RESUMEN
Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease primarily affecting premature neonates, marked by poorly understood pro-inflammatory signaling cascades. Recent advancements have shed light on a subset of endogenous molecular patterns, termed chromatin-associated molecular patterns (CAMPs), which belong to the broader category of damage-associated molecular patterns (DAMPs). CAMPs play a crucial role in recognizing pattern recognition receptors and orchestrating inflammatory responses. This review focuses into the realm of CAMPs, highlighting key players such as extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), cell-free DNA, neutrophil extracellular traps (NETs), histones, and extracellular RNA. These intrinsic molecules, often perceived as foreign, have the potential to trigger immune signaling pathways, thus contributing to NEC pathogenesis. In this review, we unravel the current understanding of the involvement of CAMPs in both preclinical and clinical NEC scenarios. We also focus on elucidating the downstream signaling pathways activated by these molecular patterns, providing insights into the mechanisms that drive inflammation in NEC. Moreover, we scrutinize the landscape of targeted therapeutic approaches, aiming to mitigate the impact of tissue damage in NEC. This in-depth exploration offers a comprehensive overview of the role of CAMPs in NEC, bridging the gap between preclinical and clinical insights.
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Alarminas , Cromatina , Enterocolitis Necrotizante , Humanos , Enterocolitis Necrotizante/metabolismo , Enterocolitis Necrotizante/inmunología , Alarminas/metabolismo , Alarminas/inmunología , Cromatina/metabolismo , Animales , Transducción de Señal , Recién Nacido , Proteína HMGB1/metabolismoRESUMEN
INTRODUCTION: Neonatal sepsis is a devastating inflammatory condition that remains a leading cause of morbidity and mortality. Milk fat globule-EGF-factor VIII (MFG-E8) is a glycoprotein that reduces inflammation, whereas extracellular cold-inducible RNA binding protein (eCIRP) worsens inflammation. This study aimed to determine the therapeutic potential of a novel MFG-E8-derived oligopeptide 3 (MOP3) designed to clear eCIRP and protect against inflammation, organ injury, and mortality in neonatal sepsis. METHODS: C57BL6 mouse pups were injected intraperitoneally with cecal slurry (CS) and treated with MOP3 (20 µg/g) or vehicle. 10 h after injection, blood, lungs, and intestines were collected for analyses, and in a 7-day experiment, pups were monitored for differences in mortality. RESULTS: MOP3 treatment protected septic pups from inflammation by reducing eCIRP, IL-6, TNFα, and LDH. MOP3 reduced lung and intestinal inflammation and injury as assessed by reductions in tissue mRNA levels of inflammatory markers, histopathologic injury, and apoptosis in lung and intestines. MOP3 also significantly improved 7-day overall survival for CS-septic mouse pups compared to vehicle (75% vs. 46%, respectively). CONCLUSION: Deriving from MFG-E8 and designed to clear eCIRP, MOP3 protects against sepsis-induced inflammation, organ injury, and mortality in a preclinical model of neonatal sepsis, implicating it as an exciting potential new therapeutic. LEVEL OF EVIDENCE: Level 1.
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Antígenos de Superficie , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Proteínas de la Leche , Sepsis Neonatal , Oligopéptidos , Animales , Ratones , Antígenos de Superficie/uso terapéutico , Sepsis Neonatal/tratamiento farmacológico , Proteínas de la Leche/uso terapéutico , Oligopéptidos/uso terapéutico , Oligopéptidos/farmacología , Proteínas de Unión al ARN/metabolismo , Animales Recién Nacidos , Pulmón/patología , Pulmón/metabolismoRESUMEN
Sepsis is a life-threatening inflammatory condition partly orchestrated by the release of various damage-associated molecular patterns such as extracellular cold-inducible RNA-binding protein (eCIRP). Despite advances in understanding the pathogenic role of eCIRP in inflammatory diseases, novel therapeutic strategies to prevent its excessive inflammatory response are lacking. Milk fat globule-epidermal growth factor-VIII (MFG-E8) is critical for the opsonic clearance of apoptotic cells, but its potential involvement in the removal of eCIRP was previously unknown. Here, we report that MFG-E8 can strongly bind eCIRP to facilitate αvß3-integrin-dependent internalization and lysosome-dependent degradation of MFG-E8/eCIRP complexes, thereby attenuating excessive inflammation. Genetic disruption of MFG-E8 expression exaggerated sepsis-induced systemic accumulation of eCIRP and other cytokines, and consequently exacerbated sepsis-associated acute lung injury. In contrast, MFG-E8-derived oligopeptide recapitulated its eCIRP binding properties, and significantly attenuated eCIRP-induced inflammation to confer protection against sepsis. Our findings suggest a novel therapeutic approach to attenuate eCIRP-induced inflammation to improve outcomes of lethal sepsis.
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Lesión Pulmonar Aguda , Sepsis , Humanos , Sepsis/tratamiento farmacológico , Sepsis/patología , Inflamación/tratamiento farmacológico , Lesión Pulmonar Aguda/tratamiento farmacológico , Proteínas de la Leche/genética , Proteínas de la Leche/metabolismo , Proteínas de la Leche/farmacología , Antígenos de Superficie/metabolismoRESUMEN
INTRODUCTION: While intravenous fluid therapy is essential to re-establishing volume status in children who have experienced trauma, aggressive resuscitation can lead to various complications. There remains a lack of consensus on whether pediatric trauma patients will benefit from a liberal or restrictive crystalloid resuscitation approach and how to optimally identify and transition between fluid phases. METHODS: A panel was comprised of physicians with expertise in pediatric trauma, critical care, and emergency medicine. A three-round Delphi process was conducted via an online survey, with each round being followed by a live video conference. Experts agreed or disagreed with each aspect of the proposed fluid management algorithm on a five-level Likert scale. The group opinion level defined an algorithm parameter's acceptance or rejection with greater than 75% agreement resulting in acceptance and greater than 50% disagreement resulting in rejection. The remaining were discussed and re-presented in the next round. RESULTS: Fourteen experts from five Level 1 pediatric trauma centers representing three subspecialties were included. Responses were received from 13/14 participants (93%). In round 1, 64% of the parameters were accepted, while the remaining 36% were discussed and re-presented. In round 2, 90% of the parameters were accepted. Following round 3, there was 100% acceptance by all the experts on the revised and final version of the algorithm. CONCLUSIONS: We present a validated algorithm for intavenous fluid management in pediatric trauma patients that focuses on the de-escalation of fluids. Focusing on this time point of fluid therapy will help minimize iatrogenic complications of crystalloid fluids within this patient population.
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Enfermedad Crítica , Resucitación , Humanos , Niño , Enfermedad Crítica/terapia , Resucitación/métodos , Fluidoterapia/métodos , Cuidados Críticos , Soluciones Cristaloides , Técnica DelphiRESUMEN
BACKGROUND: Injuries, the leading cause of death in children 1-17 years old, are often preventable. Injury patterns are impacted by changes in the child's environment, shifts in supervision, and caregiver stressors. The objective of this study was to evaluate the incidence and proportion of injuries, mechanisms, and severity seen in Pediatric Emergency Departments (PEDs) during the COVID-19 pandemic. METHODS: This multicenter, cross-sectional study from January 2019 through December 2020 examined visits to 40 PEDs for children < 18 years old. Injury was defined by at least one International Classification of Disease-10th revision (ICD-10) code for bodily injury (S00-T78). The main study outcomes were total and proportion of PED injury-related visits compared to all visits in March through December 2020 and to the same months in 2019. Weekly injury visits as a percentage of total PED visits were calculated for all weeks between January 2019 and December 2020. RESULTS: The study included 741,418 PED visits for injuries pre-COVID-19 pandemic (2019) and during the COVID-19 pandemic (2020). Overall PED visits from all causes decreased 27.4% in March to December 2020 compared to the same time frame in 2019; however, the proportion of injury-related PED visits in 2020 increased by 37.7%. In 2020, injured children were younger (median age 6.31 years vs 7.31 in 2019), more commonly White (54% vs 50%, p < 0.001), non-Hispanic (72% vs 69%, p < 0.001) and had private insurance (35% vs 32%, p < 0.001). Injury hospitalizations increased 2.2% (p < 0.001) and deaths increased 0.03% (p < 0.001) in 2020 compared to 2019. Mean injury severity score increased (2.2 to 2.4, p < 0.001) between 2019 and 2020. Injuries declined for struck by/against (- 4.9%) and overexertion (- 1.2%) mechanisms. Injuries proportionally increased for pedal cycles (2.8%), cut/pierce (1.5%), motor vehicle occupant (0.9%), other transportation (0.6%), fire/burn (0.5%) and firearms (0.3%) compared to all injuries in 2020 versus 2019. CONCLUSIONS: The proportion of PED injury-related visits in March through December 2020 increased compared to the same months in 2019. Racial and payor differences were noted. Mechanisms of injury seen in the PED during 2020 changed compared to 2019, and this can inform injury prevention initiatives.
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INTRODUCTION: Pediatric firearm injury became the leading cause of death among U.S. children in 2020. Studies evaluating wounding patterns in military and mass casualty shootings have provided insights into treatment and potential salvageability in adults, however, similar studies in the pediatric population do not exist. Hence, our study aimed to analyze wounding patterns of pediatric firearm fatalities and associated demographics and characteristics, such as place of death, to better understand pediatric firearm injuries, potential salvageability, and opportunities to reduce firearm deaths among vulnerable pediatric populations. METHODS: A retrospective review of the National Violent Death Reporting System from 2005-2017 was performed on patients 18 and younger. Mortalities were stratified by patient age: <12 years and 13-18 years and by intent- homicide, suicide, and unintentional. Comparative and exploratory analyses of demographics, location of death and anatomic location of wounds were performed. RESULTS: Of 8,527 pediatric firearm mortalities identified, 4,728 were homicides, 3,180 were suicides and 619 were unintentional injuries. Suicide victims were most likely to be dead on scene and >90% of suicide victims suffered head/neck injuries. For victims of homicide, younger children were more likely to die on scene (61% vs 44% p < 0.001). The pattern of injury in homicides differed for younger children compared to adolescents, with younger children with more head/neck injuries and older children more thoracic, thoracoabdominal, abdominal, and junctional injuries. In both age groups, children with extremity, abdominal and thoracoabdominal injuries were more likely to die later in the emergency department or inpatient setting. CONCLUSIONS: Wounding patterns across pediatric firearm mortalities in the U.S. vary by age and intent. The majority of pediatric firearm deaths were due to head/neck injuries. Children with homicide and unintentional deaths had more wounding pattern variation, including more injuries to the thorax and abdomen, and a much lower rate of dead-on scene than suicide victims. Our study of wounding patterns among U.S. children killed by firearms highlights the complexity of these injuries and offers opportunities for tailored public health strategies across varying vulnerable pediatric populations.
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Armas de Fuego , Traumatismos del Cuello , Suicidio , Heridas por Arma de Fuego , Adulto , Adolescente , Niño , Humanos , Heridas por Arma de Fuego/epidemiología , Causas de Muerte , Violencia , Vigilancia de la Población , HomicidioRESUMEN
Necrotizing enterocolitis (NEC), a cause of death among premature babies, has defied therapeutics for decades. Bacterial analyses have expanded insights into NEC pathophysiology and roles of the gut microbiome. We discuss the contribution of the gut microbiome and potential therapeutics, notably lactadherin, that may promote gut homeostasis to alleviate NEC.
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Enterocolitis Necrotizante , Enfermedades Fetales , Microbioma Gastrointestinal , Enfermedades del Prematuro , Bacterias , Enterocolitis Necrotizante/microbiología , Enterocolitis Necrotizante/terapia , Femenino , Microbioma Gastrointestinal/fisiología , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/microbiología , Enfermedades del Prematuro/terapiaRESUMEN
CONTEXT: Prior criteria to define pediatric multiple organ dysfunction syndrome (MODS) did not include gastrointestinal dysfunction. OBJECTIVES: Our objective was to evaluate current evidence and to develop consensus criteria for gastrointestinal dysfunction in critically ill children. DATA SOURCES: Electronic searches of PubMed and EMBASE were conducted from January 1992 to January 2020, using medical subject heading terms and text words to define gastrointestinal dysfunction, pediatric critical illness, and outcomes. STUDY SELECTION: Studies were included if they evaluated critically ill children with gastrointestinal dysfunction, performance characteristics of assessment/scoring tools to screen for gastrointestinal dysfunction, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. Studies of adults or premature infants, animal studies, reviews/commentaries, case series with sample size ≤10, and non-English language studies with inability to determine eligibility criteria were excluded. DATA EXTRACTION: Data were abstracted from each eligible study into a standard data extraction form along with risk of bias assessment by a task force member. RESULTS: The systematic review supports the following criteria for severe gastrointestinal dysfunction: 1a) bowel perforation, 1b) pneumatosis intestinalis, or 1c) bowel ischemia, present on plain abdominal radiograph, computed tomography (CT) scan, magnetic resonance imaging (MRI), or gross surgical inspection, or 2) rectal sloughing of gut mucosa. LIMITATIONS: The validity of the consensus criteria for gastrointestinal dysfunction are limited by the quantity and quality of current evidence. CONCLUSIONS: Understanding the role of gastrointestinal dysfunction in the pathophysiology and outcomes of MODS is important in pediatric critical illness.
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Enfermedades Gastrointestinales/diagnóstico , Insuficiencia Multiorgánica/diagnóstico , Niño , Enfermedad Crítica , Enfermedades Gastrointestinales/fisiopatología , Tracto Gastrointestinal/fisiopatología , Humanos , Puntuaciones en la Disfunción de ÓrganosRESUMEN
BACKGROUND: The Pediatric Trauma Society (PTS) is a multidisciplinary organization, with scientific presentations at its annual meeting addressing trauma care from prehospital through rehabilitation. OBJECTIVE: The purpose of this study was to identify and describe the scholarly areas of focus of presentations at the annual meeting over the society's first 5 years and evaluate research dissemination. METHODS: Data were collected on abstracts presented between 2014 and 2018, including titles, authors, and abstract classification. PubMed and Google Scholar searches identified abstracts that resulted in publications. Journal impact factors were identified. RESULTS: Over 5 years, 491 of 635 (77.3%) abstracts were accepted. The number of submitted and accepted abstracts increased, but the acceptance rate was stable (range = 72.1%-81.2%, p = NS [nonsignificant]). The most frequently accepted categories included "Epidemiology," "Abdominal or Thoracic Trauma," and "Neurosurgery or Traumatic Brain Injury (TBI)," whereas "Trauma Nursing" and "Quality Improvement" were less common. Among the 2014-2016 abstracts, 55.4% of podium and 24.3% of poster presentations were published. Abstracts categorized as "Epidemiology," "Education & Injury Prevention," and "Neurosurgery or TBI" were commonly presented but uncommonly published. The median journal impact factor of publications was 2.1 and 2.0 for podium and poster presentations, respectively (ranging from 0.11 to 10.25). CONCLUSION: Most of the scholarly effort presented at the PTS remains unpublished. Published work is mainly in low-impact factor journals. Mentorship in the publication process and encouragement of multidisciplinary collaboration within the society are needed to address limitations in the number and potential impact of the scientific content of the annual meeting. This type of analysis is relevant not only to the PTS but also to any professional society seeking to improve its impact.
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Sociedades Médicas , Heridas y Lesiones , Niño , Humanos , PediatríaRESUMEN
BACKGROUND: The disruptive effects on society and medical systems due to the coronavirus disease 2019 (COVID-19) pandemic are substantial and far-reaching. The effect of the pandemic on the quantity and quality of pediatric traumas is unclear and has a direct bearing on how scarce hospital resources should be allocated in a pandemic situation. METHODS: A retrospective review of the trauma registry was performed for trauma activations in the years 2018 through 2020 during the months of March, April, and May. Demographic and injury specific datapoints were compared across calendar years. RESULTS: There were 111, 100, and 52 trauma activations during the study interval in 2018, 2019, and 2020, respectively. There were fewer highest severity level activations in 2020 compared to 2018 and 2019 (1 vs 5 and 9; p < 0.01). The median Injury Severity Score was 5 in 2020 compared to 4 in both 2018 and 2019 (p < 0.01). More patients went directly to the operating room in 2020 compared to prior years (21.2% vs 8% and 6.1%; p < 0.01). There were fewer discharges from the emergency department (ED) (12.1% vs 36.6% and 32.7%). No increase in the number of child abuse reports and investigations was noted. There was no difference in the proportion of blunt versus penetrating trauma between years (p = 0.57). No pedestrians were struck by automobiles in 2020 compared to 12 and 14 in 2018 and 2019. However, there were a greater proportion of injuries from falls during 2020 compared to prior years. CONCLUSIONS: There were fewer trauma activations during the peak of the COVID pandemic compared to prior years. Due to the decrease in trauma volume during the peak of the pandemic, hospital resources could potentially be reallocated toward areas of greater need. LEVEL OF EVIDENCE: IV; Retrospective cohort study using historical controls.
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COVID-19/prevención & control , Pandemias/prevención & control , Grupo de Atención al Paciente/organización & administración , Pediatría , Centros Traumatológicos/organización & administración , Heridas y Lesiones/clasificación , COVID-19/epidemiología , Niño , Humanos , New York/epidemiología , Estudios Retrospectivos , SARS-CoV-2 , Centros Traumatológicos/estadística & datos numéricos , Heridas y Lesiones/cirugíaRESUMEN
STUDY DESIGN: Database study. OBJECTIVE: The purpose of this study was to use a large, nationwide database to determine prevalence of pediatric spine fractures in the United States, associated injuries, mechanisms of injury (MOI), use of safety devices, and mortality rates. SUMMARY OF BACKGROUND DATA: Spinal fractures account for 1% to 2% of pediatric injuries. However, they are associated with significant comorbidities and complications. Motor vehicle accidents (MVAs) are most responsible for increased incidence observed. METHODS: Retrospective review of National Trauma Data Bank between 2009 and 2014 (analysis in 2019) for all vertebral fractures in patients under 18âyears of age. Subanalysis included those in MVAs where protective device use data were available. Patient demographics, MOI, geographical and anatomical region of injury, concomitant musculoskeletal/organ injury, protective device usage, hospital length of stay, surgical procedures, and mortality were all analyzed. RESULTS: A total of 34,563 patients with 45,430 fractured vertebrae included. Median age was 15âyears. Most fractures (63.1%) occurred in patients aged 15 to 17âyears, most frequent MOI was MVA (66.8%), and most common geographic location was the South (38%). Males sustained more spine fractures than females, overall (58.4% vs. 41.6%; Pâ<â0.001) and in MVAs (54.4% vs. 45.6%; Pâ<â0.001). Those in MVAs wearing seatbelts had lower odds of cranial (29.6% vs. 70.4%; odds ratio [OR]â=â0.85, 95% confidence interval [CI]: 0.82-0.89; Pâ<â0.001) and thoracic (30.1% vs. 69.9%; ORâ=â0.88, 95% CI: 0.84-0.91; Pâ<â0.001) organ injury, multivertebral (30% vs. 70%; ORâ=â0.78, 95% CI: 0.73-0.83; Pâ<â0.001) and concomitant nonvertebral fractures (30.9% vs. 69.1%; ORâ=â0.89, 95% CI:0.73-0.83; Pâ<â0.001), and 21% lower odds of mortality (29.3% vs. 70.7%; ORâ=â0.79, 95% CI: 0.66-0.94; Pâ=â0.009). Over 70% of drivers were not restrained during MVA, with majority of seatbelt violations incurred by males, ages 15 to 17, in the South. CONCLUSION: Over 60% of pediatric spinal fractures occur in children aged 15 to 17âyears, coinciding with the beginning of legal driving. MVA is the most common cause and has significant association with morbidity/mortality. Nearly two- thirds pediatric spinal fractures sustained in MVAs occurred without seatbelts. Absence of seatbelts associated with >20% greater odds of mortality. Ensuring new drivers wear protective devices can greatly reduce morbidity/ mortality associated with MVA.Level of Evidence: 3.
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Accidentes de Tránsito , Conducción de Automóvil , Adolescente , Niño , Femenino , Humanos , Masculino , Vehículos a Motor , Estudios Retrospectivos , Cinturones de Seguridad , Estados Unidos/epidemiologíaRESUMEN
INTRODUCTION: The COVID-19 pandemic resulted in the suspension of nonemergent surgeries throughout New York. Our tertiary care children's hospital pivoted towards a brief trial of intravenous (IV) antibiotic therapy in all patients in order to limit operating room (OR) utilization and avoid prolonged hospital stays. We describe our pandemic-based strategy for non-operative management (NOM) of appendicitis but with a limited duration of IV antibiotics. METHODS: We performed a retrospective study of children treated for acute appendicitis at our center from 3/31/2020 to 5/3/2020 during the peak of the New York pandemic. We compared appendicitis volume to similar months in prior years. We evaluated failure of NOM, length of stay, and compared characteristics of children we successfully treated with our expanded NOM protocol to previously published inclusion criteria for NOM. RESULTS: 45.5% of children (25/55) with acute appendicitis underwent NOM. Of the 30 who underwent surgery, 13 had complicated appendicitis while 17 had simple appendicitis. Three patients were COVID-positive, although none had respiratory symptoms. The majority of patients presenting with acute appendicitis (78.2%) did not meet previously published criteria for NOM. CONCLUSIONS: We treated a similar volume of children with acute appendicitis during the pandemic compared to prior years. We applied non-operative management to nearly half our patients, even as we expanded inclusion criteria for NOM to reduce OR utilization, but limited the duration of the antibiotic trial to avoid prolonged hospital stays. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: IV.
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Apendicitis , COVID-19 , Apendicectomía , Apendicitis/tratamiento farmacológico , Apendicitis/epidemiología , Apendicitis/cirugía , Niño , Hospitales , Humanos , New York , Pandemias , Estudios Retrospectivos , SARS-CoV-2Asunto(s)
Apendicitis , COVID-19 , Apendicitis/cirugía , Niño , Refugio de Emergencia , Humanos , New York , SARS-CoV-2RESUMEN
BACKGROUND: Neonatal sepsis and the associated myocardial dysfunction remain a leading cause of infant mortality. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a ligand of triggering receptor expressed on myeloid cells-1 (TREM-1). M3 is a small CIRP-derived peptide that inhibits the eCIRP/TREM-1 interaction. We hypothesize that the eCIRP/TREM-1 interaction in cardiomyocytes contributes to sepsis-induced cardiac dysfunction in neonatal sepsis, while M3 is cardioprotective. METHODS: Serum was collected from neonates in the Neonatal Intensive Care Unit (NICU). 5-7-day old C57BL/6 mouse pups were used in this study. Primary murine neonatal cardiomyocytes were stimulated with recombinant murine (rm) CIRP with M3. TREM-1 mRNA and supernatant cytokine levels were assayed. Mitochondrial oxidative stress, ROS, and membrane potential were assayed. Neonatal mice were injected with rmCIRP and speckle-tracking echocardiography was conducted to measure cardiac strain. Sepsis was induced by i.p. cecal slurry. Mouse pups were treated with M3 or vehicle. After 16 h, echocardiography was performed followed by euthanasia for tissue analysis. A 7-day survival study was conducted. RESULTS: Serum eCIRP levels were elevated in septic human neonates. rmCIRP stimulation of cardiomyocytes increased TREM-1 gene expression. Stimulation of cardiomyocytes with rmCIRP upregulated TNF-α and IL-6 in the supernatants, while this upregulation was inhibited by M3. Stimulation of cardiomyocytes with rmCIRP resulted in a reduction in mitochondrial membrane potential (MMP) while M3 treatment returned MMP to near baseline. rmCIRP caused mitochondrial calcium overload; this was inhibited by M3. rmCIRP injection impaired longitudinal and radial cardiac strain. Sepsis resulted in cardiac dysfunction with a reduction in cardiac output and left ventricular end diastolic diameter. Both were improved by M3 treatment. Treatment with M3 attenuated serum, cardiac, and pulmonary levels of pro-inflammatory cytokines compared to vehicle-treated septic neonates. M3 dramatically increased sepsis survival. CONCLUSIONS: Inhibition of eCIRP/TREM-1 interaction with M3 is cardioprotective, decreases inflammation, and improves survival in neonatal sepsis. Trial registration Retrospectively registered.
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Cardiopatías/etiología , Cardiopatías/metabolismo , Sepsis Neonatal/complicaciones , Proteínas de Unión al ARN/metabolismo , Receptor Activador Expresado en Células Mieloides 1/metabolismo , Función Ventricular/efectos de los fármacos , Animales , Animales Recién Nacidos , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Cardiopatías/diagnóstico , Cardiopatías/tratamiento farmacológico , Humanos , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Sepsis Neonatal/etiología , Sepsis Neonatal/mortalidad , Péptidos/farmacología , Unión Proteica/efectos de los fármacos , Proteínas de Unión al ARN/sangre , Especies Reactivas de Oxígeno/metabolismoAsunto(s)
Betacoronavirus , Infecciones por Coronavirus/epidemiología , Cuidados Críticos/normas , Transmisión de Enfermedad Infecciosa/prevención & control , Pandemias , Neumonía Viral/epidemiología , Cirujanos/normas , Triaje/organización & administración , COVID-19 , Infecciones por Coronavirus/transmisión , Humanos , Neumonía Viral/transmisión , SARS-CoV-2 , Estados UnidosRESUMEN
BACKGROUND: Intestinal ischemia-reperfusion injury results in morbidity and mortality from both local injury and systemic inflammation and acute lung injury. Extracellular cold-inducible RNA-binding protein is a damage associated molecular pattern that fuels systemic inflammation and potentiates acute lung injury. We recently discovered a triggering receptor expressed on myeloid cells-1 serves as a novel receptor for extracellular cold-inducible RNA-binding protein. We developed a 7-aa peptide, named M3, derived from the cold-inducible RNA-binding protein, which interferes with cold-inducible RNA-binding protein's binding to a triggering receptor expressed on myeloid cells-1. Here, we hypothesized that M3 protects mice against intestinal ischemia-reperfusion injury. METHODS: Intestinal ischemia was induced in C57BL/6 mice via clamping of the superior mesenteric artery for 60 minutes. At reperfusion, mice were treated intraperitoneally with M3 (10 mg/kg body weight) or normal saline vehicle. Mice were killed 4 hours after reperfusion and blood and lungs were collected for various analysis. A 24-hours survival after intestinal ischemia-reperfusion was assessed. RESULTS: Serum levels of organ injury markers aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and lactate were increased with intestinal ischemia-reperfusion, while treatment with M3 significantly decreased their levels. Serum, intestinal, and lung levels of proinflammatory cytokines and chemokines were also increased by intestinal ischemia-reperfusion, and treatment with M3 significantly reduced these values. Intestinal ischemia-reperfusion caused significant histological intestinal and lung injuries, which were mitigated by M3. Treatment with M3 improved the survival from 40% to 80% after intestinal ischemia-reperfusion. CONCLUSION: Inhibition of triggering receptor expressed on myeloid cells-1 by an extracellular cold-inducible RNA-binding protein-derived small peptide (M3) decreased inflammation, reduced lung injury, and improved survival in intestinal ischemia-reperfusion injury. Thus, blocking the extracellular cold-inducible RNA-binding protein-triggering receptor expressed on myeloid cells-1 interaction is a promising therapeutic avenue for mitigating intestinal ischemia-reperfusion injury.
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Intestinos/irrigación sanguínea , Fragmentos de Péptidos/uso terapéutico , Proteínas de Unión al ARN/uso terapéutico , Daño por Reperfusión/prevención & control , Receptor Activador Expresado en Células Mieloides 1/antagonistas & inhibidores , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inmunología , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Ratones , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/farmacología , Proteínas de Unión al ARN/inmunología , Proteínas de Unión al ARN/farmacología , Daño por Reperfusión/complicaciones , Daño por Reperfusión/inmunología , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Receptor Activador Expresado en Células Mieloides 1/metabolismoRESUMEN
Pediatric robotic-assisted surgery is quickly gaining traction in pediatric surgical disciplines but presents unique challenges as compared to adult robotic surgery. Small abdominal and thoracic cavities limit working space and operative indications differ from the adult population. This article describes the development of pediatric robotic-assisted surgery, discusses technical limitations and benefits, and reviews training considerations particular to robotic surgery. Applications and published outcomes of common procedures in urology, general and thoracic surgery, otolaryngology, and pediatric surgical oncology are described. Finally, costs and the anticipated future direction of pediatric robotic-assisted surgery are discussed.
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Pediatría/métodos , Procedimientos Quirúrgicos Robotizados/métodos , Tamaño Corporal , HumanosRESUMEN
Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently discovered damage-associated molecular pattern. Understanding the precise mechanism by which it exacerbates inflammation is essential. Here we identified that eCIRP is a new biologically active endogenous ligand of triggering receptor expressed on myeloid cells-1 (TREM-1), fueling inflammation in sepsis. Surface plasmon resonance revealed a strong binding affinity between eCIRP and TREM-1, and fluorescence resonance energy transfer assay confirmed eCIRP's interaction with TREM-1 in macrophages. Targeting TREM-1 by its siRNA or a decoy peptide, LP17, or by using TREM-1-/- mice dramatically reduced eCIRP-induced inflammation. We developed a potentially novel 7-aa peptide derived from human eCIRP, M3, which blocked the interaction of TREM-1 and eCIRP. M3 suppressed inflammation induced by eCIRP or agonist TREM-1 antibody cross-linking in murine macrophages or human peripheral blood monocytes. M3 also inhibited eCIRP-induced systemic inflammation and tissue injury. Treatment with M3 further protected mice from sepsis, improved acute lung injury, and increased survival. Thus, we have discovered a potentially novel TREM-1 ligand and developed a new peptide, M3, to block eCIRP-TREM-1 interaction and improve outcomes in sepsis.