, whereas the three enzymes showed a similar pattern of degradation of type IV collagen, supporting the concept that hydrolysis of this component is critical for the destabilization of microvessel structure leading to hemorrhage. Proteomic analysis of wound exudate revealed similarities and differences between the action of the three SVMPs. Higher extent of proteolysis was observed for the PI enzyme regarding several extracellular matrix components and fibrinogen, whereas exudates from mice injected with PII and PIII SVMPs had higher amounts of some intracellular proteins. Our results provide novel clues for understanding the mechanisms by which SVMPs induce damage to the microvasculature and generate hemorrhage.This work was performed in partial fulfillment of the requirements for the PhD degree for Cristina Herrera at Universidad de Costa Rica.Peer reviewe

Biotinidase deficiency: Genotype-biochemical phenotype association in Brazilian patients

[EN] The association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent. This study aimed to investigate the genotype-biochemical phenotype association in patients with low biotinidase activity. Methods All exons, the 5'UTR and the promoter of the BTD gene were sequenced in 72 Brazilian individuals who exhibited low biotinidase activity. For each patient, the expected biochemical phenotype based on the known genotype was compared with the observed biochemical phenotype. Additional non-genetic factors that could affect the biotinidase activity were also analysed. Most individuals were identified by neonatal screening (n = 66/72). When consecutive results for the same patient were compared, age, prematurity and neonatal jaundice appeared to affect the level of biotinidase activity. The biochemical phenotype at the time of the second blood collection changed in 11/22 patients compared to results from the first sample. Three novel variants were found: c.1337T>C (p.L446P), c.1466A>G (p.N489S) and c.962G>A (p.W321*). Some patients with the same genotype presented different biochemical phenotypes. The expected and observed biochemical phenotypes agreed in 68.5% of cases (concordant patients). The non-coding variants c.-183G>A, c.-315A>G and c.-514C>T were present in heterozygosis in 5/17 discordant patients. In addition, c.- 183G>A and c.-514C>T were also present in 10/37 concordant patients. The variants found in the promoter region do not appear to have a strong impact on biotinidase activity. Since there is a disparity between the BTD genotype and biochemical phenotype, and biotinidase activity may be affected by both genetic and non-genetic factors, we suggest that the diagnosis of BD should be based on more than one measurement of plasma biotinidase activity. DNA analysis can be of additional relevance to differentiate between partial BD and heterozygosity.SIThis study received financial support from Fundo de Incentivo à Pesquisa e Eventos/Hospital de Clínicas de Porto Alegre (FIPE-HCPA) for research materials and publication fee. Post Graduate Program in Genetics and Molecular Biology (Universidade Federal do Rio Grande do Sul) funded the translation. ECN has a commercial affiliation (CTN Diagnósticos) which did not have any role or financial contribution to this research. TB have fellowship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes). FS had fellowship from the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS). IVDS, MRSC and PASF have fellowships from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). HB receives a research grant of Orphan Europe. The funders did no provide support in the form of salaries for any author, and did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section

First Report of Sylvatic DENV-2-Associated Dengue Hemorrhagic Fever in West Africa

Dengue virus (DENV) circulates in human and sylvatic cycles. Sylvatic strains are both ecologically and evolutionarily distinct from endemic viruses. Although sylvatic dengue cycles occur in West African countries and Malaysia, only a few cases of mild human disease caused by sylvatic strains and one single case of dengue hemorrhagic fever in Malaysia have been reported. Here we report a case of dengue hemorrhagic fever (DHF) with thrombocytopenia (13000/µl), a raised hematocrit (32% above baseline) and mucosal bleeding in a 27-year-old male returning to Spain in November 2009 after visiting his home country Guinea Bissau. Sylvatic DENV-2 West African lineage was isolated from blood and sera. This is the first case of DHF associated with sylvatic DENV-2 in Africa and the second case worldwide of DHF caused by a sylvatic strain

Impact of Aetiological Treatment on Conventional and Multiplex Serology in Chronic Chagas Disease

The main criterion for treatment effectiveness in Chagas Disease has been the seronegative conversion of previously reactive serology, generally achieved many years post-treatment. The lack of reliable tests to ensure parasite clearance and to examine the effect of treatment is the main difficulty in evaluating treatment for chronic Chagas disease. Decreases of conventional and non-conventional serological titers can be useful tools to monitor the early impact of treatment. We serially measured changes in antibody levels, including seronegative conversion as well as declines in titers in 53 benznidazole-treated and 89 untreated chronically T. cruzi-infected subjects. Seronegative conversion as well as decreases of titers was significantly higher in treated compared with untreated patients. A strong concordance was found between decreases of titers of conventional and non-conventional serologic tests post-treatment, reaffirming the findings. When seronegative conversion plus decreases of titers were considered altogether, the impact of treatment was higher, in a shorter follow-up period than previously considered. New tools for monitoring the effectiveness of treatment of chronic Chagas disease are necessary, and the results showed in this study is a contribution to researchers and physicians who assist patients suffering from this disease

HIV-1 Vpu Protein Mediates the Transport of Potassium in Saccharomyces cerevisiae

Human immunodeficiency virus type 1 (HIV-1) Vpu is an integral membrane protein that belongs to the viroporin family. Viroporins interact with cell membranes, triggering membrane permeabilization and promoting release of viral particles. In vitro electrophysiological methods have revealed changes in membrane ion currents when Vpu is present; however, in vivo the molecular mechanism of Vpu at the plasma membrane is still uncertain. We used the yeast Saccharomyces cerevisiae as a genetic model system to analyze how Vpu ion channel impacts cellular homeostasis. Inducible expression of Vpu impaired cell growth, suggesting that this viral protein is toxic to yeast cultures. This toxicity decreased with extracellular acidic pH. Also, Vpu toxicity diminished as the extracellular K(+) concentration was increased. However, expression of the Vpu protein suppresses the growth defect of K(+) uptake-deficient yeast (Δtrk1,2). The phenotype rescue of these highly hyperpolarized cells was almost total when they were grown in medium supplemented with high concentrations of KCl (100 mM) at pH 7.0 but was significantly reduced when the extracellular K(+) concentration or pH was decreased. These results indicate that Vpu has the ability to modify K(+) transport in both yeast strains. Here, we show also that Vpu confers tolerance to the aminoglycoside antibiotic hygromycin B in Δtrk1,2 yeast. Our results suggest that Vpu interferes with cell growth of wild-type yeast but improves proliferation of the hyperpolarized trk1,2 mutant by inducing plasma membrane depolarization. Furthermore, evaluation of the ion channel activity of the Vpu protein in Δtrk1,2 yeast could aid in the development of a high-throughput screening assay for molecules that target the retroviral protein.This study was supported by Grants PI PI05/00013 and PI08/0912 from Fondo de Investigación Sanitaria. L.H. and N.M. were holders of Predoctoral Fellowships from Instituto de Salud Carlos III.S

Social mobility and healthy behaviours from a gender perspective in the Spanish multicase-control study (MCC-Spain)

There is evidence for the influence of socioeconomic status (SES) on healthy behaviours but the effect of social mobility (SM) is not yet well known. This study aims to analyse the influence of origin and destination SES (O-SES and D-SES) and SM on healthy behaviours and co-occurrence, from an integrated gender and age perspective. Data were obtained from the controls of MCC-Spain between 2008-2013 (3,606 participants). Healthy behaviours considered: healthy diet, moderate alcohol consumption, non-smoking and physical activity. SM was categorized as stable high, upward, stable medium, downward or stable low. Binary and multinomial logistic regression models were adjusted. Those aged <65, with a low O-SES, D-SES and stable low SM are less likely to have healthy behaviours in the case of both women (physically active: OR = 0.65 CI = 0.45-0.94, OR = 0.71 CI = 0.52-0.98, OR = 0.61 CI = 0.41-0.91) and men (non-smokers: OR = 0.44 CI = 0.26-0.76, OR = 0.54 CI = 0.35-0.83, OR = 0.41 CI 0.24-0.72; physically active: OR = 0.57 CI = 0.35-0.92, OR = 0.64 CI = 0.44-0.95, OR = 0.53 CI = 0.23-0.87). However, for those aged ≥65, this probability is higher in women with a low O-SES and D-SES (non-smoker: OR = 8.09 CI = 4.18-15.67, OR = 4.14 CI = 2.28-7.52; moderate alcohol consumption: OR = 3.00 CI = 1.45-6.24, OR = 2.83 CI = 1.49-5.37) and in men with a stable low SM (physically active: OR = 1.52 CI = 1.02-1.26). In the case of men, the same behaviour pattern is observed in those with a low O-SES as those with upward mobility, with a higher probability of co-occurring behaviours (three-to-four behaviours: OR = 2.00 CI = 1.22-3.29; OR = 3.13 CI = 1.31-7.48). The relationship of O-SES, D-SES and SM with healthy behaviours is complex and differs according to age and gender.This research was supported by the “Acción Transversal del Cancer”, approved by the Spanish Council of Ministers on 11th October 2007, by the Instituto de Salud Carlos III-FEDER [grant number:PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-León, PS09/01903-Valencia, PS09/02078-Huelva, 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, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI11/01810, PI14/01219, PI11/02213, PIE16/00049, PI17/01179, PI17-00092], by the Fundación Marqués de Valdecilla [grant number: API 10/09], 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)), by the Red Temática de Investigación del Cáncer (RTICC) del ISCIII [grant number: RD12/0036/0036], by the Junta de Castilla y León [grant number: LE22A10-2], by the Consejería de Salud of the Junta de Andalucía [grant number: PI-0571-2009, PI-0306-2011, salud201200057018tra], by the Conselleria de Sanitat of the Generalitat Valenciana [grant number: AP_061/10], by the Recercaixa [grant number: 2010ACUP00310], by the Regional Government of the Basque Country, by the Consejería de Sanidad de la Región de Murcia, by the European Commission [grant number: FOOD-CT-2006-036224-HIWATE], by the Spanish Association Against Cancer (AECC) Scientific Foundation [grant number: GCTRA18022MORE], by the Catalan Government-Agency for Management of University and Research Grants (AGAUR) [grant number: 2014SGR647, 2014SGR850 and 2017SGR723], by the Fundación Caja de Ahorros de Asturias and by the University of Oviedo. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S