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Angiotensin-II (Ang-II) production is driven by deviations in blood volume and osmolality, and serves the role of regulating blood pressure and fluid intake to maintain cardiovascular and hydromineral homeostasis. These actions are mediated by Ang-II acting on its type 1a receptor (AT1aR) within the central nervous system and periphery. Of relevance, AT1aR are expressed on sensory afferents responsible for conveying cardiovascular information to the nucleus of the solitary tract (NTS). We have previously determined that optical excitation of neurons and vagal afferents within the NTS that express AT1aR (referred to as NTSAT1aR) mimics the perception of increased vascular stretch and induces compensatory responses to restore blood pressure. Here, we test whether NTSAT1aR are also involved in the modulation of water and sodium intake. We directed the light-sensitive excitatory channelrhodopsin-2 (ChR2) or inhibitory halorhodopsin (Halo) to Agtr1a-containing neurons and measured water and sodium chloride (NaCl) intake in the presence and absence of optical stimulation within the NTS during various challenges to fluid homeostasis. Optical perturbation of NTSAT1aR modulates NaCl intake, such that excitation attenuates, whereas inhibition increases intake. This effect is only observed in the water-deprived condition, suggesting that NTSAT1aR are involved in the regulation of sodium intake during an imbalance in both the intracellular and extracellular fluid compartments. Furthermore, optical excitation of NTSAT1aR increases c-Fos expression within oxytocinergic neurons of the paraventricular nucleus of the hypothalamus (PVN), indicating that the regulation of sodium intake by NTSAT1aR may be mediated by oxytocin. Collectively, these results reveal that NTSAT1aR are sufficient and necessary to modulate sodium intake relative to perceived changes in vascular stretch.
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Neuronas , Receptor de Angiotensina Tipo 1 , Núcleo Solitario , Animales , Núcleo Solitario/metabolismo , Núcleo Solitario/fisiología , Núcleo Solitario/efectos de los fármacos , Receptor de Angiotensina Tipo 1/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Masculino , Ingestión de Líquidos/fisiología , Ingestión de Líquidos/efectos de los fármacos , Neuronas Aferentes/fisiología , Neuronas Aferentes/metabolismo , Optogenética , Cloruro de Sodio/farmacologíaRESUMEN
Background: The renin-angiotensin system involves many more enzymes, receptors and biologically active peptides than originally thought. With this study, we investigated whether angiotensin-(1-5) [Ang-(1-5)], a 5-amino acid fragment of angiotensin II, has biological activity, and through which receptor it elicits effects. Methods: The effect of Ang-(1-5) (1µM) on nitric oxide release was measured by DAF-FM staining in human aortic endothelial cells (HAEC), or Chinese Hamster Ovary (CHO) cells stably transfected with the angiotensin AT 2 -receptor (AT 2 R) or the receptor Mas. A potential vasodilatory effect of Ang-(1-5) was tested in mouse mesenteric and human renal arteries by wire myography; the effect on blood pressure was evaluated in normotensive C57BL/6 mice by Millar catheter. These experiments were performed in the presence or absence of a range of antagonists or inhibitors or in AT 2 R-knockout mice. Binding of Ang-(1-5) to the AT 2 R was confirmed and the preferred conformations determined by in silico docking simulations. The signaling network of Ang-(1-5) was mapped by quantitative phosphoproteomics. Results: Key findings included: (1) Ang-(1-5) induced activation of eNOS by changes in phosphorylation at Ser1177 eNOS and Tyr657 eNOS and thereby (2) increased NO release from HAEC and AT 2 R-transfected CHO cells, but not from Mas-transfected or non-transfected CHO cells. (3) Ang-(1-5) induced relaxation of preconstricted mouse mesenteric and human renal arteries and (4) lowered blood pressure in normotensive mice - effects which were respectively absent in arteries from AT 2 R-KO or in PD123319-treated mice and which were more potent than effects of the established AT 2 R-agonist C21. (5) According to in silico modelling, Ang-(1-5) binds to the AT 2 R in two preferred conformations, one differing substantially from where the first five amino acids within angiotensin II bind to the AT 2 R. (6) Ang-(1-5) modifies signaling pathways in a protective RAS-typical way and with relevance for endothelial cell physiology and disease. Conclusions: Ang-(1-5) is a potent, endogenous AT 2 R-agonist.
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Background: Pulmonary rehabilitation is recognized widely as one of the most effective measures to promote postoperative recovery of lung transplant recipients (LTRs), and it has positive effects on both short- and long-term quality of life (QoL) and survival outcomes. However, no standardized pulmonary rehabilitation training programs exist specifically for LTRs. The pulmonary rehabilitation programs widely used in clinical practice focus mainly on exercise or respiratory training, to some extent neglecting other therapeutic methods that could promote patient health, such as nutrition support, pain control, spiritual comfort, and so on. This study aimed to develop a postoperative pulmonary rehabilitation training program for LTRs and evaluate its effectiveness. Methods: Using convenience sampling, all patients who underwent lung transplantation (LTx) at Shanghai Pulmonary Hospital from January 2021 to December 2022 were screened for inclusion and exclusion criteria, and a total of 68 patients were finally included in this study. A non-synchronous quasi-experimental design was used, with patients who underwent LTx in 2021 as the control group and patients who underwent LTx in 2022 as the experimental group. The control group received routine treatment, health education, and rehabilitation guidance when patients determined the date of surgery. In addition to this, the experimental group received pulmonary rehabilitation training. The incidence of postoperative pulmonary complications (pulmonary infections), duration of chest tube drainage, intensive care unit (ICU) length of stay, postoperative pain scores, postoperative QoL, pulmonary function, oxygenation index, and the distance in the 6-minute walking test (6MWD) were compared between the two groups. Results: The length of ICU stay and duration of chest tube drainage in the experimental group were lower than those in the control group, and the results of oxygenation index, 6MWD, and St. George's Respiratory Questionnaire (reflecting the QoL) were better than those of the control group (P<0.05). There was no significant difference in the pain of the two groups 1 week after surgery and 3 months after surgery, and the pain score of the experimental group was lower than that of the control group at 1 month after surgery (P<0.05). There was no significant difference in the incidence of complications between the two groups (P>0.05). Conclusions: The postoperative pulmonary rehabilitation training program for LTRs is safe and effective. It can shorten both the duration of chest tube drainage and ICU stay, it can also improve patients' exercise capacity and pulmonary function while also promote safety outcomes of LTRs, and improve QoL scores.
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Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a receptors (referred to as NGAT1aR) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. Using Agtr1a-Cre mice and Cre-dependent AAVs to direct tdTomato to NGAT1aR, neuroanatomical studies revealed that NGAT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (NTS), and synthesize mechanosensitive ion channels, Piezo1/2 To evaluate the functionality of NGAT1aR, we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) to Agtr1a-containing neurons. Two-photon intravital imaging in Agtr1a-GCaMP6s mice revealed that NGAT1aR couple their firing to elevated BP, induced by phenylephrine (i.v.). Furthermore, optical excitation of NGAT1aR at their soma or axon terminals within the caudal NTS of Agtr1a-ChR2 mice elicited robust frequency-dependent decreases in BP and heart rate, indicating that NGAT1aR are sufficient to elicit appropriate compensatory responses to vascular mechanosensation. Optical excitation also elicited hypotensive and bradycardic responses in ChR2-expressing mice that were subjected to deoxycorticosterone acetate (DOCA)-salt hypertension; however, the duration of these effects was altered, suggestive of hypertension-induced impairment of the baroreflex. Similarly, increased GCaMP6s fluorescence observed after administration of phenylephrine was delayed in mice subjected to DOCA-salt or chronic delivery of angiotensin II. Collectively, these results reveal the structure and function of NGAT1aR and suggest that such neurons may be exploited to discern and relieve hypertension.
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Acetato de Desoxicorticosterona , Hipertensión , Proteína Fluorescente Roja , Ratones , Masculino , Femenino , Animales , Acetato de Desoxicorticosterona/farmacología , Núcleo Solitario/fisiología , Células Receptoras Sensoriales , Presión Sanguínea/fisiología , Fenilefrina/farmacología , Canales IónicosRESUMEN
BACKGROUND: Continuous-flow left ventricular assist devices (LVADs) cause an acquired von Willebrand factor (VWF) deficiency and bleeding. Models to risk-stratify for bleeding are urgently needed. We developed a model of continuous-flow LVAD bleeding risk from patient-specific severity of VWF degradation. METHODS: In a prospective, longitudinal cohort study, paired blood samples were obtained from patients (n = 67) with a continuous-flow LVAD before and during support. After 640 ± 395 days, patients were categorized as all-cause bleeders, gastrointestinal (GI) bleeders, or nonbleeders. VWF multimers and VWF clotting function were evaluated to determine bleeding risk. RESULTS: Of 67 patients, 34 (51%) experienced bleeding, 26 (39%) experienced GI bleeding, and 33 (49%) did not bleed. In all patients, LVAD support significantly reduced high-molecular-weight VWF multimers (P < .001). Bleeders exhibited greater loss of high-molecular-weight VWF multimers (mean ± standard deviation, -10 ± 5% vs -7 ± 4%, P = .008) and reduced VWF clotting function versus nonbleeders (median [interquartile range], -12% [-31% to 4%] vs 0% [-9 to 26%], P = .01). A combined metric of VWF multimers and VWF function generated the All-Cause Bleeding Risk Score, which stratified bleeders versus nonbleeders (86 ± 56% vs 41 ± 48%, P < .001) with a positive predictive value of 86% (95% confidence interval, 66%-95%) and diagnostic odds ratio of 11 (95% confidence interval, 2.9-44). A separate GI Bleeding Risk Score stratified GI bleeders versus nonbleeders (202 ± 114 vs 120 ± 86, P = .003) with a positive predictive value of 88% (64%-97%) and diagnostic odds ratio of 18 (3.1-140). CONCLUSIONS: The severity of loss of VWF multimers and VWF clotting function generated Bleeding Risk Scores with high predictive value for LVAD-associated bleeding. This model may guide personalized antithrombotic therapy and patient surveillance.
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Corazón Auxiliar , Enfermedades de von Willebrand , Humanos , Factor de von Willebrand/metabolismo , Corazón Auxiliar/efectos adversos , Estudios Prospectivos , Estudios Longitudinales , Diseño de Prótesis , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiología , Enfermedades de von Willebrand/complicaciones , Enfermedades de von Willebrand/diagnósticoRESUMEN
Background: Pulmonary hypertension (PH), characterized by elevated pulmonary pressure and right heart failure, is a systemic disease involving inappropriate sympathetic activation and an impaired gut-brain-lung axis. Global overexpression of angiotensin converting enzyme 2 (ACE2), a cardiopulmonary protective enzyme of the renin-angiotensin system, attenuates PH induced by chronic hypoxia. Neurons within the paraventricular nucleus of the hypothalamus (PVN) that synthesize corticotropin-releasing hormone (CRH) are activated by stressors, like hypoxia, and this activation augments sympathetic outflow to cardiovascular tissues. These data coupled with our observations that ACE2 overexpression in CRH cells (CRH-ACE2KI mice) decreases anxiety-like behavior via suppression of hypothalamic-pituitary-adrenal (HPA) axis activity by decreasing CRH synthesis, led us to hypothesize that selective ACE2 overexpression in CRH neurons would protect against hypoxia-induced PH. Methods: CRH-ACE2KI and WT male and female mice were exposed to chronic hypoxia (10%O2) or normoxia (21%O2) for 4 weeks in a ventilated chamber with continuous monitoring of oxygen and carbon dioxide concentrations (n = 7-10/group). Pulmonary hemodynamics were measured with Millar pressure catheters then tissues were collected for histological analyses. Results: Chronic hypoxia induced a significant increase (36.4%) in right ventricular (RV) systolic pressure (RVSP) in WT mice, which was not observed in CRH-ACE2KI mice. No significant differences in RVSP were observed between male and female mice in any of the groups. Conclusion: Overexpression of ACE2 in CRH cells was protective against hypoxia-induced PH. Since the majority of expression of CRH is in brain nuclei such as paraventricular nucleus of the hypothalamus (PVN) and/or central nucleus of the amygdala (CeA) these data indicate that the protective effects of ACE2 are, at least in part, centrally mediated. This contributes to the systemic nature of PH disease and that CRH neurons may play an important role in PH.
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Interoception broadly refers to awareness of one's internal milieu. Vagal sensory afferents monitor the internal milieu and maintain homeostasis by engaging brain circuits that alter physiology and behavior. While the importance of the body-to-brain communication that underlies interoception is implicit, the vagal afferents and corresponding brain circuits that shape perception of the viscera are largely unknown. Here, we use mice to parse neural circuits subserving interoception of the heart and gut. We determine vagal sensory afferents expressing the oxytocin receptor, hereafter referred to as NDGOxtr, send projections to the aortic arch or stomach and duodenum with molecular and structural features indicative of mechanosensation. Chemogenetic excitation of NDGOxtr significantly decreases food and water consumption, and remarkably, produces a torpor-like phenotype characterized by reductions in cardiac output, body temperature, and energy expenditure. Chemogenetic excitation of NDGOxtr also creates patterns of brain activity associated with augmented hypothalamic-pituitary-adrenal axis activity and behavioral indices of vigilance. Recurrent excitation of NDGOxtr suppresses food intake and lowers body mass, indicating that mechanosensation of the heart and gut can exert enduring effects on energy balance. These findings suggest that the sensation of vascular stretch and gastrointestinal distention may have profound effects on whole body metabolism and mental health.
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We investigated the lateralization of gut-innervating vagal sensory neurons and their roles in feeding behavior. Using genetic, anatomical, and behavioral analyses, we discovered a subset of highly lateralized vagal sensory neurons with distinct sensory responses to intestinal stimuli. Our results demonstrated that left vagal sensory neurons (LNG) are crucial for distension-induced satiety, while right vagal sensory neurons (RNG) mediate preference for nutritive foods. Furthermore, these lateralized neurons engage different central circuits, with LNG neurons recruiting brain regions associated with energy balance and RNG neurons activating areas related to salience, memory, and reward. Altogether, our findings unveil the diverse roles of asymmetrical gut-vagal-brain circuits in feeding behavior, offering new insights for potential therapeutic interventions targeting vagal nerve stimulation in metabolic and neuropsychiatric diseases.
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Adipose plasticity is critical for metabolic homeostasis. Adipocyte transdifferentiation plays an important role in adipose plasticity, but the molecular mechanism of transdifferentiation remains incompletely understood. Here we show that the transcription factor FoxO1 regulates adipose transdifferentiation by mediating Tgfß1 signaling pathway. Tgfß1 treatment induced whitening phenotype in beige adipocytes, reducing UCP1 and mitochondrial capacity and enlarging lipid droplets. Deletion of adipose FoxO1 (adO1KO) dampened Tgfß1 signaling by downregulating Tgfbr2 and Smad3 and induced browning of adipose tissue in mice, increasing UCP1 and mitochondrial content and activating metabolic pathways. Silencing FoxO1 also abolished the whitening effect of Tgfß1 on beige adipocytes. The adO1KO mice exhibited a significantly higher energy expenditure, lower fat mass, and smaller adipocytes than the control mice. The browning phenotype in adO1KO mice was associated with an increased iron content in adipose tissue, concurrent with upregulation of proteins that facilitate iron uptake (DMT1 and TfR1) and iron import into mitochondria (Mfrn1). Analysis of hepatic and serum iron along with hepatic iron-regulatory proteins (ferritin and ferroportin) in the adO1KO mice revealed an adipose tissue-liver crosstalk that meets the increased iron requirement for adipose browning. The FoxO1-Tgfß1 signaling cascade also underlay adipose browning induced by ß3-AR agonist CL316243. Our study provides the first evidence of a FoxO1-Tgfß1 axis in the regulation of adipose browning-whitening transdifferentiation and iron influx, which sheds light on the compromised adipose plasticity in conditions of dysregulated FoxO1 and Tgfß1 signaling.
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Tejido Adiposo Pardo , Transdiferenciación Celular , Ratones , Animales , Tejido Adiposo Pardo/metabolismo , Hierro/metabolismo , Obesidad/genética , Obesidad/metabolismo , Transducción de Señal , Tejido Adiposo Blanco/metabolismo , Ratones Endogámicos C57BL , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismoRESUMEN
INTRODUCTION: Pneumothorax is associated with poor prognosis in patients with acute respiratory distress syndrome (ARDS). We sought to examine the outcomes of patients who are supported on veno-venous extracorporeal membrane oxygenation (VV ECMO) and develop a pneumothorax. METHODS: We retrospectively reviewed all adult VV ECMO patients supported for ARDS between 8/2014-7/2020 at our institution, excluding patients with recent lung resection and trauma. Clinical outcomes were compared between patients with a pneumothorax to those without a pneumothorax. RESULTS: Two hundred eighty patients with ARDS on VV ECMO were analyzed. Of those, 213 did not have a pneumothorax and 67 did. Patients with a pneumothorax had a longer duration of ECMO support (30 days [16-55] versus 12 [7-22], p < 0.001) and hospital length of stay (51 days [27-93] versus 29 [18-49], p < 0.001), and lower survival-to-discharge (58.2% versus 77.5%, p = 0.002) compared to patients without a pneumothorax. Controlling for age, BMI, sex, RESP score and pre-ECMO ventilator days, the odds ratio of survival-to-discharge was 0.41 (95% CI 0.22-0.78) in patients with a pneumothorax compared to those without. There was a lower incidence of significant bleeding when chest tubes were placed by proceduralist services (2.4% versus 16.2%, p = 0.03). Removal of the chest tube prior to ECMO decannulation compared to removal after decannulation was associated with need for replacement (14.3% versus 0%, p = 0.01). CONCLUSION: Patients who develop a pneumothorax and are supported with VV ECMO for ARDS have longer duration on ECMO and decreased survival. Further studies are needed to assess risk factors for development of pneumothorax in this patient population.
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Sodium (Na+) is crucial for numerous homeostatic processes in the body and, consequentially, its levels are tightly regulated by multiple organ systems. Sodium is acquired from the diet, commonly in the form of NaCl (table salt), and substances that contain sodium taste salty and are innately palatable at concentrations that are advantageous to physiological homeostasis. The importance of sodium homeostasis is reflected by sodium appetite, an "all-hands-on-deck" response involving the brain, multiple peripheral organ systems, and endocrine factors, to increase sodium intake and replenish sodium levels in times of depletion. Visceral sensory information and endocrine signals are integrated by the brain to regulate sodium intake. Dysregulation of the systems involved can lead to sodium overconsumption, which numerous studies have considered causal for the development of diseases, such as hypertension. The purpose here is to consider the inverse-how disease impacts sodium intake, with a focus on stress-related and cardiometabolic diseases. Our proposition is that such diseases contribute to an increase in sodium intake, potentially eliciting a vicious cycle toward disease exacerbation. First, we describe the mechanism(s) that regulate each of these processes independently. Then, we highlight the points of overlap and integration of these processes. We propose that the analogous neural circuitry involved in regulating sodium intake and blood pressure, at least in part, underlies the reciprocal relationship between neural control of these functions. Finally, we conclude with a discussion on how stress-related and cardiometabolic diseases influence these circuitries to alter the consumption of sodium.
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Hipertensión , Gusto , Humanos , Gusto/fisiología , Apetito/fisiología , Cloruro de Sodio Dietético/efectos adversos , Sodio , Hipertensión/etiologíaRESUMEN
INTRODUCTION: With the increased demand for veno-venous extracorporeal membrane oxygenation (VV ECMO) during the COVID-19 pandemic, guidelines for patient candidacy have often limited this modality for patients with a body mass index (BMI) less than 40 kg/m2. We hypothesize that COVID-19 VV ECMO patients with at least class III obesity (BMI ≥ 40) have decreased in-hospital mortality when compared to non-COVID-19 and non-class III obese COVID-19 VV ECMO populations. METHODS: This is a single-center retrospective study of COVID-19 VV ECMO patients from January 1, 2014, to November 30, 2021. Our institution used BMI ≥ 40 as part of a multi-disciplinary VV ECMO candidate screening process in COVID-19 patients. BMI criteria were not considered for exclusion criteria in non-COVID-19 patients. Univariate and multivariable analyses were performed to assess in-hospital mortality differences. RESULTS: A total of 380 patients were included in our analysis: The COVID-19 group had a lower survival rate that was not statistically significant (65.7% vs.74.9%, p = .07). The median BMI between BMI ≥ 40 COVID-19 and non-COVID-19 patients was not different (44.5 vs 45.5, p = .2). There was no difference in survival between the groups (73.3% vs. 78.5%, p = .58), nor was there a difference in survival between the COVID-19 BMI ≥ 40 and BMI < 40 patients (73.3, 62.7, p= .29). Multivariable logistic regression with the outcome of in-hospital mortality was performed and BMI was not found to be significant (OR 0.99, 95% CI 0.89, 1.01; p = .92). CONCLUSION: BMI ≥ 40 was not an independent risk factor for decreased in-hospital survival in this cohort of VV ECMO patients at a high-volume center. BMI should not be the sole factor when deciding VV ECMO candidacy in patients with COVID-19.
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COVID-19 , Oxigenación por Membrana Extracorpórea , Humanos , Índice de Masa Corporal , Estudios Retrospectivos , Pandemias , COVID-19/terapia , Obesidad/complicacionesRESUMEN
INTRODUCTION: The PREdiction of Survival on ECMO Therapy Score (PRESET-Score) predicts mortality while on veno-venous extracorporeal membrane oxygenation (VV ECMO) for acute respiratory distress syndrome. The aim of our study was to assess the association between PRESET-Score and survival in a large COVID-19 VV ECMO cohort. METHODS: This was a single-center retrospective study of COVID-19 VV ECMO patients from 15 March 2020, to 30 November 2021. Univariable and Multivariable analyses were performed to assess patient survival and score differences. RESULTS: A total of 105 patients were included in our analysis with a mean PRESET-Score of 6.74. Overall survival was 65.71%. The mean PRESET-Score was significantly lower in the survivor group (6.03 vs 8.11, p < 0.001). Patients with a PRESET-Score less than or equal to six had improved survival compared to those with a PRESET-Score greater than or equal to 8 (97.7% vs. 32.5%, p < 0.001). In a multivariable logistic regression, a lower PRESET-Score was also predictive of survival (OR 2.84, 95% CI 1.75, 4.63, p < 0.001). CONCLUSION: We demonstrate that lower PRESET scores are associated with improved survival. The utilization of this validated, quantifiable, and objective scoring system to help identify COVID-19 patients with the greatest potential to benefit from VV-ECMO appears feasible. The incorporation of the PRESET-Score into institutional ECMO candidacy guidelines can help insure and improve access of this limited healthcare resource to all critically ill patients.
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COVID-19 , Oxigenación por Membrana Extracorpórea , Síndrome de Dificultad Respiratoria , Humanos , Estudios Retrospectivos , COVID-19/terapia , Síndrome de Dificultad Respiratoria/terapia , Modelos LogísticosRESUMEN
Venovenous extracorporeal membrane oxygenation (VV ECMO) has been used to treat severe coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome; however, patient selection criteria have evolved throughout the pandemic. In this study, we sought to determine the association of patient mortality with time from positive COVID-19 test and infiltrate on chest radiograph (x-ray) to VV ECMO cannulation. We hypothesized that an increasing duration between a positive COVID-19 test or infiltrates on chest x-ray and cannulation would be associated with increased mortality. This is a single-center retrospective chart review of COVID-19 VV ECMO patients from March 1, 2020 to July 28, 2021. Unadjusted and adjusted multivariate analyses were performed to assess for mortality differences. A total of 93 patients were included in our study. Increased time, in days, from infiltrate on chest x-ray to cannulation was associated with increased mortality in both unadjusted (5-9, P = 0.002) and adjusted regression analyses (odds ratio [OR]: 1.49, 95% CI: 1.22-1.81, P < 0.01). Time from positive test to cannulation was not found to be significant between survivors and nonsurvivors (7.5-11, P = 0.06). Time from infiltrate on chest x-ray to cannulation for VV ECMO should be considered when assessing patient candidacy. Further larger cohort and prospective studies are required.
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COVID-19 , Oxigenación por Membrana Extracorpórea , Síndrome de Dificultad Respiratoria , Humanos , Estudios Retrospectivos , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Síndrome de Dificultad Respiratoria/terapia , CateterismoRESUMEN
Recent evidence suggests pulmonary hypertension (PH), a disease of the pulmonary vasculature actually has multiorgan pathophysiology and perhaps etiology. Herein, we demonstrated that fecal matter transplantation from angiotensin-converting enzyme 2 overexpressing mice counteracted the effects of chronic hypoxia to prevent pulmonary hypertension, neuroinflammation, and gut dysbiosis in wild type recipients.
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Maintaining homeostasis while navigating one's environment involves accurately assessing and interacting with external stimuli while remaining consciously in tune with internal signals such as hunger and thirst. Both atypical social interactions and unhealthy eating patterns emerge as a result of dysregulation in factors that mediate the prioritization and attention to salient stimuli. Oxytocin is an evolutionarily conserved peptide that regulates attention to exteroceptive and interoceptive stimuli in a social environment by functioning in the brain as a modulatory neuropeptide to control social behavior, but also in the periphery as a hormone acting at oxytocin receptors (Oxtr) expressed in the heart, gut, and peripheral ganglia. Specialized sensory afferent nerve endings of Oxtr-expressing nodose ganglia cells transmit cardiometabolic signals via the Vagus nerve to integrative regions in the brain that also express Oxtr(s). These brain regions are influenced by vagal sensory pathways and coordinate with external events such as those demanding attention to social stimuli, thus the sensations related to cardiometabolic function and social interactions are influenced by oxytocin signaling. This review investigates the literature supporting the idea that oxytocin mediates the interoception of cardiovascular and gastrointestinal systems, and that the modulation of this awareness likewise influences social cognition. These concepts are then considered in relation to Autism Spectrum Disorder, exploring how atypical social behavior is comorbid with cardiometabolic dysfunction.
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The brain maintains cardiovascular homeostasis, in part, via the arterial baroreflex which senses changes in blood pressure (BP) at the level of the aortic arch. Sensory afferents innervating the aortic arch employ baroreceptors to convert stretch exerted on the arterial wall into action potentials carried by the vagus nerve to second order neurons residing within the nucleus of the solitary tract (NTS). Although the baroreflex was described more than 80 years ago, the specific molecular, structural, and functional phenotype of the baroreceptors remain uncharacterized. This is due to the lack of tools that provide the genetic and target organ specificity that is required to selectively characterize baroreceptor afferents. Here, we use a novel approach to selectively target baroreceptors. Male mice on a C57BL/6J background were anesthetized with isoflurane, intubated, and artificially ventilated. Following sternotomy, the aortic arch was exposed, and a retrograde adeno-associated virus was applied to the aortic arch to direct the expression of channelrhoropsin-2 (ChR2) and/or tdTomato (tdTom) to sensory afferents presumably functioning as baroreceptors. Consistent with the structural characteristics of arterial baroreceptors, robust tdTom expression was observed in nerve endings surrounding the aortic arch, within the fibers of the aortic depressor and vagus nerves, cell bodies of the nodose ganglia (NDG), and neural projections to the caudal NTS (cNTS). Additionally, the tdTom labeled cell bodies within the NDG also expressed mRNAs coding for the mechanically gated ion channels, PIEZO-1 and PIEZO-2. In vitro electrophysiology revealed that pulses of blue light evoked excitatory post-synaptic currents in a subset of neurons within the cNTS, suggesting a functional connection between the labeled aortic arch sensory afferents and second order neurons. Finally, the in vivo optogenetic stimulation of the cell bodies of the baroreceptor expressing afferents in the NDG produced robust depressor responses. Together, these results establish a novel approach for selectively targeting sensory neurons innervating the aortic arch. This approach may be used to investigate arterial baroreceptors structurally and functionally, and to assess their role in the etiology or reversal of cardiovascular disease.
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Background In 2020, we published findings on reported outcomes of anterior cervical decompression and fusion surgery among neurosurgeons in Africa and North America. We found more similarities in outcomes than expected, however, differences still existed. Most notable was the length of stay of patients postoperatively in Africa compared to North America. We sought to examine the neurosurgical practices more closely at a single hospital in Ethiopia and compare it to our own institution, the University of Missouri in Columbia (UMC). Methods Two authors spent one week at Aabet Hospital (AH) in Ethiopia. Throughout the week, one author rotated in the clinic and OR gathering the information. Data collection for patients at UMC was collected through retrospective chart review over one week. Results A total of eight elective surgeries and four emergency procedures occurred at AH and 18 clinic patients were included in the study. The intraoperative data was collected during the elective procedures at AH. At UMC there were 99 clinic patients, and 29 elective surgeries and one emergency procedure were performed. Procedures at both institutions included cranial, spinal, vascular, and implantable/other cases. Distance travelled by patients to UMC was an average of 57 miles compared to 85 miles at AH. The median pre-op and post-op stays at AH were 2.5 and 6 days compared to 0.2 and 2.1 at UMC, respectively. Blood loss was greater at AH with a median blood loss of 175 mL. Median blood loss at UMC was 50 mL. Conclusion We found notable differences among neurosurgical practice and patient demographics at AH compared to UMC. This information will serve as the cornerstone for gathering more information about neurosurgical practice in Ethiopia where electronic medical records are unavailable.
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Here, we present a step-by-step protocol for three-dimensional reconstruction of astrocyte morphology, applied to the central amygdala oxytocin receptor-expressing astrocytes. This includes RNAse-free perfusion, combination of RNAscope and immunohistochemistry, and confocal imaging. This protocol provides detailed information about tissue handling and a comprehensive description of the RNAScope technique to label rat and mouse oxytocin receptor mRNA. We also describe three-dimensional reconstruction that allows the assessment of more than 70 different cellular parameters, powerful for studying astrocyte morphology and astrocyte-astrocyte interactions. For complete details on the use and execution of this protocol, please refer to Wahis et al. (2021) and Althammer et al. (2020).