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Stark M.J.,University of Adelaide | Stark M.J.,Womens and Childrens Hospital | Hodyl N.A.,University of Adelaide | Wright I.M.R.,John Hunter Childrens Hospital | Clifton V.L.,University of Adelaide
Placenta | Year: 2011

Glucocorticoids (GC) are known to influence fetal ROS production and anti-oxidant defences yet little attention has focused on the potential for effects in the placenta. We hypothesised that antenatal GC exposure alters placental pro-oxidant-anti-oxidant balance sex-specifically, based upon the known relationship between male sex and poor pregnancy outcome. Placentae were collected from 60 women who delivered between 24 and 31 completed weeks gestation and placental oxidative and nitrative stress (protein carbonyl, lipid hydroperoxide, and nitrotyrosine concentration) and anti-oxidant enzyme activity (glutathione peroxidase, thioredoxin reductase, and superoxide dismutase) measured. A pro-oxidant state was observed in placentae of male compared to female infants born within 72 h of antenatal GC exposure, with higher levels of protein carbonyl content (p = 0.04), lipid hydroperoxide (p < 0.01) and nitrotyrosine content (p = 0.02), and lower levels of glutathione peroxidase activity (p = 0.01). A pro-oxidant state continued to be observed in placentae of males compared to females born outside of 72 h, with higher protein carbonyl content (p = 0.04) and lower glutathione peroxidase activity (p = 0.01) than females, however no differences in placental lipid hydroperoxide and nitrotyrosine content were observed. These sex-specific alterations in products of placental oxidative stress could not purely be explained by differences in clinical illness severity (CRIB2 score). Therefore, these sex-specific alterations in placental pro-oxidant-antioxidant balance in response to antenatal betamethasone exposure, independent of illness severity, could contribute to the patho-physiologic processes underlying oxygen radical diseases of the newborn, conditions known to exhibit a male excess. © 2011 Elsevier Ltd. All rights reserved.


Lowe A.J.,University of Melbourne | Lowe A.J.,Murdoch Childrens Research Institute | Hosking C.S.,John Hunter Childrens Hospital | Bennett C.M.,University of Melbourne | And 7 more authors.
Journal of Allergy and Clinical Immunology | Year: 2011

Background: Partially hydrolyzed whey formula (pHWF) has been recommended for infants with a family history of allergic disease at the cessation of exclusive breast-feeding to promote oral tolerance and prevent allergic diseases. Objective: To determine whether feeding infants pHWF reduces their risk of allergic disease. Methods: A single-blind (participant) randomized controlled trial was conducted to compare allergic outcomes between infants fed a conventional cow's milk formula, a pHWF, or a soy formula. Before birth, 620 infants with a family history of allergic disease were recruited and randomized to receive the allocated formula at cessation of breast-feeding. Skin prick tests to 6 common allergens (milk, egg, peanut, dust mite, rye grass, and cat dander) were performed at 6, 12, and 24 months. The primary outcome was development of allergic manifestations (eczema and food reactions) measured 18 times in the first 2 years of life. Results: Follow-up was complete for 93% (575/620) at 2 years and 80% (495/620) at 6 or 7 years of age. There was no evidence that infants allocated to the pHWF (odds ratio, 1.21; 95% CI, 0.81-1.80) or the soy formula (odds ratio, 1.26; 95% CI, 0.84-1.88) were at a lower risk of allergic manifestations in infancy compared with conventional formula. There was also no evidence of reduced risk of skin prick test reactivity or childhood allergic disease. Conclusion: Despite current dietary guidelines, we found no evidence to support recommending the use of pHWF at weaning for the prevention of allergic disease in high-risk infants. © 2011 American Academy of Allergy, Asthma & Immunology.


Klocker A.A.,University of New South Wales | Phelan H.,John Hunter Childrens Hospital | Twigg S.M.,University of Sydney | Twigg S.M.,Royal Prince Alfred Hospital | And 3 more authors.
Diabetic Medicine | Year: 2013

Aim: Diabetic ketoacidosis is a life-threatening complication of Type 1 diabetes. Blood β-hydroxybutyrate testing is now widely available as an alternative to urine acetoacetate testing for detecting ketosis. The aim of this study was to review the effectiveness of capillary or serum β-hydroxybutyrate compared with urine acetoacetate testing in prevention and management of diabetic ketoacidosis. Methods: MEDLINE, EMBASE, EBM Reviews, The Cochrane Library and CINAHL (until April 2012, no language restrictions, studies in humans) were searched for experimental and observational studies comparing the effectiveness of blood β-hydroxybutyrate and urine acetoacetate testing. Outcomes examined were prevention of diabetic ketoacidosis, time to recovery from diabetic ketoacidosis, healthcare costs and patient or caregiver satisfaction. Additional sources included reference lists, conference proceedings and contact with experts in the field. Results: Four studies (two randomized controlled trials and two cohort studies) met eligibility criteria, including 299 participants across 11 centres. Risk of bias was low to moderate. Blood ketone testing compared with urine testing was associated with reduced frequency of hospitalization (one study), reduced time to recovery from diabetic ketoacidosis (three studies), cost benefits (one study) and greater satisfaction (one study, intervention group only). No study assessed prevention of diabetic ketoacidosis. Meta-analysis could not be performed because of heterogeneity in study design and published data. Conclusions: There is evidence suggesting that blood β-hydroxybutyrate testing is more effective than urine acetoacetate testing in reducing emergency department assessment, hospitalization and time to recovery from diabetic ketoacidosis, as well as potentially lowering healthcare expenditure. Further research in both young people and adults is needed. © 2013 Diabetes UK.


Coffey M.J.,University of New South Wales | Nightingale S.,John Hunter Childrens Hospital | Ooi C.Y.,Sydney Childrens Hospital Randwick
Journal of Pediatric Gastroenterology and Nutrition | Year: 2013

OBJECTIVES:: Pediatric pancreatitis remains poorly understood despite increasing incidence and risk of morbidity and mortality. Present predictive scores for severe pediatric acute pancreatitis (AP) are either extrapolated from adults or difficult to use in practice. We aimed to identify laboratory parameters for early prediction of severity of the course of pediatric AP. METHODS:: A retrospective review of children with AP (January 2000-July 2011) was performed at 2 pediatric hospitals. Predictors of severe AP using laboratory parameters measured within 24 hours of presentation were derived in the cohort from one institution and validated in the other. RESULTS:: A total of 131 pancreatitis episodes, 73 (34% severe) and 58 (24% severe) in the derivation and validation cohorts respectively, were reviewed. In the derivation cohort, serum lipase was significantly higher in severe versus mild AP (median [interquartile range] 18.1 [9.2-39.1] vs 4.9 (3.2-13.3) × upper limit of normal [ULN]; P = 0.002). Logistic regression analysis in the derivation cohort showed serum lipase ≥7 × ULN to be predictive of severe AP. This finding was confirmed in the validation cohort. Based on the combined derivation and validation data, serum lipase ≥7 × ULN was associated with an odds ratio of 7.1 (95% confidence interval 2.5-20.5; P < 0.001) for developing severe AP. Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were 85%, 56%, 46%, 89%, 1.939, and 0.27, respectively. CONCLUSIONS:: Serum lipase ≥7 × ULN within 24 hours of presentation may be a simple clinical predictor of severe AP in children. Lipase levels below this threshold are strongly associated with a milder course. Copyright © 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric.


Tsai M.-H.,University of Melbourne | Vears D.F.,University of Melbourne | Turner S.J.,University of Melbourne | Smith R.L.,John Hunter Childrens Hospital | And 4 more authors.
Epilepsia | Year: 2013

Purpose To characterize the frequency and nature of the family history of seizures in probands with epilepsy falling within the epilepsy-aphasia spectrum (EAS) in order to understand the genetic architecture of this group of disorders. Methods Patients with epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), Landau-Kleffner syndrome (LKS), atypical benign partial epilepsy (ABPE), and intermediate epilepsy-aphasia disorders (IEAD) were recruited. All affected and available unaffected relatives up to three degrees of relatedness underwent phenotyping using a validated seizure questionnaire. Pedigrees were constructed for all families. The proportion of affected relatives according to each degree of relatedness was calculated. The epilepsy phenotypes in close relatives were analyzed. The data were compared to the families of probands with benign childhood epilepsy with centrotemporal spikes (BECTS) using the same methodology. Key Findings Thirty-one probands, including five ECSWS, three LKS, one ABPE, and 22 IEAD were recruited. The mean age of seizure onset was 3.9 (range 0.5-7) years. A male predominance was seen (68%, 21/31). Sixteen (51.6%) of 31 had a positive family history of seizures. Among 1,254 relatives, 30 (2.4%) had a history of seizures: 13 (10.2%) of 128 first-degree relatives, 5 (1.7%) of 291 second-degree relatives, and 12 (1.4%) of 835 third-degree relatives. Thirteen had febrile seizures, including two who had both febrile seizures and epilepsy. Of the 19 relatives with epilepsy, 4 had BECTS, 4 epilepsies with focal seizures of unknown cause, 3 IEAD, and 7 unclassified. One had genetic generalized epilepsy. In the families of the BECTS probands, 9.8% of first-degree, 3% of second-degree, and 1.5% of third-degree relatives had seizures, which was not significantly different from the EAS cohort families. Significance The frequencies of seizures in relatives of probands with EAS suggest that the underlying genetic influence of EAS is consistent with complex inheritance and similar to BECTS. The phenotypic pattern observed in the affected relatives comprised predominantly febrile seizures and focal seizures. These findings suggest that a shared genetic predisposition to focal epilepsies underpins the epilepsy-aphasia spectrum. © Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.


Kent A.L.,Canberra Hospital | Kent A.L.,Australian National University | Wright I.M.R.,John Hunter Childrens Hospital | Wright I.M.R.,Hunter Medical Research Institute | And 2 more authors.
Pediatrics | Year: 2012

OBJECTIVES: To determine whether male gender has an effect on survival, early neonatal morbidity, and long-term outcome in neonates born extremely prematurely. METHODS: Retrospective review of the New South Wales and Australian Capital Territory Neonatal Intensive Care Unit Data Collection of all infants admitted to New South Wales and Australian Capital Territory neonatal intensive care units between January 1998 and December 2004. The primary outcome was hospital mortality and functional impairment at 2 to 3 years follow-up. RESULTS: Included in the study were 2549 neonates; 54.7% were male. Risks of grade III/IV intraventricular hemorrhage, sepsis, and major surgery were found to be increased in male neonates. Hospital mortality (odds ratio 1.285, 95% confidence interval 1.035-1.595) and moderate to severe functional disability at 2 to 3 years of age (odds ratio 1.877, 95% confidence interval 1.398-2.521) were more likely in male infants. Gender differences for mortality and long-term neurologic outcome loses significance at 27 weeks gestation. CONCLUSIONS: In the modern era of neonatal management, male infants still have higher mortality and poorer long-term neurologic outcome. Gender differences for mortality and longterm neurologic outcome appear to lose significance at 27 weeks gestation. Copyright © 2012 by the American Academy of Pediatrics.


Smart C.E.,John Hunter Childrens Hospital | Smart C.E.,University of Newcastle | King B.R.,John Hunter Childrens Hospital | Mcelduff P.,Hunter Medical Research Institute | Collins C.E.,University of Newcastle
Diabetic Medicine | Year: 2012

Aim To determine if an insulin dose calculated for a meal containing 60g carbohydrate maintains postprandial glycaemic control for meals containing 40, 50, 70 or 80g carbohydrate. Methods Thirty-four young people (age range 8.5-17.7years) using intensive insulin therapy consumed five test breakfasts with equivalent fat, protein and fibre contents but differing carbohydrate quantities (40, 50, 60, 70 and 80g of carbohydrate). The preprandial insulin dose was the same for each meal, based on the subject's usual insulin:carbohydrate ratio for 60g carbohydrate. Continuous glucose monitoring was used to monitor postprandial glucose over 180min. Results The 40-g carbohydrate meal resulted in significantly more hypoglycaemia than the other meals (P=0.003). There was a one in three chance of hypoglycaemia between 120 and 180min if an insulin dose for 60g carbohydrate was given for 40g carbohydrate. The glucose levels of subjects on the 80-g meal were significantly higher than the 60- and 70-g carbohydrate meals at all time points between 150 and 180min (P<0.01). Subjects consuming the 80-g meal were more likely to have significant hyperglycaemia (blood glucose levels ≥12mmol/l) compared with the other meals (P<0.001). Conclusions In patients using intensive insulin therapy, an individually calculated insulin dose for 60g carbohydrate results in postprandial hypoglycaemia or hyperglycaemia for meals containing 40 and 80g carbohydrate. To calculate mealtime insulin in order to maintain postprandial control, carbohydrate estimations should be within 10g of the actual meal carbohydrate. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.


Mohammadi A.,John Hunter Hospital | Walker P.,John Hunter Childrens Hospital | Walker P.,University of Newcastle | Gardner-Berry K.,Sydney Cochlear Implant Center
Journal of Laryngology and Otology | Year: 2015

Objective: To investigate whether the aetiology for hearing impairment in neonates with unilateral auditory neuropathy spectrum disorder could be explained by structural abnormalities such as cochlear nerve aplasia, a cerebellopontine angle tumour or another identifiable lesion. Methods: In this prospective case series, 17 neonates were diagnosed with unilateral auditory neuropathy spectrum disorder on electrophysiological testing. Diagnostic audiology testing, including auditory brainstem response testing, was supplemented with computed tomography and/or magnetic resonance imaging. Results: Ten of the neonates (59 per cent) showed evidence for cochlear nerve aplasia. Of the remaining seven, four were shown to have another abnormality of the temporal bone on imaging. Only three neonates (18 per cent) were not diagnosed with cochlear nerve aplasia or another lesion. Three computed tomography scans were reported as normal, but subsequent magnetic resonance imaging revealed cochlear nerve aplasia. Conclusion: Auditory neuropathy spectrum disorder as a unilateral condition mandates further investigation for a definitive diagnosis. This series demonstrates that most neonates with unilateral auditory neuropathy spectrum disorder had pathology as visualised on computed tomography and/or magnetic resonance imaging scans. Magnetic resonance imaging is an appropriate first-line imaging modality. © 2014 JLO (1984) Limited.


Levick W.R.,John Hunter Childrens Hospital | Levick W.R.,University of Newcastle
Brain Impairment | Year: 2010

Research on observer rating of memory in children is examined in relation to the potential to develop screening instruments to improve efficiency in memory assessment, to shed light on the area of everyday memory in children, and to develop observer rating to the point where it may substitute for objective assessment. Several scales including the Parent Memory Questionnaire, the Children's Memory Questionnaire, the Observer Memory Questionnaire - Parent Form and the Working Memory Rating Scale are reviewed. Only the Working Memory Rating Scale has been published. Some of the other scales have good internal consistency and test-retest reliability but none have proven to be effective screening instruments and none can yet be recommended for clinical application. Relationships with objective test results have been at best modest, an issue that requires more detailed analysis if such instruments are to become effective screeners or even substitutes for objective assessment. Further observer rating research will shed light on everyday memory in children including its relationship to objective assessment and its place in models of memory. It remains to be established whether observer ratings add unique information to memory assessment or whether they can become a reliable, cost-effective substitute for objective assessment.


Chaudhari T.,John Hunter Childrens Hospital
Cochrane database of systematic reviews (Online) | Year: 2012

Delayed neuronal death following a perinatal hypoxic insult is due partly to xanthine oxidase-mediated production of cytotoxic free radicals. Evidence exists that allopurinol, a xanthine-oxidase inhibitor, reduces delayed cell death in experimental models of perinatal asphyxia and in people with organ reperfusion injury. To determine the effect of allopurinol on mortality and morbidity in newborn infants with hypoxic-ischaemic encephalopathy. We used the standard search strategy of the Cochrane Neonatal Group. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2012, Issue 1), MEDLINE (1966 to March 2012), EMBASE (1980 to March 2012), CINAHL (1982 to March 2012), conference proceedings, and previous reviews. Randomised or quasi-randomised controlled trials that compared allopurinol administration versus placebo or no drug in newborn infants with hypoxic-ischaemic encephalopathy. We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors. We included three trials in which a total of 114 infants participated. In one trial, participants were exclusively infants with severe encephalopathy. The other trials also included infants with mild and moderately severe encephalopathy. These studies were generally of good methodological quality, but were too small to exclude clinically important effects of allopurinol on mortality and morbidity. Meta-analysis did not reveal a statistically significant difference in the risk of death (typical risk ratio 0.88; 95% confidence interval (95% CI) 0.56 to 1.38; risk difference -0.04; 95% CI -0.18 to 0.10) or a composite of death or severe neurodevelopmental disability (typical risk ratio 0.78; 95% CI 0.56 to 1.08; risk difference -0.14; 95% CI -0.31 to 0.04). The available data are not sufficient to determine whether allopurinol has clinically important benefits for newborn infants with hypoxic-ischaemic encephalopathy. Much larger trials are needed. Such trials could assess allopurinol as an adjunct to therapeutic hypothermia in infants with moderate and severe encephalopathy and should be designed to exclude important effects on mortality and adverse long-term neurodevelopmental outcomes.

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