Fetal lung hypoxia and energetic cell failure in the nitrofen-induced congenital diaphragmatic hernia rat model.

PURPOSE: Congenital diaphragmatic hernia (CDH) pathogenesis is poorly understood. We hypothesize that fetal CDH lungs are chronically hypoxic because of lung hypoplasia and tissue compression, affecting the cell bioenergetics as a possible explanation for abnormal lung development. METHODS: To investigate this theory, we conducted a study using the rat nitrofen model of CDH. We evaluated the bioenergetics status using H1 Nuclear magnetic resonance and studied the expression of enzymes involved in energy production, the hypoxia-inducible factor 1α, and the glucose transporter 1. RESULTS: The nitrofen-exposed lungs have increased levels of hypoxia-inducible factor 1α and the main fetal glucose transporter, more evident in the CDH lungs. We also found imbalanced AMP:ATP and ADP:ATP ratios, and a depleted energy cellular charge. Subsequent transcription levels and protein expression of the enzymes involved in bioenergetics confirm the attempt to prevent the energy collapse with the increase in lactate dehydrogenase C, pyruvate dehydrogenase kinase 1 and 2, adenosine monophosphate deaminase, AMP-activated protein kinase, calcium/calmodulin-dependent protein kinase 2, and liver kinase B1, while decreasing ATP synthase. CONCLUSION: Our study suggests that changes in energy production could play a role in CDH pathogenesis. If confirmed in other animal models and humans, this could lead to the development of novel therapies targeting the mitochondria to improve outcomes.

Premature Neural Progenitor Cell Differentiation Into Astrocytes in Retinoic Acid-Induced Spina Bifida Rat Model.

During embryonic spinal cord development, neural progenitor cells (NPCs) generate three major cell lines: neurons, oligodendrocytes, and astrocytes at precise times and locations within the spinal cord. Recent studies demonstrate early astrogenesis in animal models of spina bifida, which may play a role in neuronal dysfunction associated with this condition. However, to date, the pathophysiological mechanisms related to this early astrocytic response in spina bifida are poorly understood. This study aimed to characterize the development of early astrogliosis over time from Pax6+, Olig2+, or Nkx2.2+ NPCs using a retinoic acid-induced spina bifida rat model. At three gestational ages (E15, E17, and E20), spinal cords from fetuses with retinoic acid-induced spina bifida, their healthy sibling controls, or fetuses treated with the vehicle control were analyzed. Results indicated that premature astrogliosis and astrocytic activation were associated with an altered presence of Pax6+, Olig2+, and Nkx2.2+ NPCs in the lesion compared to the controls. Finally, this response correlated with an elevation in genes involved in the Notch-BMP signaling pathway. Taken together, changes in NPC patterning factor expression with Notch-BMP signaling upregulation may be responsible for the altered astrogenesis patterns observed in the spinal cord in a retinoic acid-induced spina bifida model.

Laparoscopic approach of pediatric adrenal tumors.

PURPOSE: To analyze the role of laparoscopic surgery for the management of pediatric adrenal tumors (AT). METHODS: Retrospective analysis of children diagnosed with AT, operated laparoscopically during 2003-2020. The strategy differed according to tumor extension. AT < 6 cm were resected. Locally advanced tumors (L2) or > 6 cm were biopsied. RESULTS: N = 28. Complete tumor resection (R0) in 20 (71%), tumor biopsy in 8 (R2). Age (median): 28.8 months (2 months-18 years). 14/28 left-sided, 2 bilateral. Median operating time: 78 min (45-180). Mean tumor size (for resections): 4 cm (2.5-6). Tumor pathology: neuroblastoma (n = 17), Ganglioneuroma (n = 7), Adrenocortical carcinoma (n = 1), Osteosarcoma metastasis (n = 1), Pheochromocytoma (n = 1), Venous malformation (n = 1). Mean hospital stay: 2.5 days (1-3). Mean follow up: 65.5 months (24-192). Overall survival and event-free survival were 86 and 75%, respectively (5 years event-free survival for neuroblastoma: 33% [intermediate risk], 16.6% [high risk]. No surgery-related mortality. CONCLUSION: Laparoscopic surgery for adrenal tumors is safe. Laparoscopic biopsy is useful for unresectable tumors when a percutaneous approach is not possible. With the proposed selection criteria, the laparoscopic approach should be the first option for resection of small and localized AT in pediatrics.

EXIT-to-airway: Fundamentals, prenatal work-up, and technical aspects.

Ex-utero intrapartum treatment (EXIT) is a delivery strategy developed to manage a variety of prenatally diagnosed conditions in the transition to newborn life. This procedure allows control and provides time for intervention in otherwise life-threatening malformations, such as congenital upper airway obstructions. EXIT-to-airway has changed the outcome of fetuses with these anomalies. The main purpose of this intervention is to improve the safety of establishing a reliable airway at birth. Maximal but controlled uterine relaxation to maintain feto-maternal perfusion and thus gas exchange, while keeping the fetal and maternal well-being are the paradigms of any type of EXIT. The most important aspect of fetal airway management is to consolidate a highly trained, well-coordinated, multidisciplinary team that is prepared for every contingency. A comprehensive prenatal assessment, including ultrasound, fetal echocardiogram, fetal MRI, and genetic testing is imperative for patient selection. Extensive preoperative planning, ad-hoc team meetings, and surgical simulations for challenging cases are critical strategies to achieve the best outcomes. This article outlines the prenatal work-up, decision making, technical aspects, and principles for a successful EXIT-to-airway procedure.

Erratum: Romero-Lopez et al. Lung Metabolomics Profiling of Congenital Diaphragmatic Hernia in Fetal Rats. Metabolites 2021, 11, 177.

The authors wish to make the following corrections to this paper [...].

Lung Metabolomics Profiling of Congenital Diaphragmatic Hernia in Fetal Rats.

Congenital diaphragmatic hernia (CDH) is characterized by the herniation of abdominal contents into the thoracic cavity during the fetal period. This competition for fetal thoracic space results in lung hypoplasia and vascular maldevelopment that can generate severe pulmonary hypertension (PH). The detailed mechanisms of CDH pathogenesis are yet to be understood. Acknowledgment of the lung metabolism during the in-utero CDH development can help to discern the CDH pathophysiology changes. Timed-pregnant dams received nitrofen or vehicle (olive oil) on E9.5 day of gestation. All fetal lungs exposed to nitrofen or vehicle control were harvested at day E21.5 by C-section and processed for metabolomics analysis using nuclear magnetic resonance (NMR) spectroscopy. The three groups analyzed were nitrofen-CDH (NCDH), nitrofen-control (NC), and vehicle control (VC). A total of 64 metabolites were quantified and subjected to statistical analysis. The multivariate analysis identified forty-four metabolites that were statistically different between the three groups. The highest Variable importance in projection (VIP) score (>2) metabolites were lactate, glutamate, and adenosine 5'-triphosphate (ATP). Fetal CDH lungs have changes related to oxidative stress, nucleotide synthesis, amino acid metabolism, glycerophospholipid metabolism, and glucose metabolism. This work provides new insights into the molecular mechanisms behind the CDH pathophysiology and can explore potential novel treatment targets for CDH patients.

Innovative, Stabilizing Self-Expandable Patch for Easier and Safer Thoracoscopic Repair of Congenital Diaphragmatic Hernia.

Introduction: Thoracoscopic repair of congenital diaphragmatic hernia (CDH) has become a popular approach and several benefits have been published. Patch closure requires demanding thoracoscopic skills and therefore primary closure with tight sutures is often pursued, which increases the risk of recurrence. The purpose of this study was to create and assess the performance of a new technique for thoracoscopic repair of CDH, which facilitates the surgical procedure. Materials and Methods: An innovative system for thoracoscopic repair of CDH with a novel patch was developed. The patch is self-expandable and offers a traction suture for stabilization, isolating and protecting the viscera. Its performance was assessed and compared with a conventional patch in an inanimate model of the disease through a quantitative and qualitative multivariate analysis. Results: Nine cases of CDH were repaired with each patch. The duration of the procedure was shorter (P < .05) and the level of difficulty was reported to be lower (P < .001) when using the self-expandable patch (SeP). The number of good quality knots was higher and adverse events were less common with this new technique. Conclusions: The stabilizing SeP offers safe and ergonomic performance for thoracoscopic CDH repair, facilitating the surgical technique. The main advantage is that it keeps the viscera isolated into the abdomen while offering a flap on the thoracic side for suturing in a practical manner, minimizing the risk of visceral injury and saving surgical time.

Fetal brain damage in congenital hydrocephalus.

BACKGROUND: Congenital hydrocephalus (HCP) is a developmental brain disorder characterized by the abnormal accumulation of cerebrospinal fluid within the ventricles. It is caused by genetic and acquired factors that start during early embryogenesis with disruption of the neurogerminal areas. As might be expected, early-onset hydrocephalus alters the process of brain development leading to irreparable neurological deficit. A primary alteration of the ependyma/neural stem cells (affecting vesicle trafficking and abnormal cell junctions) leads to its loss or denudation and translocation of neural progenitor cells (NPCs) and neural stem cells (NSCs) into the cerebrospinal fluid (CSF). Under these abnormal conditions, morphological and functional processes, underlying the concept of astroglial reaction, are initiated in an attempt to recover homeostasis in the periventricular zone. This astroglial reaction includes astrocyte hypertrophy, hyperplasia, and development of a new layer with reorganized functional features that resemble the ependyma. Despite decades of research, there is a lack of information concerning the biological basis of the brain abnormalities that are associated with HCP. DISCUSSION: The present review of current literature discusses the neuropathological changes during gestation following the onset of congenital hydrocephalus and the unanswered questions into the pathophysiology of the disease. A better understanding of those missing points might help create novel therapeutic strategies that can reverse or even prevent the ultimate neurological impairment that affects this population and improve long-term clinical outcome.