Abstract Congenital diaphragmatic hernia (CDH) is a birth defect characterized by incomplete closure of the diaphragm, herniation of abdominal organs into the chest, and compression of the lungs and ...the heart. Besides complications related to pulmonary hypoplasia, 1 in 4 survivors develop neurodevelopmental impairment, whose etiology remains unclear. Using a fetal rat model of CDH, we demonstrated that the compression exerted by herniated organs on the mediastinal structures results in decreased brain perfusion on ultrafast ultrasound, cerebral hypoxia with compensatory angiogenesis, mature neuron and oligodendrocyte loss, and activated microglia. In CDH fetuses, apoptosis was prominent in the subventricular and subgranular zones, areas that are key for neurogenesis. We validated these findings in the autopsy samples of four human fetuses with CDH compared to age- and sex-matched controls. This study reveals the molecular mechanisms and cellular changes that occur in the brain of fetuses with CDH and creates opportunities for therapeutic targets.
Despite advances in intensive care, several neonatal conditions typically due to prematurity affect vital organs and are associated with high mortality and long-term morbidities. Current treatment ...strategies for these babies are only partially successful or are effective only in selected patients. Regenerative medicine has been shown to be a promising option for these conditions at an experimental level, but still warrants further exploration for the development of optimal treatment. Although stem cell-based therapy has emerged as a treatment option, studies have shown that it is associated with potential risks and hazards, especially in the fragile population of babies. Recently, extracellular vesicles (EVs) have emerged as an attractive therapeutic alternative that holds great regenerative potential and is cell-free. EVs are nanosized particles endogenously produced by cells that mediate intercellular communication through the transfer of their cargo. Currently, EVs are garnering considerable attention as they are the key effectors of stem cell paracrine signaling and can epigenetically regulate target cell genes through the release of RNA species, such as microRNA. Herein, we review the emerging literature on the therapeutic potential of EVs derived from different sources for the treatment of neonatal conditions that affect the brain, retinas, spine, lungs, and intestines and discuss the challenges for the translation of EVs into clinical practice.
Necrotizing enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm neonates and causing high morbidity, high mortality, and huge costs for the family and society. The ...treatment and the outcome of the disease have not changed in recent decades. Emerging evidence has shown that stimulating the Wnt/β-catenin pathway and enhancing intestinal regeneration are beneficial in experimental NEC, and that they could potentially be used as a novel treatment. Amniotic fluid stem cells (AFSC) and AFSC-derived extracellular vesicles (EV) can be used to improve intestinal injury in experimental NEC. However, the mechanisms by which they affect the Wnt/β-catenin pathway and intestinal regeneration are unknown. In our current study, we demonstrated that AFSC and EV attenuate NEC intestinal injury by activating the Wnt signaling pathway. AFSC and EV stimulate intestinal recovery from NEC by increasing cellular proliferation, reducing inflammation and ultimately regenerating a normal intestinal epithelium. EV administration has a rescuing effect on intestinal injury when given during NEC induction; however, it failed to prevent injury when given prior to NEC induction. AFSC-derived EV administration is thus a potential emergent novel treatment strategy for NEC.
Maternal separation (MS) in neonates can lead to intestinal injury. MS in neonatal mice disrupts mucosal morphology, induces colonic inflammation and increases trans-cellular permeability. Several ...studies indicate that intestinal epithelial stem cells are capable of initiating gut repair in a variety of injury models but have not been reported in MS. The pathophysiology of MS-induced gut injury and subsequent repair remains unclear, but communication between the brain and gut contribute to MS-induced colonic injury. Corticotropin-releasing hormone (CRH) is one of the mediators involved in the brain-gut axis response to MS-induced damage. We investigated the roles of the CRH receptors, CRHR1 and CRHR2, in MS-induced intestinal injury and subsequent repair. To distinguish their specific roles in mucosal injury, we selectively blocked CRHR1 and CRHR2 with pharmacological antagonists. Our results show that in response to MS, CRHR1 mediates gut injury by promoting intestinal inflammation, increasing gut permeability, altering intestinal morphology, and modulating the intestinal microbiota. In contrast, CRHR2 activates intestinal stem cells and is important for gut repair. Thus, selectively blocking CRHR1 and promoting CRHR2 activity could prevent the development of intestinal injuries and enhance repair in the neonatal period when there is increased risk of intestinal injury such as necrotizing enterocolitis.
Purpose
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease. Amniotic fluid stem cells (AFSC) improve NEC injury but human translation remains difficult. We aimed to evaluate ...the use of extracellular vesicles (EV) derived from human AFSC.
Methods
Human AFSC (hAFSC) were cultured according to the protocol (Celprogen Inc., California, U.S.A.). Conditioned medium was obtained, ultra-centrifuged, and EV were suspended in phosphate-buffered saline (PBS). C57BL/6 pups were grouped into: (1) breast-fed (Control,
n
= 11); (2) NEC + placebo (NEC + PBS;
n
= 10); and (3) NEC + treatment (NEC + EV;
n
= 11). NEC was induced post-natal days P5-9 by (A) gavage feeding hyperosmolar formula; (B) hypoxia for 10 min; and (C) lipopolysaccharide. Intra-peritoneal injections of PBS or hAFSC-EV were given on P6-7. All animals were sacrificed on P9 and terminal ileum harvested.
Results
hAFSC-EV administration reduced intestinal injury (
p
= 0.0048), NEC incidence (score ≥ 2), and intestinal inflammation (
IL-6
p
< 0.0001;
TNF-α
p
< 0.0001). Intestinal stem cell expression (
Lgr5
+) and cellular proliferation (
Ki67
) were enhanced above control levels following hAFSC-EV administration (
Lgr5
p
= 0.0003;
Ki67
p
< 0.0001).
Conclusion
hAFSC-EV administration reduced intestinal NEC injury and inflammation while increasing stem cell expression and cellular proliferation. hAFSC-EV administration may induce similar beneficial effects to exogenous stem cells.
Because many aspects of the management of esophageal atresia (EA) are still controversial, we evaluated the practice patterns of this condition across Europe.
A survey was completed by 178 delegates ...(from 45 27 European countries; 88% senior respondents) at the EUPSA-BAPS 2012.
Approximately 66% of respondents work in centers where more than five EA repairs are performed per year. Preoperatively, 81% of respondents request an echocardiogram, and only 43% of respondents routinely perform preoperative bronchoscopy. Approximately 94% of respondents prefer an open approach, which is extrapleural in 71% of respondents. There were no differences in use of thoracoscopy between Europeans (10%) and non-Europeans (11%, p = nonsignificant). Approximately 60% of respondents measure the gap intraoperatively. A transanastomotic tube (90%) and chest drain (69%) are left in situ. Elective paralysis is adopted by 56% of respondents mainly for anastomosis tension (65%). About 72% of respondents routinely request a contrast study on postoperative day 7 (2-14). Approximately 54% of respondents use parenteral nutrition, 40% of respondents start transanastomotic feeds on postoperative day 1, and 89% of respondents start oral feeds after postoperative day 5. Pure EA: 46% of respondents work in centers that repair two or more than two pure EA a year. About 60% of respondents opt for delayed primary anastomosis at 3 months (1-12 months) with gastrostomy formation without esophagostomy. Anastomosis is achieved with open approach by 85% of respondents. About 47% of respondents attempt elongation of esophageal ends via Foker technique (43%) or with serial dilations with bougies (41%). Approximately 67% of respondents always attempt an anastomosis. Gastric interposition is the commonest esophageal substitution.
Many aspects of EA management are lacking consensus. Minimally invasive repair is still sporadic. We recommend establishment of an EA registry.
Purpose
As appendicitis in children can be managed differently according to the severity of the disease, we investigated whether commonly used serum biomarkers on admission could distinguish between ...simple and complicated appendicitis.
Methods
Admission white blood cell (WBC), neutrophil (NEU), and C-reactive protein (CRP) levels were analysed by ROC curve, and Kruskal–Wallis and contingency tests. Patients were divided according to age and histology normal appendix (NA), simple appendicitis (SA), complicated appendicitis (CA).
Results
Of 1197 children (NA = 186, SA = 685, CA = 326), 7% were <5 years, 55% 5–12, 38% 13–17. CA patients had higher CRP and WBC levels than NA and SA (
p
< 0.0001). NEU levels were lower in NA compared to SA or CA (
p
< 0.0001), but were similar between SA and CA (
p
= 0.6). CA patients had higher CRP and WBC levels than SA patients in 5–12- (
p
< 0.0001) and 13–17-year groups (
p
= 0.0075,
p
= 0.005), but not in <5-year group (
p
= 0.72,
p
= 0.81). We found CRP >40 mg/L in 58% CA and 37% SA (
p
< 0.0001), and WBC >15 × 10
9
/L in 58% CA and 43% SA (
p
< 0.0001).
Conclusions
Admission CRP and WBC levels may help the clinician predict complicated appendicitis in children older than 5 years of age. Early distinction of appendicitis severity using these tests may guide caregivers in the preoperative decision-making process.
Surgical site infections (SSI) contribute to postoperative morbidity and mortality in children. Our aim was to evaluate the prevalence and identify risk factors for SSI in neonates.
Using a defined ...strategy, three investigators searched articles on neonatal SSI published since 2000. Studies on neonates and/or patients admitted to neonatal intensive care unit following cervical/thoracic/abdominal surgery were included. Risk factors were identified from comparative studies. Meta-analysis was conducted according to PRISMA guidelines using RevMan 5.3. Data are (mean ± SD) prevalence.
Systematic review-of 885 abstracts screened, 48 studies (27,760 neonates) were included. The incidence of SSI was 5.6% (1,564 patients). SSI was more frequent in males (61.8%), premature babies (77.4%), and following gastrointestinal surgery (95.4%). Meta-analysis-10 comparative studies (16,442 neonates; 946 SSI 5.7%) showed that predictive factors for SSI development were gestational age, birth weight, age at surgery, length of surgical procedure, number of procedure per patient, length of preoperative hospital stay, and preoperative sepsis. Conversely, preoperative antibiotic use was not significantly associated with development of SSI.
Younger neonates and those undergoing abdominal procedures are at higher risk for SSI. Given the lack of evidence-based literature, prospective studies may help determine the risk factors for SSI in neonates.
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