ABSTRACT
BACKGROUND: Burns traditionally require frequent, painful dressing changes to minimize infection risk and promote wound healing. To improve care for our pediatric population, our institution adapted a skin graft donor site dressing into a "stick-down" burn dressing consisting of a one-time application of bacitracin and 3% bismuth tribromophenate/vaseline impregnated gauze (Xeroform) that adheres to the burn and peels off as new epithelialized skin forms. The goal of which is to minimize dressing change frequency and patient discomfort in a cost-effective, widely available manner. This study aimed to compare clinical outcomes of the stick-down versus traditional topical dressings. METHODS: A retrospective cohort study of pediatric patients (age <18 year) with partial-thickness burns treated at a level I pediatric trauma center for 4 years was conducted. One hundred eleven patients were included: 74 patients treated with daily silver sulfadiazene (Silvadene) dressings matched to 37 patients treated with the Xeroform stick-down dressing using 2:1 propensity score matching. Univariate analyses used Wilcoxon rank sum and Fisher exact tests. RESULTS: The cohorts had similar demographics and burn characteristics. Both groups had similar hospitalization rates (31.1% Silvadene, 32.4% Xeroform), most commonly for pain control (54.5% Silvadene, 58.3% Xeroform), with similar average daily narcotic usage (7.7 ± 12.1 morphine milliequivalents Silvadene, 5.1 ± 9.5 Xeroform; P = 0.91). The Xeroform cohort had a shorter but statistically similar hospital stay (median, 1 vs 2 days). In addition, the Xeroform cohort required significantly less dressing changes with a median of 0.5 changes compared with 12 for the Silvadene cohort ( P < 0.0001). There was no difference in time to burn reepithelialization (median, 13.0 days for Silvadene and 12.0 days for Xeroform; P = 0.20) or wound healing complications (12.5% Silvadene, 2.7% Xeroform; P = 0.15). CONCLUSIONS: The Xeroform stick-down dressing has equivalent clinical outcomes to that of standard Silvadene dressings for the treatment of pediatric partial-thickness burns with the major advantages of decreasing dressing change frequency, minimizing patient distress and pain, and streamlining clinical care.
Subject(s)
Burns , Phenols , Soft Tissue Injuries , Humans , Child , Adolescent , Silver Sulfadiazine , Retrospective Studies , Bandages , Surgical Wound Infection , Burns/therapy , PainABSTRACT
In this paper, a Distributed Discrete-time Exponential Sliding Mode Consensus (DDESMC) protocol is proposed for the leader-follower consensus of a Discrete Multi-Agent System (DMAS). The proposed protocol ensures not only the minimal consensus effort and reaching time for the consensus among the agents but also the minimum consensus deviation in the order of O(T3). The consensus stability of DMAS with the proposed protocol is analyzed using Lyapunov theory and the maximum number of reaching steps required for achieving the consensus among all agents is calculated. The proposed protocol is validated in a simulation and experimental setup comprised of multiple 2-Degree of Freedom (DOF) robotic arms where one of the robotic arms is real, and others are virtual. Further, the consensus performance compared with the existing protocol in the literature, and it is inferred that the proposed protocol outperforms it in terms of time and effort required to achieve the consensus and the deviation from the consensus.
ABSTRACT
The maternal fatty acid status plays a key role in influencing pregnancy outcomes. Omega-3 fatty acids are the precursors for E-series (RvE) and D-series resolvins (RvD) and possess anti-inflammatory properties. Pregnancy complications like gestational diabetes mellitus (GDM) are associated with excess maternal inflammation. This study reports the levels of maternal fatty acids across gestation in GDM and non-GDM women, placental fatty acids, resolvins and their association with the maternal fatty acid status. Pregnant women were recruited at 11-14 (V1) weeks and followed at 18-22 (V2) and 26-28 (V3) weeks and at delivery (V4). A total of 209 women who were diagnosed as GDM and 207 non-GDM women were included in this study. Fatty acids were estimated using gas chromatography. The protein levels of resolvins (RvE1, RvE2, RvD1 and RvD2) were measured using ELISA kits. Total PUFAs, eicosapentaenoic acid (EPA), omega-6 fatty acids, linoleic acid (LA) and arachidonic acid (AA) were lower, while saturated fatty acid (SFA) and alpha-linolenic acid (ALA) levels were higher in GDM women at 18-22 weeks. Placental AA was lower (p < 0.05) in women with GDM. Placental protein levels of RvE1, RvD1 and RvD2 were lower (p < 0.001 for all) in the GDM group. The maternal delta 5 desaturase index was positively associated, while erythrocyte omega-3 and omega-6 fatty acids were negatively associated with RvE2 at 11-14 weeks. Placental LA and ALA were positively associated with RvD1 and RvD2 (p < 0.05, for both), respectively. Our findings suggest that the maternal fatty acid status influences pro-resolving mediators which may lead to increased inflammation in GDM.
Subject(s)
Diabetes, Gestational , Fatty Acids, Omega-3 , Pregnancy , Female , Humans , Fatty Acids , Placenta , Linoleic Acid , Arachidonic Acid , Fatty Acids, Omega-6 , InflammationABSTRACT
BACKGROUND: Wistar rats are extensively used as the model for assessing toxicity and efficacy in preclinical research. Hematological and biochemical laboratory data are essential for evaluating specific variations in the physiological and functional profile of a laboratory animal. Establishing hematological and biochemical reference values for Wistar (han) rats at various age intervals was the goal of this work. Male and female Wistar rats (n = 660) of ages 6-8 weeks, 10-14 weeks and > 6 months were used in the experiment. Blood and serum were collected from these rats under fasting conditions. RESULTS: We observed that the majority of hematological and biochemical parameters were significantly influenced by sex and age. Hematological changes were significantly correlated to aging were increased red blood cells, hemoglobin, hematocrit, neutrophils, monocytes and eosinophils in both sexes, as well as decreased platelet, mean corpuscular volume, mean corpuscular hemoglobin and lymphocytes in both sexes. White blood cells of male rats were considerably higher than those of female rats in all age ranges. For biochemistry, increase in glucose, total protein and creatinine were seen in both sexes, along with increases in urea in females and alanine aminotransferase in males. Age was significantly associated with decreased alkaline phosphatase in both sexes. CONCLUSIONS: When using Wistar rats as a model, these reference values may be useful in evaluating the results.
ABSTRACT
Electrocardiographic evaluation is performed in rhesus monkeys to establish the cardiovascular safety of candidate molecules before progressing to clinical trials. These animals are usually immobilized chemically by ketamine (KTM) and tiletamine-zolazepam (TZ) to obtain a steady-state heart rate and to ensure adequate human safety. The present study aimed to evaluate the effect of these anesthetic regimens on different electrocardiographic parameters. Statistically significant lower HR and higher P-wave duration, RR, QRS, and QT intervals were observed in the KTM-anesthetized group in comparison to TZ-anesthetized animals. No significant changes were noticed in the PR interval and p-wave amplitude. Sex-based significance amongst these parameters was observed in male and female animals of TZ- and KTM-anesthetized groups. Regression analysis of four QTc formulas in TZ-anesthetized rhesus monkeys revealed that QTcNAK (Nakayama) better corrected the QT interval than QTcHAS (Hassimoto), QTcBZT (Bazett), and QTcFRD (Fridericia) formulas. QTcNAK exhibited the least correlation with the RR interval (slope closest to zero and r = .01) and displayed no statistical significance between male and female animals. These data will prove useful in the selection of anesthetic regimens for chemical restraint of rhesus monkeys in nonclinical safety evaluation studies.
Subject(s)
Anesthetics , Ketamine , Animals , Humans , Male , Female , Ketamine/toxicity , Tiletamine/toxicity , Macaca mulatta , Zolazepam/toxicity , Retrospective Studies , Anesthetics/toxicity , Heart RateABSTRACT
This paper contains a discrete-time higher-order sliding mode control for achieving the formation of a 6-Degrees of Freedom (DOF) Quadcopter swarm using the concept of a discrete Multi-agent system (DMAS). A graph theory is used to represent the communication between the Quadcopters and a leader-follower approach of DMAS is used to design the discrete super-twisting (DST) protocol for the formation of a 6-DOF Quadcopter swarm. The DST protocol not only ensures robustness but also reduces the convergence time and the chattering during the formation process of Quadcopters in a swarm. The stability condition of the formation is also derived using the Lyapunov function. The protocol is validated for the formation of 5 Quadcopters in the given pattern. The simulation results show that the formation is achieved in a finite time. Further to show the efficacy of the DST formation protocol, the results are compared with the first-order discrete-time sliding mode controllers designed by switching type reaching law and non-switching type of reaching law. As the first-order discrete-time sliding mode controllers have a significant amount of quasi-sliding mode band (QSMB) in the sliding surface during the operations, the DST protocol of higher-order discrete-time sliding mode control is preferred. From the comparative analysis, it is inferred that the DST protocol performs better for the formation of a 6-DOF Quadcopter swarm.
ABSTRACT
INTRODUCTION: Expression of nutrient transporters in the placenta affects fetal growth. This study reports the protein expression of nutrient transporters in the syncytial membranes [microvillous membrane (MVM) and basal membrane (BM)] of normotensive control and preeclampsia placentae. METHODS: Placentae were collected from fourteen normotensive control women and fourteen women with preeclampsia. The syncytiotrophoblast MVM and BM membranes were isolated. The protein expression of glucose transporter (GLUT1), vitamin B12 transporter (CD320) and fatty acid transporters (FATP2, FATP4) was assessed in both the membranes. RESULTS: Comparison between membranes demonstrates similar CD320 protein expression in normotensive group whereas, in preeclampsia placentae it was higher in the BM as compared to MVM (p < 0.05). FATP2&4 protein expression was higher in the BM as compared to their respective MVM fraction in both the groups (p < 0.01 for both). Comparison between groups demonstrates higher GLUT1 expression in the MVM (p < 0.05) and BM (p < 0.05) whereas lower CD320 expression in the MVM (p < 0.05) of preeclampsia placentae as compared to their respective membranes in normotensive control. Furthermore, GLUT1 protein expression was positively associated and CD320 protein expression was negatively associated with maternal body mass index (BMI) (p < 0.05 for both). No difference was observed in the FATP2&4 protein expression. However, FATP4 protein expression was negatively associated with maternal blood pressure (p < 0.05 for MVM; p = 0.060 for BM) and birth weight (p < 0.05 for both membranes). DISCUSSION: The current study for the first time demonstrates differential expression of various transporters in the syncytiotrophoblast membranes of the preeclampsia placentae which may influence fetal growth.
Subject(s)
Pre-Eclampsia , Trophoblasts , Pregnancy , Female , Humans , Trophoblasts/metabolism , Pre-Eclampsia/metabolism , Glucose Transporter Type 1/metabolism , Placenta/metabolism , Membrane Transport Proteins/metabolism , NutrientsABSTRACT
Mammalian retinal metabolism favors aerobic glycolysis. However, the role of glycolytic metabolism in retinal morphogenesis remains unknown. We report that aerobic glycolysis is necessary for the early stages of retinal development. Taking advantage of an unbiased approach that combines the use of eye organoids and single-cell RNA sequencing, we identify specific glucose transporters and glycolytic genes in retinal progenitors. Next, we determine that the optic vesicle territory of mouse embryos displays elevated levels of glycolytic activity. At the functional level, we show that removal of Glucose transporter 1 and Lactate dehydrogenase A gene activity from developing retinal progenitors arrests eye morphogenesis. Surprisingly, we uncover that lactate-mediated upregulation of key eye-field transcription factors is controlled by the epigenetic modification of histone H3 acetylation through histone deacetylase activity. Our results identify an unexpected bioenergetic independent role of lactate as a signaling molecule necessary for mammalian eye morphogenesis.
Subject(s)
Lactic Acid , Retina , Mice , Animals , Lactic Acid/metabolism , Retina/metabolism , Gene Expression Regulation , Energy Metabolism , Glycolysis/genetics , Morphogenesis/genetics , Eye/metabolism , Mammals/metabolismABSTRACT
Gestational diabetes mellitus (GDM) is a metabolic disorder in pregnancy whose prevalence is on the rise. Reports suggest a likely association between inflammation and maternal GDM. A balance between pro and anti-inflammatory cytokines is necessary for the regulation of maternal inflammation system throughout pregnancy. Along with various inflammatory markers, fatty acids also act as pro-inflammatory molecules. However, studies reporting the role of inflammatory markers in GDM are contradictory, suggesting the need of more studies to better understand the role of inflammation in pregnancies complicated by GDM. Inflammatory response can be regulated by angiopoietins suggesting a link between inflammation and angiogenesis. Placental angiogenesis is a normal physiological process which is tightly regulated during pregnancy. Various pro and anti-angiogenic factors influence the regulation of the feto-placental vascular development. Studies evaluating the levels of angiogenic markers in women with GDM are limited and the findings are inconsistent. This review summarizes the available literature on fatty acids, inflammatory markers and angiogenesis in women with GDM. We also discuss the possible link between them and their influence on placental development in GDM.
Subject(s)
Diabetes, Gestational , Pregnancy , Humans , Female , Diabetes, Gestational/metabolism , Placenta/metabolism , Fatty Acids/metabolism , Cytokines/metabolism , Inflammation/metabolismABSTRACT
Tissue availability remains an important limitation of single-cell genomic technologies for investigating cellular heterogeneity in human health and disease. BAL represents a minimally invasive approach to assessing an individual's lung cellular environment for diagnosis and research. However, the lack of high-quality, healthy lung reference data is a major obstacle to using single-cell approaches to study a plethora of lung diseases. Here, we performed single-cell RNA sequencing on over 40,000 cells isolated from the BAL of four healthy volunteers. Of the six cell types or lineages we identified, macrophages were consistently the most numerous across individuals. Our analysis confirmed the expression of marker genes defining cell types despite background signals because of the ambient RNA found in many single-cell studies. We assessed the variability of gene expression across macrophages and defined a distinct subpopulation of cells expressing a set of genes associated with Macrophage Inflammatory Protein 1 (MIP-1). RNA in situ hybridization and reanalysis of published lung single-cell data validated the presence of this macrophage subpopulation. Thus, our study characterizes lung macrophage heterogeneity in healthy individuals and provides a valuable resource for future studies to understand the lung environment in health and disease.
Subject(s)
Macrophage Inflammatory Proteins , Macrophages , Humans , Macrophage Inflammatory Proteins/genetics , Bronchoalveolar Lavage Fluid , Healthy Volunteers , RNAABSTRACT
Studies have shown that the maternal nutrition during critical periods of development not only influences fetal growth but also plays a significant role in determining the risk of chronic disease in later life through developmental 'programming'. The placenta acts as a tool for 'programming' as it has the ability to adapt according to the maternal environment. There are morphological adaptations and also alterations in the expression of genes as a consequence of placental adaptations; which are critical for both placental and fetal development. Maternal nutrients especially the micronutrients (folate, vitamin B12) of the one carbon cycle and long chain polyunsaturated fatty acids (LCPUFA) are essential for placental and fetal growth and development. They are interconnected through the one carbon cycle and play a critical role in determining pregnancy outcome. A disturbed one carbon cycle leads to altered methylation of genes which play an important role in placental development and fetal growth. This review discusses the role of maternal one carbon metabolites and its influence on placental 'programming' and long term health.
Subject(s)
Carbon , Placenta , Carbon/metabolism , Fatty Acids/metabolism , Female , Humans , Maternal Nutritional Physiological Phenomena , Placenta/metabolism , Placentation , Pregnancy , Vitamin B 12ABSTRACT
Maternal nutrient availability and its transport through the placenta are crucial for fetal development. Nutrients are transported to the fetus via specific transporters present on the microvillous (MVM) and basal membrane (BM) of the placenta. Glucose is the most abundant nutrient transferred to the fetus and plays a key role in the fetal growth and development. The transfer of glucose across the human placenta is directly proportional to maternal glucose concentrations, and is mediated by glucose transporter family proteins (GLUTs). Maternal glucose concentration influences expression and activity of GLUTs in the MVM (glucose uptake) and BM (glucose delivery). Alteration in the number and function of these transporters may affect the growth and body composition of the fetus. The thin-fat phenotype of the Indian baby (low ponderal index, high adiposity) is proposed as a harbinger of future metabolic risk. We propose that placental function mediated through nutrient transporters contributes to the phenotype of the baby, specifically that glucose transporters will influence neonatal fat. This review discusses the role of various glucose transporters in the placenta in determining fetal growth and body composition, in light of the above hypothesis.
Subject(s)
Glucose Transport Proteins, Facilitative , Placenta , Female , Fetal Development , Fetal Growth Retardation/metabolism , Fetus/metabolism , Glucose/metabolism , Glucose Transport Proteins, Facilitative/metabolism , Humans , Infant, Newborn , Membrane Transport Proteins/metabolism , Placenta/metabolism , PregnancyABSTRACT
OBJECTIVES: We sought to evaluate Free Open Access Medical Education (FOAM), defined as online educational content available free to anyone, anywhere, at any time, by classifying the most impactful FOAM content per the Social Media Index into the topics and subtopics of the American Board of Emergency Medicine's Model of the Clinical Practice of Emergency Medicine. We then analyzed FOAM's comprehensiveness by describing over- and underrepresentation among these topics and subtopics. METHODS: First, we searched for FOAM resources based on the most recent 12 months of relevant content for each organ system from the top 50 Social Media Index sites. Next, we classified all 898 posts into its related topics or subtopics per the American Board of Emergency Medicine's Model of the Clinical Practice of Emergency Medicine. Finally, we analyzed how comprehensively FOAM covered each organ system and the frequency of posts that covered each organ system subtopic as well as identified the subtopics with the most frequent coverage. RESULTS: The search yielded 898 FOAM posts, of which cardiology and neurology were significantly overrepresented and psychobehavioral; obstetrics and gynecology; and head, ears, eyes, nose, and throat were significantly underrepresented. Among subtopics, acute coronary syndrome had the highest subtopic coverage consisting of 55.5% of all cardiology content. Other highly represented subtopics include renal colic; diabetic ketoacidosis; sepsis; and stroke with 39, 40, 40, and 71% of each of their topic's content, respectively. CONCLUSIONS: Although residents and programs are frequently incorporating FOAM into the educational curriculum, these materials seem to lack comprehensiveness. Educators and learners must be aware of these deficits in creating comprehensive emergency medicine curricula.
ABSTRACT
Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy, we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.
Subject(s)
Acetamides/pharmacology , Alveolar Epithelial Cells/drug effects , Cyclohexylamines/pharmacology , Proteostasis/drug effects , Pulmonary Fibrosis/drug therapy , Acetamides/therapeutic use , Age Factors , Alveolar Epithelial Cells/cytology , Animals , Asbestos , Bleomycin , Cell Differentiation/drug effects , Cell Movement/drug effects , Cyclohexylamines/therapeutic use , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/physiology , Mice , Mice, Inbred C57BL , Proteostasis/physiology , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Stress, Physiological/drug effectsABSTRACT
Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging.
Subject(s)
Aging/immunology , Cellular Microenvironment/immunology , Lung/immunology , Macrophages, Alveolar/immunology , Aging/pathology , Animals , Humans , Lung/pathology , Macrophages, Alveolar/pathology , Mice , Mice, Transgenic , RNA-SeqABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a chronic disease for which novel approaches are urgently required. We reported increased sphingosine kinase 1 (SPHK1) in IPF lungs and that SPHK1 inhibition using genetic and pharmacologic approaches reduces murine bleomycin-induced pulmonary fibrosis. We determined whether PF543, a specific SPHK1 inhibitor post bleomycin or asbestos challenge mitigates lung fibrosis by reducing mitochondrial (mt) DNA damage and pro-fibrotic monocyte recruitment-both are implicated in the pathobiology of pulmonary fibrosis. Bleomycin (1.5 U/kg), crocidolite asbestos (100 µg/50 µL) or controls was intratracheally instilled in Wild-Type (C57Bl6) mice. PF543 (1 mg/kg) or vehicle was intraperitoneally injected once every two days from day 7-21 following bleomycin and day 14-21 or day 30-60 following asbestos. PF543 reduced bleomycin- and asbestos-induced pulmonary fibrosis at both time points as well as lung expression of profibrotic markers, lung mtDNA damage, and fibrogenic monocyte recruitment. In contrast to human lung fibroblasts, asbestos augmented lung epithelial cell (MLE) mtDNA damage and PF543 was protective. Post-exposure PF543 mitigates pulmonary fibrosis in part by reducing lung epithelial cell mtDNA damage and monocyte recruitment. We reason that SPHK1 signaling may be an innovative therapeutic target for managing patients with IPF and other forms of lung fibrosis.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Idiopathic Pulmonary Fibrosis/drug therapy , Methanol/analogs & derivatives , Pulmonary Fibrosis/drug therapy , Pyrrolidines/pharmacology , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Alveolar Epithelial Cells/drug effects , Animals , Asbestos/toxicity , Bleomycin/pharmacology , DNA Damage/drug effects , DNA, Mitochondrial/drug effects , DNA, Mitochondrial/genetics , Humans , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/pathology , Lung/drug effects , Lung/metabolism , Methanol/pharmacology , Mice , Mitochondria/drug effects , Mitochondria/genetics , Monocytes/drug effects , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/pathology , Signal Transduction/drug effects , SulfonesABSTRACT
Skeletal muscle dysfunction in survivors of pneumonia disproportionately affects older individuals in whom it causes substantial morbidity. We found that skeletal muscle recovery was impaired in old compared with young mice after influenza A virus-induced pneumonia. In young mice, recovery of muscle loss was associated with expansion of tissue-resident skeletal muscle macrophages and downregulation of MHC II expression, followed by a proliferation of muscle satellite cells. These findings were absent in old mice and in mice deficient in Cx3cr1. Transcriptomic profiling of tissue-resident skeletal muscle macrophages from old compared with young mice showed downregulation of pathways associated with phagocytosis and proteostasis, and persistent upregulation of inflammatory pathways. Consistently, skeletal muscle macrophages from old mice failed to downregulate MHCII expression during recovery from influenza A virus-induced pneumonia and showed impaired phagocytic function in vitro. Like old animals, mice deficient in the phagocytic receptor Mertk showed no macrophage expansion, MHCII downregulation, or satellite cell proliferation and failed to recover skeletal muscle function after influenza A pneumonia. Our data suggest that a loss of phagocytic function in a CX3CR1+ tissue-resident skeletal muscle macrophage population in old mice precludes satellite cell proliferation and recovery of skeletal muscle function after influenza A pneumonia.
Subject(s)
CX3C Chemokine Receptor 1/metabolism , Influenza A virus/pathogenicity , Macrophages/metabolism , Muscle, Skeletal/physiopathology , Phagocytosis/physiology , Pneumonia/pathology , Animals , MiceABSTRACT
Despite the widespread use of antibiotics, bacterial pneumonias in donors strongly predispose to the fatal syndrome of primary graft dysfunction (PGD) following lung transplantation. We report that bacterial endotoxin persists in human donor lungs after pathogen is cleared with antibiotics and is associated with neutrophil infiltration and PGD. In mouse models, depletion of tissue-resident alveolar macrophages (TRAMs) attenuated neutrophil recruitment in response to endotoxin as shown by compartmental staining and intravital imaging. Bone marrow chimeric mice revealed that neutrophils were recruited by TRAM through activation of TLR4 in a MyD88-dependent manner. Intriguingly, low levels of endotoxin, insufficient to cause donor lung injury, promoted TRAM-dependent production of CXCL2, increased neutrophil recruitment, and led to PGD, which was independent of donor NCMs. Reactive oxygen species (ROS) increased in human donor lungs starting from the warm-ischemia phase and were associated with increased transcription and translocation to the plasma membrane of TLR4 in donor TRAMs. Consistently, scavenging ROS or inhibiting their production to prevent TLR4 transcription/translocation or blockade of TLR4 or coreceptor CD14 on donor TRAMs prevented neutrophil recruitment in response to endotoxin and ameliorated PGD. Our studies demonstrate that residual endotoxin after successful treatment of donor bacterial pneumonia promotes PGD through ischemia/reperfusion-primed donor TRAMs.
Subject(s)
Endotoxins/toxicity , Lung Injury/immunology , Lung Transplantation , Macrophages, Alveolar/immunology , Primary Graft Dysfunction/immunology , Reperfusion Injury/immunology , Animals , Humans , Lung Injury/chemically induced , Lung Injury/genetics , Lung Injury/pathology , Macrophages, Alveolar/pathology , Mice , Mice, Transgenic , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/immunology , Neutrophil Infiltration/drug effects , Neutrophil Infiltration/immunology , Neutrophils/immunology , Neutrophils/pathology , Primary Graft Dysfunction/chemically induced , Primary Graft Dysfunction/genetics , Primary Graft Dysfunction/pathology , Reperfusion Injury/genetics , Reperfusion Injury/pathology , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/immunologyABSTRACT
Lactation benefits both lactating individuals and their infants. Despite high rates of breastfeeding initiation, physicians are a high-risk group for early cessation. Barriers to meeting lactation goals for physicians include lack of protected time, dedicated space, and collegial support. The emergency department (ED) is a uniquely challenging setting for lactating emergency physicians, given the high-stress, high-acuity environment that lacks predictability or scheduled breaks. This article presents an overview of relevant lactation physiology and evidence for specific strategies that the lactating emergency physician, colleagues, and ED leadership can implement to overcome barriers and facilitate meeting lactation goals.
Subject(s)
Breast Feeding/methods , Lactation/physiology , Physicians/psychology , Allied Health Personnel/psychology , Breast Feeding/instrumentation , Breast Feeding/trends , Emergency Service, Hospital/organization & administration , Emergency Service, Hospital/standards , Female , Goals , Humans , Infant , Leadership , Personal Space , Physicians/statistics & numerical data , Time Factors , Workplace/organization & administrationABSTRACT
Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms.We applied lineage tracing, single-cell RNA sequencing and single-molecule fluorescence in situ hybridisation to a spatially restricted model of asbestos-induced pulmonary fibrosis.We demonstrate that tissue-resident alveolar macrophages, tissue-resident peribronchial and perivascular interstitial macrophages, and monocyte-derived alveolar macrophages are present in the fibrotic niche. Deletion of monocyte-derived alveolar macrophages but not tissue-resident alveolar macrophages ameliorated asbestos-induced lung fibrosis. Monocyte-derived alveolar macrophages were specifically localised to fibrotic regions in the proximity of fibroblasts where they expressed molecules known to drive fibroblast proliferation, including platelet-derived growth factor subunit A. Using single-cell RNA sequencing and spatial transcriptomics in both humans and mice, we identified macrophage colony-stimulating factor receptor (M-CSFR) signalling as one of the novel druggable targets controlling self-maintenance and persistence of these pathogenic monocyte-derived alveolar macrophages. Pharmacological blockade of M-CSFR signalling led to the disappearance of monocyte-derived alveolar macrophages and ameliorated fibrosis.Our findings suggest that inhibition of M-CSFR signalling during fibrosis disrupts an essential fibrotic niche that includes monocyte-derived alveolar macrophages and fibroblasts during asbestos-induced fibrosis.