Enrofloxacin-based therapeutic strategy for the prevention of endometritis in susceptible mares

Enrofloxacin (EFX) is often used empirically to prevent uterine infections in mares in order to improve efficiency on Commercial Embryo Transfer Farms. This study investigated the uterine distribution of EFX and its metabolite ciprofloxacin (CFX) in mares and assessed the minimal inhibitory concentrations (MIC) of EFX against various common pathogens as a basis for establishing a rational dosing schedule. Plasma and uterine pharmacokinetic (PK) studies were performed in two groups (n = 5) of healthy mares following intravenous (i.v.) administration of EFX at either 2.5 and at 5 mg/kg bodyweight. Plasma and endometrial tissue samples, taken before for up to 48 h after treatment were analysed by Reverse Phase HPLC. MIC values for wild strains of Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive bacteria (β-haemolytic streptococci) ranged from 0.25-2 and 1.5-3.0 μg/mL respectively. In terms of tissue distribution, the sum of the endometrial concentrations of the parent drug (EFX) and its active metabolite (CFX) (in terms of AUC), exceeded those in plasma by 249% and 941% following administration of EFX at 2.5 and 5 mg/kg respectively. After i.v. treatment with EFX at 5 mg/kg, endometrial concentrations of EFX and CFX above the MIC value were detected for 36-48 and 22-43 h posttreatment for Gram-negative and -positive isolates respectively. Concentrations above MIC were maintained for much shorter periods at the lower (2.5 mg/kg) treatment dose. Based on these results, a conventional dose (5 mg/kg) of EFX given prebreeding followed by two further doses at 36-48 h postbreeding are proposed as a rational strategy for using of EFX as a preventative therapy against a variety of common bacterial strains associated with equine endometritis.Fil: González, C. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; ArgentinaFil: Moreno, L.. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fumuso, E..Fil: García, J..Fil: Rivulgo, M..Fil: Confalonieri, A..Fil: Sparo, M..Fil: Sánchez Bruni, S.

Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis

Aprendizaje automático; MielofibrosisAprenentatge automàtic; MielofibrosiMachine learning; MyelofibrosisMyelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision-making. We obtained registry data from patients diagnosed with MF in 60 Spanish institutions (N = 1386). These were randomly divided into a training set (80%) and a test set (20%). A machine learning (ML) technique (random forest) was used to model overall survival (OS) and leukemia-free survival (LFS) in the training set, and the results were validated in the test set. We derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703). No improvement was obtained with the inclusion of MPN driver mutations in the model. We were unable to adequately assess the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients. AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF. In conclusion, we have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF. The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification

Biopolymers from Waste Biomass — Extraction, Modification and Ulterior Uses

The residues coming from woodlands and agricultural exploitation constitute the most abundant biomass available on earth. Its importance as a source of renewable energy has grown in addition to the environmental impact. Biomass waste is a lignocellulosic feedstock which contains three main biopolymers: cellulose, hemicellulose and lignin. It could be utilized for the production of a number of value-added products due to their chemical composition, but it is necessary to efficiently recover the valuable biopolymer as intact as possible by different processing techniques.For different applications, the principal objective of pre-treatment is to keep the cellulose intact, meanwhile hemicellulose and lignin are removed. The yields of the fractions depend on the pre-treatment method, which is the most expensive step in biomass conversion. Traditionally, cellulose is obtained by kraft, sulphite and soda treatments. These methods are non-environmentally friendly and generate huge quantities of toxic wastes. Recently developed models considering the environmental laws encourage the sustainable processing of biomass into value-added products. The use of ionic liquids as new solvents for biomass waste and organosolv processes is reviewed, which are used to obtain cellulose. One of the possible applications of cellulose is membrane synthesis, which has been reported for other biomass materials, such as sugarcane bagasse, mango seed and newspaper. In this chapter, some green pre-treatment methods, different sustainable routes for cellulose modification and some of the results obtained on membrane development based on waste biomass are discussed

Interactive Role of Surrogate Liver Fibrosis Assessment and Insulin Resistance on the Incidence of Major Cardiovascular Events

Introduction: The combination of easy-to-obtain validated biomarkers is interesting in the prognostic evaluation of patients at cardiovascular risk in a precision medicine scenario. The evaluation of the effect modification of insulin resistance and liver fibrosis with the Triglyceride-Glucose index (TyG) and Fibrosis-4 index (FIB4) might provide prognostic information in patients at cardiovascular risk. Patients and methods: A retrospective cohort study was performed with 2055 patients recruited in the Vascular Metabolic CUN cohort. The studied outcome was the incidence rate of major cardiovascular events (MACE). The Systematic Coronary Risk Evaluation (SCORE), FIB4 and TyG indexes were calculated according to validated formulas. Results: FIB4 and TyG showed a synergistic interaction using validated cut-offs for both indexes in the prediction of MACE (Hazard ratio (HR) 1.05 CI95% 1.01–1.08) which remained after adjustment by age, sex, SCORE subgroup, presence of diabetes, or previous MACE using standardized cut-off (HR 2.29 CI95% 1.33–3.94). Finally, a subgroup with significant TyG and FIB4 showed a higher cardiovascular risk in the study population (adjusted HR 3.34 CI 95% 1.94–5.77). Conclusion: The combined interpretation of TyG and FIB4 indexes might have a potential predictive value of major cardiovascular events

Inflammation in metabolically healthy and metabolically abnormal adolescents: The HELENA study

On behalf of the HELENA study group.[Background and aims] Inflammation may influence the cardio-metabolic profile which relates with the risk of chronic diseases. This study aimed to assess the inflammatory status by metabolic health (MH)/body mass index (BMI) category and to assess how inflammatory markers can predict the cardio-metabolic profile in European adolescents, considering BMI. [Methods and results] A total of 659 adolescents (295 boys) from a cross-sectional European study were included. Adolescents were classified by metabolic health based on age- and sex-specific cut-off points for glucose, blood pressure, triglycerides, high density cholesterol and BMI. C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin (IL-6), complement factors (C3, C4) and cell adhesion molecules were assessed. [Results] Metabolically abnormal (MA) adolescents had higher values of C3 (p < 0.001) and C4 (p = 0.032) compared to those metabolically healthy (MHy). C3 concentrations significantly increased with the deterioration of the metabolic health and BMI (p < 0.001). Adolescents with higher values of CRP had higher probability of being in the overweight/obese-MH group than those allocated in other categories. Finally, high C3 and C4 concentrations increased the probability of having an unfavorable metabolic/BMI status. [Conclusions] Metabolic/BMI status and inflammatory biomarkers are associated, being the CRP, C3 and C4 the most related inflammatory markers with this condition. C3 and C4 were associated with the cardio-metabolic health consistently.The HELENA Study was supported by the European Community Sixth RTD Framework Programme (Contract FOOD-CT-2005-007034) and the Stockholm County Council. This analysis was also supported by the Spanish Ministry of Science and Innovation (JCI-2010-07055) and the gs4:European Regional Development Fund (FEDER). CCS is supported by the Spanish Ministry of Economy and Competitiveness (BES-2014-068829). FBO is supported by a grant from the Spanish Ministry of Science and Innovation (RYC-2011-09011). AIR was funded by a Juan de la Cierva-Formación stipend from the Ministry of Economy and Competitiveness of the Spanish Government (FJCI-2014-19795).Peer Reviewe

Absence of R-Ras1 and R-Ras2 causes mitochondrial alterations that trigger axonal degeneration in a hypomyelinating disease model

Fast synaptic transmission in vertebrates is critically dependent on myelin for insulation and metabolic support. Myelin is produced by oligodendrocytes (OLs) that maintain multilayered membrane compartments that wrap around axonal fibers. Alterations in myelination can therefore lead to severe pathologies such as multiple sclerosis. Given that hypomyelination disorders have complex etiologies, reproducing clinical symptoms of myelin diseases from a neurological perspective in animal models has been difficult. We recently reported that R-Ras1 and/or R-Ras2 mice, which lack GTPases essential for OL survival and differentiation processes, present different degrees of hypomyelination in the central nervous system with a compounded hypomyelination in double knockout (DKO) mice. Here, we discovered that the loss of R-Ras1 and/or R-Ras2 function is associated with aberrant myelinated axons with increased numbers of mitochondria, and a disrupted mitochondrial respiration that leads to increased reactive oxygen species levels. Consequently, aberrant myelinated axons are thinner with cytoskeletal phosphorylation patterns typical of axonal degeneration processes, characteristic of myelin diseases. Although we observed different levels of hypomyelination in a single mutant mouse, the combined loss of function in DKO mice lead to a compromised axonal integrity, triggering the loss of visual function. Our findings demonstrate that the loss of R-Ras function reproduces several characteristics of hypomyelinating diseases, and we therefore propose that R-Ras1 and R-Ras2 neurological models are valuable approaches for the study of these myelin pathologies.Spanish Ministry of Economy and Competitiveness (RTI2018-096303B-C33) to B. C., (RTI2018-096303B-C31) to F. W., and RTI2018-095166B-I00 to C. G. R. and P. L. and Instituto de Salud Carlos III and co-funded by the European Regional Development Fund (ERDF) within the “Plan Estatal de Investigación Científica y Técnica y de Innovación 2017–2020” (RD16/0008/0020; FIS/PI 18-00754

Role of targeted therapies in rheumatic patients on COVID-19 outcomes: results from the COVIDSER study

Objectives: To analyse the effect of targeted therapies, either biological (b) disease-modifying antirheumatic drugs (DMARDs), targeted synthetic (ts) DMARDs and other factors (demographics, comorbidities or COVID-19 symptoms) on the risk of COVID-19 related hospitalisation in patients with inflammatory rheumatic diseases. Methods: The COVIDSER study is an observational cohort including 7782 patients with inflammatory rheumatic diseases. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Antirheumatic medication taken immediately prior to infection, demographic characteristics, rheumatic disease diagnosis, comorbidities and COVID-19 symptoms were analysed. Results: A total of 426 cases of symptomatic COVID-19 from 1 March 2020 to 13 April 2021 were included in the analyses: 106 (24.9%) were hospitalised and 19 (4.4%) died. In multivariate-adjusted models, bDMARDs and tsDMARDs in combination were not associated with hospitalisation compared with conventional synthetic DMARDs (OR 0.55, 95% CI 0.24 to 1.25 of b/tsDMARDs, p=0.15). Tumour necrosis factor inhibitors (TNF-i) were associated with a reduced likelihood of hospitalisation (OR 0.32, 95% CI 0.12 to 0.82, p=0.018), whereas rituximab showed a tendency to an increased risk of hospitalisation (OR 4.85, 95% CI 0.86 to 27.2). Glucocorticoid use was not associated with hospitalisation (OR 1.69, 95% CI 0.81 to 3.55). A mix of sociodemographic factors, comorbidities and COVID-19 symptoms contribute to patients' hospitalisation. Conclusions: The use of targeted therapies as a group is not associated with COVID-19 severity, except for rituximab, which shows a trend towards an increased risk of hospitalisation, while TNF-i was associated with decreased odds of hospitalisation in patients with rheumatic disease. Other factors like age, male gender, comorbidities and COVID-19 symptoms do play a role.This Project has been financed by Bristol-Myers Squibb, Galapagos Biopharma Spain SLU, Gebro Pharma, Roche Farma and Sanofi Aventis

The importance of nutrition in the prevention of endometriosis: systematic review

Antecedentes y objetivo: la endometriosis es un trastorno dependiente de hormonas que se caracteriza por la presencia de tejido similar al endometrial en sitios extrauterinos, lo que puede desencadenar una reacción inflamatoria crónica. Esta enfermedad afecta principalmente a mujeres en edad fértil y puede tener un impacto negativo en su bienestar físico, mental y social. Existen patrones alimentarios considerados antiinflamatorios, como el de dieta mediterránea, que podrían ayudar en la prevención y el tratamiento de la endometriosis. El objetivo de esta revisión fue conocer la relación entre el consumo de diferentes grupos de alimentos y la prevención de la endometriosis. Materiales y métodos: se realizó una revisión sistemática siguiendo la metodología PRISMA. Se consultaron las bases de datos PubMed, Scopus, Cochrane Library y Web of Science. Se seleccionaron estudios publicados entre 2013 y 2023, que fueran accesibles en texto completo, escritos en inglés y español y que incluyeran una muestra de mujeres con endometriosis y/o mujeres sanas, además de evaluar la relación entre la alimentación y la endometriosis. Se excluyeron artículos no relacionados, revisiones sistemáticas o metaanálisis y estudios piloto y realizados en animales. Resultados: se incluyeron diez estudios en total. El consumo de frutas, verduras (no crucíferas), lácteos, pescados, patatas, legumbres, vitaminas (A, C, D y B12), ácidos grasos monoinsaturados y poliinsaturados y minerales (calcio, potasio y magnesio) parece reducir el riesgo de endometriosis. Conclusiones: se necesitan más estudios que investiguen la relación entre el consumo de los diferentes grupos de alimentos y el riesgo de endometriosis.Background and objective: endometriosis is a hormone-dependent disorder characterized by the presence of endometrial-like tissue in extrauterine sites, which can trigger a chronic inflammatory reaction. This disease mainly affects women of childbearing age and can have a negative impact on their physical, mental and social well-being. There are eating patterns considered as anti-inflammatory, such as the Mediterranean diet, which could help in the prevention and treatment of endometriosis. The objective of this review was to know the relationship between the consumption of different food groups and the prevention of endometriosis. Materials and methods: a systematic review was carried out following the PRISMA methodology. PubMed, Scopus, Cochrane Library and Web of Science databases were consulted. Studies published between 2013 and 2023 were selected, accessible in full text, written in English and Spanish and including a sample of women with endometriosis and/or healthy women, in addition to evaluating the relationship between diet and endometriosis. Unrelated articles, systematic reviews or meta-analyses, pilot studies and studies conducted in animals were excluded. Results: a total of ten studies were included. The consumption of fruits, vegetables (not cruciferous), dairy products, fish, potatoes, legumes, vitamins (A, C, D and B12), monounsaturated and polyunsaturated fatty acids and minerals (calcium, potassium and magnesium) seems to reduce the risk of endometriosis. Conclusions: further studies investigating the relationship between consumption of different food groups and risk of endometriosis are needed

RNA-Seq reveals the existence of a CDKN1C-E2F1-TP53 axis that is altered in human T-cell lymphoblastic lymphomas

BACKGROUND: Precursor T-cell lymphoblastic lymphomas (T-LBL) are rare aggressive hematological malignancies that mainly develop in children. As in other cancers, the loss of cell cycle control plays a prominent role in the pathogenesis in these malignancies that is primarily attributed to loss of CDKN2A (encoding protein p16INK4A). However, the impact of the deregulation of other genes such as CDKN1C, E2F1, and TP53 remains to be clarified. Interestingly, experiments in mouse models have proven that conditional T-cell specific deletion of Cdkn1c gene may induce a differentiation block at the DN3 to DN4 transition, and that the loss of this gene in the absence of Tp53 led to aggressive thymic lymphomas. RESULTS: In this manuscript, we demonstrated that the simultaneous deregulation of CDKN1C, E2F1, and TP53 genes by epigenetic mechanisms and/or the deregulation of specific microRNAs, together with additional impairing of TP53 function by the expression of dominant-negative isoforms are common features in primary human T-LBLs. CONCLUSIONS: Previous experimental work in mice revealed that T-cell specific deletion of Cdkn1c accelerates lymphomagenesis in the absence of Tp53. If, as expected, the consequences of the deregulation of the CDKN1C-E2F1-TP53 axis were the same as those experimentally demonstrated in mouse models, the disruption of this axis might be useful to predict tumor aggressiveness, and to provide the basis towards the development of potential therapeutic strategiesin human T-LBL.The authors would like to thank the Spanish Ministry of Economy and Competitiveness (SAF2015–70561-R; MINECO/FEDER, EU) and the Autonomous Community of Madrid, Spain (B2017/BMD-3778; LINFOMAS-CM) for funding this work. Institutional grants from the Fundación Ramón Areces and Banco de Santander are also acknowledged.S

LITIO COMO TERAPIA NEUROPROTECTORA EN EL MODELO APPSL/PS1M146L DE LA ENFERMEDAD DE ALZHEIMER

El litio se utiliza desde hace varias décadas en el tratamiento de trastornos bipolares y la depresión, y recientemente se debate su uso potencial en patologías neurodegenerativas como la enfermedad de Alzheimer (AD). Diversos estudios han puesto de manifiesto su efecto positivo como potente inhibidor de GSK3beta disminuyendo la fosforilación de tau, la producción de Abeta e incrementando plasticidad sináptica. Sin embargo, su posible efecto neuroprotector previniendo la muerte neuronal in vivo no ha sido aun demostrado ya que la mayoría de los modelos transgénicos de AD no presentan pérdida neuronal. Nuestro modelo APPSL/PS1M146L sufre una pérdida significativa de neuronas SOM/NPY en hipocampo y corteza entorrinal desde edades tempranas (6 meses) con un marcado desarrollo de distrofias axonales. En este trabajo hemos estudiado el posible efecto neuroprotector del litio en este modelo animal mediante tratamiento crónico en la dieta desde los 3 hasta los 9 meses de edad. Se han utilizado técnicas imnunohistoquímicas, western blots y análisis por RT-PCR, y además se ha determinado la carga amiloide, el grado de compactación y el tamaño de las placas. El resultado más relevante de este estudio fue la preservación de la población de interneuronas SOM/NPY tanto en hipocampo como corteza entorrinal en los animales tratados, mientras que en los no tratados existió una pérdida significativa de esta supoblación neuronal. El efecto neuroprotector del litio se manifestó también en una marcada disminución de tau fosforilado, distrofias axonales y marcadores sinápticos, junto con una mejora cognitiva de los animales utilizando el test de reconocimiento de objetos. Este efecto preventivo del litio parece estar asociado con cambios en la formación de placas de Abeta que podrían afectar a su toxicidad, ya que los animales tratados presentaron placas más pequeñas y apariencia más compacta. Financiación: FIS PI12/01431 (AG) y FIS PI12/01439 (JV).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech