GSDMD gene knockout alleviates hyperoxia-induced hippocampal brain injury in neonatal mice.

BACKGROUND: Neonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain's inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found pharmacological inhibition of caspase-1, which blocks GSDMD activation, attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury. METHODS: Newborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O2) from postnatal days 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1) and CD68, markers of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes. RESULTS: Hyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O2 exposure did not increase AIF1 + , CD68 + , or TUNEL + cell numbers or decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air-exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, hypoxia-induced factor 1 pathway, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO. CONCLUSIONS: GSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants.

Multimodal magnetic resonance imaging after experimental moderate and severe traumatic brain injury: A longitudinal correlative assessment of structural and cerebral blood flow changes.

Traumatic brain injury (TBI) is a worldwide problem that results in death or disability for millions of people every year. Progressive neurological complications and long-term impairment can significantly disrupt quality of life. We demonstrated the feasibility of multiple magnetic resonance imaging (MRI) modalities to investigate and predict aberrant changes and progressive atrophy of gray and white matter tissue at several acute and chronic time points after moderate and severe parasagittal fluid percussion TBI. T2-weighted imaging, diffusion tensor imaging (DTI), and perfusion weighted imaging (PWI) were performed. Adult Sprague-Dawley rats were imaged sequentially on days 3, 14, and 1, 4, 6, 8, and 12 months following surgery. TBI caused dynamic white and gray matter alterations with significant differences in DTI values and injury-induced alterations in cerebral blood flow (CBF) as measured by PWI. Regional abnormalities after TBI were observed in T2-weighted images that showed hyperintense cortical lesions and significant cerebral atrophy in these hyperintense areas 1 year after TBI. Temporal DTI values indicated significant injury-induced changes in anisotropy in major white matter tracts, the corpus callosum and external capsule, and in gray matter, the hippocampus and cortex, at both early and chronic time points. These alterations were primarily injury-severity dependent with severe TBI exhibiting a greater degree of change relative to uninjured controls. PWI evaluating CBF revealed sustained global reductions in the cortex and in the hippocampus at most time points in an injury-independent manner. We next sought to investigate prognostic correlations across MRI metrics, timepoints, and cerebral pathology, and found that diffusion abnormalities and reductions in CBF significantly correlated with specific vulnerable structures at multiple time points, as well as with the degree of cerebral atrophy observed 1 year after TBI. This study further supports using DTI and PWI as a means of prognostic imaging for progressive structural changes after TBI and emphasizes the progressive nature of TBI damage.

Post-stroke low-frequency whole-body vibration improves cognition in middle-aged rats of both sexes.

Low-frequency whole-body vibration (WBV; 40 Hz), a low impact form of exercise, intervention for a month following moderate transient middle-cerebral artery occlusion (tMCAO) reduces infarct volume and improves motor function in reproductively senescent, middle-aged female rats. Since post-stroke cognitive decline remains a significant problem, the current study aims to investigate the efficacy of WBV in ameliorating post-tMCAO cognitive deficits and to determine the underlying putative mechanism(s) conferring benefits of WBV in middle-aged rats. Middle-aged rats of both sexes were randomly assigned to tMCAO (90 min) or sham surgery followed by exposure to either WBV (twice a day for 15 min each for 5 days a week over a month) or no WBV treatment groups. Following the last WBV treatment, rats were tested for hippocampus-dependent learning and memory using a water maze followed by harvesting brain and blood samples for histopathological and inflammatory marker analyses, respectively. Results show that post-tMCAO WBV significantly lessens cognitive deficits in rats of both sexes. Post-tMCAO WBV significantly decreased circulating pro-inflammatory cytokines and increased serum levels of irisin, a muscle-derived hormone that may play a role in brain metabolism and inflammation regulation, which suggests putative beneficial mechanisms of WBV.

Long-Term Stability Analysis Toward <10-14 Level for a Highly Compact POP Rb Cell Atomic Clock.

Long-term frequency instabilities in vapor-cell clocks mainly arise from fluctuations of the experimental and environmental parameters that are converted to clock frequency fluctuations via various physical processes. Here, we discuss the frequency sensitivities and the resulting stability limitations at one-day timescale for a rubidium vapor-cell clock based on a compact magnetron-type cavity operated in air (no vacuum environment). Under ambient laboratory conditions, the external atmospheric pressure fluctuations may dominantly limit the clock stability via the barometric effect. We establish a complete long-term instability budget for our clock operated under stable pressure conditions. Where possible, the fluctuations of experimental parameters are measured via the atomic response. The measured clock instability of at one day is limited by the intensity light-shift effect, which could further be reduced by active stabilization of the laser intensity or stronger optical pumping. The analyses reported here show the way toward simple, compact, and low-power vapor-cell atomic clocks with excellent long-term stabilities ≤ 10-14 at one day when operated in ambient laboratory conditions.

Barometric Effect in Vapor-Cell Atomic Clocks.

Vapor-cell atomic clocks are compact and high-performance frequency references employed in various applications ranging from telecommunication to global positioning systems. Environmental sensitivities are often the main sources of long-term instabilities of the clock frequency. Among these sensitivities, the environmental pressure shift describes the clock frequency change with respect to the environmental pressure variations. We report here on our theoretical and experimental analysis of the environmental pressure shift on rubidium atomic frequency standards (RAFSs) operated under open atmosphere. By using an unsealed high-performance laser-pumped rubidium standard, we demonstrate that the deformation of the vapor-cell volume induced by the environmental pressure changes (i.e., barometric effect) is the dominant environmental pressure shift in a standard laboratory environment. An experimental barometric coefficient of /hPa is derived, in good agreement with theory and with previously reported measurements of frequency shifts of RAFS operated when transiting to vacuum.

Characterization of Frequency-Doubled 1.5- m Lasers for High-Performance Rb Clocks.

We report on the characterization of two fiber-coupled 1.5- diode lasers, frequency-doubled and stabilized to Rubidium (Rb) atomic resonances at 780 nm. Such laser systems are of interest in view of their implementation in Rb vapor-cell atomic clocks, as an alternative to lasers emitting directly at 780 nm. The spectral properties and the instabilities of the frequency-doubled lasers are evaluated against a state-of-the-art compact Rb-stabilized laser system based on a distributed-feedback laser diode emitting at 780 nm. All three lasers are frequency stabilized using essentially identical Doppler-free spectroscopy schemes. The long-term optical power fluctuations at 780 nm are measured, simultaneously with the frequency instability measurements done by three beat notes established between the three lasers. One of the frequency-doubled laser systems shows at 780 nm excellent spectral properties. Its relative intensity noise <10-12 Hz-1 is one order of magnitude lower than the reference 780-nm laser, and the frequency noise <106 Hz2/Hz is limited by the laser current source. Its optical frequency instability is at s, limited by the reference laser, and better than at all timescales up to one day. We also evaluate the impact of the laser spectral properties and instabilities on the Rb atomic clock performance, in particular taking into account the light-shift effect. Optical power instabilities on long-term timescales, largely originating from the frequency-doubling stage, are identified as a limitation in view of high-performance Rb atomic clocks.

Rb vapor-cell clock demonstration with a frequency-doubled telecom laser.

We employ a recently developed laser system, based on a low-noise telecom laser emitting around 1.56 µm, to evaluate its impact on the performance of an Rb vapor-cell clock in a continuous-wave double-resonance scheme. The achieved short-term clock instability below 2.5·10-13·τ-1/2 demonstrates, for the first time, the suitability of a frequency-doubled telecom laser for this specific application. We measure and study quantitatively the impact of laser amplitude and frequency noises and of the ac Stark shift, which limit the clock frequency stability on short timescales. We also report on the detailed noise budgets and demonstrate experimentally that, under certain conditions, the short-term stability of the clock operated with the low-noise telecom laser is improved by a factor of three compared to clock operation using the direct 780-nm laser.

Una aproximación desde la física a las consecuencias patológicas de la longitud excesiva del cordón umbilical / A physics approach to the consequences of excess umbilical cord length

Introducción: el cordón umbilical es una estructura incomprendida a pesar de transportar todo lo que un feto necesita para crecer y subsistir. Cada una de sus características es relevante, y la principal es la longitud, la cual, cuando está alterada, se relaciona con pobre pronóstico neurológico y muerte fetal. Materiales y métodos: con base en la revisión de principios físicos, se proponen fórmulas que podrían explicar la importancia de la longitud del cordón por sus repercusiones hemodinámicas. Resultados: se analizó la circulación fetal desde el corazón hasta la red capilar vellositaria en el plato placentario y, por medio de fórmulas físicas, se plantea la importancia de la longitud del cordón en la perfusión fetal. Conclusiones: las complicaciones clínicas conocidas para la excesiva longitud del cordón umbilical fueron analizadas desde el punto de vista de la física, dejando listas las fórmulas para ser alimentadas con datos reales provenientes de doppler fetales y mediciones del cordón umbilical.

Introduction: Despite its role of transporting all the things that a foetus needs to grow and survive, the umbilical cord is still poorly understood. All of its characteristics are relevant, and paramount among them is its length. When abnormal, length is associated with poor neurological prognosis and foetal demise. Materials and methods: Based on a review of physics principles, formulae were proposed in an attempt to explain the importance of umbilical cord length on the basis of its haemodynamic repercussions. Results: Foetal circulation was analysed from the heart to the placental villous capillaries and physics formulae were used to describe the importance of umbilical cord length in foetal perfusion. Conclusions: Clinical complications known to be associated with excess umbilical cord length were analysed from the physics perspective, and formulae were established for use with real data derived from foetal Doppler scans and umbilical cord measurements.

Periodic 17ß-estradiol pretreatment protects rat brain from cerebral ischemic damage via estrogen receptor-ß.

Although chronic 17ß-estradiol (E2) has been shown to be a cognition-preserving and neuroprotective agent in animal brain injury models, concern regarding its safety was raised by the failed translation of this phenomenon to the clinic. Previously, we demonstrated that a single bolus of E2 48 hr prior to ischemia protected the hippocampus from damage in ovariectomized rats via phosphorylation of cyclic-AMP response element binding protein, which requires activation of estrogen receptor subtype beta (ER-ß). The current study tests the hypothesis that long-term periodic E2-treatment improves cognition and reduces post-ischemic hippocampal injury by means of ER-ß activation. Ovariectomized rats were given ten injections of E2 at 48 hr intervals for 21 days. Hippocampal-dependent learning, memory and ischemic neuronal loss were monitored. Results demonstrated that periodic E2 treatments improved spatial learning, memory and ischemic neuronal survival in ovariectomized rats. Additionally, periodic ER-ß agonist treatments every 48 hr improved post-ischemic cognition. Silencing of hippocampal ER-ß attenuated E2-mediated ischemic protection suggesting that ER-ß plays a key role in mediating the beneficial effects of periodic E2 treatments. This study emphasizes the need to investigate a periodic estrogen replacement regimen to reduce cognitive decline and cerebral ischemia incidents/impact in post-menopausal women.

Evolución clínica y radiológica de pacientes intervenidos de artroplastia total de cadera con prótesis de resuperficialización metal-metal. Reporte preliminar / Clinical and radiological patients undergoing total hip arthroplasty with prosthetic metal-metal resurfacing. preliminary report

La degeneración articular de la cadera en pacientes jóvenes requiere alternativas específicas de tratamiento para el manejo de esta población. Las prótesis de resuperficialización con superficies metal metal son una opción. Los reportes con seguimientos a corto y mediano plazo son muy prometedores, además los diferentes estudios de laboratorio soportan las bases teóricas para su éxito. En este estudio descriptivo, observacional tipo serie de casos se describe la evolución clínica y radiológica de pacientes intervenidos de artroplastia total de cadera con prótesis de resuperficialización metal-metal en el Hospital El Tunal de Bogotá. Se presentan los resultados de 31 caderas (27 pacientes) con una edad promedio de 50 años y un seguimiento medio de 16 meses, con un buen resultado funcional POP con una mediana de 96 puntos en la Escala de Harris. Se describen las complicaciones y su relación con los diferentes factores analizados.

Accidentes cerebrovasculares hemorrágicos intraparenquimatosos / Cerebrovascular injuries intraparenchymotous hemorrhage

Los Accidentes Cerebrovasculares (AVC) constituyen una importante causa de morbimortalidad en las estadísticas de todos los países del mundo. Aproximadamente el 10 por ciento de los ACV son de tipo hemorrágico. La Hipertensión Arterial (HTA) es el factor de riesgo más frecuentemente asociado a esta entidad, en especial por los cambios que produce a nivel vascular. Se presentan los resultados obtenidos en un estudio retrospectivo y descriptivo del comportamiento clínico de esta entidad en pacientes ingresados en el Hospital Militar "Dr. Carlos Arvelo" en el lapso comprendido entre enero de 1980 y dieciembre de 1994. Se estudiaron 106 pacietes con un promedio de edad de 57 años (rango: 21 a 93 años), la mayoría del sexo masculino (67 por ciento). En 32 por ciento se apreciaron antecedentes de ACV previo, casi siempre de tipo isquémico. En 55 por ciento los síntomas se iniciaron en forma súbita. El factor etiológico ms frecuente fue la HTA (58,4 por ciento) y en menor proporción se observaron lesiones de ocupación de espacio, aneurismas y otras malformaciones vasculares, uso de anticoagulantes y drogas de abuso. El déficit motor fue la manifestación clínica más frecuente (89 por ciento). Los núcleos de la base constituyen la localización más observada (55,7 por ciento). En 12,2 por ciento de los pacientes se evidenció drenaje de la hemorragia al sistema ventricular. Se analizan las modalidades terapéuticas médicas y quirúrgicas.