Role of eprinomectin as inhibitor of the ruminant ABCG2 transporter: Effects on plasma distribution of danofloxacin and meloxicam in sheep.

Therapeutic outcome results of the coadministration of several drugs in veterinary medicine is affected by, among others, the relationship between drugs and ATP-binding cassette (ABC) transporters, such as ABCG2. ABCG2 is an efflux protein involved in the bioavailability and milk secretion of drugs. The aim of this work was to determine the role of eprinomectin, a macrocyclic lactone (ML) member of avermectin class, as inhibitor of ABCG2. The experiments were carried out through in vitro inhibition assays based on mitoxantrone accumulation and transport assays in ovine ABCG2 transduced cells using the antimicrobial drug danofloxacin and the anti-inflammatory drug meloxicam, both widely used in veterinary medicine and well known ABCG2 substrates. The inhibition results obtained showed that eprinomectin was an efficient in vitro ABCG2 inhibitor, tested in mitoxantrone accumulation assays. In addition, this ML decreased ovine ABCG2-mediated transport of danofloxacin and meloxicam. To evaluate the role of eprinomectin in systemic exposure of drugs, pharmacokinetic assays based on subcutaneous coadministration of eprinomectin with danofloxacin (1.25 mg/kg) or meloxicam (0.5 mg/kg) in sheep were performed obtaining a significant increase of systemic exposure of these drugs. Especially relevant was the increase of the systemic concentration of meloxicam, since coadministration with eprinomectin increased significantly the plasma concentration of meloxicam, obtaining an increase of AUC (0-72 h) value of more than 40%.

Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets.

Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and type 2 diabetes mellitus, among other comorbidities. To date, only therapeutic strategies based on lifestyle changes have exhibited a beneficial impact on patients with NAFLD, but unfortunately this approach is often difficult to implement, and shows poor long-term adherence. For this reason, great efforts are being made to elucidate and integrate the underlying pathological molecular mechanism, and to identify novel and promising druggable targets for therapy. In this regard, a large number of clinical trials testing different potential compounds have been performed, albeit with no conclusive results yet. Importantly, many other clinical trials are currently underway with results expected in the near future. Here, we summarize the key aspects of NAFLD pathogenesis and therapeutic targets in this frequent disorder, highlighting the most recent advances in the field and future research directions.

A Role for Gut Microbiome Fermentative Pathways in Fatty Liver Disease Progression.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease in which environmental and genetic factors are involved. Although the molecular mechanisms involved in NAFLD onset and progression are not completely understood, the gut microbiome (GM) is thought to play a key role in the process, influencing multiple physiological functions. GM alterations in diversity and composition directly impact disease states with an inflammatory course, such as non-alcoholic steatohepatitis (NASH). However, how the GM influences liver disease susceptibility is largely unknown. Similarly, the impact of strategies targeting the GM for the treatment of NASH remains to be evaluated. This review provides a broad insight into the role of gut microbiota in NASH pathogenesis, as a diagnostic tool, and as a therapeutic target in this liver disease. We highlight the idea that the balance in metabolic fermentations can be key in maintaining liver homeostasis. We propose that an overabundance of alcohol-fermentation pathways in the GM may outcompete healthier, acid-producing members of the microbiota. In this way, GM ecology may precipitate a self-sustaining vicious cycle, boosting liver disease progression.

Mineralisation of tubular bones is affected differently by low phosphorus supply in growing-finishing pigs.

BACKGROUND: Phosphorus (P) supply is essential for bone mineralisation. Reduced P may result in osteopenia, whereas excessive P may result in environmental impacts. The objective was to study the long-term effect of three dietary P levels on net bone mineralisation in growing-finishing pigs. Eighteen female pigs were fed low P (LP (4.1)), medium P (MP (6.2)) or high P (HP (8.9 g P kg-1 DM)) from 39.7 until 110 kg. Trabecular, cortical and overall bone mineral density (BMD), ash, calcium (Ca) and P were determined after slaughter. RESULTS: The LP diet generally reduced the BMD, ash, Ca and P in all bones, though all measures were markedly lowered in femur compared with humerus. The trabecular BMD in LP pigs was only different in the distal section compared to the MP-fed pigs (P < 0.05). In addition, ash, Ca and P were lower in the proximal and distal sections. No significant effect of HP was seen. Conclusively, LP caused lower net bone mineralisation, mainly of femur. The trabecular tissue of the distal bones seems to be most metabolically active. CONCLUSIONS: The MP level was sufficient for net bone mineralisation. Femur is recommended for studying bone fragility whereas humerus seems useful to study increased P retention. © 2019 The Authors. Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Different in vitro proliferation and cytokine-production inhibition of memory T-cell subsets after calcineurin and mammalian target of rapamycin inhibitors treatment.

Calcineurin inhibitors (CNI) and mammalian target of rapamycin inhibitors (mTORi) are the main immunosuppressants used for long-term maintenance therapy in transplant recipients to avoid acute rejection episodes. Both groups of immunosuppressants have wide effects and are focused against the T cells, although different impacts on specific T-cell subsets, such as regulatory T cells, have been demonstrated. A greater knowledge of the impact of immunosuppression on the cellular components involved in allograft rejection could facilitate decisions for individualized immunosuppression when an acute rejection event is suspected. Memory T cells have recently gained focus because they might induce a more potent response compared with naive cells. The impact of immunosuppressants on different memory T-cell subsets remains unclear. In the present study, we have studied the specific impact of CNI (tacrolimus) and mTORi (rapamycin and everolimus) over memory and naive CD4(+) T cells. To do so, we have analysed the proliferation, phenotypic changes and cytokine synthesis in vitro in the presence of these immunosuppressants. The present work shows a more potent effect of CNI on proliferation and cytokine production in naive and memory T cells. However, the mTORi permit the differentiation of naive T cells to the memory phenotype and allow the production of interleukin-2. Taken together, our data show evidence to support the combined use of CNI and mTORi in transplant immunosuppression.

Thermal epiphysiodesis performed with radio frequency in a porcine model.

BACKGROUND AND PURPOSE: Current techniques for epiphysiodesis involve opening of cortical windows; use of staples, screws, and tension devices; and fusion with curettes or drills. Complications may have serious consequences. There is a need for a more reliable, precise, and less traumatic procedure that overcomes the known complications from existing techniques. We analyzed a new epiphysiodesis technique using radio-frequency ablation (RFA) in a porcine model. METHODS: Six 35-kg and two 25-kg immature pigs were used. 1 hind leg of each animal was randomly selected and the proximal tibia growth plate was ablated laterally and medially. The contralateral leg was used as a control. MR images were obtained immediately after the ablation and 12 weeks later for 6 animals, and 24 weeks later for the other 2 animals. CT was done for the 2 animals that were followed for 24 weeks for proof of bone bridges. RESULTS: Both tibias were equal in length initially. At the 12-week follow-up, there was an average leg length discrepancy of 3.9 mm (95% CI: 3.0-4.8), and at 24 weeks the difference was 8.4 mm and 7.5 mm. No damage to the adjacent tissue was found. Bone bridges and physeal closure were found after 24 weeks. The pigs showed no discomfort after the intervention. INTERPRETATION: We found RFA to be feasible for epiphysiodesis in a pig model. The method is minimally invasive and recovery may be quick compared to conventional methods. We recommend that the method should be tested in larger-scale safety studies before clinical application.

Gangliocitoma selar asociado a adenoma hipofisario productor de hormona de crecimiento. Caso clínico / No disponible

Introducción Los gangliocitomas intraselares son entidades poco frecuentes que en raras ocasiones pueden encontrarse asociados a adenomas funcionantes. Caso clínico Mujer de 49 años estudiada por acromegalia, con lesión selar que se reseca por vía transesfenoidal endoscópica. El resultado histopatológico es de gangliocitoma con adenoma somatotrófico asociado. Discusión Encontramos descritos en la literatura 85 casos de gangliocitomas intraselares asociados con adenomas hipofisarios funcionantes, de los cuales podemos distinguir: 50 productores de hormona de crecimiento (GH) (59%), 15 mixtos (productores de GH y prolactina) (17%), 11 productores de prolactina (13%), 7 productores de hormona adrenocorticotropa (ACTH) (8%) y 2 productores de hormona liberadora de corticotropina (CRH) (2%).Conclusiones En estas entidades es más común la asociación a secreción de GH y la presentación en mujeres de edad media. El diagnóstico es histopatológico. Es importante el conocimiento de esta entidad, por la posible limitación de respuesta terapéutica en la resección incompleta (AU)

[Intrasellar gangliocytoma associated with growth hormone-producing pituitary adenoma. Case report]. / Gangliocitoma selar asociado a adenoma hipofisario productor de hormona de crecimiento. Caso clínico.

INTRODUCTION: Intrasellar gangliocytomas are uncommon entities which, unusually, may be found in association with hormone-releasing pituitary adenomas. CASE REPORT: The patient was a 49-year-old female who presented a sellar lesion with associated acromegaly. A trans-sphenoidal tumour was removed, with no medical improvement. Histopathological analysis revealed a gangliocytoma with an associated somatotroph adenoma. DISCUSSION: We found 85 cases of intrasellar gangliocytomas with associated hormone-releasing pituitary adenomas reported in the literature, with the following distribution: 50 growth hormone-releasing (GH) cases (59%), 15 mixed (GH and prolactin-releasing) cases (17%), 11 prolactin-releasing cases (13%), 7 adrenocorticotropic hormone-releasing (ACTH) cases (8%) and 2 corticotropin hormone-releasing (CRH) cases (2%). CONCLUSIONS: Mixed gangliocytomas-adenomas are uncommon entities. Association with growth hormone-releasing cases is more frequent and the most common presentation is among middle-aged females. Diagnosis is histopathological. Identification of this entity is important because it may lead to a limitation in therapeutic response in incomplete resections.

El código de ética en la experimentación animal no puede ser letra muerta / The ethics code in animal experimentation cannot be a dead letter

El trabajo tiene como objetivo dar nuestra apreciación sobre el comportamiento ético. Se revisan en la literatura las consideraciones sobre ética en la experimentación animal y se hace énfasis en la necesidad de sensibilizar al personal que labora en actividades que involucran animales de experimentación, desde etapas tempranas de su formación, continuando a lo largo de su vida laboral. El código de ética no es un documento muerto, sino que tiene que estar incorporado de manera consciente a la actividad diaria del experimentador(AU)