Neuroprotective effects of meloxicam on transient brain ischemia in rats: the two faces of anti-inflammatory treatments.

The inflammatory response plays an important role in neuroprotection and regeneration after ischemic insult. The use of non-steroidal anti-inflammatory drugs has been a matter of debate as to whether they have beneficial or detrimental effects. In this context, the effects of the anti-inflammatory agent meloxicam have been scarcely documented after stroke, but its ability to inhibit both cyclooxygenase isoforms (1 and 2) could be a promising strategy to modulate post-ischemic inflammation. This study analyzed the effect of meloxicam in a transient focal cerebral ischemia model in rats, measuring its neuroprotective effect after 48 hours and 7 days of reperfusion and the effects of the treatment on the glial scar and regenerative events such as the generation of new progenitors in the subventricular zone and axonal sprouting at the edge of the damaged area. We show that meloxicam's neuroprotective effects remained after 7 days of reperfusion even if its administration was restricted to the two first days after ischemia. Moreover, meloxicam treatment modulated glial scar reactivity, which matched with an increase in axonal sprouting. However, this treatment decreased the formation of neuronal progenitor cells. This study discusses the dual role of anti-inflammatory treatments after stroke and encourages the careful analysis of both the neuroprotective and the regenerative effects in preclinical studies.

Anaplastic thyroid tumor as an embolic source of metastasis.

Tumor-based arterial thromboembolism in patients with cancer is a poorly described concept that lacks evidence for surgical indications owing to its unusual occurrence. The study and understanding of this condition's etiology is, however, essential because it could constitute the initial presentation or determine the prognosis of oncologic disease. In the present report, we have described the case of a 77-year-old female patient with multiple cerebral, splenic, and upper limb arterial embolic episodes. Embolectomy for acute upper limb ischemia revealed the histopathologic diagnosis of an anaplastic thyroid tumor.

Trombectomía mecánica reolítica en urgencia oncológica / Rheolytic mechanical thrombectomy in an oncological emergency

Introducción: la trombosis de las venas hepáticas y de la vena cava inferior puede aparecer hasta en un 10 % de pacientes con tumores intrahepáticos. El fenómeno de tromboembolismo venoso por compresión maligna con o sin sobreinfección presenta mal pronóstico a corto plazo.Caso clínico:paciente de 66 años con historia de colangiocarcinoma tratado mediante resección y nuevo rescate quirúrgico años después por recaída hepática tumoral. En el posoperatorio tuvo un síndrome de Budd-Chiari y una fístula biliar, que se manejaron de forma conservadora. Posteriormente sufrió shock séptico que precisó su ingreso en la Unidad de Cuidados Intensivos. Se realizó angiotomografía computarizada que evidenció un defecto de repleción parcial de la vena cava inferior infra- y supradiafragmática. Se realizó trombectomía mecánica reolítica con dispositivo AngioJet™. Hubo resolución completa de la trombosis sin complicaciones derivadas de la intervención y con remisión tumoral a siete meses del seguimiento.Discusión:la trombectomía reolítica de la vena cava inferior puede ser una alternativa de baja invasividad y segura en pacientes con trombosis de cava de estadio IIIa.(AU)

Introduction: suprahepatic veins and inferior vena cava thrombosis can occur in up to 10 % of patients with intrahepatic tumours. The phenomenon of malignant compression venous thromboembolism with or without added superinfection has a short-term poor prognosis. although there is no gold standard in its management, it has been suggested that thrombectomy can prevent death and major complications.Case report:66-year-old patient with a history of cholangiocarcinoma, treated by resection and a new surgical rescue with chemotherapy and neoadjuvant radiotherapy due to liver tumour relapse. a postoperative complica- tion was registered, due to Budd-Chiari syndrome and a biliary fi stula that were managed conservatively. Weeks later, a septic shock was diagnosed which required admission into Intensive Care Unit. a computed tomography angiography was performed, which showed an almost complete fi lling defect of the infra and supradiaphragmatic inferior vena cava. a rheolytic mechanical thrombectomy with an AngioJet™ device was performed. Complete resolution of the thrombosis without complications derived from the intervention and with tumour remission at six months of subsequent follow-up.Discussion:rheolytic thrombectomy of the inferior vena cava can be a safe and low-invasive alternative in patients with stage IIIa thrombosis.(AU)

Trucos y consejos para optimizar el tiempo de cateterización de arterias visceralesen dispositivos fenestrados (FEVAR) / Tips and tricks to optimize catheterization time of target vessel in fenestrated devices (FEVAR)

Introducción: el tratamiento de aneurismas complejos mediante FEVAR incluye entre sus objetivos un tiempoquirúrgico reducido para poder alcanzar el éxito técnico y clínico. Sin embargo, la canulación y el implante de losstents puente en múltiples arterias viscerales pueden suponer un factor limitante. Para evitar un tiempo de escopia y una dosis de radiación prolongados existen algunas maniobras que pueden ayudar a optimizar el tiempo de cateterización. Material y métodos: se realiza una revisión de los últimos casos tratados mediante endoprótesis fenestradas custom made de Zenith Cook® durante el año 2021 en un servicio de angiología, cirugía vascular y endovascular. El objetivo es mostrar las técnicas que sirven para optimizar el tratamiento de aneurismas complejos y que el cirujano puede emplear con el material habitual. Para ello se muestran varios fragmentos de vídeos de estos procedimientos grabados con el sistema OneView. Resultados: el primer paso clave consiste en la liberación del dispositivo fenestrado. La endoprótesis de Cook® presenta una o varias ligaduras de reducción que la mantienen fruncida hasta garantizar una correcta orientación y un correcto posicionamiento. Asimismo, ofrece la opción de canular las arterias viscerales entre la pared arterial y el dispositivo. Con una planifi cación adecuada y un abordaje sistematizado, el uso de guías coaxiales, catéteres de punta simple o reversa e introductores es esencial. El techo de la endoprótesis permite el avance de guías y de introductores con el soporte sufi ciente para su canulación. Los sistemas precargados permiten la canulación desde el miembro superior o el inferior. En este último caso, se utiliza una guía buddy de 0,014" que ofrece soporte al introductor, ya que lo acerca más aún a la fenestración, de tal modo que potencia el momento de torsión (torque) y el empuje del catéter.

Introduction: the treatment of complex aneurysms using FEVAR includes among its objectives a reduced surgicaltime in order to achieve technical and clinical success. However, cannulation and implantation of bridging stentsin multiple visceral arteries can be a limiting factor. To avoid a protracted scope time and radiation dose, there aresome maneuvers that can help optimize catheterization time. Material and methods: a review of the last cases treated with custom made Zenith Cook® fenestrated endoprostheses during the year 2021 is performed in an angiology, vascular and endovascular surgery service. The objective is to show video clips recorded with the OneView system of these techniques that the surgeon can use with the usual material to optimize the treatment of complex aneurysms.Results: the first key step is the release of the fenestrated device. The Cook® endoprosthesis has one or morereduction ligatures that keep it puckered until it guarantees correct orientation and positioning, as well as theoption of cannulating the visceral arteries between the arterial wall and the device.With proper planning and a systematic approach, the use of coaxial guides with single or reverse tip cathetersand introducers are essential. The roof of the endoprosthesis allows the advancement of guides and introducerswith sufficient support for their cannulation. The preloaded systems allow cannulation from the upper or lowerlimb. In the latter case, a 0.014” buddy guide is used to provide support for the introducer, bringing it even closerto fenestration in such a way as to enhance the torque and thrust of the catheter.

Extracellular Vesicles and Alveolar Epithelial-Capillary Barrier Disruption in Acute Respiratory Distress Syndrome: Pathophysiological Role and Therapeutic Potential.

Extracellular vesicles (EVs) mediate intercellular communication by transferring genetic material, proteins and organelles between different cells types in both health and disease. Recent evidence suggests that these vesicles, more than simply diagnostic markers, are key mediators of the pathophysiology of acute respiratory distress syndrome (ARDS) and other lung diseases. In this review, we will discuss the contribution of EVs released by pulmonary structural cells (alveolar epithelial and endothelial cells) and immune cells in these diseases, with particular attention to their ability to modulate inflammation and alveolar-capillary barrier disruption, a hallmark of ARDS. EVs also offer a unique opportunity to develop new therapeutics for the treatment of ARDS. Evidences supporting the ability of stem cell-derived EVs to attenuate the lung injury and ongoing strategies to improve their therapeutic potential are also discussed.

Tratamiento endovascular con dispositivos ramificados ilíacos: estudio multicéntrico / Endovascular treatment with iliac branch devices: multicenter study

INTRODUCCIÓN: se estima que entre 18 y un 39 % de los pacientes con aneurismas del sector aortoilíaco sometidos a tratamiento endovascular presentan zonas no aptas para el sellado distal en arterias ilíacas comunes. Tradicionalmente, una de las opciones disponibles para abordar dicha situación consiste en realizar un sellado distal a nivel de las arterias ilíacas externas, ocluyendo las arterias hipogástricas. Sin embargo, esto conlleva la aparición de manifestaciones clínicas derivadas de la isquémica pélvica en el 28-55 % de los casos. La utilización de dispositivos ramificados ilíacos (DRI) permite mantener el flujo anterógrado a las arterias hipogástricas, lo que evita este tipo de complicaciones. El objetivo de nuestro estudio es analizar los resultados a medio plazo de la exclusión endovascular de aneurismas del sector aortoilíaco utilizando DRI. MÉTODOS: estudio descriptivo retrospectivo multicéntrico que incluye los DRI utilizados para el tratamiento endovascular de aneurismas de aorta con afectación del sector aortoilíaco entre enero de 2008 y julio de 2019. Se recogieron datos demográficos, anatómicos, intra- y perioperatorios y de seguimiento en tres centros. Las variables de interés analizadas fueron: éxito técnico, mortalidad perioperatoria, incidencia de isquemia pélvica, permeabilidad primaria de rama hipogástrica y rama ilíaca externa, reintervención relacionada con DRI y mortalidad relacionada con el aneurisma. RESULTADOS: se incluyeron 80 DRI implantados en 61 pacientes: 28 (35 %) Gore(R) Excluder(R) Iliac Branch Endoprosthesis y 52 (65 %) Cook(R) Zenith(R) Branch Endovascular Graft. Se implantaron DRI bilaterales en 18 casos (29,5 %). La tasa de éxito técnico fue del 95 % sin que existieran casos de muertes en el periodo perioperatorio. El seguimiento medio fue de 30,1 meses (± 26,3). Se presentaron seis casos de isquemia pélvica durante el seguimiento. La permeabilidad de la rama hipogástrica fue del 97,5 %, del 94,5 % y del 90,6 % a los 6, 12 y 24 meses, respectivamente. La permeabilidad de la rama ilíaca externa fue del 100 %, del 97,3 % y del 95,5 % a los 6, 12 y 24 meses, respectivamente. La tasa libre de reintervención secundaria al DRI fue del 100 %, del 96,8 % y del 94,7 % a los 6, 12 y 24 meses, respectivamente. Se produjo un caso de muerte relacionada con el aneurisma durante el seguimiento. CONCLUSIONES: en nuestra experiencia, los DRI presentan buenos resultados a medio plazo en la exclusión endovascular de aneurismas con afectación del sector aortoilíaco. Estos dispositivos permiten mantener la permeabilidad de las arterias hipogástricas, minimizando la incidencia de isquemia pélvica. A pesar de las escasas complicaciones tardías y la baja tasa de reintervenciones, es necesario realizar un seguimiento a largo plazo para mantener el éxito técnico

INTRODUCTION: it is estimated that between 18-39 % of patients with aorto-iliac aneurysms undergoing endovascular treatment have a no suitable zone for distal sealing in common iliac arteries. Traditionally, one of the options is to perform a distal seal at the external iliac arteries occluding the hypogastric arteries. However, this can lead to complications derived from pelvic ischemia in 28-55 % of cases. The use of iliac branched devices (IBD) allow to maintain the antegrade flow to the hypogastric arteries, avoiding these complications. The objective of our study is to analyze the medium-term results of endovascular exclusion of aorto-iliac aneurysms using IBD. METHODS: a descriptive multicenter retrospective study including the IBD for the endovascular treatment of aneurysms with involvement of the aorto-iliac sector was conducted between January 2008 and July 2019. Demographic, anatomical, intra-perioperative and follow-up data was collected at 3 centers. The variables of interest analyzed were: technical success, perioperative mortality, incidence of pelvic ischemia, primary patency of the hypogastric branch and external iliac branch, DRI-related reoperation, and aneurysm-related mortality. RESULTS: eighty IBDs were included from 61 patients: 28 (35 %) Gore(R) Excluder(R) Iliac Branch Endoprosthesis, and 52 (65 %) Cook(R) Zenith(R) Branch Endovascular Graft. Bilateral IBDs were implanted in 18 cases (29.5 %). The technical success was achieved in 95 % of cases, with no perioperative deaths. The mean follow-up was 30.1 (± 26.3) months. 6 patients presented pelvic ischemia during follow-up. The patency of the hypogastric side branch was 97.5 %, 94.5 %, and 90.6 %, at 6, 12, and 24 months, respectively. The patency of the external iliac side branch was 100 %, 97.3 %, and 95.5 %, at 6, 12, 24 months, respectively. Freedom from reintervention rate secondary to IBD was 100 %, 96.8 %, and 94.7 %, at 6, 12, and 24 months, respectively. There was 1 case of aneurysm-related death during follow-up. CONCLUSIONS: in our experience, IBDs show good medium-term results in endovascular treatment of aorto-iliac aneurysms. These devices allow to maintain the perfusion of the hypogastric arteries, minimizing the incidence of pelvic ischemia. Although the appearance of late complications and the need for reinterventions is low, a long-term follow-up should be carried out to maintain the success of the procedure

Celecoxib-Dependent Neuroprotection in a Rat Model of Transient Middle Cerebral Artery Occlusion (tMCAO) Involves Modifications in Unfolded Protein Response (UPR) and Proteasome.

Stroke is one of the main causes of death and disability worldwide. Ischemic stroke results in unfolded/misfolded protein accumulation in endoplasmic reticulum (ER), a condition known as ER stress. We hypothesized that previously reported neuroprotection of celecoxib, a selective inhibitor of cyclooxygenase-2, in transient middle cerebral artery occlusion (tMCAO) model, relies on the ER stress decrease. To probe this hypothesis, Sprague-Dawley rats were subjected to 1 h of tMCAO and treated with celecoxib or vehicle 1 and 24 h after ischemia. Protein and mRNA levels of the main hallmarks of ER stress, unfolded protein response (UPR) activation, UPR-induced cell death, and ubiquitin proteasome system (UPS) and autophagy, the main protein degradation pathways, were measured at 12 and 48 h of reperfusion. Celecoxib treatment decreased polyubiquitinated protein load and ER stress marker expression such as glucose-related protein 78 (GRP78), C/EBP (CCAAT/enhancer-binding protein) homologous protein (CHOP), and caspase 12 after 48 h of reperfusion. Regarding the UPR activation, celecoxib promoted inositol-requiring enzyme 1 (IRE1) pathway instead of double-stranded RNA-activated protein kinase-like ER kinase (PERK) pathway. Furthermore, celecoxib treatment increased proteasome catalytic subunits transcript levels and decreased p62 protein levels, while the microtubule-associated protein 1 light chain 3 (LC3B) II/I ratio remained unchanged. Thus, the ability of celecoxib treatment on reducing the ER stress correlates with the enhancement of IRE1-UPR pathway and UPS degradation. These data support the ability of anti-inflammatory therapy in modulating ER stress and reveal the IRE1 pathway as a promising therapeutic target in stroke therapy.Graphical abstract.

Post-ischemic salubrinal administration reduces necroptosis in a rat model of global cerebral ischemia.

Ischemic stroke is one of the most important causes of death and disability worldwide. Subroutines underlying cell death after stroke are largely unknown despite their importance in the design of novel therapies for this pathology. Necroptosis, a recently described form of regulated cell death, has been related with inflammation and, in some models, with endoplasmic reticulum (ER) stress. We hypothesize that alleviation of ER stress following a salubrinal treatment will reduce the ischemic-dependent necroptosis. To probe the hypothesis, we measured, at 48 and 72 h after transient global cerebral ischemia in rat, in cerebral cortex and cornu ammonis 1, the main hallmarks of necroptosis: mRNA levels and phosphorylation of mixed lineage kinase domain like pseudokinase as well as receptor interacting serine/threonine protein kinase 3, along the years 2017-2018. Selective neuronal loss after 7 days of the ischemic insult, and other markers related with the inflammatory response were also measured. This study shows that necroptosis in cerebral cortex can be detected after 72 h of the insult and seems to be elicited before 48 h of reperfusion. The type of necroptosis here observed seems to be tumor necrosis factor receptor 1 independent. Necroptotic response is less evident in the cornu ammonis 1 hippocampal area than in cerebral cortex. The treatment with salubrinal administered 1 and 24 h after the ischemia, decreased the necroptotic marker levels and reduced the areas of selective neuronal loss, supporting the presence of ischemic-dependent necroptosis, and the notion that ER stress is involved in the necroptotic response. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/.

Brain-derived neurotrophic factor alleviates the oxidative stress induced by oxygen and glucose deprivation in an ex vivo brain slice model.

Brain-derived neurotrophic factor (BDNF) is considered as a putative therapeutic agent against stroke. Since BDNF role on oxidative stress is uncertain, we have studied this role in a rat brain slice ischemia model, which allows BDNF reaching the neural parenchyma. Hippocampal and cerebral cortex slices were subjected to oxygen and glucose deprivation (OGD) and then returned to normoxic conditions (reperfusion-like, RL). OGD/RL increased a number of parameters mirroring oxidative stress in the hippocampus that were reduced by the BDNF presence. BDNF also reduced the OGD/RL-increased activity in a number of antioxidant enzymes in the hippocampus but no effects were observed in the cerebral cortex. In general, we conclude that alleviation of oxidative stress by BDNF in OGD/RL-exposed slices relies on decreasing cPLA2 activity, rather than modifying antioxidant enzyme activities. Moreover, a role for the oxidative stress in the differential ischemic vulnerability of cerebral cortex and hippocampus is also supported.

Salubrinal and robenacoxib treatment after global cerebral ischemia. Exploring the interactions between ER stress and inflammation.

BACKGROUND: Blood reperfusion of the ischemic tissue after stroke promotes increases in the inflammatory response as well as accumulation of unfolded/misfolded proteins in the cell, leading to endoplasmic reticulum (ER) stress. Both Inflammation and ER stress are critical processes in the delayed death of the cells damaged after ischemia. The aim of this study is to check the putative synergic neuroprotective effect by combining anti-inflammatory and anti-ER stress agents after ischemia. METHODS: The study was performed on a two-vessel occlusion global cerebral ischemia model. Animals were treated with salubrinal one hour after ischemia and with robenacoxib at 8 h and 32 h after ischemia. Parameters related to the integrity of the blood-brain barrier (BBB), such as matrix metalloproteinase 9 and different cell adhesion molecules (CAMs), were analyzed by qPCR at 24 h and 48 h after ischemia. Microglia and cell components of the neurovascular unit, including neurons, endothelial cells and astrocytes, were analyzed by immunofluorescence after 48 h and seven days of reperfusion. RESULTS: Pharmacologic control of ER stress by salubrinal treatment after ischemia, revealed a neuroprotective effect over neurons that reduces the transcription of molecules involved in the impairment of the BBB. Robenacoxib treatment stepped neuronal demise forward, revealing a detrimental effect of this anti-inflammatory agent. Combined treatment with robenacoxib and salubrinal after ischemia prevented neuronal loss and changes in components of the neurovascular unit and microglia observed when animals were treated only with robenacoxib. CONCLUSION: Combined treatment with anti-ER stress and anti-inflammatory agents is able to provide enhanced neuroprotective effects reducing glial activation, which opens new avenues in therapies against stroke.