ABSTRACT
BACKGROUND: Low-income Hispanic families face marked disparities in obesity, but interventions for obesity prevention and treatment have rarely been designed with this population as a focus. Hispanic culture is characterized by Familism, a value that prioritizes familial respect, cooperation, and togetherness. We describe the rationale and design of a trial of the Healthy Living Program (HeLP), a bilingual whole-family behavioral obesity prevention and treatment intervention designed around the value Familism and addressing food insecurity. METHODS/DESIGN: This two-group randomized comparative effectiveness trial will compare the effects of HeLP versus a primary care counseling intervention (Recommended Treatment of Obesity in Primary Care, or RTOP) on decreasing body mass index (BMI; kg/m2) in Hispanic children 2-16 years of age with obesity and preventing BMI increase among siblings without obesity. 164 families per arm will be recruited from primary care practices. Families randomized to HeLP will participate in 12 two-hour sessions, followed by booster sessions. HeLP sessions include family meals and instruction in parenting skills, nutrition, culinary skills, fitness, and mindfulness delivered at community recreation centers by bilingual health educators and athletic trainers. Families randomized to RTOP will be offered individual visits in primary care every 3 months throughout the 18-month follow-up period. Secondary outcomes include changes to objectively measured child fitness, the home environment related to nutrition, physical activity, and media usage, food insecurity, child eating behaviors, quality of life, parent BMI and waist circumference, and implementation outcomes. DISCUSSION: This protocol paper describes the rationale and planned methods for the comparative effectiveness trial. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT05041855 (6/13/2023).
Subject(s)
Health Promotion , Hispanic or Latino , Obesity , Humans , Health Promotion/methods , Healthy Lifestyle , Pediatric Obesity/ethnology , Pediatric Obesity/prevention & control , Quality of Life , Family , Obesity/ethnology , Obesity/prevention & control , Randomized Controlled Trials as TopicABSTRACT
Endothelial progenitor cells (EPCs) contribute to de novo angiogenesis, tissue regeneration, and remodeling. Interleukin 10 (IL-10), an anti-inflammatory cytokine that primarily signals via STAT3, has been shown to drive EPC recruitment to injured tissues. Our previous work demonstrated that overexpression of IL-10 in dermal wounds promotes regenerative tissue repair via STAT3-dependent regulation of fibroblast-specific hyaluronan synthesis. However, IL-10's role and specific mode of action on EPC recruitment, particularly in dermal wound healing and neovascularization in both normal and diabetic wounds, remain to be defined. Therefore, inducible skin-specific STAT3 knockdown mice were studied to determine IL-10's impact on EPCs, dermal wound neovascularization and healing, and whether it is STAT3-dependent. We show that IL-10 overexpression significantly elevated EPC counts in the granulating wound bed, which was associated with robust capillary lumen density and enhanced re-epithelialization of both control and diabetic (db/db) wounds at day 7. We noted increased VEGF and high C-X-C motif chemokine 12 (CXCL12) levels in wounds and a favorable CXCL12 gradient at day 3 that may support EPC mobilization and infiltration from bone marrow to wounds, an effect that was abrogated in STAT3 knockdown wounds. These findings were supported in vitro. IL-10 promoted VEGF and CXCL12 synthesis in primary murine dermal fibroblasts, with blunted VEGF expression upon blocking CXCL12 in the media by antibody binding. IL-10-conditioned fibroblast media also significantly promoted endothelial sprouting and network formation. In conclusion, these studies demonstrate that overexpression of IL-10 in dermal wounds recruits EPCs and leads to increased vascular structures and faster re-epithelialization.
Subject(s)
Diabetes Mellitus , Endothelial Progenitor Cells , Interleukin-10/metabolism , Animals , Culture Media, Conditioned/metabolism , Diabetes Mellitus/metabolism , Endothelial Progenitor Cells/metabolism , Interleukin-10/genetics , Mice , Neovascularization, Physiologic/physiology , STAT3 Transcription Factor/metabolism , Vascular Endothelial Growth Factor A/metabolism , Wound Healing/physiologyABSTRACT
INTRODUCTION: Adrenal mass management guidelines are insufficiently applied, and timeliness of treatment is unknown. We evaluated missed opportunities to promptly diagnose and treat adrenal tumors that ultimately required adrenalectomy. METHODS: From the Veterans Affairs Corporate Data Warehouse, we identified patients who underwent adrenalectomy (2010-2016) in the South-Central Veterans Affairs HealthCare Network and reviewed their records. Diagnostic timeliness was assessed by the interval between initial (index) imaging with adrenal abnormality and the next diagnostic step. Workup was defined as early (interval ≤6 mo) or late (>6 mo). Adrenalectomy was considered prompt when the interval between index imaging and adrenalectomy was ≤12 mo and delayed when this was >12 mo. We quantified diagnostic and treatment delays and assessed factors associated with delayed adrenalectomy. RESULTS: During the study period, 84 patients underwent adrenalectomy: male (86.9%), White (57.1%), with a mean age of 58.7 y (±8.8). Of those, 25 (29.8%) had late workup, and 36 (42.9%) had delayed surgery (median interval: 44 mo, range 14-282). Late hormonal workup occurred in 24 of 36 (66.7%) patients with delayed surgery, compared with one of 48 (2.1%, P < 0.001) with prompt surgery. CONCLUSIONS: Missed opportunities in prompt diagnosis and treatment were common in patients with adrenal masses ultimately requiring adrenalectomy. Late hormonal workup is associated with delayed adrenalectomy. Interventions are needed to aid clinicians to recognize the presence, promptly evaluate, and make guideline-informed decisions on the management of an adrenal mass.
Subject(s)
Adrenal Gland Neoplasms , Laparoscopy , Adrenal Gland Neoplasms/diagnosis , Adrenal Gland Neoplasms/surgery , Adrenalectomy/methods , Humans , Laparoscopy/methods , Male , Middle Aged , Retrospective StudiesABSTRACT
Hyaluronan (HA) is abundant in the skin; while HA can be synthesized by the synthases (HAS1-3), HAS2 is the leading contributor. Dysregulation and accumulation of HA is implicated in the pathogenesis of diseases such as keloid scarring, lymphedema and metastatic melanoma. To understand how HA synthesis contributes to skin physiology, and pathologic and fibrotic disorders, we propose the development of skin-specific HA inhibition model, which tests an optimal delivery system of topical 4-methylumbelliferone (4-MU). A design-of-experiments (DOE) approach was employed to develop an optimal 4-MU skin-delivery formulation comprising propylene glycol, ethanol, and water, topically applied to dorsal skin in male and female C57BL/6J wildtype mice to determine the effect on HAS gene expression and HA inhibition. Serum and skin samples were analyzed for HA content along with analysis of expression of HAS1-3, hyaluronidases (HYAL 1-2), and KIAA1199. Using results from DOE and response surface methodology with genetic algorithm optimization, we developed an optimal topical 4-MU formulation to result in â¼70% reduction of HA in dorsal skin, with validation demonstrating â¼50% reduction in HA in dorsal skin. 4-MU topical application resulted in significant decrease in skin HAS2 expression in female mice only. Histology showed thicker dermis in male mice, whereas female mice had thinner dermal layer with more adiposity; and staining for HA-binding protein showed that topical 4-MU resulted in breakdown in HA. Our data suggest a topical 4-MU formulation-based dermal HA inhibition model that would enable elucidating the skin-specific effects of HA in normal and pathologic states.
Subject(s)
Drug Delivery Systems , Hyaluronic Acid/metabolism , Hyaluronoglucosaminidase/genetics , Hymecromone/administration & dosage , Administration, Cutaneous , Animals , Ethanol/chemistry , Female , Gene Knockdown Techniques , Hymecromone/pharmacology , Male , Mice , Mice, Inbred C57BL , Propylene Glycol/chemistry , Water/chemistryABSTRACT
OBJECTIVE: Infected or contaminated wound sites have historically been managed with incision and drainage. Here, the authors review their experience with skin closure over vessel loops and assess the results of this technique in a variety of clinical situations, hypothesizing that minimally invasive drainage strategies are associated with a decrease in common postoperative complications. METHODS: Investigators retrospectively reviewed the data of all children with infected or contaminated wound sites operated on by a single surgeon with skin closure over vessel loops from September 2016 to September 2018. Demographics, indications for surgery, complications, and follow-up were assessed. RESULTS: Over a 2-year period, 33 children underwent skin closure over vessel loops. The majority were female (82%), Hispanic/Latino (40%), and younger than 5 years (58%; range, 4 months to 16 years). One-third were obese. Reasons for intervention included skin and soft tissue infection (64%), trauma (15%), and ostomy closure (6%). Median postoperative length of stay was 1 day. Three-quarters (76%) of the patients returned to the clinic for follow-up and/or vessel loop removal. At 30 days after operation, no patients in this cohort returned to the ED with recurrent infection or wound dehiscence. CONCLUSIONS: This minimally invasive technique for contaminated wound management demonstrates no evidence of subsequent infection in standard follow-up. These results are indicative of specific advantages related to vessel loop drainage, including shorter lengths of stay and ease of wound maintenance, in a variety of challenging clinical scenarios.
Subject(s)
Minimally Invasive Surgical Procedures/methods , Surgical Wound Dehiscence/prevention & control , Surgical Wound Infection/prevention & control , Wound Healing , Wounds and Injuries/therapy , Adolescent , Child , Child, Preschool , Cohort Studies , Female , Humans , Male , Retrospective Studies , Surgical Wound , Treatment OutcomeABSTRACT
BACKGROUND: Congenital lung malformations (CLMs) have a variable natural history: some patients require urgent perinatal surgical intervention (UPSI) and others remain asymptomatic. These lesions have potential growth until 26-28 wk gestation. CLM volume ratio (CVR) has been shown to predict the risk of hydrops in CLMs. However, no criteria exist to delineate lesions requiring urgent surgical intervention in the perinatal period. Our goal was to determine prenatal diagnostic features that predict the need for UPSI in patients diagnosed with CLM. METHODS: Records and imaging features of all fetuses evaluated by our fetal center between May 2015 and December 2018 were retrospectively reviewed. Data included demographics, fetal ultrasound and magnetic resonance imaging, CVR, surgical treatment, and outcome. Features were analyzed for their ability to predict the need for UPSI. RESULTS: Sixty-four patients were referred for CLM, with 48 patients serially followed. Nine (18.8%) patients were followed nonoperatively, 35 (72.9%) underwent resection, and four (8.3%) were lost to follow-up. Of the patients who underwent resection, 24 (68.5%) were electively resected and 11 were urgently resected. Five (14.3%) patients underwent ex utero intrapartum treatment resection, and six (17.1%) were urgently resected for symptomatic CLM. There were no cases of UPSI with final CVR <1.1. Of the patients with final CVR 1.1-1.7, 43% required urgent resection. CVR ≥1.1 has 100% sensitivity and 87.8% specificity to predict patients requiring UPSI (area under the curve of 0.98). CONCLUSIONS: A final CVR ≥1.1 is highly predictive for UPSI. Patients with a final CVR ≥1.1 should be referred for delivery at centers with pediatric surgeons equipped for potential UPSI for CLM.
Subject(s)
Emergency Treatment/statistics & numerical data , Hydrops Fetalis/epidemiology , Perinatal Care/statistics & numerical data , Respiratory System Abnormalities/diagnosis , Ultrasonography, Prenatal , Emergency Treatment/methods , Female , Follow-Up Studies , Humans , Hydrops Fetalis/etiology , Infant , Infant Mortality , Infant, Newborn , Lung/abnormalities , Lung/diagnostic imaging , Lung/surgery , Male , Perinatal Care/methods , Predictive Value of Tests , Pregnancy , Prognosis , Respiratory System Abnormalities/complications , Respiratory System Abnormalities/mortality , Respiratory System Abnormalities/surgery , Retrospective Studies , Risk Assessment/methodsABSTRACT
GENERAL PURPOSE: To provide wound care information that considers the specific physiology of neonates. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Differentiate the use of hydrocolloids, hydrogels, foam dressings, and barrier creams in the neonatal population.2. Identify issues related to the use of solvents, alginates, collagen dressings, and negative-pressure wound therapy in neonates. ABSTRACT: OBJECTIVETo discuss what is known about the wound milieu in premature and full-term neonates, including the unique challenges pediatric clinicians face, the therapies that have proven effective, and the therapies contraindicated for use in neonatal wound healing to guide treatment that accounts for the specific physiological characteristics of this often overlooked population. DATA SOURCES: Data were collected on neonatal wound healing from a wide variety of sources, including PubMed, Google Scholar, journals, and textbooks. STUDY SELECTION: Selection criteria included publications focused on the differences and nuances of wound healing in neonates in comparison with all other age groups. DATA EXTRACTION: Data were extracted based on articles covering wound healing therapies with proven effectiveness in neonates. Terms for neonatal wound care were compiled, and then a comprehensive literature search was performed by the authors. DATA SYNTHESIS: Although many therapies are safe for treatment of older children and adolescents, most have not been explicitly tested for neonatal use. This article reviews therapies with proven effectiveness and/or specific concerns in the neonatal population. CONCLUSION: This review sheds light on the advantages and disadvantages of current standards of care regarding wound healing for neonates to direct researchers and clinicians toward developing treatments specifically for this delicate population.
To discuss what is known about the wound milieu in premature and full-term neonates, including the unique challenges pediatric clinicians face, the therapies that have proven effective, and the therapies contraindicated for use in neonatal wound healing to guide treatment that accounts for the specific physiological characteristics of this often overlooked population. Data were collected on neonatal wound healing from a wide variety of sources, including PubMed, Google Scholar, journals, and textbooks. Selection criteria included publications focused on the differences and nuances of wound healing in neonates in comparison with all other age groups. Data were extracted based on articles covering wound healing therapies with proven effectiveness in neonates. Terms for neonatal wound care were compiled, and then a comprehensive literature search was performed by the authors. Although many therapies are safe for treatment of older children and adolescents, most have not been explicitly tested for neonatal use. This article reviews therapies with proven effectiveness and/or specific concerns in the neonatal population. This review sheds light on the advantages and disadvantages of current standards of care regarding wound healing for neonates to direct researchers and clinicians toward developing treatments specifically for this delicate population.
Subject(s)
Cicatrix/prevention & control , Debridement/nursing , Dermatologic Agents/therapeutic use , Skin Care/nursing , Wound Healing/physiology , Wounds and Injuries/nursing , Adolescent , Bandages/statistics & numerical data , Child , Humans , Infant, Newborn , Negative-Pressure Wound Therapy/methods , Ointments/therapeutic useABSTRACT
Renal fibrosis features exaggerated inflammation, extracellular matrix (ECM) deposition, and peritubular capillary loss. We previously showed that IL-10 stimulates high-molecular weight hyaluronan (HMW-HA) expression by fibroblasts, and we hypothesize that HMW-HA attenuates renal fibrosis by reducing inflammation and ECM remodeling. We studied the effects of IL-10 overexpression on HA production and scarring in mouse models of unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) to investigate whether IL-10 antifibrotic effects are HA dependent. C57BL/6J mice were fed with the HA synthesis inhibitor, 4-methylumbelliferone (4-MU), before UUO. We observed that in vivo injury increased intratubular spaces, ECM deposition, and HA expression at day 7 and onward. IL-10 overexpression reduced renal fibrosis in both models, promoted HMW-HA synthesis and stability in UUO, and regulated cell proliferation in I/R. 4-MU inhibited IL-10-driven antifibrotic effects, indicating that HMW-HA is necessary for cytokine-mediated reduction of fibrosis. We also found that IL-10 induces in vitro HMW-HA production by renal fibroblasts via STAT3-dependent upregulation of HA synthase 2. We propose that IL-10-induced HMW-HA synthesis plays cytoprotective and antifibrotic roles in kidney injury, thereby revealing an effective strategy to attenuate renal fibrosis in obstructive and ischemic pathologies.
Subject(s)
Fibroblasts/metabolism , Kidney/injuries , Kidney/metabolism , Molecular Weight , Animals , Cell Proliferation/drug effects , Cytokines/metabolism , Extracellular Matrix/metabolism , Inflammation/metabolism , Kidney/pathology , Mice, Inbred C57BLABSTRACT
Objective: Gastrostomy tubes (GTs) are one of the most common procedures in neonatal surgery, and their malfunction represents one of the most common complaints in the emergency room and clinic. Complications can occur in up to one-third of patients and include pain, peristomal leak, and infection, but can range in severity. We hypothesize that a preventative strategy employing a GT fixation dressing at the time of operation minimizes these postoperative complications in neonates. Approach: All patients less than 1 year of age who underwent laparoscopic GT placement by a single surgeon in the study period were reviewed. All tubes were secured in place on the external abdominal wall for 2 weeks postoperatively. Demographics and outcomes were evaluated. Results: Fifty-three percent of our cohort were male, and 47% were premature. The most common indication for placement was failure to thrive (59%), and common comorbid conditions were characterized as neurologic (71%), and cardiac (59%). The dressing did not prevent hypertrophic granulation tissue formation, but no patient experienced surgical site infection or device-related pressure injury at 30 and 120 days postoperatively. No patient required reoperation or readmission. Innovation: This simple, one-time, cost-effective fixation dressing has the potential to reduce some of the most common postoperative surgical issues in neonatal patients and can be applied in almost any health care setting. Conclusions: A dressing aimed at tube fixation and immobilization for the first two postoperative weeks averts some of the major complications of GT placement over a standard follow-up period as compared with the literature.
Subject(s)
Bandages , Gastrostomy/instrumentation , Postoperative Complications/prevention & control , Surgical Wound Infection/prevention & control , Abdomen , Female , Gastrostomy/adverse effects , Humans , Infant, Newborn , Laparoscopy/adverse effects , Male , Retrospective StudiesABSTRACT
Significance: Fibrosis is the endpoint of chronic disease in multiple organs, including the skin, heart, lungs, intestine, liver, and kidneys. Pathologic accumulation of fibrotic tissue results in a loss of structural integrity and function, with resultant increases in morbidity and mortality. Understanding the pathways governing fibrosis and identifying therapeutic targets within those pathways is necessary to develop novel antifibrotic therapies for fibrotic disease. Recent Advances: Given the connection between inflammation and fibrogenesis, Interleukin-10 (IL-10) has been a focus of potential antifibrotic therapies because of its well-known role as an anti-inflammatory mediator. Despite the apparent dissimilarity of diseases associated with fibrotic progression, pathways involving IL-10 appear to be a conserved molecular theme. More recently, many groups have worked to develop novel delivery tools for recombinant IL-10, such as hydrogels, and cell-based therapies, such as ex vivo activated macrophages, to directly or indirectly modulate IL-10 signaling. Critical Issues: Some efforts in this area, however, have been stymied by IL-10's pleiotropic and sometimes conflicting effects. A deeper, contextual understanding of IL-10 signaling and its interaction with effector cells, particularly immune cells, will be critical to future studies in the field. Future Directions: IL-10 is clearly a gatekeeper of fibrotic/antifibrotic signaling. The development of novel therapeutics and cell-based therapies that capitalize on targets within the IL-10 signaling pathway could have far-reaching implications for patients suffering from the consequences of organ fibrosis.
Subject(s)
Interleukin-10/metabolism , Intestines/pathology , Kidney/pathology , Myocardium/pathology , Pulmonary Fibrosis/metabolism , Skin/pathology , Animals , Extracellular Matrix/metabolism , Fibrosis/metabolism , Fibrosis/therapy , Humans , Inflammation/metabolism , Mice , Pulmonary Fibrosis/therapy , Signal TransductionABSTRACT
Objective: While tissue injury and repair are known to involve adaptive immunity, the profile of lymphocytes involved and their contribution to dermal scarring remain unclear. We hypothesized that restoration of T cell deficiency attenuates dermal scarring. Approach: We assessed the temporal-spatial distribution of T lymphocytes and their subtypes during the physiological dermal wound repair process in mice. Also, we compared the scarring outcomes between wild-type (WT) and severe combined immunodeficient (SCID) mice, which are lymphocyte deficient. Complementary gain-of-function experiments were performed by adoptively transferring lymphocyte subsets to validate their contribution to tissue repair in wounded SCID mice. Results: CD4+ T lymphocytes were present within dermal wounds of WT mice beginning on day 1 and remained through day 30. Wounds of SCID mice exhibited accelerated closure, increased inflammation, limited neovascularization, and exacerbated scarring compared with WT mice. Conversely, transfer of either mixed B and T lymphocytes or CD4+ lymphocytes alone into SCID mice resulted in moderated healing with less inflammation, collagen deposition, and scarring than control SCID wounds. In contrast, transfer of other lymphocyte subsets, including helper T lymphocytes (CD3+CD4+CD25-), CD8+ T cells and B cells, or regulatory T lymphocytes (CD4+CD25+CD127low), did not reduce scar. Innovation: The finding that lymphocytes delay wound healing but reduce scar is novel and provides new insights into how dermal scarring is regulated. Conclusion: Our data support a suppressive role for CD4+ T cells against inflammation and collagen deposition, with protective effects in early-stage dermal wound healing. These data implicate adaptive immunity in the regulation of scarring phenotypes.
ABSTRACT
PURPOSE OF REVIEW: The current review highlights the complexity of the pediatric and adolescent gynecology subspecialty as well as the recent and exciting opportunities for innovation within the field. RECENT FINDINGS: The opportunities for concept, treatment, instrument, and knowledge-transfer innovation to better serve the specific needs of pediatric gynecology patients include novel approaches to neovagina creation using magnets, improving postoperative vaginal wound healing through newly designed and degradable vaginal stents, and complex Mullerian reconstructive surgical planning using virtual reality immersive experiential training. SUMMARY: There is a significant window of opportunity to address the needs of pediatric, adolescent and adult gynecological patients with new innovative concepts and tools.
Subject(s)
Gynecology/methods , Pediatrics/methods , Vagina/surgery , Adolescent , Child , Female , Gynecology/education , Humans , Pediatrics/education , Vagina/abnormalitiesABSTRACT
BACKGROUND: Pediatric surgeons have long been advocates of basic science research. However, new challenges facing the scientific community have threatened the success of academic surgeons pursuing basic science careers. The purpose of this study was to compare academic pediatric surgeons' perceptions of their ability to effectively conduct basic science research to those of other surgical subspecialties. METHODS: An online survey was distributed to all members of the Association for Academic Surgery and Society of University Surgeons. A total of 1033 members (41%) responded, and 137 (13.3%) were pediatric surgeons. Comparisons were made between the five most-represented surgical subspecialties. Data are presented as reporting percentage and P values by Student's t-test. RESULTS: Among the specialists studied, pediatric surgeons are those most likely to believe that surgeons can succeed as basic scientists in today's research environment. Pediatric surgery reported the highest rates of National Institutes of Health funding of all surgical specialties and the lowest rates of perceived external pressures related to clinical demands, hospital administrative duties, and work-life balance concerns than their surgical peers. CONCLUSIONS: Pediatric surgeons have a more optimistic perspective on the state of basic science research in surgery while exhibiting an enhanced ability to overcome the challenges that surgeon-scientists currently face. Our findings suggest that pediatric surgery may provide a model for succeeding in basic science in today's challenging surgical research environment.
Subject(s)
Academies and Institutes , Pediatrics , Science , Surgeons , Biomedical Research , HumansABSTRACT
BACKGROUND: Central venous catheter (CVC) use is common in the management of critically ill children, especially those with congenital heart disease. CVCs are known to augment the risk of deep vein thrombosis (DVT), but data on CVC-associated DVTs in the pediatric cardiac intensive care unit (CICU) are limited. In this study, we aim to identify the incidence of and risk factors for CVC-related DVT in this high-risk population, as its complications are highly morbid. MATERIALS AND METHODS: The PC4 database and a radiologic imaging database were retrospectively reviewed for the demographics and outcomes of patients admitted to the Texas Children's Hospital CICU requiring CVC placement, as well as the incidence of DVT and its complications. RESULTS: Between January 2017 and December 2017, 1215 central lines were placed over 851 admissions. DVT was diagnosed in 8% of admissions with a CVC, 29% of which demonstrated thrombus in the inferior vena cava. The risk factors significantly associated with DVT included the presence of >1 line, higher total line hours, longer intubation times, and extended CICU stay. A diagnosis of low cardiac output syndrome, sepsis, central line-associated bloodstream infection, and cardiac catheterization were also significant risk factors. Interestingly, cardiac surgery with cardiopulmonary bypass appeared to be protective of clot development. DVT was a highly significant risk factor for mortality in these patients. CONCLUSIONS: CVC-related DVTs in critically ill children with congenital heart disease are associated with higher risks of morbidity and mortality, highlighting the need for well-designed studies to determine the best preventative and treatment strategies and to establish guidelines for appropriate monitoring and follow-up of these patients.
Subject(s)
Catheterization, Central Venous/adverse effects , Heart Defects, Congenital/surgery , Intensive Care Units, Pediatric/statistics & numerical data , Venous Thrombosis/epidemiology , Cardiopulmonary Bypass/statistics & numerical data , Catheterization, Central Venous/instrumentation , Catheterization, Central Venous/methods , Central Venous Catheters/adverse effects , Child , Child, Preschool , Female , Heart Defects, Congenital/mortality , Humans , Incidence , Infant , Length of Stay/statistics & numerical data , Male , Retrospective Studies , Risk Factors , Survival Rate , Time Factors , Venous Thrombosis/etiologyABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a life-threatening progressive lung disorder with limited therapeutic options. While interleukin-10 (IL-10) is a potent anti-inflammatory and anti-fibrotic cytokine, its utility in treating lung fibrosis has been limited by its short half-life. We describe an innovative hydrogel-based approach to deliver recombinant IL-10 to the lung for the prevention and reversal of pulmonary fibrosis in a mouse model of bleomycin-induced lung injury. Our studies show that a hyaluronan and heparin-based hydrogel system locally delivers IL-10 by capitalizing on the ability of heparin to reversibly bind IL-10 without bleeding or other complications. This formulation is significantly more effective than soluble IL-10 for both preventing and reducing collagen deposition in the lung parenchyma after 7 days of intratracheal administration. The anti-fibrotic effect of IL-10 in this system is dependent on suppression of TGF-ß driven collagen production by lung fibroblasts and myofibroblasts. We conclude that hydrogel-based delivery of IL-10 to the lung is a promising therapy for fibrotic lung disorders.
Subject(s)
Bleomycin/toxicity , Hydrogels/chemistry , Interleukin-10/administration & dosage , Interleukin-10/therapeutic use , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Animals , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Fluorescent Antibody Technique , Humans , Hyaluronic Acid/chemistry , Immunohistochemistry , MiceABSTRACT
BACKGROUND: The benefits to early repair (<72â¯h postcannulation) of infants with congenital diaphragmatic hernia (CDH) on extracorporeal membrane oxygenation (ECMO) are increasingly recognized. Yet it is not known if even earlier repair (<24â¯h) results in comparable or improved patient outcomes. The goal of this study was to compare "super-early" (<24â¯h) to early repair (24-72â¯h) of CDH patients on ECMO. METHODS: A retrospective review of infants with CDH placed on ECMO (2004-2017; nâ¯=â¯72) was performed. Data collected on the patients repaired while on ECMO within 72â¯h of cannulation (nâ¯=â¯33) included pre- and postnatal disease severity stratification variables and postnatal outcomes. Comparison groups were those patients repaired within 24â¯h of cannulation (nâ¯=â¯14) and those repaired between 24 and 72â¯h postcannulation (nâ¯=â¯19). RESULTS: Patients undergoing "super-early" (<24â¯h) repair had an average survival of 71.4% compared to the average survival of 59.7% in the early repair group. Pre- and postnatal variables predicting disease severity were not significantly different between the groups. Mean hospital stays, ventilator days, and cannulation days were statistically similar between the groups. CONCLUSIONS: Repair of patients with CDH patients on ECMO at less than 24â¯h postcannulation achieves outcomes that are comparable to those of repair between 24 and 72â¯h. While the present data suggest that there is not a "too early" time point for CDH repair on ECMO, larger multicenter studies are needed to validate our findings and determine the overall benefits. TYPE OF STUDY: Retrospective comparative study. LEVEL OF EVIDENCE: Level III.
Subject(s)
Extracorporeal Membrane Oxygenation/statistics & numerical data , Hernias, Diaphragmatic, Congenital/surgery , Herniorrhaphy/methods , Time-to-Treatment/statistics & numerical data , Female , Hernias, Diaphragmatic, Congenital/mortality , Humans , Infant, Newborn , Length of Stay/statistics & numerical data , Male , Retrospective Studies , Severity of Illness Index , Survival RateABSTRACT
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of the neonate characterized by impaired alveolarization and vascular growth. BPD is more common in premature male infants, but the reasons underlying sexually dimorphic outcomes are not known. It is thought that alterations in fibroblast phenotype in response to environmental stress such as hyperoxia contribute to BPD. Notch signaling creates a profibrotic environment in the lung. However, the role of hyperoxia on differential Notch pathway activation in male vs. female neonatal lung fibroblasts is not known. Primary murine lung fibroblasts from 10-day-old male and female mice were exposed to room air (21% O2, 5% CO2) or hyperoxia (95% O2, 5% CO2), and changes in cell proliferation, viability and expression of fibrosis-related genes and Notch pathway mediators were measured. Upon exposure to hyperoxia, cell proliferation was arrested in male and female fibroblasts, but cell viability was preserved. Increased Notch pathway activation was noted in male fibroblasts along with differential sex-specific modulation of key Notch pathway mediators in response to hyperoxia. α-Smooth muscle actin expression was increased in both male and female fibroblasts upon exposure to hyperoxia. Male and female fibroblasts further demonstrated distinct changes in expression of key fibrosis-related genes upon exposure to hyperoxia. Differential Notch pathway activation and distinct differences in the expression of key fibrosis-related genes might contribute to the sex-specific differences seen in hyperoxia-induced fibrosis and inhibition of lung development in BPD, with more severe implications in male neonates.