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The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks of AD, including amyloid ß-protein (Aß) deposits and abnormal tau protein isoforms, in the retinas of AD patients and animal models. Moreover, structural and functional vascular abnormalities such as reduced blood flow, vascular Aß deposition, and blood-retinal barrier damage, along with inflammation and neurodegeneration, have been described in retinas of patients with mild cognitive impairment and AD dementia. Histological, biochemical, and clinical studies have demonstrated that the nature and severity of AD pathologies in the retina and brain correspond. Proteomics analysis revealed a similar pattern of dysregulated proteins and biological pathways in the retina and brain of AD patients, with enhanced inflammatory and neurodegenerative processes, impaired oxidative-phosphorylation, and mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific amyloid deposits, as well as vasculopathy and neurodegeneration in the retina of living AD patients, suggesting alterations at different disease stages and links to brain pathology. Current and exploratory ophthalmic imaging modalities, such as optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, and hyperspectral imaging, may offer promise in the clinical assessment of AD. However, further research is needed to deepen our understanding of AD's impact on the retina and its progression. To advance this field, future studies require replication in larger and diverse cohorts with confirmed AD biomarkers and standardized retinal imaging techniques. This will validate potential retinal biomarkers for AD, aiding in early screening and monitoring.
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Enfermedad de Alzheimer , Retina , Enfermedades de la Retina , Enfermedad de Alzheimer/fisiopatología , Humanos , Enfermedades de la Retina/fisiopatología , Enfermedades de la Retina/diagnóstico , Retina/fisiopatología , Animales , Tomografía de Coherencia Óptica/métodos , Péptidos beta-Amiloides/metabolismo , Vasos Retinianos/fisiopatología , Vasos Retinianos/diagnóstico por imagenRESUMEN
Recent preclinical studies demonstrate a direct pathological role for the interleukin-6 (IL-6) pathway in mediating structural and functional delirium-like phenotypes in animal models of acute lung injury. Tocilizumab, an IL-6 pathway inhibitor, has shown reduced duration of ventilator dependency and mortality in critically ill patients with COVID-19. In this study, we test the hypothesis that tocilizumab is associated with reduced delirium/coma prevalence in critically ill patients with COVID-19. 253 patients were included in the study cohort, 69 in the tocilizumab group and 184 in the historical control group who did not receive tocilizumab. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) with a positive score indicating delirium. Coma was defined as a Richmond Agitation-Sedation Scale score of - 4 or - 5. Tocilizumab was associated with significantly greater number of days alive without delirium/coma (tocilizumab [7 days (IQR: 3-9 days)] vs control [3 days (IQR: 1-8 days)]; p < 0.001). These results remained significant after adjusting for age, sex, sepsis, Charlson Comorbidity Index, Sequential Organ Failure Assessment score, and median daily dose of analgesics/sedatives ( ß ^ = 0.671, p = 0.010). There were no significant differences in mortality ( ß ^ = - 0.204, p = 0.561), ventilator duration ( ß ^ = 0.016, p = 0.956), and ICU or hospital length of stay ( ß ^ = - 0.134, p = 0.603; ß ^ = 0.003, p = 0.991, respectively). Tocilizumab use was associated with significantly increased number of days without delirium/coma. Confirmation of these findings in randomized prospective studies may inform a novel paradigm of pharmacological amelioration of delirium/coma during critical illness.
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Anticuerpos Monoclonales Humanizados , COVID-19 , Coma , Enfermedad Crítica , Delirio , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Delirio/tratamiento farmacológico , Masculino , Femenino , COVID-19/complicaciones , COVID-19/mortalidad , Persona de Mediana Edad , Coma/etiología , Coma/tratamiento farmacológico , Anciano , Tratamiento Farmacológico de COVID-19 , Unidades de Cuidados Intensivos , SARS-CoV-2/aislamiento & purificación , Interleucina-6RESUMEN
BACKGROUND: The modified Brain Injury Guidelines (mBIG) were developed to stratify traumatic brain injuries (TBIs) and improve health care utilization by selectively requiring repeat imaging, intensive care unit admission, and neurosurgical (NSG) consultation. The goal of this study is to assess safety and potential resource savings associated with the application of mBIG on interhospital patient transfers for TBI. METHODS: Adult patients with TBI transferred to our Level I trauma center from January 2017 to December 2022 meeting mBIG inclusion criteria were retrospectively stratified into mBIG1, mBIG2, and mBIG3 based on initial clinicoradiological factors. At the time, our institution routinely admitted patients with TBI and intracranial hemorrhage (ICH) to the intensive care unit and obtained a repeat head computed tomography with NSG consultation, independent of TBI severity or changes in neurological examination. The primary outcome was progression of ICH on repeat imaging and/or NSG intervention. Secondary outcomes included length of stay and financial charges. Subgroup analysis on isolated TBI without significant extracranial injury was performed. RESULTS: Over the 6-year study period, 289 patients were classified into mBIG1 (61; 21.1%), mBIG2 (69; 23.9%), and mBIG3 (159; 55.0%). Of mBIG1 patients, 2 (2.9%) had radiological progression to mBIG2 without clinical decline, and none required NSG intervention. Of mBIG2, 2 patients (3.3%) progressed to mBIG3, and both required NSG intervention. More than 35% of transferred patients had minor isolated TBI. For mBIG1 and mBIG2, the median hospitalization charges per patient were $152,296 and $149,550, respectively, and the median length of stay was 4 and 5 days, respectively, with the majority downgraded from the intensive care unit within 48 hours. CONCLUSION: Clinically significant progression of ICH occurred infrequently in 1.5% of patients with mBIG1 and mBIG2 injuries. More than 35% of interfacility transfers for minor isolated TBI meeting mBIG1 and 2 criteria are low value and may potentially be safely deferred in an urban health care setting. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.
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Transferencia de Pacientes , Centros Traumatológicos , Humanos , Transferencia de Pacientes/estadística & datos numéricos , Transferencia de Pacientes/economía , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Centros Traumatológicos/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Tiempo de Internación/economía , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Conmoción Encefálica/terapia , Conmoción Encefálica/economía , Unidades de Cuidados Intensivos/estadística & datos numéricos , Unidades de Cuidados Intensivos/economía , Guías de Práctica Clínica como Asunto , AncianoRESUMEN
Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproved. The NHLBI of the NIH assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and well-being of ARDS survivors.
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Síndrome de Dificultad Respiratoria , Sobrevivientes , Humanos , Síndrome de Dificultad Respiratoria/terapia , Síndrome de Dificultad Respiratoria/fisiopatología , Estados Unidos , National Heart, Lung, and Blood Institute (U.S.) , Calidad de Vida , Encéfalo/fisiopatologíaAsunto(s)
Procedimientos Quirúrgicos Cardíacos , Monitorización Neurofisiológica Intraoperatoria , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Monitorización NeurofisiológicaRESUMEN
Delirium is a common, morbid, and costly syndrome that is closely linked to Alzheimer's disease (AD) and AD-related dementias (ADRD) as a risk factor and outcome. Human studies of delirium have advanced our knowledge of delirium incidence and prevalence, risk factors, biomarkers, outcomes, prevention, and management. However, understanding of delirium neurobiology remains limited. Preclinical and translational models for delirium, while challenging to develop, could advance our knowledge of delirium neurobiology and inform the development of new prevention and treatment approaches. We discuss the use of preclinical and translational animal models in delirium, focusing on (1) a review of current animal models, (2) challenges and strategies for replicating elements of human delirium in animals, and (3) the utility of biofluid, neurophysiology, and neuroimaging translational markers in animals. We conclude with recommendations for the development and validation of preclinical and translational models for delirium, with the goal of advancing awareness in this important field.
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Enfermedad de Alzheimer , Delirio , Animales , Humanos , Enfermedad de Alzheimer/complicaciones , Factores de Riesgo , Neuroimagen , Incidencia , Delirio/epidemiologíaRESUMEN
BACKGROUND AND OBJECTIVES: There is significant heterogeneity in the reporting of outcome measures in aneurysmal subarachnoid hemorrhage (aSAH) research. The modified Rankin scale (mRS) is the most commonly reported functional outcome measure. The mRS focuses on physical disability; however, many aSAH survivors experience sequalae in other domains, and the mRS may therefore not capture outcomes important to aSAH survivors. The objective of this study was to assess the clinical relevance of the mRS as a research outcome measure to people with lived aSAH experience. METHODS: We conducted an international cross-sectional survey of 355 aSAH survivors, family members, and caregivers to evaluate patient-perceived outcomes in relation to the mRS. The mRS was assessed using a previously validated web-based tool. RESULTS: Response rate was 60%; respondents from 7 continents were composed of 86% aSAH survivors and 14% family members/caregivers. Agreement between self-assessed outcome and the mRS was poor (Kappa 0.26 [CI 0.14-0.39]). Of the 172 respondents who self-assessed as having had a good aSAH outcome, 122 (71%) had a score of 0-2 on the mRS. Approximately 19% of respondents with a good outcome, based on a measured mRS score of 0-2, self-assessed as having had a poor aSAH outcome. When the mRS score was dichotomized as 0-3 corresponding to a good outcome, agreement between the score and self-assessed outcome remained poor with a Kappa score of 0.40 (CI 0.20-0.60). Approximately 30% of respondents believed that the mRS should not be used as an outcome measure in future aSAH trials. DISCUSSION: The findings suggest that there is poor agreement between aSAH survivors' self-assessed outcome, their actual mRS score, and the dichotomization of the mRS score into good/poor outcomes. Patient-centered and patient-informed outcome measurement tools are needed to guide the aSAH research agenda.
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Hemorragia Subaracnoidea , Humanos , Hemorragia Subaracnoidea/diagnóstico , Hemorragia Subaracnoidea/terapia , Estudios Transversales , Evaluación de Resultado en la Atención de Salud , Pacientes , Estudios RetrospectivosRESUMEN
Nonhepatic hyperammonemia syndrome is a rare cause of neurologic dysfunction and cerebral edema and has most commonly been reported in posttransplant patients. Only recently has opportunistic infection with Ureaplasma species and Mycoplasma hominis been found to be key to the pathogenesis. We describe the cases of 3 immunosuppressed patients who developed hyperammonemia syndrome with new-onset refractory status epilepticus and diffuse cerebral edema. PCR was positive for M hominis in 1 patient and Ureaplasma parvum in the other 2. Despite early diagnostic suspicion and aggressive management with empirical antibiotics, seizure control, hypertonic saline, and ammonia elimination, none of our patients survived this life-threatening infection. Nonhepatic hyperammonemia and new-onset seizures can be presenting features of disseminated Ureaplasma species and M hominis infections in posttransplant patients. Immunosuppression in the absence of organ transplantation is likely sufficient to trigger this entity, as was the case in our third patient. When suspected, empiric combination antibiotics should be used due to high likelihood of resistance. The diagnostic test of choice is PCR. Patients with hyperammonemia syndrome associated with these infections typically have a poor prognosis. Early recognition and aggressive multimodal interventions may be key to ameliorating the high mortality and severe neurologic sequelae from this entity.
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Edema Encefálico , Hiperamonemia , Mycoplasma , Estado Epiléptico , Humanos , Ureaplasma , Edema Encefálico/terapia , Edema Encefálico/complicaciones , Hiperamonemia/complicaciones , Hiperamonemia/terapia , Antibacterianos/uso terapéutico , Estado Epiléptico/terapia , Estado Epiléptico/complicacionesRESUMEN
Prone positioning is an established treatment for severe acute lung injury conditions. Neuronal dysfunction frequently occurs with mechanical ventilation-induced acute lung injury (VILI) and clinically manifests as delirium. We previously reported a pathological role for systemic interleukin 6 (IL-6) in mediating neuronal injury. However, currently no studies have investigated the relationship between prone or supine positioning and IL-6 mediated neuronal dysfunction. Here, we hypothesize that prone positioning mitigates neuronal injury, via decreased IL-6, in a model of VILI. VILI was induced by subjecting C57BL/6J mice to high tidal volume (35 cc/kg) mechanical ventilation. Neuronal injury markers [cleaved caspase-3 (CC3), c-fos, heat shock protein 90 (Hsp90)] and inflammatory cytokines (IL-6, IL-1ß, TNF-α) were measured in the frontal cortex and hippocampus. We found statistically significantly less neuronal injury (CC3, c-Fos, Hsp90) and inflammatory cytokines (IL-6, IL-1ß, TNF-α) in the frontal cortex and hippocampus with prone compared to supine positioning (p < 0.001) despite no significant group differences in oxygen saturation or inflammatory infiltrates in the bronchoalveolar fluid (p > 0.05). Although there were no group differences in plasma IL-6 concentrations, there was significantly less cortical and hippocampal IL-6 in the prone position (p < 0.0001), indicating supine positioning may enhance brain susceptibility to systemic IL-6 during VILI via the IL-6 trans-signaling pathway. These findings call for future clinical studies to assess the relationship between prone positioning and delirium and for investigations into novel diagnostic or therapeutic paradigms to mitigate delirium by reducing expression of systemic and cerebral IL-6.
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Urinary tract infections (UTIs) are common and frequently precipitate delirium-like states. Advanced age coincident with the postmenopausal period is a risk factor for delirium following UTIs. We previously demonstrated a pathological role for interleukin-6 (IL-6) in mediating delirium-like phenotypes in a murine model of UTI. Estrogen has been implicated in reducing peripheral IL-6 expression, but it is unknown whether the increased susceptibility of postmenopausal females to developing delirium concomitant with UTIs reflects diminished effects of circulating estrogen. Here, we tested this hypothesis in a mouse model of UTI. Female C57BL/6J mice were oophorectomized, UTIs induced by transurethral inoculation of E. coli, and treated with 17ß-estradiol. Delirium-like behaviors were evaluated prior to and following UTI and 17ß-estradiol treatment. Compared to controls, mice treated with 17ß-estradiol had less neuronal injury, improved delirium-like behaviors, and less plasma and frontal cortex IL-6. In vitro studies further showed that 17ß-estradiol may also directly mediate neuronal protection, suggesting pleiotropic mechanisms of 17ß-estradiol-mediated neuroprotection. In summary, we demonstrate a beneficial role for 17ß-estradiol in ameliorating acute UTI-induced structural and functional delirium-like phenotypes. These findings provide pre-clinical justification for 17ß-estradiol as a therapeutic target to ameliorate delirium following UTI.
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Delirio , Infecciones Urinarias , Ratones , Femenino , Animales , Escherichia coli , Modelos Animales de Enfermedad , Interleucina-6 , Ratones Endogámicos C57BL , Estradiol/farmacología , Infecciones Urinarias/tratamiento farmacológico , Estrógenos/farmacología , Fenotipo , Delirio/tratamiento farmacológicoRESUMEN
Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury; however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.
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Lesión Pulmonar Aguda , Delirio , Lesión Pulmonar Inducida por Ventilación Mecánica , Lesión Pulmonar Aguda/complicaciones , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Delirio/complicaciones , Modelos Animales de Enfermedad , Interleucina-6 , Ratones , Fenotipo , Lesión Pulmonar Inducida por Ventilación Mecánica/patologíaRESUMEN
Intrathecal methotrexate (IT MTX) resulting in severe adverse events including life-threatening cerebral edema is not well described. We report a rare case of death in a 37-year-old BRCA1+ woman with metastatic triple-negative breast cancer status post mastectomy following administration of IT MTX for leptomeningeal carcinomatosis. Within the 24 hours after intraoperative IT MTX delivery, she developed neurologically devastating diffuse cerebral edema leading to uncal and cerebellar tonsillar herniation. This case report highlights a rare but devastating side effect of IT MTX.
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Acute kidney injury is a known clinical risk factor for delirium, an acute cognitive dysfunction that is commonly encountered in the critically ill population. In this comprehensive review of clinical and basic research studies, we detail the epidemiology, clinical implications, pathogenesis, and management strategies of patients with acute kidney injury-associated delirium. Specifically addressed are the pathological roles of endogenous toxin or drug accumulation, acute kidney injury-mediated neuroinflammation, and acute kidney injury-associated volume overload as discrete potential biological mechanisms of the condition. The optimization of clinical contributors and normalization of renal function are reviewed as pragmatic management strategies in addition to potential and emerging therapeutic approaches.
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Lesión Renal Aguda , Delirio , Desequilibrio Hidroelectrolítico , Enfermedad Crítica , Humanos , Factores de RiesgoRESUMEN
Urinary tract infection (UTI) is a common precipitant of acute neurological deterioration in patients with Parkinson's disease (PD) and a leading cause of delirium, functional decline, falls, and hospitalization. Various clinical features of PD including autonomic dysfunction and altered urodynamics, frailty and cognitive impairment, and the need for bladder catheterization contribute to an increased risk of UTI. Sepsis due to UTI is a feared consequence of untreated or undertreated UTI and a leading cause of morbidity in PD. Emerging research suggests that immune-mediated brain injury may underlie the pathogenesis of UTI-induced deterioration of PD symptoms. Existing strategies to prevent UTI in patients with PD include use of topical estrogen, prophylactic supplements, antibiotic bladder irrigation, clean catheterization techniques, and prophylactic oral antibiotics, while bacterial interference and vaccines/immunostimulants directed against common UTI pathogens are potentially emerging strategies that are currently under investigation. Future research is needed to mitigate the deleterious effects of UTI in PD.
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Enfermedad de Parkinson , Infecciones Urinarias , Antibacterianos/uso terapéutico , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Infecciones Urinarias/complicaciones , Infecciones Urinarias/tratamiento farmacológicoRESUMEN
BACKGROUND: Urinary tract infection (UTI) is frequently implicated as a precipitant of delirium, which refers to an acute confusional state that is associated with high mortality, increased length of stay, and long-term cognitive decline. The pathogenesis of delirium is thought to involve cytokine-mediated neuronal dysfunction of the frontal cortex and hippocampus. We hypothesized that systemic IL-6 inhibition would mitigate delirium-like phenotypes in a mouse model of UTI. METHODS: C57/BL6 mice were randomized to either: (1) non-UTI control, (2) UTI, and (3) UTI + anti-IL-6 antibody. UTI was induced by transurethral inoculation of 1 × 108 Escherichia coli. Frontal cortex and hippocampus-mediated behaviors were evaluated using functional testing and corresponding structural changes were evaluated via quantification of neuronal cleaved caspase-3 (CC3) by immunohistochemistry and western blot. IL-6 in the brain and plasma were evaluated using immunohistochemistry, ELISA, and RT-PCR. RESULTS: Compared to non-UTI control mice, mice with UTI demonstrated significantly greater impairments in frontal and hippocampus-mediated behaviors, specifically increased thigmotaxis in Open Field (p < 0.05) and reduced spontaneous alternations in Y-maze (p < 0.01), while treatment of UTI mice with systemic anti-IL-6 fully reversed these functional impairments. These behavioral impairments correlated with frontal and hippocampal neuronal CC3 changes, with significantly increased frontal and hippocampal CC3 in UTI mice compared to non-UTI controls (p < 0.0001), and full reversal of UTI-induced CC3 neuronal changes following treatment with systemic anti-IL-6 antibody (p < 0.0001). Plasma IL-6 was significantly elevated in UTI mice compared to non-UTI controls (p < 0.01) and there were positive and significant correlations between plasma IL-6 and frontal CC3 (r2 = 0.5087/p = 0.0028) and frontal IL-6 and CC3 (r2 = 0.2653, p < 0.0001). CONCLUSIONS: These data provide evidence for a role for IL-6 in mediating delirium-like phenotypes in a mouse model of UTI. These findings provide pre-clinical justification for clinical investigations of IL-6 inhibitors to treat UTI-induced delirium.
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Delirio/metabolismo , Modelos Animales de Enfermedad , Interleucina-6/metabolismo , Fenotipo , Infecciones Urinarias/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Delirio/patología , Femenino , Interleucina-6/antagonistas & inhibidores , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Infecciones Urinarias/patologíaRESUMEN
Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.
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Anticuerpos/farmacología , Apoptosis/efectos de los fármacos , Delirio/metabolismo , Interleucina-6/antagonistas & inhibidores , Neuronas/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/metabolismo , Animales , Delirio/tratamiento farmacológico , Delirio/patología , Modelos Animales de Enfermedad , Femenino , Lóbulo Frontal/lesiones , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Proteínas HSP90 de Choque Térmico/metabolismo , Hipocampo/lesiones , Hipocampo/metabolismo , Hipocampo/patología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/metabolismo , Ratones , Neuronas/patología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Represoras/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/tratamiento farmacológico , Lesión Pulmonar Inducida por Ventilación Mecánica/patologíaRESUMEN
Background: Patients with traumatic brain injury (TBI) frequently develop leukocytosis, fever, and tachycardia that may lead to extensive medical investigations to rule out an infectious process. Cerebrospinal fluid (CSF) is often acquired during this workup, however, the utility of this practice has not been studied previously. We hypothesized that CSF cultures would unlikely yield positive results in patients with TBI. Patients and Methods: A retrospective review was conducted of all patients with TBI admitted to two level 1 trauma centers at urban, academic institutions from January 2009 to December 2016. Data collected included patient demographics, presenting Glasgow Coma Score (GCS), injury profile, injury severity scores (ISS), regional abbreviated injury scale (AIS), hospital and intensive care unit (ICU) length of stay (LOS), ventilator days, and culture results. For purposes of the analysis, CSF cultures with Staphylococcus epidermidis, Staphylococcus aureus, or Candida underwent a chart review and were considered contaminates if indicated. Results: There were 145 patients who had CSF cultures obtained with a median age of 39 years; 77.2% were male. The majority of patients presented after blunt trauma with median GCS of 6, head AIS of 4, and ISS of 25. These patients had prolonged median ICU and hospital stays at 13 and 22 days, respectively. Six (4.1%) CSF cultures demonstrated growth. Four (2.8%) were deemed contaminants, with two growing Staphylococcus epidermidis only, one with both Staphylococcus epidermidis and Staphylococcus aureus, and one with Candida. Two cultures (1.4%) were positive and grew Enterobacter cloacae. Of note, both patients had prior instrumentation with an external ventricular drain. Conclusion: Obtaining CSF cultures in patients with TBI is of low yield, especially in patients without prior external ventricular drain. Other sources of infectious etiologies should be considered in this patient population.
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Lesiones Traumáticas del Encéfalo , Adulto , Humanos , Puntaje de Gravedad del Traumatismo , Tiempo de Internación , Masculino , Estudios Retrospectivos , Centros TraumatológicosRESUMEN
Adrenoceptor and calcium channel modulating medications are widely used in clinical practice for acute neurological and systemic conditions. It is generally assumed that the cerebrovascular effects of these drugs mirror that of their systemic effects - and this is reflected in how these medications are currently used in clinical practice. However, recent research suggests that there are distinct cerebrovascular-specific effects of these medications that are related to the unique characteristics of the cerebrovascular anatomy including the regional heterogeneity in density and distribution of adrenoceptor subtypes and calcium channels along the cerebrovasculature. In this review, we critically evaluate existing basic science and clinical research to discuss known and putative interactions between adrenoceptor and calcium channel modulating pharmacotherapies, the neurovascular unit, and cerebrovascular anatomy. In doing so, we provide a rationale for selecting vasoactive medications based on lesion location and lay a foundation for future investigations that will define neuroprotective paradigms of adrenoceptor and calcium channel modulating therapies to improve neurological outcomes in acute neurological and systemic disorders.
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Adrenérgicos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio/efectos de los fármacos , Trastornos Cerebrovasculares/tratamiento farmacológico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Receptores Adrenérgicos/efectos de los fármacos , Animales , Humanos , Vasoconstrictores/farmacología , Vasoconstrictores/uso terapéuticoRESUMEN
Extensive effort has been made studying retinal pathology in Alzheimer's disease (AD) to improve early noninvasive diagnosis and treatment. Particularly relevant are vascular changes, which appear prominent in early brain pathogenesis and could predict cognitive decline. Recently, we identified platelet-derived growth factor receptor beta (PDGFRß) deficiency and pericyte loss associated with vascular Aß deposition in the neurosensory retina of mild cognitively impaired (MCI) and AD patients. However, the pathological mechanisms of retinal vascular changes and their possible relationships with vascular amyloidosis, pericyte loss, and blood-retinal barrier (BRB) integrity remain unknown. Here, we evaluated the retinas of transgenic APPSWE/PS1ΔE9 mouse models of AD (ADtg mice) and wild-type mice at different ages for capillary degeneration, PDGFRß expression, vascular amyloidosis, permeability and inner BRB tight-junction molecules. Using a retinal vascular isolation technique followed by periodic acid-Schiff or immunofluorescent staining, we discovered significant retinal capillary degeneration in ADtg mice compared to age- and sex-matched wild-type mice (P < 0.0001). This small vessel degeneration reached significance in 8-month-old mice (P = 0.0035), with males more susceptible than females. Degeneration of retinal capillaries also progressively increased with age in healthy mice (P = 0.0145); however, the phenomenon was significantly worse during AD-like progression (P = 0.0001). A substantial vascular PDGFRß deficiency (~ 50% reduction, P = 0.0017) along with prominent vascular Aß deposition was further detected in the retina of ADtg mice, which inversely correlated with the extent of degenerated capillaries (Pearson's r = - 0.8, P = 0.0016). Importantly, tight-junction alterations such as claudin-1 downregulation and increased BRB permeability, demonstrated in vivo by retinal fluorescein imaging and ex vivo following injection of FITC-dextran (2000 kD) and Texas Red-dextran (3 kD), were found in ADtg mice. Overall, the identification of age- and Alzheimer's-dependent retinal capillary degeneration and compromised BRB integrity starting at early disease stages in ADtg mice could contribute to the development of novel targets for AD diagnosis and therapy.
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Enfermedad de Alzheimer/patología , Amiloidosis/patología , Barrera Hematorretinal/patología , Capilares/patología , Permeabilidad Capilar , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Vasos Retinianos/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Barrera Hematorretinal/metabolismo , Capilares/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Presenilina-1/genética , Vasos Retinianos/metabolismo , Proteínas de Uniones Estrechas/metabolismoRESUMEN
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