RESUMO
Gastroschisis is a common congenital abdominal wall defect, likely influenced by environmental factors in utero, with increasing prevalence in the United States. Early detection of gastroschisis in utero has become the standard with improved prenatal care and screening. There are multiple surgical management techniques, though sutureless closure is being used more frequently. Postoperative feeding difficulty is common and requires vigilance for complications, such as necrotizing enterocolitis. Infants with simple gastroschisis are expected to have eventual catch-up growth and normal development, while those with complex gastroschisis have higher morbidity and mortality. Management requires collaboration amongst several perinatal disciplines, including obstetrics, maternal fetal medicine, neonatology, pediatric surgery, and pediatric gastroenterology for optimal care and long-term outcomes.
Assuntos
Enterocolite Necrosante , Doenças Fetais , Gastroenterologistas , Gastrosquise , Doenças do Recém-Nascido , Criança , Enterocolite Necrosante/diagnóstico , Enterocolite Necrosante/epidemiologia , Enterocolite Necrosante/cirurgia , Feminino , Gastrosquise/diagnóstico , Gastrosquise/epidemiologia , Gastrosquise/cirurgia , Humanos , Lactente , Recém-Nascido , GravidezRESUMO
BACKGROUND: Necrotizing enterocolitis (NEC) develops through exaggerated toll-like receptor 4 (TLR4) signaling in the intestinal epithelium. Breast milk is rich in non-digestible oligosaccharides and prevents NEC through unclear mechanisms. We now hypothesize that the human milk oligosaccharides 2'-fucosyllactose (2'-FL) and 6'-sialyllactose (6'-SL) can reduce NEC through inhibition of TLR4 signaling. METHODS: NEC was induced in newborn mice and premature piglets and infant formula was supplemented with 2'-FL, 6'-SL, or lactose. Intestinal tissue was obtained at surgical resection. HMO inhibition of TLR4 was assessed in IEC-6 enterocytes, mice, and human tissue explants and via in silico modeling. RESULTS: Supplementation of infant formula with either 2'-FL and/or 6'-SL, but not the parent sugar lactose, reduced NEC in mice and piglets via reduced apoptosis, inflammation, weight loss, and histological appearance. Mechanistically, both 2'-FL and 6'-SL, but not lactose, reduced TLR4-mediated nuclear factor kappa light-chain enhancer of activated B cells (NF-kB) inflammatory signaling in the mouse and human intestine. Strikingly, in silico modeling revealed 2'-FL and 6'-SL, but not lactose, to dock into the binding pocket of the TLR4-MD2 complex, explaining their ability to inhibit TLR4 signaling. CONCLUSIONS: 2'-FL and 6'-SL, but not lactose, prevent NEC in mice and piglet models and attenuate NEC inflammation in the human ileum, in part through TLR4 inhibition. IMPACT: Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants that occurs in the setting of bacterial colonization of the gut and administration of formula feeds and activation by the innate immune receptor toll-like receptor 4 (TLR4). Breast milk prevents NEC through unclear mechanisms. We now show that breast milk-enriched human milk oligosaccharides (HMOs) that are derived from lactose prevent NEC through inhibition of TLR4. The human milk oligosaccharides 2'-FL and 6'-SL, but not the backbone sugar lactose, prevent NEC in mice and piglets. 2'-FL and 6'-SL but not lactose inhibited TLR4 signaling in cultured enterocytes, in enteroids derived from mouse intestine, and in human intestinal explants obtained at the time of surgical resection for patients with NEC. In seeking the mechanisms involved, 2'-FL and 6'-SL but not lactose were found to directly bind to TLR4, explaining the inhibition and protection against NEC. These findings may impact clinical practice by suggesting that administration of HMOs could serve as a preventive strategy for premature infants at risk for NEC development.
Assuntos
Enterocolite Necrosante/prevenção & controle , Íleo/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Lactose/análogos & derivados , Leite Humano/química , Receptor 4 Toll-Like/antagonistas & inibidores , Trissacarídeos/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/metabolismo , Enterocolite Necrosante/patologia , Humanos , Íleo/imunologia , Íleo/metabolismo , Íleo/patologia , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Lactose/isolamento & purificação , Lactose/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Transdução de Sinais , Sus scrofa , Receptor 4 Toll-Like/metabolismo , Trissacarídeos/isolamento & purificação , Redução de Peso/efeitos dos fármacosRESUMO
Angiotensin-converting enzyme 2 (ACE2) is a potent negative regulator capable of restraining overactivation of the renin-angiotensin system, which contributes to exuberant inflammation after bacterial infection. However, the mechanism through which ACE2 modulates this inflammatory response is not well understood. Accumulating evidence indicates that infectious insults perturb ACE2 activity, allowing for uncontrolled inflammation. In the current study, we demonstrate that pulmonary ACE2 levels are dynamically varied during bacterial lung infection, and the fluctuation is critical in determining the severity of bacterial pneumonia. Specifically, we found that a pre-existing and persistent deficiency of active ACE2 led to excessive neutrophil accumulation in mouse lungs subjected to bacterial infection, resulting in a hyperinflammatory response and lung damage. In contrast, pre-existing and persistent increased ACE2 activity reduces neutrophil infiltration and compromises host defense, leading to overwhelming bacterial infection. Further, we found that the interruption of pulmonary ACE2 restitution in the model of bacterial lung infection delays the recovery process from neutrophilic lung inflammation. We observed the beneficial effects of recombinant ACE2 when administered to bacterially infected mouse lungs following an initial inflammatory response. In seeking to elucidate the mechanisms involved, we discovered that ACE2 inhibits neutrophil infiltration and lung inflammation by limiting IL-17 signaling by reducing the activity of the STAT3 pathway. The results suggest that the alteration of active ACE2 is not only a consequence of bacterial lung infection but also a critical component of host defense through modulation of the innate immune response to bacterial lung infection by regulating neutrophil influx.
Assuntos
Inflamação/imunologia , Neutrófilos/imunologia , Peptidil Dipeptidase A/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Enzima de Conversão de Angiotensina 2 , Animais , Modelos Animais de Doenças , Feminino , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Leucina/administração & dosagem , Leucina/análogos & derivados , Leucina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Testes de Sensibilidade Microbiana , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Peptidil Dipeptidase A/deficiência , Peptidil Dipeptidase A/genética , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/efeitos dos fármacosRESUMO
Short bowel syndrome is a major cause of morbidity and mortality in children. Despite decades of experience in the management of short bowel syndrome, current therapy is primarily supportive. Definitive treatment often requires intestinal transplantation, which is associated with significant morbidity and mortality. In order to develop novel approaches to the treatment of short bowel syndrome, we and others have focused on the development of an artificial intestine, by placing intestinal stem cells on a bioscaffold that has an absorptive surface resembling native intestine, and taking advantage of neovascularization to develop a blood supply. This review will explore recent advances in biomaterials, vascularization, and progress toward development of a functional epithelium and mesenchymal niche, highlighting both success and ongoing challenges in the field.
Assuntos
Intestino Delgado/cirurgia , Síndrome do Intestino Curto/cirurgia , Engenharia Tecidual , Animais , Materiais Biocompatíveis/química , Proliferação de Células , Criança , Sistema Nervoso Entérico/fisiologia , Humanos , Camundongos , Peristaltismo , Polímeros/química , Células-Tronco/citologia , Alicerces Teciduais/químicaRESUMO
INTRODUCTION: Complete tumor resection of primary malignant liver tumors offers the best chance of survival. However, many of these children may experience anemia and failure to thrive. This study analyzes the association of preoperative anemia and nutritional support with outcomes in children undergoing major resection of primary malignant liver tumors. METHODS: Using the National Surgical Quality Improvement Program Pediatric database from 2012 to 2015, children undergoing major liver resections for primary malignant hepatic tumors were selected. Patient demographics, comorbidities, and 30-d outcomes were compared with respect to the presence of preoperative anemia and the need for nutritional support. Outcomes included 30-d postoperative complications, perioperative blood transfusions, and hospital readmissions. Propensity score matching was performed to control for significant confounders. RESULTS: One hundred ten children were included, 76 (69.1%) with preoperative anemia, and 36 (32.7%) receiving nutritional support. Anemia was associated with preoperative chemotherapy (P = 0.02) and steroids (P = 0.03). Nutritional support was associated with cardiac (P = 0.01), respiratory (P < 0.01), neurologic (P < 0.01), and hematologic comorbidities (P = 0.02). There were 20 (18.2%) postoperative complications and 6 (5.5%) hospital readmissions. After propensity score matching, there was no difference in complications between anemic and nonanemic patients (P = 0.13). Preoperative nutritional support was associated with an increased rate of complications (P < 0.01). Neither anemia (P = 1.00) nor nutritional support (P = 0.49) were associated with readmissions. CONCLUSIONS: The need for nutritional support is common in children undergoing resection of primary malignant hepatic tumors. Anemia was not significantly associated with postoperative complications. In this study, nutritional support was associated with an increased risk of postoperative complications. The need for nutritional support may warrant special attention to the patient's overall conditioning during operative planning.
Assuntos
Anemia/complicações , Neoplasias Hepáticas/cirurgia , Estado Nutricional , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Apoio Nutricional , Complicações Pós-Operatórias/etiologiaRESUMO
The first discovery of primary hyperaldosteronism secondary to an aldosterone-secreting adrenal adenoma has been credited solely to Dr. Jerome Conn, an endocrinologist at the University of Michigan and for whom, Conn syndrome was named. Dr. William Baum, a urologist at the University of Michigan, however, was instrumental in the appropriate operation and historical aldosteronoma resection. Despite Dr. Baum's important role in this discovery, he was never included as an author in any of the subsequent papers describing Conn syndrome and, few today would recognize his name. So, who was Dr. Baum and what happened? This historical article aims to revisit the history surrounding the discovery of aldosteronoma as a cause of Conn's syndrome and to catalog the life and involvement of Dr. William C. Baum in that discovery.
Assuntos
Hiperaldosteronismo/história , Urologia/história , Adenoma/complicações , Adenoma/história , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/história , Adrenalectomia/história , Aldosterona/metabolismo , História do Século XX , Humanos , Hiperaldosteronismo/etiologia , Michigan , Estados UnidosRESUMO
OBJECTIVE: To evaluate the perioperative risk factors for 30-day complications of the Kasai procedure in a large, cross-institutional, modern dataset. STUDY DESIGN: The 2012-2015 National Surgical Quality Improvement Program Pediatric database was used to identify patients undergoing the Kasai procedure. Patients' characteristics were compared by perioperative blood transfusions and 30-day outcomes, including complications, reoperations, and readmissions. Multivariable logistic regression was used to identify risk factors predictive of outcomes. Propensity matching was performed for perioperative blood transfusions to evaluate its effect on outcomes. RESULTS: 190 children were included with average age of 62 days. Major cardiac risk factors were seen in 6.3%. Perioperative blood transfusions occurred in 32.1%. The 30-day post-operative complication rate was 15.8%, reoperation 6.8%, and readmission 15.3%. After multivariate analysis, perioperative blood transfusions (OR 3.94; p < 0.01) and major cardiac risk factors (OR 7.82; p < 0.01) were found to increase the risk of a complication. Perioperative blood transfusion (OR 4.71; p = 0.01) was associated with an increased risk of reoperation. Readmission risk was increased by prematurity (OR 3.88; p = 0.04) and 30-day complication event (OR 4.09; p = 0.01). After propensity matching, perioperative blood transfusion was associated with an increase in complications (p < 0.01) and length of stay (p < 0.01). CONCLUSION: Major cardiac risk factors and perioperative blood transfusions increase the risk of post-operative complications in children undergoing the Kasai procedure. Further research is warranted in the perioperative use of blood transfusions in this population. LEVEL OF EVIDENCE: IV.
Assuntos
Atresia Biliar/cirurgia , Portoenterostomia Hepática/efeitos adversos , Transfusão de Sangue/estatística & dados numéricos , Bases de Dados Factuais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Readmissão do Paciente , Complicações Pós-Operatórias , Nascimento Prematuro , Reoperação , Fatores de RiscoRESUMO
PURPOSE OF REVIEW: This article discusses the current state of the art in artificial intestine generation in the treatment of short bowel syndrome. RECENT FINDINGS: Short bowel syndrome defines the condition in which patients lack sufficient intestinal length to allow for adequate absorption of nutrition and fluids, and thus need parenteral support. Advances toward the development of an artificial intestine have improved dramatically since the first attempts in the 1980s, and the last decade has seen significant advances in understanding the intestinal stem cell niche, the growth of complex primary intestinal stem cells in culture, and fabrication of the biomaterials that can support the growth and differentiation of these stem cells. There has also been recent progress in understanding the role of the microbiota and the immune cells on the growth of intestinal cultures on scaffolds in animal models. Despite recent progress, there is much work to be done before the development of a functional artificial intestine for short bowel syndrome is successfully achieved. SUMMARY: Continued concerted efforts by cell biologists, bioengineers, and clinician-scientists will be required for the development of an artificial intestine as a clinical treatment modality for short bowel syndrome.
Assuntos
Intestinos/transplante , Síndrome do Intestino Curto/cirurgia , Animais , Técnicas de Cultura de Células , Humanos , Intestinos/irrigação sanguínea , Engenharia Tecidual , Resultado do TratamentoRESUMO
Typically, internal carotid artery (ICA) occlusion precludes carotid endarterectomy. Extracranial branches of the ICA are uncommon. If this anomaly occurs in the setting of total proximal ICA occlusion then revascularization is feasible. We describe a unique example of such a case.
Assuntos
Artérias Carótidas/cirurgia , Artéria Carótida Interna/cirurgia , Estenose das Carótidas/cirurgia , Revascularização Cerebral/métodos , Artéria Carótida Interna/anormalidades , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Subclávia/cirurgiaRESUMO
OBJECTIVES: The optimal time for intervention in surgical necrotizing enterocolitis (sNEC) remains to be elucidated. Surgical management varies between peritoneal drain (PD), laparotomy (LAP), and PD with subsequent LAP (PD + LAP). We propose that some infants with surgical NEC benefit from late (>48 h) operative intervention to allow for resuscitation. METHODS: A retrospective comparison of clinical information in infants with sNEC from 2012 to 2022 was performed. Early intervention was defined as less than 48 hours from time of NEC diagnosis to surgical intervention. RESULTS: 118 infants were identified, 92 underwent early intervention (62 LAP; 22 PD; 8 PD + LAP) and 26 underwent late intervention (20 LAP; 2 PD; 4 PD + LAP). Infants with early intervention were diagnosed younger (DOL 8 [6, 15] vs 20 [11, 26]; P=< .05) with more pneumoperitoneum (76% vs 23%; P=< .05). The early intervention group had a higher mortality (35% vs 15%; P=< .05). When excluding infants with pneumoperitoneum, the early intervention group had a higher mortality rate (10/22 (45%), 4/26 (15%); P < .05) and had more bowel resected (29 ± 17 cm vs 9 ± 8 cm; P < .05), with the same number of patients scoring above 3 on the MD7 criteria. CONCLUSION: Infants with NEC who underwent early surgical intervention had a higher mortality and more bowel resected. While this study has a provocative finding, it is severely limited by the non-specific 48-hour cut off. However, our data suggests that a period of medical optimization may improve outcomes in infants with sNEC and thus more in-depth studies are needed.
Assuntos
Enterocolite Necrosante , Laparotomia , Humanos , Enterocolite Necrosante/cirurgia , Enterocolite Necrosante/mortalidade , Estudos Retrospectivos , Recém-Nascido , Masculino , Feminino , Laparotomia/métodos , Tempo para o Tratamento , Resultado do Tratamento , Fatores de Tempo , Drenagem/métodos , Lactente , Recém-Nascido Prematuro , Doenças do Prematuro/cirurgia , Doenças do Prematuro/mortalidadeRESUMO
Background: We sought to investigate the clinical determinants and outcomes of cholestasis in preterm infants with surgical necrotizing enterocolitis (sNEC). Methods: Retrospective comparison of clinical information in preterm infants who developed cholestasis vs those who did not. Results: Sixty-two (62/91, 68.1%) infants with NEC developed cholestasis at any time following the onset of illness. Cholestasis was seen more frequently in those who had received ionotropic support at 24 hours following sNEC diagnosis (87.1% vs 58.6%; p = 0.002), had higher mean C-reactive protein levels 2 weeks after NEC diagnosis (p = 0.009), had blood culture-positive sepsis [25 (40.3%) vs 4 (13.8%); p = 0.011], received parenteral nutrition (PN) for longer durations (108.4 ± 56.63 days vs 97.56 ± 56.05 days; p = 0.007), had higher weight-for-length z scores at 36 weeks' postmenstrual age [-1.0 (-1.73, -0.12) vs -1.32 (-1.76, -0.76); p = 0.025], had a longer length of hospital stay (153.7 ± 77.57 days vs 112.51 ± 85.22 days; p = 0.024), had intestinal failure more often (61% vs 25.0%, p = 0.003), had more surgical complications (50% vs 27.6%; p = 0.044), and had >1 complication (21% vs 3.4%; p = 0.031). Using linear regression, the number of days after surgery when feeds could be started [OR 15.4; confidence interval (CI) 3.71, 27.13; p = 0.009] and the postoperative ileus duration (OR 11.9, CI 1.1, 22.8; p = 0.03) were independently associated with direct bilirubin between 2 and 5 mg/dL (mild-moderate cholestasis) at 2 months of age. The duration of PN was independently associated with direct bilirubin >5 mg/dL (severe cholestasis) at 2 months of age in these patients. Conclusion: Cholestasis was seen in 68% of infants following surgical NEC. The most likely contributive factors are intestinal failure and subsequent PN dependence for longer periods. Our data suggest that identification and prevention of risk factors such as sepsis and surgical complications and early feeds following NEC surgery may improve outcomes.
RESUMO
Tissue-engineered small intestinal implants are being widely investigated as a potential treatment for children with short bowel syndrome, yet are currently limited by their growth potential and relatively low surface area. To address this gap in the field, several investigators have utilized whole organ decellularization of the small intestine as a platform for subsequent growth of intestinal tissue. However, such scaffold-cell constructs require sterilization as a prerequisite for implantation, and the effects of the different pathogen-clearance techniques used on the tissue architecture remains unknown. The effects of four different published protocols for pathogen clearance of decellularized intestine, namely 0.1% peracetic acid (PAA), 0.18% PAA +4.8% ethanol (EtOH), 0.08% PAA +1% hydrogen peroxide (H2O2), and ultraviolet (UV) sterilization were compared using qualitative and quantitative techniques to assess changes to the extracellular matrix, cytocompatibility, and biocompatibility. All methods of sterilization of decellularized intestine were found to be equally effective and each method had similar histologic and scanning electron microscopy appearance of the sterilized tissue. In addition, collagen and glycosaminoglycan quantities, and the ability to support cell growth were similar among all methods. This study provides insights into the change in crypt villous architecture of the extracellular matrix with all sterilization techniques studied. Our findings demonstrate that sterilization affects the microarchitecture significantly, which has not been well accounted for in studies to date, and we were unable to identify a single best agent to achieve tissue sterilization while preserving the microarchitectural features of the tissue.
Assuntos
Matriz Extracelular/química , Intestino Delgado/citologia , Esterilização/métodos , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Animais , Sistema Livre de Células , Intestino Delgado/transplante , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos LewRESUMO
BACKGROUND & AIMS: Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by Toll-like receptor 4 (TLR4)-dependent intestinal inflammation and enterocyte death. Given that necroptosis is a proinflammatory cell death process that is linked to bacterial signaling, we investigated its potential role in NEC, and the mechanisms involved. METHODS: Human and mouse NEC intestine were analyzed for necroptosis gene expression (ie, RIPK1, RIPK3, and MLKL), and protein activation (phosphorylated RIPK3). To evaluate a potential role for necroptosis in NEC, the effects of genetic (ie, Ripk3 knockout or Mlkl knockout) or pharmacologic (ie, Nec1s) inhibition of intestinal inflammation were assessed in a mouse NEC model, and a possible upstream role of TLR4 was assessed in Tlr4-deficient mice. The NEC-protective effects of human breast milk and its constituent milk oligosaccharides on necroptosis were assessed in a NEC-in-a-dish model, in which mouse intestinal organoids were cultured as either undifferentiated or differentiated epithelium in the presence of NEC bacteria and hypoxia. RESULTS: Necroptosis was activated in the intestines of human and mouse NEC in a TLR4-dependent manner, and was up-regulated specifically in differentiated epithelium of the immature ileum. Inhibition of necroptosis genetically and pharmacologically reduced intestinal-epithelial cell death and mucosal inflammation in experimental NEC, and ex vivo in the NEC-in-a-dish system. Strikingly, the addition of human breast milk, or the human milk oligosaccharide 2 fucosyllactose in the ex vivo system, reduced necroptosis and inflammation. CONCLUSIONS: Necroptosis is activated in the intestinal epithelium upon TLR4 signaling and is required for NEC development, and explains in part the protective effects of breast milk.
Assuntos
Enterocolite Necrosante/patologia , Enterócitos/patologia , Mucosa Intestinal/patologia , Leite Humano/química , Necroptose/imunologia , Animais , Modelos Animais de Doenças , Enterocolite Necrosante/tratamento farmacológico , Enterocolite Necrosante/genética , Enterocolite Necrosante/imunologia , Enterócitos/efeitos dos fármacos , Enterócitos/imunologia , Feminino , Humanos , Recém-Nascido , Mucosa Intestinal/efeitos dos fármacos , Camundongos , Camundongos Knockout , Necroptose/efeitos dos fármacos , Proteínas Quinases/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Trissacarídeos/farmacologia , Trissacarídeos/uso terapêutico , Regulação para CimaRESUMO
Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants, and is associated with the development of severe lung inflammation. The pathogenesis of NEC-induced lung injury remains unknown, yet infiltrating immune cells may play a role. In support of this possibility, we now show that NEC in mice and humans was associated with the development of profound lung injury that was characterized by an influx of Th17 cells and a reduction in T regulatory lymphocytes (Tregs). Importantly, the adoptive transfer of CD4 T cells isolated from lungs of mice with NEC into the lungs of immune incompetent mice (Rag1 mice) induced profound inflammation in the lung, while the depletion of Tregs exacerbated NEC induced lung injury, demonstrating that imbalance of Th17/Treg in the lung is required for the induction of injury. In seeking to define the mechanisms involved, the selective deletion of toll-like receptor 4 (TLR4) from the Sftpc1 pulmonary epithelial cells reversed lung injury, while TLR4 activation induced the Th17 recruiting chemokine (C-C motif) ligand 25 (CCL25) in the lungs of mice with NEC. Strikingly, the aerosolized inhibition of both CCL25 and TLR4 and the administration of all trans retinoic acid restored Tregs attenuated NEC-induced lung injury. In summary, we show that TLR4 activation in Surfactant protein C-1 (Sftpc1) cells disrupts the Treg/Th17 balance in the lung via CCL25 leading to lung injury after NEC and reveal that inhibition of TLR4 and stabilization of Th17/Treg balance in the neonatal lung may prevent this devastating complication of NEC.
Assuntos
Lesão Pulmonar/metabolismo , Linfócitos/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Células Cultivadas , Quimiocinas CC/metabolismo , Enterocolite/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/metabolismoRESUMO
IMPACT STATEMENT: This study is significant because it demonstrates an attempt to design a scaffold specifically for small intestine using a novel fabrication method, resulting in an architecture that resembles intestinal villi. In addition, we use the versatile polymer poly(glycerol sebacate) (PGS) for artificial intestine, which has tunable mechanical and degradation properties that can be harnessed for further fine-tuning of scaffold design. Moreover, the utilization of PGS allows for future development of growth factor and drug delivery from the scaffolds to promote artificial intestine formation.
Assuntos
Intestinos/citologia , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Animais , Materiais Biocompatíveis/química , Decanoatos/química , Glicerol/análogos & derivados , Glicerol/química , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Polímeros/química , SuínosRESUMO
AIMS: Extracorporeal membrane oxygenation (ECMO) is a commonly used modality of life support for children with cardiopulmonary failure. Consensus on pediatric cannulation strategies and management does not currently exist. The goal of this study was to investigate individual surgeon approaches towards ECMO cannulations in children. METHODS: A 21-question online survey was developed and disseminated to the American Pediatric Surgical Association (APSA) membership. Participant responses were summarized as counts and percentages. Effect of ECMO volume and surgeon experience on responses was assessed. RESULTS: There were 252 APSA members who participated in this study for a response rate of 21%, with 225 (89.3%) performing ECMO. Sixty respondents (28.3%) reported using neck vessels exclusively for cannulation regardless of age or weight of the patient. After neck decannulation, 13 (6.6%) repaired the carotid artery for all patients, and 21 (10.7%) repaired only for children older than 5years. Of those performing femoral cannulation, 56 (26.4%) would perform at 5years or older and 66 (31.1%) at 12years. The most common challenge for femoral cannulation was the need for distal perfusion (n=119; 59.8%). Assistance from vascular surgery was requested by 32 (16.4%) for distal perfusion catheter placement, and by 79 (40.5%) for decannulation. Regarding femoral cannulation, lack of training was more likely to be a challenge if performing <5 cannulations per year (25.2% vs 12.5%; p=0.03). Surgeons with <10years of experience were more likely to consult vascular surgery compared to those with >10years of experience (18.5% vs 8%; p=0.03). CONCLUSION: Considerable variation exists in individual surgeon cannulation practices in pediatric ECMO, in particular in the management of school age and adolescent VA ECMO. Mixed approaches across several ECMO management case study questions indicate that further work is needed to evaluate specific risks with cannulations in children. LEVEL OF EVIDENCE: IV.
Assuntos
Cateterismo/métodos , Oxigenação por Membrana Extracorpórea/métodos , Pediatria/normas , Adolescente , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos , Sociedades Médicas , Inquéritos e Questionários , Estados UnidosRESUMO
Short bowel syndrome (SBS) is a major cause of morbidity and mortality in the pediatric population, for which treatment options are limited. To develop novel approaches for the treatment of SBS, we now focus on the development of a tissue-engineered intestine (also known as an "artificial intestine"), in which intestinal stem cells are cultured onto an absorbable bioscaffold, followed by implantation into the host. To enhance the translational potential of these preclinical studies, we have developed three clinically relevant models in neonatal piglets, which approximate the size of the human infant and were evaluated after implantation and establishment of intestinal continuity over the long term. The models included (1) a staged, multioperation approach; (2) a single operation with a de-functionalized loop of small intestine; and (3) a single operation with an intestinal bypass. The first model had complications related to multiple operations in a short time period, including surgical site infections and wound hernias. The second model avoided wound complications, but was associated with high ostomy output, local skin breakdown, and systemic dehydration with associated electrolyte imbalances. The third model was the most effective, although resulted in stoma prolapse. In summary, we have now developed and evaluated three operative methods for the long-term evaluation of the artificial intestine in the piglet, and conclude that a single operation with a de-functionalized loop of small intestine may be an optimal approach for evaluation over the long term.
Assuntos
Modelos Animais de Doenças , Intestino Delgado/cirurgia , Intestino Delgado/transplante , Infecção da Ferida Cirúrgica/terapia , Engenharia Tecidual , Animais , Animais Recém-Nascidos , Intestino Delgado/patologia , SuínosRESUMO
BACKGROUND/PURPOSE: The role of process measures used to predict quality in pediatric colorectal surgery enhanced recovery protocols has not been described. The purpose of this study was to demonstrate the feasibility of abstracting and monitoring process measures over protocol improvement iteration. METHODS: Patients enrolled in the Pediatric Colorectal Enhanced Recovery After Surgery pathway at our institution were grouped by stage of implementation. We used a quality improvement database to compare multistage enhanced recovery process measures and 30-day patient outcomes. RESULTS: We identified 58 surgical patients with 28(48%) cases enrolled in the pathway. There was increased use of regional anesthesia techniques in pathway patients (83% versus 20%, pâ¯<â¯0.001). All preoperative process measures clinically improved between early and full implementation. Improvements included a dramatic increase in formal preoperative education (56% versus 0%, pâ¯=â¯0.004) and administration of preoperative medication (pâ¯=â¯0.025). Overall, 12 (21%) patients experienced postoperative complications, which were similarly distributed between implementation groups. Readmissions were highest during the early implementation phase (40%, pâ¯=â¯0.029). Children in the late implementation group experienced fewer complications, which clinically correlated with process measure adherence. CONCLUSIONS: Process measures complement outcome measures in assessing quality and effectiveness of a pediatric colorectal recovery protocol. Adherence to processes may reduce complications. LEVEL OF EVIDENCE: Treatment study, Level III.