Early-life stress elicits peripheral and brain immune activation differently in wild type and 5xFAD mice in a sex-specific manner.

BACKGROUND: The risk of developing Alzheimer's disease (AD) is modulated by genetic and environmental factors. Early-life stress (ELS) exposure during critical periods of brain development can impact later brain function and health, including increasing the risk of developing AD. Microglial dysfunction and neuroinflammation have been implicated as playing a role in AD pathology and may be modulated by ELS. To complicate matters further, sex-specific effects have been noted in response to ELS and in the incidence and progression of AD. METHODS: Here, we subjected male and female mice with either a wild type or 5xFAD familial AD-model background to maternal separation (MS) from postnatal day 2 to 14 to induce ELS. RESULTS: We detected hippocampal neuroinflammatory alterations already at postnatal day 15. By 4 months of age, MS mice presented increased immobility time in the forced swim test and a lower discrimination index in the novel object recognition memory test compared to controls. We found altered Bdnf and Arc expression in the hippocampus and increased microglial activation in the prefrontal cortex due to MS in a sex-dependent manner. In 5xFAD mice specifically, MS exacerbated amyloid-beta deposition, particularly in females. In the periphery, the immune cell population was altered by MS exposure. CONCLUSION: Overall, our results demonstrate that MS has both short- and long-term effects on brain regions related to memory and on the inflammatory system, both in the brain and periphery. These ELS-related effects that are detectable even in adulthood may exacerbate pathology and increase the risk of developing AD via sex-specific mechanisms.

Dissolution/permeation: The importance of the experimental setup for the prediction of formulation effects on fenofibrate in vivo performance.

The evaluation of formulation strategies in early drug development requires in vitro methods that correctly predict oral drug absorption. The present study aimed to define key parameters for the predictability of dissolution/permeation experiments. Dissolution/permeation experiments were performed in various setups. The IDAS1 chamber, Ussing chamber, and transwells were used as Caco-2 cell based dissolution/permeation models to study the impact of chamber volumes and vertical or horizontal membrane orientation. Dissolution/permeation experiments in Ussing chambers with excised rat intestine were performed to depict the impact of the permeation membrane. Fenofibrate served as model compound in formulations of different particle size. Caco-2 cell based dissolution/permeation experiments with a vertical membrane orientation correctly depicted the formulation effect seen in vivo. The chamber volumes did not affect the outcome. A horizontal membrane orientation achieved no distinction. Experiments using excised rat intestinal sheets did not distinguish between the formulations, and the permeation was much lower than across Caco-2 cells. Mucus might present an artificially enhanced barrier for fenofibrate. Factors that greatly affected the predictivity of the dissolution/permeation experiments were thus the type and orientation of the permeation membrane, whereas chamber volumes only had a minor influence. Vertically mounted Caco-2 cells resulted in the best formulation distinction.

Continuous thoracic paravertebral analgesia after minimally invasive atrial septal defect closure surgery in pediatric population: Effectiveness and safety analysis.

INTRODUCTION: Lateral thoracotomy is replacing traditional median sternotomy for atrial septal defect (ASD) closure in children in order to improve cosmetic outcomes. Continuous paravertebral block has been described as an effective and safe analgesic technique in children. The aim of this study is to assess pain management by continuous perfusion of local anesthetic through a thoracic paravertebral catheter (PVC) in a pediatric population after thoracotomy closure of ASD, and its effectiveness in a fast-track program. METHODS: Descriptive cross-sectional study. Analgesic effectiveness, perioperative and safety-related data were analyzed in 21 patients who underwent thoracotomy closure of ASD with PVC. In the postoperative period, patients received continuous perfusion of bupivacaine 0.125% and fentanyl (1 mcg.ml-1) at 0.2 ml.kg-1.h-1 through the PVC. RESULTS: The median of mean pain scale score for each patient was 1.5. All patients were extubated in the operating theatre. No patient with PVC required opioid rescue. The median length of stay in the Pediatric Intensive Care Unit was 48 hours. There were 3 adverse events related to PVC: 1 due to malposition and 2 due to accidental removal. No other complications or cases of local anesthetic toxicity were recorded. CONCLUSIONS: PVC provides effective, safe, opioid-saving analgesia in the postoperative period of ASD closure by thoracotomy in the context of a fast-track protocol.

Patients with initial nodal involvement due to breast cancer who have received neoadjuvant chemotherapy: Combined sentinel node-radioguided surgery of the pathological node.

OBJECTIVE: To study the feasibility and usefulness of ultrasound-guided pre-chemotherapy marking of pathologic lymph node followed by sentinel lymph node biopsy (SLNB)-pathologic node radioguided biopsy (ROLL) combined technique, in axillary involvement breast cancer patients undergoing neoadjuvant chemotherapy (NACT). MATERIAL AND METHODS: Prospective diagnostic study of 30 patients with breast cancer and cN1 axillary staging with NACT indication. Before NACT, the biopsied node was marked with a clip (MBN). After NACT an ultrasound was performed and in case of good response a SLNB (99mTc-nanocolloids) plus targeted axillary dissection MBN ROLL biopsy (99mTc-albumin macroaggregates) was performed. Axillary lymph node dissection (ALND) was performed if SLNB and/or MBN were positive for tumor cells. The localization-removal rate of the sentinel lymph node (SLN) and MBN were evaluated. False-negative rate (FNR) and positive predictive value (PPV) of SLNB alone were also evaluated. RESULTS: Thirty patients were included in the study. SLN could be detected in all patients while MBN was successfully removed in 27 (90%). The SLN coincided with MBN in 15 patients (50%). In 12 patients SLNB was negative while MBN positive, leading to a FNR of 44.4% for SLNB alone. We found a PPV of 37% for the SLNB. In 5 patients (18.5%) both SLNB and MBN were negative, avoiding ALND. CONCLUSIONS: SLNB-MBN radioguided biopsy ROLL combined technique is a useful and accessible procedure for accurate axillary restaging after NACT, avoiding the high rate of FNR of SLNB alone in this group of patients and avoiding a great number of ALND.

Fotopic and scotopic retinal sensitivity and foveal fixation normal values using microperimetry in healthy population.

PURPOSE: To determine normal values of fotopic and scotopic retinal sensitivity and foveal fixation obtained by microperimetry, using MP3-S microperimeter (Nidek, Gamagori, Japan), in a healthy population. METHODS: Observational, crossectional, single centre study. Fotopic and scotopic microperimetry was performed using with a customized 13-point fovea-centered pattern in healthy volunteers without ocular pathology. A intraclass correlation coefficient (ICC) was performed to evaluate fotopic and scotopic microperimetry reliability. RESULTS: We analyzed 102 eyes of 54 patients with a mean age of 49.8 +/- 15 years old. The fotopic and scotopic mean retinal sensitivity (MRS) was 28.55±3.3dB (95% CI=[27.87-29.23]) and 15.72±1.9dB (95% CI=[15.35-16.09]) respectively, showing a significant statistical difference (p<0.05). No differences were found when comparing SRM by gender group. However, when analyzing the SRM by age groups, statistically significant differences were found in both modalities of the test; SRM being higher in the group of subjects under 35 years of age with 30.3±1.7dB in the photopic and 16.3±1.3dB in the scotopic; and lower in the group of older than 65 years with 26.7±2.2dB in the photopic and 13.8±1.8dB in the scotopic with p=0.0001. The reliability analysis of both tests, revealed an excellent reliability of the fotopic microperimetry with a Crombach alpha of 0.958 and a good reliability of 0.841 in scotopic microperimetry. CONCLUSIONS: Microperimetry is a test with good reliability both under photopic and scotopic conditions. SRM and fixation stability under photopic and scotopic conditions do not differ according to sex, but it does decrease with age. There is a positive correlation between photopic and scotopic SRM.

Anesthetic planning and management for a caesarian section in a pregnant woman affected by SARS-COV-2 pneumonía. / Planificación y manejo anestésico para cesárea en gestante con neumonía por SARS-CoV-2.

Pregnant women experience physiological and immunological changes which make them more prone to all kind of viral and bacterial infections, this is because they have been considered as vulnerable group if infected by SARS-CoV-2. They could even deploy a severe form of this disease which may require to end pregnancy to improve oxygenation and to safeguard foetal wellbeing the in case the mother situation gets worse. In this scenario, any intervention would require a detailed planning by the whole surgical team, and, specifically, by the anaesthesiologists, in order to guarantee both mother and child wellbeing and to prevent from infections all the healthcare team. We describe the case of 37week pregnant woman, admitted in our Critical Care Unit with respiratory high flows device support, due to severe respiratory failure due to COVID-19 which needed an urgent caesarean section.

Endotracheal intubation through laryngeal Ambu® Auragain™ mask airway mask in paediatric patients affected by congenital infiltrating lipomatosis. / Intubación orotraqueal a través de mascarilla laríngea Ambu® Auragain™ en paciente pediátrico con lipomatosis infiltrante congénita.

Congenital defects that affect paediatric airway could lead to several difficulties for effective ventilation, intubation, or even both, increasing the risk of hypoxaemia. It is essential for the paediatric anaesthesiologist to have accurate knowledge of the anatomy of patient́s airway, as well as judicious preoperative planning. Increasingly, more devices have been designed for the control of difficult airway in the paediatric patient. This case report describes the application of a third-generation laryngeal mask (- Ambu® Auragain ™) for endotracheal intubation of a child with anticipated difficult airway, secondary to congenital diffuse infiltrating facial lipomatosis.

Biomechanical Description of Phonation in Children Affected by Williams Syndrome.

The voice of persons with Williams syndrome (WS) is described as hoarse with a deep and unstable fundamental frequency (f0). These observations may be justified by the deficit of elastin due to a haplo-insufficiency in the ELN gene characteristic of the syndrome. In view of the possible relationship between elastin deficit and dysphonia, a study of the dynamic function of WS phonation was conducted by means of biomechanical analysis. In order to assess the presence of dysphonic symptoms and their degree of severity, the biomechanical description of WS phonation has been evaluated in terms of dynamic mass and viscoelasticity estimates. Glottal biomechanical features such as vocal fold dynamic mass, stiffness, unbalances, and laryngeal tremor of 12 children with WS aged 3 to 8 years (five girls and seven boys) have been estimated and compared with the normative phonation of 97 children with typical development (53 girls and 44 boys). The results show that WS children show differences in f0, vocal fold mass and stiffness, phonation stability, glottal contact defects, and laryngeal tremor. The conclusions may help to make a more complete view of the connection between WS and dysphonia based on objective assessments.

Results and functional outcomes of acute ischemic stroke patients who underwent mechanical thrombectomy admitted to intensive care unit. / Resultados y evolución funcional de pacientes críticos con ictus isquémico sometidos a trombectomía mecánica.

PURPOSE: To study the results and complications of endovascular treatment (EVT) in acute ischemic stroke patients admitted to Intensive Care Unit (ICU). To analyse the possible factors related to mortality and level of disability at ICU discharge and one year after stroke. DESIGN: Observational prospective study. SETTING: Mixed ICU. Third level hospital. PATIENTS: Sixty adult patients. Consecutive sample. INTERVENTIONS: None. VARIABLES OF INTEREST: Epidemiological data, time from symptom onset to EVT, angiographic result, length of stay, days on mechanical ventilation, neurological complications, National Institutes of Health Stroke Scale (NIHSS) at ICU admission and discharge, modified Rankin scale score (mRS) at one year. RESULTS: Mean age 68,90±8,84years. Median time from symptom onset to EVT: 180minutes. Median NIHSS at admission: 17,5; at discharge: 3. Distal flow was achieved in 90% of cases. Median ICU stay: 3 days. Mechanical ventilation: 81,7.%. Functional independence (mRS≤2) 50% at one year. Deaths: 22 (36,6%) of which 8 (13,3%) died during UCI stay and the rest during the first year. CONCLUSIONS: The factors relating to a worse functional outcome were symptomatic hemorrhage transformation, lack of recanalization and complications during EVT. The factors relating to mortality were symptomatic hemorrhage and hydrocephalus. Distal flow was achieve in most cases with a low complication rate. Half of the patients presented functional independence one year after the stroke.

Analgesia paravertebral torácica continua tras cirugía mínimamente invasiva de cierre de comunicación interauricular en población pediátrica: análisis de eficacia y seguridad / Continuous thoracic paravertebral analgesia after minimally invasive atrial septal defect closure surgery in pediatric population: Effectiveness and safety analysis

Introducción: La toracotomía lateral está sustituyendo la esternotomía media clásica para el cierre de la comunicación interauricular (CIA) en niños con objetivo de obtener un menor impacto estético. El bloqueo paravertebral continuo se ha descrito como una técnica analgésica efectiva y segura en niños. El objetivo del estudio es valorar el control analgésico tras el cierre de CIA por toracotomía, mediante la administración de anestésico local en perfusión continua a través de un catéter paravertebral torácico (CPV) en población pediátrica, y su efectividad en un programa fast-track. Métodos: Estudio transversal descriptivo. Se analizaron datos de efectividad analgésica, datos perioperatorios y relacionados con la seguridad en 21 pacientes intervenidos de cierre de CIA mediante toracotomía con CPV. En el periodo postoperatorio se empleó una perfusión continua a través del CPV de bupivacaína al 0,125% y fentanilo (1μg.ml-1) a 0,2ml.kg-1.h-1. Resultados: La mediana de las puntuaciones medias en las escalas de dolor de cada paciente fue 1,5. Todos los pacientes se extubaron en quirófano. Ningún paciente con CPV requirió rescate con opioides. La mediana de tiempo de estancia en la unidad de cuidados intensivos pediátricos fue de 48h. Se objetivaron 3 eventos adversos relacionados con el CPV: uno debido a mala posición y 2 por salida accidental. No se registraron otras complicaciones ni casos de toxicidad por anestésicos locales. Conclusiones: El CPV proporciona una analgesia efectiva y segura en el postoperatorio de cierre de CIA mediante toracotomía en el contexto de un protocolo fast-track disminuyendo el consumo postoperatorio de opioides.(AU)

Introduction: Lateral thoracotomy is replacing traditional median sternotomy for atrial septal defect (ASD) closure in children in order to improve cosmetic outcomes. Continuous paravertebral block has been described as an effective and safe analgesic technique in children. The aim of this study is to assess pain management by continuous perfusion of local anesthetic through a thoracic paravertebral catheter (PVC) in a pediatric population after thoracotomy closure of ASD, and its effectiveness in a fast-track program. Methods: Descriptive cross-sectional study. Analgesic effectiveness, perioperative and safety-related data were analyzed in 21 patients who underwent thoracotomy closure of ASD with PVC. In the postoperative period, patients received continuous perfusion of bupivacaine 0.125% and fentanyl (1 μg.ml-1) at 0.2ml.kg-1.h-1 through the PVC. Results: The median of mean pain scale score for each patient was 1.5. All patients were extubated in the operating theatre. No patient with PVC required opioid rescue. The median length of stay in the Pediatric Intensive Care Unit was 48hours. There were 3 adverse events related to PVC: 1 due to malposition and 2 due to accidental removal. No other complications or cases of local anesthetic toxicity were recorded. Conclusions: PVC provides effective, safe, opioid-saving analgesia in the postoperative period of ASD closure by thoracotomy in the context of a fast-track protocol.(AU)

Planificación y manejo anestésico para cesárea en gestante con neumonía por SARS-CoV-2 / Anesthetic planning and management for a caesarian section in a pregnant woman affected by SARS-COV-2 pneumonía

Las mujeres embarazadas experimentan cambios fisiológicos e inmunológicos que les hacen más susceptibles a infecciones víricas o bacterianas, por lo que se les ha considerado grupo vulnerable frente al SARS-CoV-2. Así mismo, pueden desarrollar una forma grave de la enfermedad que requiera finalizar la gestación para mejorar la situación respiratoria o para salvaguardar el bienestar fetal que puede verse afectado por el estado crítico de la madre. En este contexto, cualquier intervención demanda una minuciosa planificación por parte del equipo quirúrgico en general y del anestesiólogo en particular tanto para asegurar el bienestar maternofetal como para evitar posibles contagios del personal sanitario. Describimos el caso de una gestante de 37semanas ingresada en la Unidad de Reanimación con soporte ventilatorio mediante alto flujo por insuficiencia respiratoria severa debida a COVID-19 que precisa ser sometida a cesárea urgente.(AU)

Pregnant women experience physiological and immunological changes which make them more prone to all kind of viral and bacterial infections, this is because they have been considered as vulnerable group if infected by SARS-CoV-2. They could even deploy a severe form of this disease which may require to end pregnancy to improve oxygenation and to safeguard foetal wellbeing the in case the mother situation gets worse. In this scenario, any intervention would require a detailed planning by the whole surgical team, and, specifically, by the anaesthesiologists, in order to guarantee both mother and child wellbeing and to prevent from infections all the healthcare team. We describe the case of 37week pregnant woman, admitted in our Critical Care Unit with respiratory high flows device support, due to severe respiratory failure due to COVID-19 which needed an urgent caesarean section.(AU)

Transport of a large neutral amino acid (phenylalanine) in a human intestinal epithelial cell line: Caco-2.

We have characterized the transcellular transport of a large neutral amino acid (LNAA) in Caco-2 cell monolayers. The apical (AP) to basolateral (BL) transport of phenylalanine (Phe) was approximately 10-times faster than BL-to-AP transport. The evidence for the carrier-mediated AP-to-BL transport of Phe include: (a) temperature dependence and saturability, (b) Phe transport was not affected by a reverse gradient, (c) the activation energy for transport was 12.0 kcal/mol, and (d) an excess amount of unlabeled Phe caused a 75% reduction in transport rate and a delay (lag time) in the appearance of Phe in the BL side. The Vm and Km for Phe transport were 572.4 pmol.mg protein-1.min-1 and 0.56 mM, respectively. Phe transport was decreased in the absence of glucose and in the presence of sodium azide or ouabain. The carrier interacted with LNAAs and with cationic amino acids but not with small neutral or anionic amino acids.

Transport of bile acids in a human intestinal epithelial cell line, Caco-2.

The transport of taurocholic acid (TA) across Caco-2 cell monolayers was dependent on time in culture and reached a plateau after 28 days, at which time the apical (AP)-to-basolateral (BL) transport was 10-times greater than BL-to-AP transport. The amounts of TA inside the cells following application of 10 nM [14C]TA to the AP or BL side of the monolayers (30 min) were approximately equal (54.4 +/- 2.7 and 64.6 +/- 2.8 fmol/mg protein, respectively). AP-to-BL transport of TA was saturable and temperature-dependent. Vmax and Km for transport were 13.7 pmol/mg protein per min and 49.7 microM, respectively. The transport of TA had an activation energy of 13.2 kcal.mol-1, required Na+ and glucose. AP-to-BL transport of [14C]TA was inhibited by the co-administration (on the AP side) of either unlabeled TA or deoxycholate, but it was not reduced by the presence of unlabeled TA on the BL side.

Planificación y manejo anestésico para cesárea en gestante con neumonía por SARS-CoV-2 / Anesthetic planning and management for a caesarian section in a pregnant woman affected by SARS-COV-2 pneumonía

Las mujeres embarazadas experimentan cambios fisiológicos e inmunológicos que les hacen más susceptibles a infecciones víricas o bacterianas, por lo que se les ha considerado grupo vulnerable frente al SARS-CoV-2. Así mismo, pueden desarrollar una forma grave de la enfermedad que requiera finalizar la gestación para mejorar la situación respiratoria o para salvaguardar el bienestar fetal que puede verse afectado por el estado crítico de la madre. En este contexto, cualquier intervención demanda una minuciosa planificación por parte del equipo quirúrgico en general y del anestesiólogo en particular tanto para asegurar el bienestar maternofetal como para evitar posibles contagios del personal sanitario. Describimos el caso de una gestante de 37semanas ingresada en la Unidad de Reanimación con soporte ventilatorio mediante alto flujo por insuficiencia respiratoria severa debida a COVID-19 que precisa ser sometida a cesárea urgente

Pregnant women experience physiological and immunological changes which make them more prone to all kind of viral and bacterial infections, this is because they have been considered as vulnerable group if infected by SARS-CoV-2. They could even deploy a severe form of this disease which may require to end pregnancy to improve oxygenation and to safeguard foetal wellbeing the in case the mother situation gets worse. In this scenario, any intervention would require a detailed planning by the whole surgical team, and, specifically, by the anaesthesiologists, in order to guarantee both mother and child wellbeing and to prevent from infections all the healthcare team. We describe the case of 37week pregnant woman, admitted in our Critical Care Unit with respiratory high flows device support, due to severe respiratory failure due to COVID-19 which needed an urgent caesarean section

Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence.

Dilated cardiomyopathy (DCM) is the most frequent cause of heart failure and the leading indication for heart transplantation. Here we show that epigenetic regulator and central transcriptional instructor in adult stem cells, Bmi1, protects against DCM by repressing cardiac senescence. Cardiac-specific Bmi1 deletion induces the development of DCM, which progresses to lung congestion and heart failure. In contrast, Bmi1 overexpression in the heart protects from hypertrophic stimuli. Transcriptome analysis of mouse and human DCM samples indicates that p16(INK4a) derepression, accompanied by a senescence-associated secretory phenotype (SASP), is linked to severely impaired ventricular dimensions and contractility. Genetic reduction of p16(INK4a) levels reverses the pathology of Bmi1-deficient hearts. In parabiosis assays, the paracrine senescence response underlying the DCM phenotype does not transmit to healthy mice. As senescence is implicated in tissue repair and the loss of regenerative potential in aging tissues, these findings suggest a source for cardiac rejuvenation.

Assessing the absorption of new pharmaceuticals.

The advent of more efficient methods to synthesize and screen new chemical compounds is increasing the number of chemical leads identified in the drug discovery phase. Compounds with good biological activity may fail to become drugs due to insufficient oral absorption. Selection of drug development candidates with adequate absorption characteristics should increase the probability of success in the development phase. To assess the absorption potential of new chemical entities numerous in vitro and in vivo model systems have been used. Many laboratories rely on cell culture models of intestinal permeability such as, Caco-2, HT-29 and MDCK. To attempt to increase the throughput of permeability measurements, several physicochemical methods such as, immobilized artificial membrane (IAM) columns and parallel artificial membrane permeation assay (PAMPA) have been used. More recently, much attention has been given to the development of computational methods to predict drug absorption. However, it is clear that no single method will sufficient for studying drug absorption, but most likely a combination of systems will be needed. Higher throughput, less reliable methods could be used to discover 'loser' compounds, whereas lower throughput, more accurate methods could be used to optimize the absorption properties of lead compounds. Finally, accurate methods are needed to understand absorption mechanisms (efflux-limited absorption, carrier-mediated, intestinal metabolism) that may limit intestinal drug absorption. This information could be extremely valuable to medicinal chemists in the selection of favorable chemo-types. This review describes different techniques used for evaluating drug absorption and indicates their advantages and disadvantages.

Polarized transport of docetaxel and vinblastine mediated by P-glycoprotein in human intestinal epithelial cell monolayers.

The expression of the multidrug transporter P-glycoprotein has been studied in two human intestinal epithelial cell lines. No functional expression of P-glycoprotein was found in the differentiated HT29-18-C1 cell line. The expression of P-glycoprotein in the Caco-2 cell line was very high, as judged by immunoblotting and by active efflux of vinblastine. The polarized transport of vinblastine in the basolateral to apical direction was temperature and energy dependent, and was reduced by P-glycoprotein inhibitors such as verapamil, chlorpromazine and reserpine. This adds further evidence that the polarized transport of vinblastine across Caco-2 monolayers is mediated by P-glycoprotein. The anticancer drug docetaxel (Taxotere) was transported in a polarized manner: basolateral to apical permeability was 20-fold higher than in the reverse direction. This polarized transport was inhibited by verapamil, chlorpromazine and reserpine, thus demonstrating that docetaxel is a substrate of P-glycoprotein. The implications of these results for the pharmacokinetics and toxicity of taxoids are discussed.

Somatomedin-C and growth hormone levels in anorexia nervosa in relation to the puberal or post puberal stages.

1. Plasma concentrations of somatomedin-C and GH were determined in 21 patients diagnosed as anorexia nervosa (AN) and in 44 controls. 2. Somatomedin-C concentrations were significantly lower in pubertal AN patients than in controls, but not in post pubertal patients. 3. GH was increased in both pubertal and post pubertal AN patients, although more in pubertal AN patients. 4. Our results suggest that the hormonal alterations that appear in AN constitute a mechanism of defense against starvation. The activation of these defense mechanisms and the degree of modification produced in normal hormonal patterns depend not only on caloric intake but also on metabolic requirements.