Systemic Insults Research Articles

Microglial depletion rescues spatial memory impairment caused by LPS administration in adult mice

Recent studies have highlighted the importance of microglia, the resident macrophages in the brain, in regulating cognitive functions such as learning and memory in both healthy and diseased states. However, there are conflicting results and the underlying mechanisms are not fully understood. In this study, we examined the effect of depleting adult microglia on spatial learning and memory under both physiological conditions and lipopolysaccharide (LPS)-induced neuroinflammation. Our results revealed that microglial depletion by PLX5622 caused mild spatial memory impairment in mice under physiological conditions; however, it prevented memory deficits induced by systemic LPS insult. Inactivating microglia through minocycline administration replicated the protective effect of microglial depletion on LPS-induced memory impairment. Furthermore, our study showed that PLX5622 treatment suppressed LPS-induced neuroinflammation, microglial activation, and synaptic dysfunction. These results strengthen the evidence for the involvement of microglial immunoactivation in LPS-induced synaptic and cognitive malfunctions. They also suggest that targeting microglia may be a potential approach to treating neuroinflammation-associated cognitive dysfunction seen in neurodegenerative diseases.

Differential Mitochondrial Bioenergetics in Neurons and Astrocytes Following Ischemia-Reperfusion Injury and Hypothermia.

The close interaction between neurons and astrocytes has been extensively studied. However, the specific behavior of these cells after ischemia-reperfusion injury and hypothermia remains poorly characterized. A growing body of evidence suggests that mitochondria function and putative transference between neurons and astrocytes may play a fundamental role in adaptive and homeostatic responses after systemic insults such as cardiac arrest, which highlights the importance of a better understanding of how neurons and astrocytes behave individually in these settings. Brain injury is one of the most important challenges in post-cardiac arrest syndrome, and therapeutic hypothermia remains the single, gold standard treatment for neuroprotection after cardiac arrest. In our study, we modeled ischemia-reperfusion injury by using in vitro enhanced oxygen-glucose deprivation and reperfusion (eOGD-R) and subsequent hypothermia (HPT) (31.5 °C) to cell lines of neurons (HT-22) and astrocytes (C8-D1A) with/without hypothermia. Using cell lysis (LDH; lactate dehydrogenase) as a measure of membrane integrity and cell viability, we found that neurons were more susceptible to eOGD-R when compared with astrocytes. However, they benefited significantly from HPT, while the HPT effect after eOGD-R on astrocytes was negligible. Similarly, eOGD-R caused a more significant reduction in adenosine triphosphate (ATP) in neurons than astrocytes, and the ATP-enhancing effects from HPT were more prominent in neurons than astrocytes. In both neurons and astrocytes, measurement of reactive oxygen species (ROS) revealed higher ROS output following eOGD-R, with a non-significant trend of differential reduction observed in neurons. HPT after eOGD-R effectively downregulated ROS in both cells; however, the effect was significantly more effective in neurons. Lipid peroxidation was higher after eOGD-R in neurons, while in astrocytes, the increase was not statistically significant. Interestingly, HPT had similar effects on the reduction in lipoperoxidation after eOGD-R with both types of cells. While glutathione (GSH) levels were downregulated after eOGD-R in both cells, HPT enhanced GSH in astrocytes, but worsened GSH in neurons. In conclusion, neuron and astrocyte cultures respond differently to eOGD-R and eOGD-R + HTP treatments. Neurons showed higher sensitivity to ischemia-reperfusion insults than astrocytes; however, they benefited more from HPT therapy. These data suggest that given the differential effects from HPT in neurons and astrocytes, future therapeutic developments could potentially enhance HPT outcomes by means of neuronal and astrocytic targeted therapies.

A Life Saving Exchange: A Case of Severe Direct Hyperbilirubinemia And Liver Failure in Leptospirosis Successfully Treated with Plasma Exchange

Leptospirosis is an infection with multiorgan involvement and a high mortality rate. Extreme hyperbilirubinemia in leptospirosis has been reported to exert multiple cellular toxic effects on kidney and liver cells. We describe a young man with leptospirosis who had extreme hyperbilirubinemia, acute liver injury, coagulopathy, hepatic encephalopathy, and pulmonary haemorrhages. Early initiation of therapeutic plasma exchange (PEX) dramatically improved patient’s clinical and biochemical parameters. We conclude that, in addition to the mortality benefit provided by PEX in severe pulmonary hemorrhage syndrome in leptospirosis, PEX is also beneficial in reducing systemic toxic insults of hyperbilirubinemia.

Mitochondrial dysfunction precedes hippocampal IL-1β transcription and cognitive impairments after low-dose lipopolysaccharide injection in aged mice

Acute cognitive impairments termed delirium often occur after inflammatory insults in elderly patients. While previous preclinical studies suggest mitochondria as a target for reducing neuroinflammation and cognitive impairments after LPS injection, fewer studies have evaluated the effects of a low-grade systemic inflammation in the aged brain. Thus, to identify the significance of mitochondrial dysfunction after a clinically relevant systemic inflammatory stimulus, we injected old-aged mice (18–20 months) with low-dose lipopolysaccharide (LPS, 0.04 mg/kg). LPS injection reduced mitochondrial respiration in the hippocampus 24 h after injection (respiratory control ratio [RCR], state3u/state4o; control = 2.82 ± 0.19, LPS = 2.57 ± 0.08). However, gene expression of the pro-inflammatory cytokine IL-1β was increased (RT-PCR, control = 1.00 ± 0.30; LPS = 2.01 ± 0.67) at a more delayed time point, 48 h after LPS injection. Such changes were associated with cognitive impairments in the Barnes maze and fear chamber tests. Notably, young mice were unaffected by low-dose LPS, suggesting that mitochondrial dysfunction precedes neuroinflammation and cognitive decline in elderly patients following a low-grade systemic insult. Our findings highlight mitochondria as a potential therapeutic target for reducing delirium in elderly patients.

Early systemic insults following traumatic brain injury: association with biomarker profiles, therapy for intracranial hypertension, and neurological outcomes—an analysis of CENTER-TBI data

PurposeWe analysed the impact of early systemic insults (hypoxemia and hypotension, SIs) on brain injury biomarker profiles, acute care requirements during intensive care unit (ICU) stay, and 6-month outcomes in patients with traumatic brain injury (TBI).MethodsFrom patients recruited to the Collaborative European neurotrauma effectiveness research in TBI (CENTER-TBI) study, we documented the prevalence and risk factors for SIs and analysed their effect on the levels of brain injury biomarkers [S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and protein Tau], critical care needs, and 6-month outcomes [Glasgow Outcome Scale Extended (GOSE)].ResultsAmong 1695 TBI patients, 24.5% had SIs: 16.1% had hypoxemia, 15.2% had hypotension, and 6.8% had both. Biomarkers differed by SI category, with higher S100B, Tau, UCH-L1, NSE and NfL values in patients with hypotension or both SIs. The ratio of neural to glial injury (quantified as UCH-L1/GFAP and Tau/GFAP ratios) was higher in patients with hypotension than in those with no SIs or hypoxia alone. At 6 months, 380 patients died (22%), and 759 (45%) had GOSE ≤ 4. Patients who experienced at least one SI had higher mortality than those who did not (31.8% vs. 19%, p < 0.001).ConclusionThough less frequent than previously described, SIs in TBI patients are associated with higher release of neuronal than glial injury biomarkers and with increased requirements for ICU therapies aimed at reducing intracranial hypertension. Hypotension or combined SIs are significantly associated with adverse 6-month outcomes. Current criteria for hypotension may lead to higher biomarker levels and more negative outcomes than those for hypoxemia suggesting a need to revisit pressure targets in the prehospital settings.

Abstract TP297: Focused Mouse Brain Irradiation Model to Define the Neurovascular Unit

Purpose: This project aimed to develop a stereotactic radiosurgery mouse model of radiation-induced brain injury to study endothelial damage within the neurovascular unit (NVU). Classification of focal endothelial damage and the resulting inflammatory cascade has never been cataloged for assessing intrinsic changes versus extrinsic factors of inflammation at the NVU. The study of endothelial damage with invasive models, such as open transcranial injury or vessel occlusion, introduces multiple variables into the system that our model can help overcome to study secondary or systemic insults of the NVU. Methods: Using an X-ray image-guided radiation therapy system, mice were focally irradiated with 30, 45, and 70 Gy to a 5 mm brain target. Mice were followed up at 2, 4, 6, 12 and 18 weeks after irradiation with contrast-enhanced CT imaging for volumetric quantification of radiation effects. Brains were harvested for characterization by histology and immune-multiplexing of reactionary and inflammatory changes to the NVU. Whole coronal slides were scanned and analyzed using machine learning classifiers to quantify cell types within the NVU in the radiated vs. control hemispheres. Results: Radiation-induced changes such as telangiectasias, vessel hyalinization, and white matter necrosis were observed. An inflammatory response with a predominance of T cells was observed, as well as an increase in microglial cells and reactive astrogliosis. These changes were time and dose-dependent after radiation. Serial CTs allowed for determining the development of radiation damage, and the contrast enhancement was proportional to the degree of radiation-induced changes. Conclusions: This radiation model allows precise image-guided targeting with a steep radiation fall-off into surrounding tissues. The NVU’s response to focal insult of endothelial damage presents a novel method of brain injury to specifically study diseases associated with endothelial dysfunction.

Clinical evaluation of a fully electronic microfluidic white blood cell analyzer.

The White Blood Cell (WBC) count is one of the key parameters signaling the health of the immune system. Abnormal WBC counts often signal a systemic insult to the body such as an underlying infection or an adverse side effect to medication. Typically, the blood collected is sent to a central lab for testing, and results come back within hours, which is often inconvenient and may delay time-sensitive diagnosis or treatment. Here, we present the CytoTracker, a fully electronic, microfluidic based instant WBC analyzer with the potential to be used at point-of-care. The CytoTracker is a lightweight, portable, affordable platform capable of quantifying WBCs within minutes using only 50 μl of blood (approximately one drop of blood). In this study, we clinically evaluated the accuracy and performance of CytoTracker in measuring WBC and granulocyte counts. A total of 210 adult patients were recruited in the study. We validated the CytoTracker against a standard benchtop analyzer (Horiba Point of Care Hematology Analyzer, ABX Micros 60). Linear dynamic ranges of 2.5 k/μl- 35 k/μl and 0.6 k/μl- 26 k/μl were achieved for total WBC count and granulocyte count with correlation coefficients of 0.97 and 0.98. In addition, we verified CytoTracker's capability of identifying abnormal blood counts with above 90% sensitivity and specificity. The promising results of this clinical validation study demonstrate the potential for the use of the CytoTracker as a reliable and accurate point-of-care WBC analyzer.

Effect of resistance exercise on secondary inflammatory insult in Alzheimer’s disease models

AbstractBackgroundPhysical exercise improves cognition in human and animal studies associated with Alzheimer’s Disease (AD). However, resistance‐type regimes remain poorly investigated. Acute illness or injury can influence the rate AD progression and trigger accelerated cognitive decline.MethodTo evaluate the role of RE in modulating pre‐existing cognitive impairment, female 3xTg and 5xFAD mice underwent a five‐week RE training protocol. An acute systemic inflammatory insult: laparotomy or intraperitoneally‐injected LPS, was performed to investigate the effect of RE under these challenges. Behavior tests was used to probe for cognition and learning. Brain homogenates were harvested for western blot analysis, qPCR, or post‐fixed in neutral‐buffered formalin solution for immuno‐histochemical exploration.ResultRE showed improved cognitive function, reduced P‐S396‐tau, decreased ionized calcium‐binding adapter molecule 1 (Iba‐1), and decreased inflammatory cytokine transcripts compared to sedentary controls. RE significantly reduced anxiety‐like behavior and cognitive deficit stimulated by acute systemic inflammation episode.ConclusionRE attenuates exaggerated cellular responses and improves cognitive functions in AD and accelerated cognitive impairment triggered by secondary inflammation insult.

Nonconvulsive Status Epilepticus: A Review for Emergency Clinicians

BackgroundStatus epilepticus is associated with significant morbidity and mortality and is divided into convulsive status epilepticus and nonconvulsive status epilepticus (NCSE). ObjectiveThis review provides a focused evaluation of NCSE for emergency clinicians. DiscussionNCSE is a form of status epilepticus presenting with prolonged seizure activity. This disease is underdiagnosed, as it presents with nonspecific signs and symptoms, most commonly change in mental status without overt convulsive motor activity. Causes include epilepsy, cerebral pathology or injury, any systemic insult such as infection, and drugs or toxins. Mortality is primarily related to the underlying condition. Patients most commonly present with altered mental status, but other signs and symptoms include abnormal ocular movements and automatisms such as lip smacking or subtle motor twitches in the face or extremities. The diagnosis is divided into electrographic and electroclinical, and although electroencephalogram (EEG) is recommended for definitive diagnosis, emergency clinicians should consider this disease in patients with prolonged postictal state after a seizure with no improvement in mental status, altered mental status with acute cerebral pathology (e.g., stroke, hypoxic brain injury), and unexplained altered mental status. Assessment includes laboratory evaluation and neuroimaging with EEG. Management includes treating life-threatening conditions, including compromise of the airway, hypoglycemia, hyponatremia, and hypo- or hyperthermia, followed by rapid cessation of the seizure activity with benzodiazepines and other antiseizure medications. ConclusionsAn understanding of the presentation and management of NCSE can assist emergency clinicians in the care of these patients.

Development of a neonatal Göttingen Minipig model for dose precision in perinatal asphyxia: technical opportunities, challenges, and potential further steps.

Animal models provide useful information on mechanisms in human disease conditions, but also on exploring (patho)physiological factors affecting pharmacokinetics, safety, and efficacy of drugs in development. Also, in pediatric patients, nonclinical data can be critical for better understanding the disease conditions and developing new drug therapies in this age category. For perinatal asphyxia (PA), a condition defined by oxygen deprivation in the perinatal period and possibly resulting in hypoxic ischemic encephalopathy (HIE) or even death, therapeutic hypothermia (TH) together with symptomatic drug therapy, is the standard approach to reduce death and permanent brain damage in these patients. The impact of the systemic hypoxia during PA and/or TH on drug disposition is largely unknown and an animal model can provide useful information on these covariates that cannot be assessed separately in patients. The conventional pig is proven to be a good translational model for PA, but pharmaceutical companies do not use it to develop new drug therapies. As the Göttingen Minipig is the commonly used pig strain in nonclinical drug development, the aim of this project was to develop this animal model for dose precision in PA. This experiment consisted of the instrumentation of 24 healthy male Göttingen Minipigs, within 24 h of partus, weighing approximately 600 g, to allow the mechanical ventilation and the multiple vascular catheters inserted for maintenance infusion, drug administration and blood sampling. After premedication and induction of anesthesia, an experimental protocol of hypoxia was performed, by decreasing the inspiratory oxygen fraction (FiO2) at 15%, using nitrogen gas. Blood gas analysis was used as an essential tool to evaluate oxygenation and to determine the duration of the systemic hypoxic insult to approximately 1 h. The human clinical situation was mimicked for the first 24 h after birth in case of PA, by administering four compounds (midazolam, phenobarbital, topiramate and fentanyl), frequently used in a neonatal intensive care unit (NICU). This project aimed to develop the first neonatal Göttingen Minipig model for dose precision in PA, allowing to separately study the effect of systemic hypoxia versus TH on drug disposition. Furthermore, this study showed that several techniques that were thought to be challenging or even impossible in these very small animals, such as endotracheal intubation and catheterization of several veins, are feasible by trained personnel. This is relevant information for laboratories using the neonatal Göttingen Minipig for other disease conditions or drug safety testing.

CNP-miR146a improves outcomes in a two-hit acute- and ventilator-induced lung injury model

Acute respiratory distress syndrome (ARDS) has high mortality (~40 %) and requires the lifesaving intervention of mechanical ventilation. A variety of systemic inflammatory insults can progress to ARDS, and the inflamed and injured lung is susceptible to ventilator-induced lung injury (VILI). Strategies to mitigate the inflammatory response while restoring pulmonary function are limited, thus we sought to determine if treatment with CNP-miR146a, a conjugate of novel free radical scavenging cerium oxide nanoparticles (CNP) to the anti-inflammatory microRNA (miR)-146a, would protect murine lungs from acute lung injury (ALI) induced with intratracheal endotoxin and subsequent VILI. Lung injury severity and treatment efficacy were evaluated via lung mechanical function, relative gene expression of inflammatory biomarkers, and lung morphometry (stereology). CNP-miR146a reduced the severity of ALI and slowed the progression of VILI, evidenced by improvements in inflammatory biomarkers, atelectasis, gas volumes in the parenchymal airspaces, and the stiffness of the pulmonary system.

The Oral Health of a Group of 19th Century South Australian Settlers in Relation to Their General Health and Compared with That of Contemporaneous Samples.

The aims of this study are to determine the oral health status of a rare sample of 19th-century migrant settlers to South Australia, how oral conditions may have influenced their general health, and how the oral health of this group compares with contemporaneous samples in Australia, New Zealand, and Britain. Dentitions of 18 adults and 22 subadults were investigated using non-destructive methods (micro-CT, macroscopic, radiographic). Extensive carious lesions were identified in seventeen adults and four subadults, and from this group one subadult and sixteen adults had antemortem tooth loss. Sixteen adults showed evidence of periodontal disease. Enamel hypoplastic (EH) defects were identified in fourteen adults and nine subadults. Many individuals with dental defects also had skeletal signs of comorbidities. South Australian individuals had the same percentage of carious lesions as the British sample (53%), more than other historic Australian samples, but less than a contemporary New Zealand sample. Over 50% of individuals from all the historic cemeteries had EH defects, suggesting systemic health insults during dental development were common during the 19th century. The overall oral health of the South Australian settlers was poor but, in some categories, (tooth wear, periapical abscess, periodontal disease), better than the other historic samples.

Brain injury biomarkers do not predict delirium in acutely ill older patients: a prospective cohort study

Delirium is a common, serious, and often preventable neuropsychiatric emergency mostly characterized by a disturbance in attention and awareness. Systemic insult and inflammation causing blood–brain-barrier (BBB) damage and glial and neuronal activation leading to more inflammation and cell death is the most accepted theory behind delirium's pathophysiology. This study aims to evaluate the relationship between brain injury biomarkers on admission and delirium in acutely ill older patients. We performed a prospective cohort study which analyzed plasma S100B levels at admission in elderly patients. Our primary outcome was delirium diagnosis. Secondary outcomes were association between S100B, NSE and Tau protein and delirium diagnosis and patients’ outcomes (admissions to intensive care, length of hospital stay, and in-hospital mortality). We analyzed 194 patients, and 46 (24%) developed delirium, 25 on admission and 21 during hospital stay. Median of S100B at admission in patients who developed delirium was 0.16 and median was 0.16 in patients who didn’t develop delirium (p: 0.69). Levels S100B on admission did not predict delirium in acutely ill elderly patients.Trial registration: The study was approved by the local institutional review board (CAPPESq, no. 77169716.2.0000.0068, October 11, 2017) and registered in Brazilian Clinical Trials Registry (ReBEC, no. RBR-233bct).

Premature infants born

Despite a growing understanding of bronchopulmonary dysplasia (BPD) and advances in management, BPD rates remain stable. There is mounting evidence that BPD may be due to a systemic insult, such as acute kidney injury (AKI). Our hypothesis was that severe AKI would be associated with BPD. We conducted a secondary analysis of premature infants [24-27 weeks gestation] in the Recombinant Erythropoietin for Protection of Infant Renal Disease cohort (N = 885). We evaluated the composite outcome of Grade 2/3 BPD or death using generalized estimating equations. In an exploratory analysis, urinary biomarkers of angiogenesis (ANG1, ANG2, EPO, PIGF, TIE2, FGF, and VEGFA/D) were analyzed. 594 (67.1%) of infants had the primary composite outcome of Grade 2/3 BPD or death. Infants with AKI (aOR: 1.69, 95% CI: 1.16-2.46) and severe AKI (aOR: 2.05, 95% CI: 1.19-3.54). had increased risk of the composite outcome after multivariable adjustment Among 106 infants with urinary biomarkers assessed, three biomarkers (VEGFA, VEGFD, and TIE2) had AUC > 0.60 to predict BPD. Infants with AKI had a higher likelihood of developing BPD/death, with the strongest relationship seen in those with more severe AKI. Three urinary biomarkers of angiogenesis may have potential to predict BPD development. AKI is associated with lung disease in extremely premature infants, and urinary biomarkers may predict this relationship. Infants with AKI and severe AKI have higher odds of BPD or death. Three urinary angiogenesis biomarkers are altered in infants that develop BPD. These findings have the potential to drive future work to better understand the mechanistic pathways of BPD, setting the framework for future interventions to decrease BPD rates. A better understanding of the mechanisms of BPD development and the role of AKI would have clinical care, cost, and quality of life implications given the long-term effects of BPD.

Chapter 4: Development Defects of Enamel and Dentine and Coronal Caries.

The development of the human dentition is prone to disruption due to its delicate and complex nature - including variations in tooth number and anatomical form and in the characteristics of enamel, dentine, and cementum. This chapter will focus on developmental defects of dental enamel (DDE) and dentine (DDD), which can be associated with considerable treatment burden on an individual, often related to the change in dental hard tissue characteristics in those at increased caries risk. DDE are prevalent and can be related to genetic conditions such as amelogenesis imperfecta and environmental challenges such as direct physical trauma to the developing tooth or systemic insults during the different phases of amelogenesis. Phenotypical variability can be great, making diagnosis difficult in many cases. There are two major enamel defects - the quantitative defect of hypoplasia and the qualitative defect of hypomineralization. DDDs are less prevalent than DDEs, with two major DDD types: dentinogenesis imperfecta and dentine dysplasia. The main features of the DDDs are enamel fracture exposing the dentine and subsequent wear, with enlarged pulp spaces in some variants. The appearance may be affected, with bulbous teeth and grey-blue to brown opalescent colouring. With respect to dental caries, developmental defects of the teeth, in themselves, do not cause caries risk; however, they can change the manifestation of the disease due to creating niches for biofilm accumulation and thereby increasing cleaning difficulty and changing the physical and chemical characteristics of dental hard tissues and how they react to cariogenic challenges.

Macrophage infiltration in the cornea in a mouse model of sepsis

AbstractPurpose: To analyse the effect of a systemic inflammatory insult induced by lipopolysaccharide (LPS) administration on the cornea in mice.Methods: Male and female C57BL/6J mice were injected with a single intraperitoneal injection of LPS (5 mg/kg). Intact animals were used as control. At 21 days after LPS administration animals were sacrificed with sodium pentobarbital. Corneas were dissected as flat mounts or histological sections (16 μM) and Iba1 (microglia and macrophages) and CD45 (activated microglia and macrophages) immunodetected.Results: In LPS treated animals but not in intact ones, microglia/macrophages were found in all corneal layers while in corneal flat mounts Iba1 + Cd45+ cells were observed through the corneal surface with higher density in the periphery.Conclusions: Sepsis causes infiltration and activation of microglia/ macrophages in the murine cornea that lasts up to 21 days.

Comparison of Clinical Characteristics and Predictors of Mortality between Direct and Indirect ARDS.

Background and Objectives: Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous syndrome that encompasses lung injury from a direct pulmonary or indirect systemic insult. Studies have shown that direct and indirect ARDS differ in their pathophysiologic process. In this study, we aimed to compare the different clinical characteristics and predictors of 28-day mortality between direct and indirect ARDS. Materials and Methods: The data of 1291 ARDS patients from September 2012 to December 2021 at the Second Affiliated Hospital of Chongqing Medical University were reviewed. We enrolled 451 ARDS patients in our study through inclusion and exclusion criteria. According to the risk factors, each patient was divided into direct (n = 239) or indirect (n = 212) ARDS groups. The primary outcome was 28-day mortality. Results: The patients with direct ARDS were more likely to be older (p &lt; 0.001) and male (p = 0.009) and have more comorbidity (p &lt; 0.05) and higher 28-day mortality (p &lt; 0.001) than those with indirect ARDS. Age and multiple organ dysfunction syndrome (MODS) were predictors of 28-day mortality in the direct ARDS group, while age, MODS, creatinine, prothrombin time (PT), and oxygenation index (OI) were independent predictors of 28-day mortality in the indirect ARDS group. Creatinine, PT, and OI have interactions with ARDS types (all p &lt; 0.01). Conclusions: The patients with direct ARDS were more likely to be older and male and have worse conditions and prognoses than those with indirect ARDS. Creatinine, PT, and OI were predictors of 28-day mortality only in the indirect ARDS group. The differences between direct and indirect ARDS suggest the need for different management strategies of ARDS.

Lipopolysaccharide Exposure Differentially Alters Plasma and Brain Inflammatory Markers in Adult Male and Female Rats.

Humans and rodents have sexually dimorphic immune responses, which could influence the brain’s response to a systemic inflammatory insult. Lipopolysaccharide (LPS) is a stimulator of the innate immune system and is routinely used in animal models to study blood–brain barrier (BBB) dysfunction under inflammatory conditions. Therefore, we examined whether inflammatory response to LPS and the associated BBB disruption differed in male and female adult rats. Rats were treated with saline or two injections of 1 mg/kg LPS and studied 24 h after the second LPS injection. Plasma isolated from trunk blood and brain tissue homogenates of the prefrontal cortex (PFC), dorsal striatum (DS), hippocampus, and cerebellum were analyzed for cytokines and chemokines using a 9-plex panel from Meso Scale Discovery. BBB disruption was analyzed with tight junction proteins claudin-5 and VE-cadherin via Western blotting and VEGF by ELISA. This allowed us to compare sex differences in the levels of individual cytokines as well as associations among cytokines and expression of tight junction proteins between the plasma and specific brain regions. Higher levels of interferon-γ, interleukin-10 (IL-10), IL-13, IL-4, CXCL-1, and VEGF in the plasma were revealed compared to the brain homogenates, and higher levels of TNFα, IL-1β, IL-6, and IL-5 in the PFC were seen compared with plasma and other brain regions in males. Females showed higher levels of plasma CXCL1 and VEGF compared to males, and males showed higher levels of PFC TNFα, IL-6, IL-4, and VEGF compared to females. LPS induced significant increases in plasma cytokines and VEGF in both sexes. LPS did not significantly alter cytokines in brain tissue homogenates, however, it increased chemokines in the PFC, DS, and hippocampus. In the PFC, LPS produced BBB disruption, which is evident as reduced expression of claudin-5 in males and reduced expression of VE-cadherin in both sexes. Taken together, our results reveal significant sex differences in pro-inflammatory cytokine and chemokine levels in plasma and brain that were associated with BBB disruption after LPS, and validate the use of multiplex assay for plasma and brain tissue samples.

COVID-19 and Long-Term Outcomes: Lessons from Other Critical Care Illnesses and Potential Mechanisms.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that is currently causing a pandemic and has been termed coronavirus disease (COVID-19). The elderly or those with preexisting conditions like diabetes, hypertension, coronary heart disease, chronic obstructive pulmonary disease, cerebrovascular disease, or kidney dysfunction are more likely to develop severe cases when infected. Patients with COVID-19 admitted to the ICU have higher mortality than non-ICU patients. Critical illness has consistently posed a challenge not only in terms of mortality but also in regard to long-term outcomes of survivors. Patients who survive acute critical illness including, but not limited to, pulmonary and systemic insults associated with acute respiratory distress syndrome, pneumonia, systemic inflammation, and mechanical ventilation, will likely suffer from post-ICU syndrome, a phenomenon of cognitive, psychiatric, and/or physical disability after treatment in the ICU. Post-ICU morbidity and mortality continue to be a cause for concern when considering large-scale studies showing 12-month mortality risks of 11.8-21%. Previous studies have demonstrated that multiple mechanisms, including cytokine release, mitochondrial dysfunction, and even amyloids, may lead to end-organ dysfunction in patients. We hypothesize that COVID-19 infection will lead to post-ICU syndrome via potentially similar mechanisms as other chronic critical illnesses and cause long-term morbidity and mortality in patients. We consider a variety of mechanisms and questions that not only consider the short-term impact of the COVID-19 pandemic but its long-term effects that may not yet be imagined.

576 Comparison of Survival Benefit Between Direct Emergency Department Admissions and Inter-hospital Transfers in Burn Victims

IntroductionSevere burn injuries create systemic insults that are life threatening and require immediate stabilization, resuscitation, and, potentially, emergent surgery. Non-burn emergencies, such as stroke, have shown improved survival benefit and outcomes when patients are immediately transferred to specialized facilities. Our objective was to compare the outcomes between burn patients who were transferred to the burn unit from outside hospitals (HT) to controls who were directly admitted from our own emergency department (ED). We hypothesized that HT patients were at increased risk for mortality, wound healing complications, and infectious sequelae relative to the ED cohort.MethodsA matched retrospective cohort study from July 1, 2015 to November 1, 2019 was performed at an ABA-verified burn center. HT patients were identified and matched with ED patients by age and percent total body surface area burned (TBSA). HT and ED cohorts were compared as a whole and then stratified into groups according to % TBSA burned (< 10%, 11-20%, 21-40%, and > 40%). Patient and burn characteristics were recorded. The primary outcome was mortality, and secondary outcomes included total length of stay (LOS), ICU requirement and complications.ResultsA total of 410 HT and 377 ED patients were identified. There were no significant differences in age (P=0.17), burn severity (TBSA: P=0.27; full thickness burns: P=0.13), and inhalation injury (P=0.29). There were no demographic differences when comparing cohorts according to TBSA. For the primary outcome, there were no significant differences in mortality in the cohorts at large (P=0.48) nor between the groups when stratifying for TBSA (< 10% : P=0.35; 11-20% : P=0.44; 21-40% : P=0.30; >40% : P=0.26). For the secondary outcomes at large, there was no significant difference in LOS (P=0.35), ICU requirement (P=0.17), or wound and infectious complications (P=0.14). HT patients at large, however, spent less time in the ICU (P=0.03).ConclusionsThere was no significant difference in overall mortality rates between the HT and ED groups regardless of TBSA. Additionally, there was no difference in hospital course between the cohorts except for longer ICU stays in those admitted directly from the ED. Once the transfer process is initiated, our unit maintains close physician-to-physician communication with the transferring facility throughout the transfer process, including guiding initial resuscitation efforts. This may play a role in the parity of outcomes between groups.