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Simon Eaton - Top 30 Publications

Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders.

High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders.

Protocol for a randomised pilot multiple centre trial of conservative versus liberal oxygenation targets in critically ill children (Oxy-PICU).

Optimal targets for systemic oxygenation in paediatric critical illness are unknown. Observational data indicate that high levels of arterial oxygenation are associated with poor outcomes in resuscitation of the newborn and in adult critical illness. Within paediatric intensive care units (PICUs), staff prevent severe hypoxia wherever possible, but beyond this there is no consensus. Practice varies widely with age, diagnosis, treating doctor and local or national guidelines followed, though peripheral blood oxygen saturations (SpO2) of >95% are often targeted. The overall aim of this pilot study is to determine the feasibility of performing a randomised trial in critically ill children comparing current practice of liberal SpO2 targets with a more conservative target.

Non-operative management of appendicitis in children.

While appendicectomy has been considered the mainstay of treatment for children with acute appendicitis for many decades, there has been a great deal of recent interest in non-operative treatment (NOT) with antibiotics alone. Initial results suggest that many children with appendicitis can indeed be safely treated with NOT and can be spared the surgeon's knife. Many as yet unanswered questions remain, however, before NOT can be considered a realistic and reliable alternative to surgery. This review summaries current knowledge and understanding of the role of NOT in children with appendicitis and outlines and discusses the outstanding knowledge gaps.

Let sleeping dogs lie: To leave the appendix at the time of a Ladd procedure.

A systematic review and meta-analysis on fetal ovarian cysts: impact of size, appearance and prenatal aspiration.

The objective of the study is to compare outcomes of ultrasound-guided aspiration of fetal ovarian cysts with conservative management.

Erratum: Primary versus Staged Closure of Exomphalos Major: Cardiac Anomalies Do Not Affect Outcome.

Current Management of Congenital Pulmonary Airway Malformations: A "European Pediatric Surgeons' Association" Survey.

 To define current management of congenital pulmonary airway malformation (CPAM).

Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: A mechanistic insight into the medium-chain triglyceride ketogenic diet.

The medium-chain triglyceride (MCT) ketogenic diet contains both octanoic (C8) and decanoic (C10) acids. The diet is an effective treatment for pharmacoresistant epilepsy. Although the exact mechanism for its efficacy is not known, it is emerging that C10, but not C8, interacts with targets that can explain antiseizure effects, for example, peroxisome proliferator-activated receptor-γ (eliciting mitochondrial biogenesis and increased antioxidant status) and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. For such effects to occur, significant concentrations of C10 are likely to be required in the brain.

Intraoperative acidosis and hypercapnia during thoracoscopic repair of congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistula.

Intraoperative hypercapnia and acidosis have been associated with thoracoscopic repair of both congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistula.

A patient led, international study of long term outcomes of esophageal atresia: EAT 1.

Long term outcomes of esophageal atresia (OA) are poorly understood. The Federation of Esophageal Atresia and Tracheo-Esophageal Fistula support groups (EAT), a collaboration of patient support groups aimed to define patient reported long term outcomes and quality of life (QoL) in a large international cohort of OA patients.

Long-term cryopreservation of decellularised oesophagi for tissue engineering clinical application.

Oesophageal tissue engineering is a therapeutic alternative when oesophageal replacement is required. Decellularised scaffolds are ideal as they are derived from tissue-specific extracellular matrix and are non-immunogenic. However, appropriate preservation may significantly affect scaffold behaviour. Here we aim to prove that an effective method for short- and long-term preservation can be applied to tissue engineered products allowing their translation to clinical application. Rabbit oesophagi were decellularised using the detergent-enzymatic treatment (DET), a combination of deionised water, sodium deoxycholate and DNase-I. Samples were stored in phosphate-buffered saline solution at 4°C (4°C) or slow cooled in medium with 10% Me2SO at -1°C/min followed by storage in liquid nitrogen (SCM). Structural and functional analyses were performed prior to and after 2 and 4 weeks and 3 and 6 months of storage under each condition. Efficient decellularisation was achieved after 2 cycles of DET as determined with histology and DNA quantification, with preservation of the ECM. Only the SCM method, commonly used for cell storage, maintained the architecture and biomechanical properties of the scaffold up to 6 months. On the contrary, 4°C method was effective for short-term storage but led to a progressive distortion and degradation of the tissue architecture at the following time points. Efficient storage allows a timely use of decellularised oesophagi, essential for clinical translation. Here we describe that slow cooling with cryoprotectant solution in liquid nitrogen vapour leads to reliable long-term storage of decellularised oesophageal scaffolds for tissue engineering purposes.

Design of Studies for Antibiotic Treatment of Acute Appendicitis in Children: In Support of RCTs.

Response to Letter: Is Antibiotic Alternative to Appendectomy?

Primary versus Staged Closure of Exomphalos Major: Cardiac Anomalies Do Not Affect Outcome.

Current Research on the Epidemiology, Pathogenesis, and Management of Necrotizing Enterocolitis.

Despite decades of research on necrotizing enterocolitis, we still do not fully understand the pathogenesis of the disease, or how to prevent or how to treat it. However, as a result of recent significant advances in the microbiology, molecular biology, and cell biology of the intestine of preterm infants and infants with necrotizing enterocolitis, there is some hope that research into this devastating disease will yield some important translation into effective prevention, more rapid diagnosis, and novel therapies.

Active observation versus interval appendicectomy after successful non-operative treatment of an appendix mass in children (CHINA study): an open-label, randomised controlled trial.

Despite a scarcity of supporting evidence, most surgeons recommend routine interval appendicectomy after successful non-operative treatment of an appendix mass in children. We aimed to compare routine interval appendicectomy with active observation.

Inhibition of neuronal mitochondrial complex I or lysosomal glucocerebrosidase is associated with increased dopamine and serotonin turnover.

Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic and serotoninergic signalling. A number of pathogenic mechanisms have been implicated including loss of mitochondrial function at the level of complex I, and lysosomal metabolism at the level of lysosomal glucocerebrosidase (GBA1). In order to investigate further the potential involvement of complex I and GBA1 in PD, we assessed the impact of loss of respective enzyme activities upon dopamine and serotonin turnover. Using SH-SY5Y cells, complex I deficiency was modelled by using rotenone whilst GBA1 deficiency was modelled by the use of conduritol B epoxide (CBE). Dopamine, its principal metabolites, and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the extracellular medium were quantified by HPLC. Inhibition of complex I significantly increased extracellular concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-HIAA. Comparable results were observed with CBE. These results suggest increased monoamine oxidase activity and provide evidence for involvement of impaired complex I or GBA1 activity in the dopamine/serotonin deficiency seen in PD. Use of extracellular media may also permit relatively rapid assessment of dopamine/serotonin metabolism and permit screening of novel therapeutic agents.

Efficacy and Safety of Nonoperative Treatment for Acute Appendicitis: A Meta-analysis.

Nonoperative treatment (NOT) with antibiotics alone of acute uncomplicated appendicitis (AUA) in children has been proposed as an alternative to appendectomy.

Human Amniocytes Are Receptive to Chemically Induced Reprogramming to Pluripotency.

Restoring pluripotency using chemical compounds alone would be a major step forward in developing clinical-grade pluripotent stem cells, but this has not yet been reported in human cells. We previously demonstrated that VPA_AFS cells, human amniocytes cultivated with valproic acid (VPA) acquired functional pluripotency while remaining distinct from human embryonic stem cells (hESCs), questioning the relationship between the modulation of cell fate and molecular regulation of the pluripotency network. Here, we used single-cell analysis and functional assays to reveal that VPA treatment resulted in a homogeneous population of self-renewing non-transformed cells that fulfill the hallmarks of pluripotency, i.e., a short G1 phase, a dependence on glycolytic metabolism, expression of epigenetic modifications on histones 3 and 4, and reactivation of endogenous OCT4 and downstream targets at a lower level than that observed in hESCs. Mechanistic insights into the process of VPA-induced reprogramming revealed that it was dependent on OCT4 promoter activation, which was achieved independently of the PI3K (phosphatidylinositol 3-kinase)/AKT/mTOR (mammalian target of rapamycin) pathway or GSK3β inhibition but was concomitant with the presence of acetylated histones H3K9 and H3K56, which promote pluripotency. Our data identify, for the first time, the pluripotent transcriptional and molecular signature and metabolic status of human chemically induced pluripotent stem cells.

Necrotizing enterocolitis symposium: Epidemiology and early diagnosis.

Despite decades of research on necrotizing enterocolitis (NEC), the outlook for infants afflicted by this devastating disease is all too often bleak. The aim of this symposium at the BAPS conference in Amsterdam was to highlight recent advances in the knowledge of the epidemiology and diagnosis of NEC. There were important contributions on the disease in the United Kingdom, both from a neonatal and from a surgical point of view, whereas colleagues from the Netherlands and elsewhere in Europe shared their insights into novel diagnostic tools, both biofluid and imaging based.

European Paediatric Surgeons' Association Survey on the Management of Hirschsprung Disease.

Aim This study aims to define patterns of Hirschsprung disease (HD) management. Methods An online questionnaire was sent to all European Paediatric Surgeons' Association (EUPSA) members. Results A total of 294 members (61 countries) answered (response rate: 61%).

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.

Optimization of Liver Decellularization Maintains Extracellular Matrix Micro-Architecture and Composition Predisposing to Effective Cell Seeding.

Hepatic tissue engineering using decellularized scaffolds is a potential therapeutic alternative to conventional transplantation. However, scaffolds are usually obtained using decellularization protocols that destroy the extracellular matrix (ECM) and hamper clinical translation. We aim to develop a decellularization technique that reliably maintains hepatic microarchitecture and ECM components. Isolated rat livers were decellularized by detergent-enzymatic technique with (EDTA-DET) or without EDTA (DET). Histology, DNA quantification and proteomics confirmed decellularization with further DNA reduction with the addition of EDTA. Quantification, histology, immunostaining, and proteomics demonstrated preservation of extracellular matrix components in both scaffolds with a higher amount of collagen and glycosaminoglycans in the EDTA-DET scaffold. Scanning electron microscopy and X-ray phase contrast imaging showed microarchitecture preservation, with EDTA-DET scaffolds more tightly packed. DET scaffold seeding with a hepatocellular cell line demonstrated complete repopulation in 14 days, with cells proliferating at that time. Decellularization using DET preserves microarchitecture and extracellular matrix components whilst allowing for cell growth for up to 14 days. Addition of EDTA creates a denser, more compact matrix. Transplantation of the scaffolds and scaling up of the methodology are the next steps for successful hepatic tissue engineering.

Intestinal epithelial cell injury is rescued by hydrogen sulfide.

Oxidative stress is implicated in the pathogenesis of necrotizing enterocolitis (NEC). Hydrogen sulfide (H2S) has been reported to have a protective function against oxidative stress in the gut. We hypothesize that administration of H2S can help decrease intestinal epithelial cell injury in vitro.

Laparoscopy in pediatric surgery: Implementation in Canada and supporting evidence.

The purpose of this study was to assess the diffusion of laparoscopy usage in Canadian pediatric centers and the relationship between uptake of laparoscopic surgery and the level of evidence supporting its use.

Effect of gestational age at birth on neonatal outcomes in gastroschisis.

Induced birth of fetuses with gastroschisis from 34weeks gestational age (GA) has been proposed to reduce bowel damage. We aimed to determine the effect of birth timing on time to full enteral feeds (ENT), length of hospital stay (LOS), and sepsis.

Current research in necrotizing enterocolitis.

Despite decades of research on necrotizing enterocolitis, we still do not fully understand the pathogenesis of the disease, how to prevent or how to treat the disease. However, as a result of recent significant advances in the microbiology, molecular biology, and cell biology of the intestine of premature infants and infants with necrotizing enterocolitis, there is some hope that research into this devastating disease will yield some important translation into improved outcomes.

Outcome after introduction of laparoscopic appendectomy in children: A cohort study.

Acute appendicitis in children is common and the optimal treatment modality is still debated, even if recent data suggest that laparoscopic surgery may result in shorter postoperative length of stay without an increased number of complications. The aim of the study was to compare the outcome of open and laparoscopic appendectomies during a transition period.

The Value of Surveys in Pediatric Surgery.

Surveys are an important research tool to evaluate the practice patterns of physicians. In the medical literature, practice surveys are increasingly used in specialties, such as pediatric surgery, characterized by the lack of sufficient evidence-based literature due to the rarity of the conditions treated. To maintain a level that yields to a meaningful scientific contribution the design, data collection and analysis of the survey have to be rigorous. Herein, we describe the general principles of survey methodology, we report the benefits and limitations of this statistical method, and we discuss the value of surveys in pediatric surgery.

International Survey on the Management of Congenital Diaphragmatic Hernia.

This study aims to define patterns in the management of congenital diaphragmatic hernia (CDH).