Anesthesia-induced hippocampal-cortical hyperactivity and tau hyperphosphorylation impair remote memory retrieval in Alzheimer's disease.

INTRODUCTION: Anesthesia often exacerbates memory recall difficulties in individuals with Alzheimer's disease (AD), but the underlying mechanisms remain unclear. METHODS: We used in vivo Ca2+ imaging, viral-based circuit tracing, and chemogenetic approaches to investigate anesthesia-induced remote memory impairment in mouse models of presymptomatic AD. RESULTS: Our study identified pyramidal neuron hyperactivity in the anterior cingulate cortex (ACC) as a significant contributor to anesthesia-induced remote memory impairment. This ACC hyperactivation arises from the disinhibition of local inhibitory circuits and increased excitatory inputs from the hippocampal CA1 region. Inhibiting hyperactivity in the CA1-ACC circuit improved memory recall after anesthesia. Moreover, anesthesia led to increased tau phosphorylation in the hippocampus, and inhibiting this hyperphosphorylation prevented ACC hyperactivity and subsequent memory impairment. DISCUSSION: Hippocampal-cortical hyperactivity plays a role in anesthesia-induced remote memory impairment. Targeting tau hyperphosphorylation shows promise as a therapeutic strategy to mitigate anesthesia-induced neural network dysfunction and retrograde amnesia in AD.

TrkB-mediated activation of the phosphatidylinositol-3-kinase/Akt cascade reduces the damage inflicted by oxygen-glucose deprivation in area CA3 of the rat hippocampus.

The selective vulnerability of hippocampal area CA1 to ischemia-induced injury is a well-known phenomenon. However, the cellular mechanisms that confer resistance to area CA3 against ischemic damage remain elusive. Here, we show that oxygen-glucose deprivation-reperfusion (OGD-RP), an in vitro model that mimic the pathological conditions of the ischemic stroke, increases the phosphorylation level of tropomyosin receptor kinase B (TrkB) in area CA3. Slices preincubated with brain-derived neurotrophic factor (BDNF) or 7,8-dihydroxyflavone (7,8-DHF) exhibited reduced depression of the electrical activity triggered by OGD-RP. Consistently, blockade of TrkB suppressed the resistance of area CA3 to OGD-RP. The protective effect of TrkB activation was limited to area CA3, as OGD-RP caused permanent suppression of CA1 responses. At the cellular level, TrkB activation leads to phosphorylation of the accessory proteins SHC and Gab as well as the serine/threonine kinase Akt, members of the phosphoinositide 3-kinase/Akt (PI-3-K/Akt) pathway, a cascade involved in cell survival. Hence, acute slices pretreated with the Akt antagonist MK2206 in combination with BDNF lost the capability to resist the damage inflicted with OGD-RP. Consistently, with these results, CA3 pyramidal cells exhibited reduced propidium iodide uptake and caspase-3 activity in slices pretreated with BDNF and exposed to OGD-RP. We propose that PI-3-K/Akt downstream activation mediated by TrkB represents an endogenous mechanism responsible for the resistance of area CA3 to ischemic damage.

Protein Tyrosine Kinase Fyn Regulates TLR4-Elicited Responses on Mast Cells Controlling the Function of a PP2A-PKCα/ß Signaling Node Leading to TNF Secretion.

Mast cells produce proinflammatory cytokines in response to TLR4 ligands, but the signaling pathways involved are not fully described. In this study, the participation of the Src family kinase Fyn in the production of TNF after stimulation with LPS was evaluated using bone marrow-derived mast cells from wild-type and Fyn-deficient mice. Fyn(-/-) cells showed higher LPS-induced secretion of preformed and de novo-synthesized TNF. In both cell types, TNF colocalized with vesicle-associated membrane protein (VAMP)3-positive compartments. Addition of LPS provoked coalescence of VAMP3 and its interaction with synaptosomal-associated protein 23; those events were increased in the absence of Fyn. Higher TNF mRNA levels were also observed in Fyn-deficient cells as a result of increased transcription and greater mRNA stability after LPS treatment. Fyn(-/-) cells also showed higher LPS-induced activation of TAK-1 and ERK1/2, whereas IκB kinase and IκB were phosphorylated, even in basal conditions. Increased responsiveness in Fyn(-/-) cells was associated with a lower activity of protein phosphatase 2A (PP2A) and augmented activity of protein kinase C (PKC)α/ß, which was dissociated from PP2A and increased its association with the adapter protein neuroblast differentiation-associated protein (AHNAK, desmoyokin). LPS-induced PKCα/ß activity was associated with VAMP3 coalescence in WT and Fyn-deficient cells. Reconstitution of MC-deficient Wsh mice with Fyn(-/-) MCs produced greater LPS-dependent production of TNF in the peritoneal cavity. Our data show that Fyn kinase is activated after TLR4 triggering and exerts an important negative control on LPS-dependent TNF production in MCs controlling the inactivation of PP2Ac and activation of PKCα/ß necessary for the secretion of TNF by VAMP3(+) carriers.

The economic impact of prematurity and bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is one of the most serious chronic lung diseases in infancy and one of the most important sequels of premature birth (prevalence of 15-50%). Our objective was to estimate the cost of BPD of one preterm baby, with no other major prematurity-related complications, during the first 2 years of life in Spain. Data from the Spanish Ministry of Health regarding costs of diagnosis-related group of preterm birth, hospital admissions and visits, palivizumab administration, and oxygen therapy in the year 2013 were analyzed. In 2013, 2628 preterm babies were born with a weight under 1500 g; 50.9% were males. The need for respiratory support was 2.5% needed only oxygen therapy, 39.5% required conventional mechanical ventilation, and 14.9% required high-frequency ventilation. The incidence of BPD was of 34.9%. The cost of the first 2 years of life of a preterm baby with BPD and no other major prematurity-related complications ranged between 45,049.81 € and 118,760.43 €, in Spain, depending on birth weight and gestational age. If the baby required home oxygen therapy or developed pulmonary hypertension, this cost could add up to 181,742.43 €. CONCLUSION: Prematurity and BPD have an elevated cost, even for public health care systems. This cost will probably increase in the coming years if the incidence and survival of preterm babies keeps rising. The development of new therapies and preventive strategies to decrease the incidence of BPD and other morbidities associated with prematurity should be a priority. What is known: • Bronchopulmonary dysplasia (BPD) is a serious chronic lung disease related with premature birth. • BPD is an increasing disease due to the up-rise in the number of premature births. What is new: • The economic cost of preterm birth and BPD has never before been estimated in Spain nor published with European data. • Preterm babies with BPD and a good clinical outcome carry also an important economic and social burden.

Neuronal hypofunction and network dysfunction in a mouse model at an early stage of tauopathy.

We previously reported altered neuronal Ca 2+ dynamics in the motor cortex of 12-month-old JNPL3 tauopathy mice during quiet wakefulness or forced running, with a tau antibody treatment significantly restoring the neuronal Ca 2+ activity profile and decreasing pathological tau in these mice 1 . Whether neuronal functional deficits occur at an early stage of tauopathy and if tau antibody treatment is effective in younger tauopathy mice needed further investigation. In addition, neuronal network activity and neuronal firing patterns have not been well studied in behaving tauopathy models. In this study, we first performed in vivo two-photon Ca 2+ imaging in JNPL3 mice in their early stage of tauopathy at 6 months of age, compared to 12 month old mice and age-matched wild-type controls to evaluate neuronal functional deficits. At the animal level, frequency of neuronal Ca 2+ transients decreased only in 6 month old tauopathy mice compared to controls, and only when animals were running on a treadmill. The amplitude of neuronal transients decreased in tauopathy mice compared to controls under resting and running conditions in both age groups. Total neuronal activity decreased only in 6 month old tauopathy mice compared to controls under resting and running conditions. Within either tauopathy or wild-type group, only total activity decreased in older wild-type animals. The tauopathy mice at different ages did not differ in neuronal Ca 2+ transient frequency, amplitude or total activity. In summary, neuronal function did significantly attenuate at an early age in tauopathy mice compared to controls but interestingly did not deteriorate between 6 and 12 months of age. A more detailed populational analysis of the pattern of Ca 2+ activity at the neuronal level in the 6 month old cohort confirmed neuronal hypoactivity in layer 2/3 of primary motor cortex, compared to wild-type controls, when animals were either resting or running on a treadmill. Despite reduced activity, neuronal Ca 2+ profiles exhibited enhanced synchrony and dysregulated responses to running stimulus. Further ex vivo electrophysiological recordings revealed reduction of spontaneous excitatory synaptic transmission onto and in pyramidal neurons and enhanced excitability of inhibitory neurons in motor cortex, which were likely responsible for altered neuronal network activity in this region. Lastly, tau antibody treatment reduced pathological tau and gliosis partially restored the neuronal Ca 2+ activity deficits but failed to rescue altered network changes. Taken together, substantial neuronal and network dysfunction occurred in the early stage of tauopathy that was partially alleviated with acute tau antibody treatment, which highlights the importance of functional assessment when evaluating the therapeutic potential of tau antibodies. Highlights: Layer 2/3 motor cortical neurons exhibited hypofunction in awake and behaving mice at the early stage of tauopathy.Altered neuronal network activity disrupted local circuitry engagement in tauopathy mice during treadmill running.Layer 2/3 motor cortical neurons in tauopathy mice exhibited enhanced neuronal excitability and altered excitatory synaptic transmissions.Acute tau antibody treatment reduced pathological tau and gliosis, and partially restored neuronal hypofunction profiles but not network dysfunction.

Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer's disease model mice.

There is a demand for noninvasive methods to ameliorate disease. We investigated whether 40-Hz flickering light entrains gamma oscillations and suppresses amyloid-ß in the brains of APP/PS1 and 5xFAD mouse models of Alzheimer's disease. We used multisite silicon probe recording in the visual cortex, entorhinal cortex or the hippocampus and found that 40-Hz flickering simulation did not engage native gamma oscillations in these regions. Additionally, spike responses in the hippocampus were weak, suggesting 40-Hz light does not effectively entrain deep structures. Mice avoided 40-Hz flickering light, associated with elevated cholinergic activity in the hippocampus. We found no reliable changes in plaque count or microglia morphology by either immunohistochemistry or in vivo two-photon imaging following 40-Hz stimulation, nor reduced levels of amyloid-ß 40/42. Thus, visual flicker stimulation may not be a viable mechanism for modulating activity in deep structures.

Population Dynamic of the Annual Halophyte Salicornia ramosissima in Salt Pans: Towards a Sustainable Exploitation of Its Wild Populations.

Halophyte species growing under stressful conditions, such as the annual species of the Salicornia genus, have been recognized as a source of metabolites of pharmacological and nutraceutical interest. Therefore, planning the extraction of individual plants from wild populations in a sustainable way is especially important in the case of annual species. We studied the environmental matrix and population dynamic of four Salicornia ramosissima populations growing at two elevations in salt pans under a Mediterranean climate. In elevated areas, S. ramosissima populations presented maximum plant densities of between 628-6288 plants m-2 that remained almost constant until fruiting. In contrast, populations in depressed zones presented five-times greater soil-seed-bank densities and maximum plant densities than populations in elevated zones. In this context, populations in depressed zones lost c. 60% of their maximum plant densities from the end of spring and through summer. In whatever way the environmental matrix seemed to control the population dynamic of S. ramosissima in depressed zones, the effects of a stressful environment would interact with plant densities. In this sense, we recorded the density-dependent mortality for the densest population (max. 51,558 plants m-2). Our results are useful for planning a sustainable harvesting of natural populations of S. ramosissima.

A Unique Approach to Project-Based Learning (PjBL) in a Veterinary Anatomy Course.

INTRODUCTION: Project-based learning (PjBL) is a teaching methodology designed to engage students in solving real-world problems, acknowledging that students are active agents of their learning process. This methodology has historically been popular in architecture and industrial sciences; however, its use in teaching veterinary anatomy is scarcely published. METHODS: Using information and communication technologies, the PjBL methodology was implemented in a first-year veterinary anatomy course. The methodology included teamwork and the selection of a routine object in the veterinary clinic at the beginning of the academic semester. The project's goal was to analyze the object and associate it with both a domestic animal species and an anatomical region, along with making and presenting a video or a simulation model about the object. RESULTS: More than 80% of students prefer active learning classes compared to traditional classes. In addition, 66% and 86% of students indicate that PjBL allowed them to improve their understanding of theoretical content for the first and second years of post-implementation, respectively. Students' self-assessment indicates that more than 80% of the students (first and second year post-implementation) felt they were responsible for the execution of the project, able to conduct research, and able to develop autonomous learning skills. After 2 years of PjBL implementation, failure rates in the course decreased by 21%. DISCUSSION: In general, PjBL results show that veterinary students prefer active learning activities that allow them to learn in a team-based learning process as well as to develop soft skills such as self-learning, responsibility, and teamwork. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-021-01205-1.

Effects of heavy metal pollution on germination and early seedling growth in native and invasive Spartina cordgrasses.

Seed germination and seedling establishment are the stages most sensitive to abiotic stress in the plant life cycle. We analyzed the effects of copper, zinc and nickel on seed germination and early seedling growth of native Spartina maritima and invasive S. densiflora from polluted and non-polluted estuaries. Germination percentages for either species were not affected by any metal at any tested concentration (up to 2000 µM). However, the increase in metal concentration had negative effects on S. densiflora seedlings. The primary effect was on radicle development, representing initial seedling emergence. Spartina densiflora seedlings emerging from seeds from Tinto Estuary, characterized by high bioavailable metal loads, showed higher tolerance to metals than those from less polluted Odiel and Piedras Estuaries. Comparing our results to metal concentrations in the field, we expect S. densiflora seedling development would be negatively impacted in the most metal-polluted areas in Odiel and Tinto Estuaries.

Prognostic impact of the SYNTAX score II in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: analysis of a four-year all-comers registry.

AIMS: This study aimed to investigate the prognostic impact of the SYNTAX score II (SS-II) on ST-segment elevation myocardial infarction (STEMI) patients undergoing a primary percutaneous coronary intervention (pPCI). METHODS AND RESULTS: This retrospective cohort study included 1,689 patients with STEMI who underwent pPCI between January 2008 and December 2016. The patients were categorised into three groups based on SS-II tertiles (SS-II low tertile <24 [n=585], SS-II intermediate tertile ≥24 and ≤34 [n=567], and SS-II high tertile >34 [n=537]). In-hospital mortality was significantly lower in patients with low and mid SS-II when compared with high SS-II (0.7% vs 0.5% vs 16.4%, p=0.001). During follow-up (median 2.35 years), a high SS-II was positively correlated with MACE (12.3% for low SS-II vs 18.3% for mid SS-II vs 43.2% for high SS-II, p=0.001), all-cause mortality (1.5% vs 3.9% vs 14.2%, p=0.001) and heart failure (0.3% vs 2.7% vs 8.2%, p=0.001). The SS-II showed additive value on top of GRACE, anatomical SYNTAX score and residual SYNTAX score. CONCLUSIONS: The SS-II in patients with STEMI undergoing pPCI adds important prognostic information regarding midterm adverse outcomes, being an independent and powerful predictor of MACE, heart failure and all-cause mortality during follow-up.

Reconsiderando la clasificación psicopatológica desde el punto de vista psicoanalítico-relacional. Lo histérico/ histriónico como modelo / The psychopathological classification revisited from the psychoanalytic-relational standpoint. The hysterical / histrionic as a model

En el momento presente la clasificación psicopatológica destaca por su gran complejidad y confusión, que da lugar a incontables debates. Realizamos una indagación en este terreno partiendo del concepto de "histeria" por tratarse de un diagnóstico proteico y esquivo, que en cierta medida se solapa con el más de moda, pero no menos confuso, "trastorno límite", y con otros trastornos, como la psicosis, lo que hace de él un caso paradigmático dentro de la discusión diagnóstica en general y psicoanalítica en particular. Su presentación multiforme posiblemente ha llevado, en tiempos de positivismo dominante, a su desprestigio y práctica eliminación de los sistemas de clasificación oficiales. Sin embargo, cuando hablamos de "diagnóstico" al referirnos a la personalidad no debemos entenderlo tanto en el sentido de agrupación de signos y síntomas sino como la valoración y descripción de esas pautas complejas de comportamiento cuyo nivel privilegiado de análisis es el de la relación interpersonal, relación que cuando se constituye como área principal de desadaptación permite hablar de "Trastornos de la personalidad". Concluimos que, a pesar de su complejidad, la personalidad histriónica (PH) es un patrón relacional que conserva una presencia muy importante en la clínica psicoterapéutica, en salud mental y en otros ámbitos de la salud, y que precisamente su adecuada valoración y diferenciación de otros patrones relacionales permitirá afinar los sistemas clasificatorios futuros (AU)

Nowadays psychopathological classification is characterized by a great complexity and confusion, which produces innumerable debates. We make here an inquiry focusing on the concept of "hysteria" as starting point, for it is an elusive and protean diagnostic term, which overlaps to some extent to the more fashionable - but not less fuzzy - one of "borderline disorder", as well as to other disorders, the psychosis for instance, making it a paradigmatic case inside the general discussion in psychopathology and psychoanalysis. In these times of positivist thinking the multiform presentation of hysteria has led to its discredit and virtual elimination from the official classification systems. However, when we use the word "diagnostics" for the personality we should not take it as a mere aggregate of signs and symptoms but as the appraisal and description of those complex behavioral patterns whose privileged level of analysis is the interpersonal relationship. When the relationship is the main area of maladjustment constitutes just what is called "personality disorder". We reach the conclusion that histrionic personality is, in spite of its complexity, a relational pattern with a huge presence in the psychotherapeutic clinic, in mental health and in other domains of the health care system, and that its accurate assessment and differentiation from other patterns will improve future classification systems (AU)

Vigilancia de la evolución de 6030 heridas quirúrgicas / Vigilance of the evolution of 6030 surgical wounds

Las infecciones de las heridas quirúrgicas representan una complicación que en algunos casos se asocia a muerte, por lo que el control de las mismas debe ser tarea cotidiana en los servicios de cirugía general. El sistema de vigilancia de heridas parece ser un método efectivo para disminuir las infecciones postoperatorias. Por lo anterior en 1983 se implantó el sistema de vigilancia de heridas quirúrgicas, evaluando los resultados cuatro años después. El primer año de vigilancia sirvió de línea base para analizar el conportamiento de la frecuencia de infecciones. Las heridas se catalogaron en cuatro grupos: I. herida limpia; II. herida limpia-contaminada; III. herida contaminada; IV. herida sucia. La frecuencia de infecciones durante el primer año del estudio fue de 6.3, y en el cuarto año de 4.7 por ciento. El tratamiento de las infecciones de cada grupo dio resultados satisfactorios en los grupos II, III, y IV, en que la reducción fue estadísticamente significativa; en el grupo I ayudó a mantener la frecuencia en cifras aceptables. Se recomienda la vigilancia de las heridas como método útil para el control de las infecciones

Ruptura de hemangioma cavernoso simulando embarazo ectópico / Rupture of hemangioma cavernoso simulation ectopic pregnancy

Los hemangiomas son de muy rara localización en pelvis u órganos genitales femeninos. No se toman en cuenta, habitualmente, entre las posibilidades de diagnóstico diferencial con embarazo ectópico. La literatura sobre el tema es escasa. En esta comunicación se describe el caso de una paciente con hemangioma cavernoso paraovárico, que se presentó con dolor pelviano agudo y prueba positiva para gonadotrofina coriónica humana en sangre. Se hacen consideraciones en torno al actual conocimiento de la localización pelviana de estos tumores y la secreción ectópica de hormonas gonadotróficas

Reconocimiento visual de cadáveres calcinados posterior a la aplicación de dos técnicas de autopsia bucal: un estudio comparativo / Visual identification of calcinated cadavers, following the application of two techniques of oral autopsy: a comparative study

La evidencia dental es determinante en la identificación de cadáveres provenientes de desastres masivos, especialmente cuando éstos involucran la exposición directa al fuego. Si en estos cadáveres son aplicadas las técnicas convencionales de autopsia bucal, se produce la pérdida de la configuración facial, dificultándose el reconocimiento visual por parte de familiares, el cual es importante especialmente cuando los registros dentales antemortem no están disponibles. Se examinaron 166 cadáveres carbonizados o con quemaduras de tercer a cuarto grado, no identificados, los cuales fueron ubicados en dos grupos: grupo 1, con 49 cadáveres a los que se les aplicó el protocolo de autopsia bucal que se sigue de rutina en la Medicatura Forense de la Ciudad de Maracaibo, y grupo 2, con 117 cadáveres examinados según el protocolo de autopsia bucal para cadáveres calcinados, propuesto por Ferreira y cols. (1997). En el grupo 2, se obtuvo como resultado un mayor porcentaje de identificaciones logradas mediante evidencia no dental, gracias a la naturaleza conservadora de la técnica aplicada

La experticia odontológica en el proceso penal / Dental capability in the penal process

El odontólogo forense juega un papel fundamental como testigo experto antes los juzgados civiles cuando se considera la evidencia dental. Se reporta un caso donde el cadáver de una mujer de 28 años fue sepultado en mayo de 1990, víctima aparente de un arrollamiento por vehículo automotor. La necropsia reveló fracturas complejas con deformidad de los huesos de cráneo y cara, producidas por objeto contundente. Posteriormente, la madre de la occisa consignó ante las autoridades una pieza dental y un fragmento de esmalte dentario, que habían sido encontrados en un sitio diferente al descrito como lugar del accidente. Este hallazgo, aunado a otras experticias policiales, planteó la posibilidad de que se estuviera en presencia de un homicidio, siendo el esposo de la víctima el principal sospechoso. Iniciadas las investigaciones, se ordenó la exhumación. Durante la autopsia bucal, pudo comprobarse que la evidencia dental aportada correspondía a la dentadura de la occisa, complementando así la investigación policial que condujo al esclerecimiento de un crimen, a la identificación del autor material y al dictado de una sentencia firme. Constituyéndose de esta manera, la experticia odontológica en un factor determinante en el proceso penal