Neuroprotective effect of Src kinase in hypoxia-ischemia: A systematic review.

Background: Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality worldwide. While the application of therapeutic hypothermia has improved neurodevelopmental outcomes for some survivors of HIE, this lone treatment option is only available to a subset of affected neonates. Src kinase, an enzyme central to the apoptotic cascade, is a potential pharmacologic target to preserve typical brain development after HIE. Here, we present evidence of the neuroprotective effects of targeting Src kinase in preclinical models of HIE. Methods: We performed a comprehensive literature search using the National Library of Medicine's MEDLINE database to compile studies examining the impact of Src kinase regulation on neurodevelopment in animal models. Each eligible study was assessed for bias. Results: Twenty studies met the inclusion criteria, and most studies had an intermediate risk for bias. Together, these studies showed that targeting Src kinase resulted in a neuroprotective effect as assessed by neuropathology, enzymatic activity, and neurobehavioral outcomes. Conclusion: Src kinase is an effective neuroprotective target in the setting of acute hypoxic injury. Src kinase inhibition triggers multiple signaling pathways of the sub-membranous focal adhesions and the nucleus, resulting in modulation of calcium signaling and prevention of cell death. Despite the significant heterogeneity of the research studies that we examined, the available evidence can serve as proof-of-concept for further studies on this promising therapeutic strategy.

The Neurodevelopmental Perspective of Surgical Necrotizing Enterocolitis: The Role of the Gut-Brain Axis.

This state-of-the-art review article aims to highlight the most recent evidence about the therapeutic options of surgical necrotizing enterocolitis, focusing on the molecular basis of the gut-brain axis in relevance to the neurodevelopmental outcomes of primary peritoneal drainage and primary laparotomy. Current evidence favors primary laparotomy over primary peritoneal drainage as regards neurodevelopment in the surgical treatment of necrotizing enterocolitis. The added exposure to inhalational anesthesia in infants undergoing primary laparotomy is an additional confounding variable but requires further study. The concept of the gut-brain axis suggests that bowel injury initiates systemic inflammation potentially affecting the developing central nervous system. Signals about microbes in the gut are transduced to the brain and the limbic system via the enteric nervous system, autonomic nervous system, and hypothalamic-pituitary axis. Preterm infants with necrotizing enterocolitis have significant differences in the diversity of the microbiome compared with preterm controls. The gut bacterial flora changes remarkably prior to the onset of necrotizing enterocolitis with a predominance of pathogenic organisms. The type of initial surgical approach correlates with the length of functional gut and microbiome equilibrium influencing brain development and function through the gut-brain axis. Existing data favor patients who were treated with primary laparotomy over those who underwent primary peritoneal drainage in terms of neurodevelopmental outcomes. We propose that this is due to the sustained injurious effect of the remaining diseased and necrotic bowel on the developing newborn brain, in patients treated with primary peritoneal drainage, through the gut-brain axis and probably not due to the procedure itself.

Abdominal Pain Caused by a Potentially Fatal Attraction.

Abdominal pain is a challenging presentation in children. Examination findings and etiology vary greatly, spanning a vast spectrum from flatulence to frank peritonitis with septic shock. Here, we discuss a 10-year-old boy with 24 hours of progressively worsening lower abdominal pain, nausea, and subjective fevers. History and physical examination findings were consistent with appendicitis. However, physicians were surprised when the single-view abdominal radiograph showed an unanticipated, somewhat perplexing discovery.

High rates of metal allergy amongst Nuss procedure patients dictate broader pre-operative testing.

PURPOSE: A previous study from our group estimated that as few as 2.2% of pectus excavatum patients suffered from allergy to the implanted metal bar. We sought to assess recent changes in incidence of metal allergy and identify the benefit of metal allergy testing prior to surgery. METHODS: A retrospective review was performed of all consenting patients undergoing pectus repair during the six years between 9/2004 and 12/2010 at our institution. Incidence was based on clinical symptoms and/or T.R.U.E.® patch testing. Demographic data, history of atopy and history of metal allergy were collected. Type and number of bars used, suture site infection, skin rash and wound infection rates were reviewed. RESULTS: Forty one of 639 patients (6.4%) had clinical or patch test evidence of metal allergy. Family history of metal allergy and pre-operative history of metal sensitivity were found to be statistically significant correlates. CONCLUSIONS: The rate of metal allergy in the pectus excavatum population may be higher than previously reported. Patient or family history of metal allergy or metal sensitization may indicate increased risk. Metal allergy testing should be performed before Nuss procedure.

Outer membrane vesicles from pathogenic bacteria initiate an inflammatory response in human endothelial cells.

INTRODUCTION: Gram-negative bacteria release outer membrane vesicles (OMVs) during growth that contain various membrane components involved in eliciting an inflammatory response, including lipopolysaccharide and virulence factors. However, little is known about the role of OMVs in sepsis. The objective of this study was to determine how OMVs, derived from Escherichia (E.) coli, elicit the cellular responses involved in activating the inflammatory cascade, and to determine whether additional virulence factors in pathogenic OMVs augment the inflammatory response. METHODS: Human umbilical endothelial cells were inoculated with OMVs from non-pathogenic E. coli (npOMV) or pathogenic E. coli (pOMV) and analyzed for adhesion protein synthesis, cytokine production, and necrosis factor (NF)-κB translocation. RESULTS: Flow cytometry demonstrated that human umbilical vein endothelial cells exposed to npOMV or pOMV significantly increased expression of E-selectin and intercellular adhesion molecule, with a large population of cells demonstrating increased expression of both proteins. Interleukin-6 levels were significantly elevated by 4 h after exposure to npOMV and pOMVs. NF-κB translocation to the nucleus was shown to be induced by npOMV and pOMVs. However, the role of additional virulence factors associated with pOMVs remains undefined. CONCLUSIONS: Both npOMVs and pOMVs are capable of initiating the inflammatory cascade in endothelial cells. OMVs trigger NF-κB translocation to the nucleus, resulting in up-regulation of adhesion molecules and cytokines, presumably for the recruitment of leukocytes. By eliciting an inflammatory response, OMVs could facilitate the transition from a localized infection to a systemic response, and ultimately sepsis.

Circulating bacterial membrane vesicles cause sepsis in rats.

Gram-negative bacteria remain the leading cause of sepsis, a disease that is consistently in the top 10 causes of death internationally. Curing bacteremia alone does not necessarily end the disease process as other factors may cause inflammatory damage. Bacterial outer membrane vesicles (OMVs) are naturally produced blebs from the outer membrane of gram-negative bacteria, which contain various proteins and lipopolysaccharide (LPS). We hypothesize that these vesicles initiate an inflammatory response independent of the parent bacteria. Outer membrane vesicles were isolated from cultures of Escherichia coli, and the concentration of LPS in the OMVs was measured. Adult male Sprague-Dawley rats were separated into five treatment groups: OMV, 2xOMV, LPS, lactated Ringer's, and sham. Our findings show that infused OMVs elicit physiological, histological, and molecular changes in rats that are consistent with sepsis. Hyperdynamic changes in heart rates and mean arterial pressures are observed as well as the elevation of the proinflammatory cytokines tumor necrosis factor α and interleukin 6. Downstream events such as the recruitment of neutrophils into tissues due to the presentation of vascular adhesion molecules also occur in OMV-treated animals. Although soluble LPS elicits stronger responses than did OMVs, responses to the latter consistently exceeded those associated with lactated Ringer's infusion. These results indicate OMVs, independent of the parent bacteria, do initiate an inflammatory response; however, further studies are required to better characterize the temporal biomolecular interactions involved.