Design and testing of hydrophobic core/hydrophilic shell nano/micro particles for drug-eluting stent coating

In this study, we designed a novel drug-eluting coating for vascular implants consisting of a core coating of the anti-proliferative drug docetaxel (DTX) and a shell coating of the platelet glycoprotein IIb/IIIa receptor monoclonal antibody SZ-21. The core/shell structure was sprayed onto the surface of 316L stainless steel stents using a coaxial electrospray process with the aim of creating a coating that exhibited a differential release of the two drugs. The prepared stents displayed a uniform coating consisting of nano/micro particles. In vitro drug release experiments were performed, and we demonstrated that a biphasic mathematical model was capable of capturing the data, indicating that the release of the two drugs conformed to a diffusion-controlled release system. We demonstrated that our coating was capable of inhibiting the adhesion and activation of platelets, as well as the proliferation and migration of smooth muscle cells (SMCs), indicating its good biocompatibility and anti-proliferation qualities. In an in vivo porcine coronary artery model, the SZ-21/DTX drug-loaded hydrophobic core/hydrophilic shell particle coating stents were observed to promote re-endothelialization and inhibit neointimal hyperplasia. This core/shell particle-coated stent may serve as part of a new strategy for the differential release of different functional drugs to sequentially target thrombosis and in-stent restenosis during the vascular repair process and ensure rapid re-endothelialization in the field of cardiovascular disease

Managing gestation in cattle

Once a cow becomes pregnant, the effect of pregnancy loss on its reproductive cycle is a topic of great interest for dairy herds. This paper reviews the factors of a non-infectious nature that affect the pregnancy maintenance during the late embryonic/early fetal period. Some clinical suggestions on bovine neosporosis and coxiellosis are also highlighted

Managing gestation in cattle

Once a cow becomes pregnant, the effect of pregnancy loss on its reproductive cycle is a topic of great interest for dairy herds. This paper reviews the factors of a non-infectious nature that affect the pregnancy maintenance during the late embryonic/early fetal period. Some clinical suggestions on bovine neosporosis and coxiellosis are also highlighted

Relationships between peripheral maternal immune status during the peripartum period and postpartum reproductive disorders

Pregnancy and peripartum period are characterised by transient changes in the maternal immune system, noticeable at the peripheral level. The aim of the study was to determinate the effect of placental retention and metritis on peripheral white blood cells in 91 pregnant dairy cows from day 200 of pregnancy to 30 postpartum. Blood samples were automatically analysed with HemaVet® Multispecies Haematology system and total and differential leukocyte counts were recorded. Data was statistically analysed using GLM repeated measures ANOVA to test the effect of reproductive disorders on peripheral white blood cells. Cows with placental retention had significantly lower leukocyte, neutrophil and lymphocyte counts (P<0.05), and cows with metritis had lower neutrophil and eosinophil counts (P<0.01) than cows not suffering reproductive disorders during the peripartum period. Day of pregnancy and parturition also affected peripheral lymphocyte and monocyte counts (P<0.01). Maternal immune dysfunction during the peripartum period may predispose to reproductive disorders postpartu

Plasma progesterone concentration is not reduced in pregnant non-aborting heifers experimentally infected with neospora caninum

El feto mamífero es antigénicamente un cuerpo extraño para la madre y para sobrevivir se producen una serie de interacciones de inmunosupresión entre la madre y el mismo. La hormona clave que provoca inmunotolerancia fetal por parte de la madre es la progesterona (Hansen et al. 1986), produciendo un cambio hacia la respuesta inmune tipo Th2 y evitando así el aborto que produciría una excesiva respuesta Th1 (Roberston, 2000). El efecto regulador de la progesterona es ejercido directa o indirectamente a través de mediadores secundarios como las serpinas uterinas, conocidas como SERPINA14, que se encuentran presentes en el endometrio, fluidos fetales y el ovario (Padua y Hansen, 2010). Neospora caninum es un protozoo intracelular obligado considerado la causa más importante de aborto en vacuno lechero a nivel mundial. En las granjas lecheras la ruta de infección más frecuente es la transplacentaria, donde las madres infectadas naturalmente transmiten el parasito a los fetos durante la gestación (Almería y López-Gatius, 2013). La mayoría de terneros nacen clínicamente normales, aunque aproximadamente un 95% están infectados por N. caninum. El aborto o la infección congénita ocurren cuando el parásito atraviesa la barrera placentaria e infecta al feto, provocando el aborto principalmente hacia los 5-7 meses de gestación (Almería y López-Gatius, 2013). Las razones por las cuales algunas vacas infectadas abortan y otras no, siguen siendo desconocidas. Es bien conocido que la infección por N. caninum modifica los patrones hormonales durante la gestación en vacuno lechero. Por ejemplo, la seropositividad frente a este parásito ha sido asociada con incremento de prolactina y progesterona plasmática (Garcia-Ispierto et al. 2010, 2013) y reducción de glicoprotefnas asociadas a gestación (PAGs) (Garcia-Ispierto et al., 2015). También, se ha observado una correlación negativa entre la expresión génica de SERP/NA 14 en la placenta y la respuesta adaptativa humoral y celular en la placenta y linfonodos uterinos de vacas infectadas experimentalmente con N. caninum (Serrano-Pérez et al., 2016, 2017). El presente estudio se realizó durante el segundo trimestre de gestación en terneras gestantes experimentalmente infectadas con N. caninum el dla 11 O de gestación. Se seleccionó este momento de infección debido a que es cuando la mayoría de abortos tienen lugar en animales infectados en condiciones de campo. Debido al tropismo del parásito por el folículo ovárico (Silva et al., 2012) y al aumento de progesterona detectado en animales seropositivos a N. caninum, el objetivo de este estudio fue determinar si las novillas infectadas experimentalmente mostraban cambios en Ja concentración plasmática de progesterona tras la infección. Un segundo objetivo fue correlacionar la expresión génica de SERPINA 14 en el cuerpo lúteo con la concentración plasmática de progesterona.Neospora caninum is a majar cause of abortion in cattle worldwide. However,immune-endocrine interactions during pregnancy in Neospora-infected cows remainunknown. This study examines plasma progesterone concentration in dairy heifers experimentally infected with N. caninum that did not abort, and also assessed possible interrelations between expression patterns of SERPINA 14 in corpus luteum tissues and plasma progesterone concentrations. The study population was constituted of tour noninfected controls and three heifers experimentally infected wíth N. caninum on Day 11 O of pregnancy with live foetuses at euthanasia. Both groups were euthanized on Day 152 of gestation. At euthanasia, blood samples were collected to determine progesterone concentrations. Samples of corpus luteum tissues (CL) were collected to determine gene expression of SERPINA14. No relationships were detected between infection and plasma progesterone concentration (12.5 ± 1.5 ng/ml in controls vs. 12.8 ± 3.7 ng/ml in infected dams). There was not significan! correlation between plasma progesterone concentration and SERPINA14 expression in CL (r: 0.607, P=0.148). In conclusion, N. caninum had no impacts on luteal funclion, at least in terms of repercussions on plasma progesterone concentrations.Este estudio fue financiado por MINECO (AGL2012-39830-C02-01/02) y fondos FEDER. R. Mur-Novales disfruta de una beca FPI (BES-2013-063215).Publishe

TDP-43 modulation by Tau-Tubulin kinase 1 inhibitors: A new avenue for future amyotrophic lateral sclerosis therapy

68 p.-16 fig.-4 tab.+8 fig. supl.-5 tab. supl.Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without any effective treatment. Protein TDP-43 is a pathological hallmark of ALS in both sporadic and familiar patients. Post-translational modifications of TDP-43 promote its aggregation in the cytoplasm. Tau-Tubulin kinase (TTBK1) phosphorylates TDP-43 in cellular and animal models; thus, TTBK1 inhibitors emerge as a promising therapeutic strategy for ALS. The design, synthesis, biological evaluation, kinase–ligand complex structure determination, and molecular modeling studies confirmed novel pyrrolopyrimidine derivatives as valuable inhibitors for further development. Moreover, compound 29 revealed good brain penetration in vivo and was able to reduce TDP-43 phosphorylation not only in cell cultures but also in the spinal cord of transgenic TDP-43 mice. A shift to M2 anti-inflammatory microglia was also demonstrated in vivo. Both these activities led to motor neuron preservation in mice, proposing pyrrolopyrimidine 29 as a valuable lead compound for future ALS therapy.This work was supported by Comunidad de Madrid (grant B2017/BMD-3813), the European Social Fund+ (ESF+), MINECO (Grants SAF2016-76693-R to A.M., RTI2018-0988885-B-I00 to E.d.L., and CTQ2015-66313-R to A.M.R.), AIE (RTI2018-099318-B-I00 to D.L., cofunded by the European Regional Development Fund (FEDER)), ISCiii CIBERNED (CB18/05/00040 to A.M., V.P., and A.M.R. and CB06/05/0089 to E.dL.), MECD (FPU16/04466 to V.N.), Cost Action CA15135 “MuTaLig” (COST-STSM-CA15135-37514 to L.M.G.), FONDECYT (Grant 11180604 to D.R.). V.P. has received financial support through the Postdoctoral Junior Leader Fellowship Program (LCF/BQ/PR18/11640007) from “la Caixa” Banking Foundation.Peer reviewe