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Biomedical subjects

Simon Eaton

Publications and source records attributed to Simon Eaton.

At least 19 recordsLinked to original sources
PubMed2007

Factors predicting failure of redo Nissen fundoplication in children.

Recurrence of gastro-oesophageal reflux (GOR) following redo Nissen fundoplication represents a significant clinical problem. The aim of this study was to identify factors predicting failure of redo Nissen fundoplication. The notes of children who underwent redo Nissen fundoplication for recurrent GOR in a single institution between June 1994 and May 2005 were reviewed. Data are reported as median (range), or as numbers of cases. Multiple logistic regression analysis, using type of first fundoplication, neurological status, presence of gastrostomy, age-weight, retching-gas bloat after first fundoplication, associated anomalies, oesophageal atresia and length of follow-up as factors, was used to generate a model to identify factors predicting recurrent vomiting (failure) after redo. Eighty-one children underwent redo Nissen fundoplication 15.9 months (0.2-176) after the initial Nissen fundoplication. In 29, the first Nissen was laparoscopic. Age at redo Nissen fundoplication was 3.3 years (0.3-15.9) and weight 12.8 kg (5-60). Thirty-four children (42%) presented with recurrent vomiting (failure). Overall, the model successfully predicted vomiting (failure) after redo fundoplication (P = 0.009). Open surgery at first fundoplication (P = 0.011) and neurological impairment (P = 0.046) were both significant predictors of redo failure in the model, whereas presence of gastrostomy (P = 0.035) and older-heavier age-weight (P = 0.028) were associated with significantly better results. Retching-gas bloat, associated anomalies and oesophageal atresia were not significant predictors of failure. Redo Nissen fundoplication has a high failure rate. Risk factors are open fundoplication at first operation and neurological impairment. Redo fundoplication after primary laparoscopic Nissen has a lower risk of failure.

Adolescent↗
PubMed2006

Ornithine transcarbamylase and arginase I deficiency are responsible for diminished urea cycle function in the human hepatoblastoma cell line HepG2.

A possible cell source for a bio-artificial liver is the human hepatblastoma-derived cell line HepG2 as it confers many hepatocyte functions, however, the urea cycle is not maintained resulting in the lack of ammonia detoxification via this cycle. We investigated urea cycle activity in HepG2 cells at both a molecular and biochemical level to determine the causes for the lack of urea cycle expression, and subsequently addressed reinstatement of the cycle by gene transfer. Metabolic labelling studies showed that urea production from 15N-ammonium chloride was not detectable in HepG2 conditioned medium, nor could 14C-labelled urea cycle intermediates be detected. Gene expression data from HepG2 cells revealed that although expression of three urea cycle genes Carbamoyl Phosphate Synthase I, Arginosuccinate Synthetase and Arginosuccinate Lyase was evident, Ornithine Transcarbamylase and Arginase I expression were completely absent. These results were confirmed by Western blot for arginase I, where no protein was detected. Radiolabelled enzyme assays showed that Ornithine Transcarbamylase functional activity was missing but that Carbamoyl Phosphate Synthase I, Arginosuccinate Synthetase and Arginosuccinate Lyase were functionally expressed at levels comparable to cultured primary human hepatocytes. To restore the urea cycle, HepG2 cells were transfected with full length Ornithine Transcarbamylase and Arginase I cDNA constructs under a CMV promoter. Co-transfected HepG2 cells displayed complete urea cycle activity, producing both labelled urea and urea cycle intermediates. This strategy could provide a cell source capable of urea synthesis, and hence ammonia detoxificatory function, which would be useful in a bio-artificial liver.

Arginase↗
PubMed2006

Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis.

OBJECTIVES: (1) To characterise neurodevelopmental outcome of neonates with necrotizing enterocolitis (NEC); (2) to define whether NEC increases risk of neurodevelopmental impairment in very low birth weight neonates; (3) to investigate whether stage of disease or need for surgery increase risk of poor outcome. DESIGN: A systematic review was performed. Searches identified 182 relevant papers. Ten studies compared extremely low birthweight neonates with NEC to infants of similar age and gestation who did not develop NEC. Data are reported as OR (95% CIs, p values for test for overall effect) and compared by chi2. RESULTS: 7843 children (821 with NEC) were included in the meta-analysis. Median follow-up was 20 months (range 12 to 156). Overall, 45% of children who had neonatal NEC were neurodevelopmentally impaired. Infants with NEC were significantly more likely than infants of similar age and gestation who did not develop NEC to be neurodevelopmentally impaired (1.6 (1.3 to 2.0), p = 0.0001) including a higher risk of cerebral palsy (1.5 (1.2 to 2.0), p = 0.001), visual (2.3 (1.0 to 5.1), p = 0.04), cognitive (1.7 (1.4 to 2.2), p<0.0001) and psychomotor impairment (1.7 (1.3 to 2.2), p<0.0001). The odds ratio of neurodevelopmental impairment was also 2.3 times higher in neonates with Bell's stage III disease or requiring surgery ((1.5 to 3.6), p = 0.0001). CONCLUSIONS: NEC is associated with significantly worse neurodevelopmental outcome than prematurity alone. Presence of advanced NEC and need for surgery increase the risk of neurological impairment.

Cognition Disorders↗
PubMed2006

Free radical scavenging inhibits STAT phosphorylation following in vivo ischemia/reperfusion injury.

The signal transducer and activator of transcription (STAT) family are latent transcription factors involved in a variety of signal transduction pathways, including cell death cascades. STAT1 has been shown to have a crucial role in regulating cardiac cell apoptosis in the myocardium exposed to ischemia/reperfusion (I/R) injury. The free radical scavenger, tempol, is known to have cardioprotective properties, although little is known about the molecular mechanism(s) by which it acts. In the present study, we assessed the levels of phosphorylated STAT1 and STAT3 and examined whether tempol was able to affect STAT activation after in vivo cardiac I/R injury. We observed a reperfusion time-dependent increase in the tyrosine phosphorylation of STAT1 and STAT3 at residues 701 and 705, respectively. Here we show for the first time that tempol dramatically reduced STAT1 and 3 phosphorylation. The reduction in STAT1 and 3 phosphorylation was accompanied by a concomitant decrease in cellular malondialdehyde (MDA) levels. To verify the role of STAT1 in modulating the cardioprotective effect of tempol, rats were injected with the STAT1 activator, IFN-gamma, and tempol during I/R injury. We found that the presence of IFN-gamma abrogated the protective effects of tempol, suggesting that the protective effects of tempol may partly operate by decreasing the phosphorylation of STAT1. This study demonstrates that careful dissection of the molecular mechanisms that underpin I/R injury may reveal cardioprotective targets for future therapy.

Animals↗
PubMed2006

An investigation of minimisation criteria.

BACKGROUND: Minimisation can be used within treatment trials to ensure that prognostic factors are evenly distributed between treatment groups. The technique is relatively straightforward to apply but does require running tallies of patient recruitments to be made and some simple calculations to be performed prior to each allocation. As computing facilities have become more widely available, minimisation has become a more feasible option for many. Although the technique has increased in popularity, the mode of application is often poorly reported and the choice of input parameters not justified in any logical way. METHODS: We developed an automated package for patient allocation which incorporated a simulation arm. We here demonstrate how simulation of data can help to determine the input parameters to be used in a subsequent application of minimisation. RESULTS: Several scenarios were simulated. Within the selected scenarios, increasing the number of factors did not substantially adversely affect the extent to which the treatment groups were balanced with respect to the prognostic factors. Weighting of the factors tended to improve the balance when factors had many categories with only a slight negative effect on the factors with fewer categories. When interactions between factors were included as minimisation factors, there was no major reduction in the balance overall. CONCLUSION: With the advent of widely available computing facilities, researchers can be better equipped to implement minimisation as a means of patient allocation. Simulations prior to study commencement can assist in the choice of minimisation parameters and can be used to justify those selections.

Age Distribution↗
PubMed2006

The biochemical basis of antioxidant therapy in critical illness.

During critical illness free radical production may increase as a result of, for example, sepsis or tissue trauma. In addition, because of a potential for increased losses, and the possibility of inadequate nutrition, the antioxidant defences of the body may become compromised. Thus, the delicate balance between free radicals and antioxidants may be disturbed. Various nutritional and pharmacological strategies to enhance antioxidant defences have been proposed, which aim either to maintain or enhance endogenous antioxidant stores or to provide alternative antioxidant agents. Trace elements and amino acids are particularly important, and their synergistic role in the maintenance of the body's antioxidant defence network will be discussed.

Antioxidants↗
PubMed2006

Selenium in critical illness.

PURPOSE OF REVIEW: Selenium is a trace element essential to human health. Critical illness is associated with the generation of oxygen free radicals resulting in a condition of oxidative stress. Supplementing critically ill patients with antioxidant nutrients may improve survival. Selenium levels can be low due to redistribution to high-priority organs and dilution associated with aggressive resuscitation of the patient. The purpose of this review is to investigate the benefit of selenium supplementation in critically ill patients. RECENT FINDINGS: Most of the selenium-supplementation trials were performed in relatively small patient populations presenting with trauma, sepsis, burns and adult respiratory distress syndrome. Widely varying doses of selenium of between 200 and 1000 microg were used, either alone or in combination with other antioxidants. Significant improvements have been demonstrated in length of hospital stay, rate of infection and need for haemodialysis in these patients. However, no trial has demonstrated a statistically significant improvement in mortality. Two recent meta-analyses suggest a trend towards reduced mortality with selenium supplementation. SUMMARY: Selenium, by supporting antioxidant function, may be associated with a reduction in mortality. To demonstrate this large, well-designed randomized trials are required.

Antioxidants↗
PubMed2006

Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress.

Following our identification of PTEN-induced putative kinase 1 (PINK1) gene mutations in PARK6-linked Parkinson's disease (PD), we have recently reported that PINK1 protein localizes to Lewy bodies (LBs) in PD brains. We have used a cellular model system of LBs, namely induction of aggresomes, to determine how a mitochondrial protein, such as PINK1, can localize to aggregates. Using specific polyclonal antibodies, we firstly demonstrated that human PINK1 was cleaved and localized to mitochondria. We demonstrated that, on proteasome inhibition with MG-132, PINK1 and other mitochondrial proteins localized to aggresomes. Ultrastructural studies revealed that the mechanism was linked to the recruitment of intact mitochondria to the aggresome. Fractionation studies of lysates showed that PINK1 cleavage was enhanced by proteasomal stress in vitro and correlated with increased expression of the processed PINK1 protein in PD brain. These observations provide valuable insights into the mechanisms of LB formation in PD that should lead to a better understanding of PD pathogenesis.

Animals↗
PubMed2005

Prevalence of diabetes in rural Victoria.

AIMS: To compare the prevalence of diabetes in adults in small and medium sized towns in a part of rural Victoria MATERIALS AND METHODS: Participants were usual residents, aged >or=25 years, from randomly selected households in the crossroads undiagnosed disease study (CUDS: six small rural towns and their regional center in rural Victoria). Response rates to an initial census at the household and attendance at a subsequent biomedical examination involved were 70% and 61% (1454), respectively. All non-diabetic participants had an oral glucose tolerance test. RESULTS: Prevalence of diabetes, IGT, IFG were 7.3 (5.5-9.5)%, 6.9 (5.1-9.9)% and 3.2 (2.0-4.7)% respectively in the regional center and 8.9 (6.9-11.1)%, 4.9 (3.5-6.7)%, 3.0 (1.9-4.5)% in the Shire Capitals. Overall, 31/118 (26.3%) of those with diabetes were previously undiagnosed. Most (83.9%) of those with undiagnosed diabetes remembered having been screened for diabetes in the previous 2 years. Overall screening rates for diabetes were higher than across Victoria as a whole. CONCLUSIONS: The prevalence of diabetes has probably doubled over the last 15 years in this area. Undiagnosed diabetes is less common than expected, possibly as a result of a more vigorous approach to screening in general practice and in spite of the lower numbers of GPs in the area.

Adult↗
PubMed2005

The synthesis of internal standards for the quantitative determination of sphingolipids by tandem mass spectrometry.

Novel internal standards have been synthesised for the quantitative determination by tandem mass spectrometry (MS/MS) of the sphingolipids that accumulate in lysosomal storage diseases. The [d4]C16- and [d47]C24-isoforms of galactosylceramide (CMH), lactosylceramide (CDH), globotriaosylceramide (CTH), cerebroside sulphate, sphingomyelin and G(M1)-, G(M2)- and G(M3)-gangliosides were synthesised by the reaction of their lyso-forms with the acid chlorides of hexadecanoic 5,5,6,6-d4 acid ([d4]-palmitic acid) and tetracosanoic-d47 acid ([d47]-lignoceric acid), respectively. The acid chlorides were formed using oxalyl chloride. The structures of the internal standards were confirmed by MS/MS. The fragmentation pattern of each novel compound was similar to that of the corresponding natural form of the sphingolipid, making it a good internal standard for the quantitative determination of the natural sphingolipid by ESI-MS/MS. Characteristic product ions were identified for each compound.

Lysosomal Storage Diseases↗
PubMed2005

Hyperinsulinism of infancy associated with a novel splice site mutation in the SCHAD gene.

Fatty acids play an important role in regulating insulin secretion, but the mechanisms are unclear. We report a case of a novel splice site mutation in the short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) gene associated with hyperinsulinism. This mutation resulted in a nearly complete absence of immunoreactive protein and a decrease in fibroblast SCHAD activity.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2005

Total glutathione is not decreased in infants with necrotizing enterocolitis.

BACKGROUND: Glutathione (GSH) is the major intracellular antioxidant protecting against free radical-mediated damage. Oxidative stress is implicated in the pathogenesis of necrotizing enterocolitis (NEC), and damage could be enhanced by a relative deficiency of GSH. We hypothesized that infants with NEC would have lower levels of erythrocyte GSH when compared with controls. METHODS: Total erythrocyte GSH concentration (per gram of hemoglobin [g Hb]) was determined in blood samples from infants with NEC (n = 16) referred for surgical intervention. Nonseptic infants referred for other conditions (eg, patent ductus arteriosus ligation) served as controls (n = 10). RESULTS: Controls and infants with NEC were demographically similar. Mean erythrocyte GSH concentration in infants with NEC was 0.076 +/- 0.004 micromol/g Hb and in controls it was 0.078 +/- 0.005 micromol/g Hb (P = .73). There was no significant correlation between GSH concentration and weight, gestational age, or C-reactive protein levels. In infants with NEC, there was no difference in GSH levels between infants with stage 2 and stage 3 diseases nor between those who died and survived, but a trend toward lower GSH levels in infants with more extensive diseases exists. CONCLUSIONS: Total GSH levels are similar in infants with NEC and controls. It is possible that a relative rather than absolute deficiency of antioxidant compounds exists and may contribute to the development of NEC.

Birth Weight↗
PubMed2005

Inflammatory response in children after laparoscopic vs open Nissen fundoplication: randomized controlled trial.

UNLABELLED: We performed a randomized controlled trial to compare the inflammatory and immune responses to Nissen fundoplication in infants and children undergoing either open or laparoscopic surgery. METHODS: Forty children undergoing Nissen fundoplication were randomized to laparoscopy or open surgery using minimization with respect to age, neurologic status, and operating surgeon. Intraoperative and postoperative analgesias were standardized. Inflammatory markers (plasma malondialdehyde, nitrate plus nitrite level, and cytokines) and monocyte class II major histocompatibility complex expression were measured preoperatively, at end of surgery, 4, 24, and 48 hours postoperatively. Postoperative changes were compared between open and laparoscopic groups. RESULTS: There were no significant changes in circulating malondialdehyde, nitrates plus/ nitrite, interleukin-10, or tumor necrosis factor alpha in the postoperative period in either group. Interleukin-1 receptor antagonist (IL-1rA) and IL-6 were significantly increased in both groups, with a tendency for greater elevation of IL-1rA in the open group. Monocyte major histocompatibility complex expression fell significantly in both groups; however, this fall appeared to be slightly more marked in the open group. CONCLUSIONS: The postoperative cytokine response is similar in children undergoing open and laparoscopic Nissen fundoplication. This trial indicates that laparoscopy may partly reduce postoperative immune suppression.

Child↗
PubMed2005

P-selectin expression, neutrophil infiltration, and histologic injury in neonates with necrotizing enterocolitis.

BACKGROUND/PURPOSE: P-selectin promotes adherence of leukocytes to the endothelium in inflammatory processes. The aim of this study was to investigate the expression of P-selectin and its role in the development of inflammation in neonates with necrotizing enterocolitis (NEC). METHODS: Twenty-nine intestinal specimens from 13 neonates with NEC and 7 control neonates with congenital gastrointestinal abnormalities were studied. Histologic damage, immunohistochemical expression of P-selectin, and polymorphonuclear cell infiltrate were graded blindly. Mann-Whitney U and Spearman rank tests were used to compare grades. RESULTS: Expression of P-selectin was increased in NEC compared with controls in both medium-sized vessels (P = .03) and in the microcirculation (P = .03). P-selectin expression on medium-sized vessels correlated with the degree of histologic injury (P = .02, r = 0.425). P-selectin expression was greatest in areas of active inflammation but markedly lower in necrotic areas. The degree of polymorphonuclear cell infiltration strongly correlated with P-selectin expression on both medium-sized vessels (P = .004, r = 0.513) and the microcirculation (P = .001, r = 0.578). CONCLUSIONS: Expression of P-selectin is increased in medium-sized vessels and in the microcirculation in intestinal specimens of neonates with NEC compared with neonatal controls. Expression of P-selectin is associated with the recruitment of polymorphonuclear cells and the severity of histologic injury, although P-selectin expression is lost in necrotic tissue.

Enterocolitis, Necrotizing↗
PubMed2005

Moderate hypothermia protects against systemic oxidative stress in a rat model of intestinal ischemia and reperfusion injury.

Multisystem organ failure represents a major cause of mortality in intestinal ischemia and reperfusion (I/R), and oxidative stress plays a key role in its pathogenesis. Hypothermia is beneficial in I/R injury, but its effects on systemic oxidative stress have not been elucidated. The aim of this study was to evaluate the effects of moderate hypothermia on systemic oxidative stress after intestinal I/R injury. Anaesthetized adult rats (n = 10 per group) underwent 60 min of intestinal ischemia followed by 120 min of reperfusion or sham operation at normothermia (36 degrees C-38 degrees C) or moderate hypothermia (30 degrees C-32 degrees C). At sacrifice, ileum, liver, lungs, and kidneys were removed to determine the concentration of malondialdehyde (a marker of lipid peroxidation), reduced and oxidized glutathione (a major endogenous antioxidant), and glutathione redox state. Plasma malondialdehyde and nitrate plus nitrite (reflecting nitric oxide production) were also analyzed. A marked elevation of malondialdehyde was observed after I/R at normothermia in plasma, ileum, and lungs; however, hypothermia during I/R prevented this increase. I/R at normothermia caused a profound decrease in reduced glutathione and glutathione redox state in the ileum, but this was not observed in I/R at hypothermia. Interestingly, hypothermia increased glutathione content of control intestine. Nitric oxide production was increased only in normothermic I/R animals. Moderate hypothermia attenuates systemic oxidative stress associated with experimental intestinal I/R in an animal model by decreasing lipid peroxidation in plasma, ileum, lungs, and kidneys, by preventing the depletion of gut glutathione, and by reducing systemic nitric oxide production. However, whether these effects persist after rewarming is unknown.

Animals↗
PubMed2004

The cardioprotective effect of urocortin during ischaemia/reperfusion involves the prevention of mitochondrial damage.

We have previously shown, using Affymetrix gene chip technology, that urocortin induces the expression of several diverse genes in cardiac myocytes. An ATP sensitive inwardly rectifying potassium channel, Katp (Kir6.1), the enzyme calcium independent phospholipase A2 (iPLA2), and protein kinase C epsilon (PKCepsilon) and that these genes are involved in the cardioprotective mechanism of action of urocortin. Here we demonstrate that these gene products are localized to cardiac myocyte mitochondria and for the first time show that urocortin protects cardiac myocytes from ischaemia/reperfusion induced cell death by preventing mitochondrial damage. Using pharmacological agents to Katp channels and iPLA2 and synthetic peptide inhibitors of PKCepsilon, we go on to demonstrate that these three gene products are involved in the urocortin induced protection of cardiac myocyte mitochondria. These proteins may interact at the mitochondria to produce the protective effect.

Aldehydes↗