A Humanized Mouse Model Coupled with Computational Analysis Identifies Potent Glycolipid Agonist of Invariant NKT Cells.

Invariant natural killer T (iNKT) cells play an important role in many innate and adaptive immune responses, with potential applications in cancer immunotherapy. The glycolipid KRN7000, an α-galactosylceramide, potently activates iNKT cells but has shown limited anticancer effects in human clinical trials conducted so far. In spite of almost three decades of structure-activity relationship studies, no alternative glycolipid has yet emerged as a superior clinical candidate. One reason for the slow progress in this area is that standard mouse models do not accurately reflect the specific ligand recognition by human iNKT cells and their requirements for activation. Here we evaluated a series of KRN7000 analogues using a recently developed humanized mouse model that expresses a human αTCR chain sequence and human CD1d. In this process, a more stimulatory, previously reported but largely overlooked glycolipid was identified, and its activity was probed and rationalized via molecular simulations.

Long-term effects of status epilepticus during infancy in male rats: Sexual behavior and brain response upon exposure to sexually receptive females.

Previous research in female rats showed that induction of status epilepticus (SE) during infancy impairs proceptive sexual behavior at the long run in adulthood but temporarily, since full proceptivity is recovered after four mating trials. In male rats, such equivalent effects have not been explored yet. Thus, SE was experimentally induced by injecting lithium chloride (3 mEq/kg, i.p.) in thirteen-day-old (P13) male pups and then, on P14, pilocarpine hydrochloride (100 mg/kg, s.c.). Controls received the same volume of saline. For Experiment 1, at P90, we analyzed c-Fos immunoreactivity (c-Fos-IR) as a measure of unconditioned brain activity after exposing them to sexually receptive females, but without physical contact. For Experiment 2, a different group of males was tested for locomotor activity, and their sexual behavior was assessed during five trials. Then, serum testosterone and corticosterone levels were measured. Our results showed that a lower proportion of SE males performed mounts, intromissions, and ejaculations, and repeated training did not improve their behavior. The levels of testosterone in SE males were reduced, but corticosterone, c-Fos-IR, and locomotion were similar to controls. These results suggest that SE during infancy impairs adult sexual behavior by reducing testosterone.

Heterosexual experience prevents the development of conditioned same-sex partner preference in male rats.

Sexual partner preferences can be strengthened, weakened or even drastically modified via Pavlovian conditioning. For example, conditioned same-sex partner preference develops in sexually-naïve male rats that undergo same-sex cohabitation under the effects of quinpirole (QNP, D2 agonist). Here, we assessed the effect of prior heterosexual experience on the probability to develop a conditioned same-sex preference. Naïve or Sexually-experienced males received either Saline or QNP and cohabited during 24h with a male partner that bore almond scent on the back as conditioned stimulus. This was repeated every 4days for a total of three trials and resulted in four groups (Saline-naïve, Saline-experienced, QNP-naïve, QNP-experienced). Social and sexual preference were assessed four days after the last conditioning trial in a drug-free test in which experimental males chose between the scented familiar male and a novel sexually receptive female. Results showed that Saline-naïve, Saline-experienced and QNP-experienced displayed a clear preference for the female (opposite-sex). By contrast, only QNP-naïve males displayed a same-sex preference. Accordingly, QNP-experienced males were not affected by the conditioning process and continued to prefer females. We discuss the effects of copulation and D2 agonists on the facilitation and/or disruption of conditioned partner preferences.

[Perioperative control of vitamin K antagonists in elective surgery]. / Control perioperatorio de la anticoagulacion con antagonistas de la vitamina K en cirugía electiva.

Anti-coagulated patients who undergo elective surgery require temporary interruption of vitamin K antagonists. The aim of this study was to evaluate the incidence of thromboembolic events and bleeding complications in anti-coagulated patients undergoing elective invasive procedures by using an institutional management protocol. This was a descriptive study with prospective follow-up that included patients over 18 year old anti-coagulated with vitamin K antagonists, undergoing elective surgery. Those with atrial fibrillation (AF) at moderate and high risk of thromboembolic events, with mechanical heart valve (MCV) at moderate and high risk of thromboembolic events, and patients' venous thromboembolism (VTE) at high risk of thromboembolic events received bridging therapy with enoxaparin. Embolic and bleeding events in the pre-operative period were recorded. Seventy-eight received bridging, mean age 69.4 ± 11.9 years. Twenty-eight had AF (36.4 %), 12 had VTE (15.6 %) and 37 had MCV (48.1 %). Postoperatively, 1 embolic event (1.6 %) and 12 bleeding events (15.4 %) were documented, of which 10 were minor (12.8 %) and 2 major (2.6 %). The safety of bridging therapy is still under debate, and we should await the result of randomized studies comparing different strategies of bridging vs. interruption of anticoagulant therapy in the pre-operative period prior to reaching a definitive conclusion.

Control perioperatorio de la anticoagulación con antagonistas de la vitamina K en cirugía electiva

Los pacientes anticoagulados crónicamente que son sometidos a cirugías electivas requieren la suspensión temporaria de los antagonistas de vitamina K. El objetivo del presente trabajo fue evaluar la incidencia de eventos tromboembólicos y hemorrágicos en pacientes anticoagulados sometidos a un procedimiento invasivo, aplicando un protocolo de manejo de anticoagulación en el perioperatorio. Se realizó un estudio descriptivo, con datos obtenidos de manera prospectiva, donde se incluyeron mayores de 18 años que ingresaron para la realización de una cirugía electiva. Recibieron sustitución con enoxaparina aquellos con fibrilación auricular(FA) de moderado y alto riesgo de evento tromboembólico, pacientes con reemplazo con válvula cardíaca mecánica(VCM) de moderado y alto riesgo de evento tromboembólico y con tromboembolismo venoso(TEV) de alto riesgo de evento tromboembólico. Se evaluaron los eventos embólicos y hemorrágicos en el perioperatorio. Setenta y ocho recibieron sustitución con enoxaparina en el perioperatorio, edad promedio de 69.4 ± 11.9 años. Veintiocho tenían FA (36.4%), 12 TEV (15.6%) y 37 VCM (48.1%). En el postoperatorio hubo un evento embólico (1.6%) y 12 eventos hemorrágicos (15.4%) de los cuales 10 fueron menores (12.8%) y 2mayores (2.6%). La seguridad de la sustitución con enoxaparina aún es cuestionable, y se deberán esperar estudios aleatorizados, comparando diferentes estrategias de sustitución con heparinas versus la suspensión del tratamiento anticoagulante en el período perioperatorio para una conclusión definitiva.(AU)

Anti-coagulated patients who undergo elective surgery require temporary interruption of vitamin K antagonists. The aim of this study was to evaluate the incidence of thromboembolic events and bleeding complications in anti-coagulated patients undergoing elective invasive procedures by using an institutional management protocol. This was a descriptive study with prospective follow-up that included patients over 18 year old anti-coagulated with vitamin K antagonists, undergoing elective surgery. Those with atrial fibrillation (AF) at moderate and high risk of thromboembolic events, with mechanical heart valve (MCV) at moderate and high risk of thromboembolic events, and patients venous thromboembolism (VTE) at high risk of thromboembolic events received bridging therapy with enoxaparin. Embolic and bleeding events in the pre-operative period were recorded. Seventy- eight received bridging, mean age 69.4 ± 11.9 years. Twenty-eight had AF (36.4 %), 12 had VTE (15.6 %) and 37 had MCV (48.1 %). Postoperatively, 1 embolic event (1.6 %) and 12 bleeding events (15.4 %) were documented, of which 10 were minor (12.8 %) and 2 major (2.6 %). The safety of bridging therapy is still under debate, and we should await the result of randomized studies comparing different strategies of bridging vs. interruption of anticoagulant therapy in the pre-operative period prior to reaching a definitive conclusion.(AU)

Control perioperatorio de la anticoagulación con antagonistas de la vitamina K en cirugía electiva

Los pacientes anticoagulados crónicamente que son sometidos a cirugías electivas requieren la suspensión temporaria de los antagonistas de vitamina K. El objetivo del presente trabajo fue evaluar la incidencia de eventos tromboembólicos y hemorrágicos en pacientes anticoagulados sometidos a un procedimiento invasivo, aplicando un protocolo de manejo de anticoagulación en el perioperatorio. Se realizó un estudio descriptivo, con datos obtenidos de manera prospectiva, donde se incluyeron mayores de 18 años que ingresaron para la realización de una cirugía electiva. Recibieron sustitución con enoxaparina aquellos con fibrilación auricular(FA) de moderado y alto riesgo de evento tromboembólico, pacientes con reemplazo con válvula cardíaca mecánica(VCM) de moderado y alto riesgo de evento tromboembólico y con tromboembolismo venoso(TEV) de alto riesgo de evento tromboembólico. Se evaluaron los eventos embólicos y hemorrágicos en el perioperatorio. Setenta y ocho recibieron sustitución con enoxaparina en el perioperatorio, edad promedio de 69.4 ± 11.9 años. Veintiocho tenían FA (36.4%), 12 TEV (15.6%) y 37 VCM (48.1%). En el postoperatorio hubo un evento embólico (1.6%) y 12 eventos hemorrágicos (15.4%) de los cuales 10 fueron menores (12.8%) y 2mayores (2.6%). La seguridad de la sustitución con enoxaparina aún es cuestionable, y se deberán esperar estudios aleatorizados, comparando diferentes estrategias de sustitución con heparinas versus la suspensión del tratamiento anticoagulante en el período perioperatorio para una conclusión definitiva.

Anti-coagulated patients who undergo elective surgery require temporary interruption of vitamin K antagonists. The aim of this study was to evaluate the incidence of thromboembolic events and bleeding complications in anti-coagulated patients undergoing elective invasive procedures by using an institutional management protocol. This was a descriptive study with prospective follow-up that included patients over 18 year old anti-coagulated with vitamin K antagonists, undergoing elective surgery. Those with atrial fibrillation (AF) at moderate and high risk of thromboembolic events, with mechanical heart valve (MCV) at moderate and high risk of thromboembolic events, and patients' venous thromboembolism (VTE) at high risk of thromboembolic events received bridging therapy with enoxaparin. Embolic and bleeding events in the pre-operative period were recorded. Seventy- eight received bridging, mean age 69.4 ± 11.9 years. Twenty-eight had AF (36.4 %), 12 had VTE (15.6 %) and 37 had MCV (48.1 %). Postoperatively, 1 embolic event (1.6 %) and 12 bleeding events (15.4 %) were documented, of which 10 were minor (12.8 %) and 2 major (2.6 %). The safety of bridging therapy is still under debate, and we should await the result of randomized studies comparing different strategies of bridging vs. interruption of anticoagulant therapy in the pre-operative period prior to reaching a definitive conclusion.

Control perioperatorio de la anticoagulacion con antagonistas de la vitamina K en cirugía electiva. / [Perioperative control of vitamin K antagonists in elective surgery].

Anti-coagulated patients who undergo elective surgery require temporary interruption of vitamin K antagonists. The aim of this study was to evaluate the incidence of thromboembolic events and bleeding complications in anti-coagulated patients undergoing elective invasive procedures by using an institutional management protocol. This was a descriptive study with prospective follow-up that included patients over 18 year old anti-coagulated with vitamin K antagonists, undergoing elective surgery. Those with atrial fibrillation (AF) at moderate and high risk of thromboembolic events, with mechanical heart valve (MCV) at moderate and high risk of thromboembolic events, and patients venous thromboembolism (VTE) at high risk of thromboembolic events received bridging therapy with enoxaparin. Embolic and bleeding events in the pre-operative period were recorded. Seventy-eight received bridging, mean age 69.4 ± 11.9 years. Twenty-eight had AF (36.4

), 12 had VTE (15.6

) and 37 had MCV (48.1

). Postoperatively, 1 embolic event (1.6

) and 12 bleeding events (15.4

) were documented, of which 10 were minor (12.8

) and 2 major (2.6

). The safety of bridging therapy is still under debate, and we should await the result of randomized studies comparing different strategies of bridging vs. interruption of anticoagulant therapy in the pre-operative period prior to reaching a definitive conclusion.