***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVE : The goal was to examine biochemical , neurophysiologic , anatomic , and clinical changes associated with erythropoietin administration to neonates with hypoxic-ischemic encephalopathy ( HIE ) . METHODS : We conducted a prospect i ve case-control study with 45 neonates in 3 groups , a normal healthy group ( N = 15 ) , a HIE-erythropoietin group ( N = 15 ; infants with mild/moderate HIE who received human recombinant erythropoietin , 2500 IU/kg , subcutaneously , daily for 5 days ) , and a HIE-control group ( N = 15 ; did not receive erythropoietin ) .  Serum concentrations of nitric oxide ( NO ) were measured at enrollment for the normal healthy neonates and at enrollment and after 2 weeks for the 2 HIE groups . The 2 HIE groups underwent electroencephalography at enrollment and at 2 to 3 weeks .  Brain MRI  was performed at 3 weeks . Neurologic evaluations and Denver Developmental Screening Test II assessment s were performed at 6 months . RESULTS : Compared with normal healthy neonates , the 2 HIE groups had greater blood NO concentrations ( P < .001 ) . At enrollment , the 2 HIE groups did not differ in clinical severity , seizure incidence , NO concentrations , or electroencephalographic findings . At 2 weeks of age , electroencephalographic background s improved significantly ( P = .01 ) and NO concentrations decreased ( P < .001 ) in the HIE-erythropoietin group , compared with the HIE-control group ; MRI findings did not differ between groups . At 6 months of age , infants in the HIE-erythropoietin group had fewer neurologic ( P = .03 ) and developmental ( P = .03 ) abnormalities . CONCLUSION : This study demonstrates the feasibility of early administration of human recombinant erythropoietin to term neonates with HIE , to protect against encephalopathy Background Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine . The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals , thereby limiting the amount of hypoxia-reperfusion damage . In case of suspected intra-uterine hypoxia , both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy . Methods / Design The proposed trial is a r and omized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia .  Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected . Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace , preferably accompanied by either significant ST-wave abnormalities ( as detected by the STAN-monitor ) or an abnormal foetal blood scalp sampling ( pH < 7.20 ) . Primary outcome measures are the amount of S100B ( a marker for brain tissue damage ) and the severity of oxidative stress ( measured by isoprostane , neuroprostane , non protein bound iron and hypoxanthine ) , both measured in umbilical cord blood . Secondary outcome measures are neonatal mortality , serious composite neonatal morbidity and long-term neurological outcome . Furthermore pharmacokinetics and pharmacodynamics will be investigated . We expect an inclusion of 220 patients ( 110 per group ) to be feasible in an inclusion period of two years . Given a suspected mean value of S100B of 1.05 ug/L ( SD 0.37 ug/L ) in the placebo group this trial has a power of 90 % ( alpha 0.05 ) to detect a mean value of S100B of 0.89 ug/L ( SD 0.37 ug/L ) in the ' allopurinol-treated ' group ( z-test2-sided ) . Analysis will be by intention to treat and it allows for one interim analysis . Discussion In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia . Trial registration number Clinical Trials , protocol registration system : Background Despite progresses in neonatal care , the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements . In countries with a high level of perinatal care , the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2–3 per 1000 term newborns . Recent trials have demonstrated that moderate hypothermia , started within 6 hours after birth and protracted for 72 hours , can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy . It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia . Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy . However , the association of mild hypothermia and topiramate treatment has never been studied in human newborns . The objective of this research project is to evaluate , through a multicenter r and omized controlled trial , whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment . Methods / Design Term newborns ( gestational age ≥ 36 weeks and birth weight ≥ 1800 g ) with precocious metabolic , clinical and electroencephalographic ( EEG ) signs of hypoxic-ischemic encephalopathy will be r and omized , according to their EEG pattern , to receive topiramate added to st and ard treatment with moderate hypothermia or st and ard treatment alone . Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life . Topiramate concentrations will be measured on serial dried blood spots . 64 participants will be recruited in the study . To evaluate the safety  of topiramate administration , cardiac and respiratory parameters will be continuously monitored . Blood samplings will be performed to check renal , liver and metabolic balance . To evaluate the efficacy of topiramate , the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations . Visual function will be evaluated by means of behavioural st and ardized tests . Discussion This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia . Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns . Trial registration Current Controlled Trials IS RCT N62175998 ; Clinical Trials.gov Identifier NCT01241019 ; EudraCT Number 2010 - 018627 - Free radicals have been implicated in the pathogenesis of neonatal asphyxia and its complications . This study measured a product of lipid peroxidation , malondialdehyde , and the nitrite/nitrate levels in the serum of 20 asphyxiated newborns before and after treatment with the antioxidant melatonin given within the first 6 hr of life . Ten asphyxiated newborns received a total of 80 mg of melatonin ( 8 doses of 10 mg each separated by 2-hr intervals ) orally . One blood sample was collected before melatonin administration and two additional blood sample s ( at 12 and 24 hr ) were collected after giving melatonin . A third group of healthy newborn children served as controls . Serum malondialdehyde and nitrite+nitrate concentrations in newborns with asphyxia before treatment were significantly higher than those in infants without asphyxia . In the asphyxiated newborns given melatonin , there were significant reductions in malondialdehyde and nitrite/nitrate levels at both 12 and 24 hr . Three of the 10 asphyxiated children not given melatonin  died within 72 hr after birth ; none of the 10 asphyxiated newborns given melatonin  died . The results indicate that the melatonin may be beneficial in the treatment of newborn infants with asphyxia . The protective actions of melatonin in this study may relate to the antioxidant properties of the indole as well as to the ability of melatonin to increase the efficiency of mitochondrial electron transport Hypoxia-ischemia produces brain damage by processes that continue for many hours after reoxygenation/reperfusion . This provides a window of opportunity for therapy aim ed at preventing further loss of brain cells . Sulfate magnesium can prevent posthypoxic brain injury by blocking glutamate receptors within the calcium ( Ca++ ) ion channel . We used sulfate magnesium in nine newborn infant after perinatal hypoxia . We investigated the brain damage , by ultrasound examination , on third day , in first , second and third week , and third , sixth month of life . We have estimated the neurological development in the first week of life and third and twelfth month of life . We did not find deviations in ultrasound examination . We did not observe convulsions . We did not observe any side effect of this therapy . The examination at 1 of year of life in all of children was correct BACKGROUND : Fetal hypoxia is an important determinant of neonatal encephalopathy caused by birth asphyxia , in which hypoxia-induced free radical formation plays an important role . HYPOTHESIS : Maternal treatment with allopurinol , will cross the placenta during fetal hypoxia ( primary outcome ) and reduce S-100B and free radical formation ( secondary outcome ) . METHODS : In a r and omized , double-blind feasibility study , 53 pregnant women in labor ( 54 fetuses ) with a gestational age of > 36 weeks and fetal hypoxia , as indicated by abnormal/nonreassuring fetal heart rate tracing or fetal scalp pH of < 7.20 , received 500 mg of allopurinol or placebo intravenously . Severity of fetal hypoxia , brain damage and free radical formation were assessed by arterial cord blood lactate , S-100B and non-protein-bound-iron concentrations , respectively . At birth , maternal and cord blood concentrations of allopurinol and its active metabolite oxypurinol were determined . RESULTS : Allopurinol and oxypurinol concentrations were within the therapeutic range in the mother ( allopurinol > 2 mg/L and /or oxypurinol > 4 mg/L ) but not always in arterial cord blood . We therefore created 3 groups : a placebo ( n = 27 ) , therapeutic allopurinol ( n = 15 ) , and subtherapeutic allopurinol group ( n = 12 ) . Cord lactate concentration did not differ , but S-100B was significantly lower in the therapeutic allopurinol group compared with the placebo and subtherapeutic allopurinol groups ( P < .01 ) . Fewer therapeutic allopurinol cord sample s had measurable non – protein-bound iron concentrations compared with placebo ( P < .01 ) . CONCLUSIONS : Maternal allopurinol/oxypurinol crosses the placenta during fetal hypoxia . In fetuses/newborns with therapeutic allopurinol/oxypurinol concentrations in cord blood , lower plasma levels of the brain injury marker protein S-100B were detected . A larger allopurinol trial in compromised fetuses at term seems warranted . The allopurinol dosage must be adjusted to achieve therapeutic fetal allopurinol/oxypurinol concentrations Opinion statementNeonatal Hypoxic-ischemic encephalopathy in full term infants has been associated with a high risk for morbidity and mortality . The patho-physiology of brain injury following hypoxia-ischemia , noted in pre clinical models , is a cascade of events result ing from excitotoxic and oxidative injury culminating in cell death . Hypothermia has been noted to be protective by inhibiting various events in the cascade of injury . Major r and omized clinical trials in neonatal HIE have demonstrated reduction in death and disability and continued safety and efficacy of neuroprotection in childhood . There is now clinical and imaging evidence for hypothermia as neuroprotection . Hypothermia should be offered to term infants with either severe acidosis at birth or resuscitation needing continued ventilation and evidence of either moderate or severe encephalopathy within 6 hours of birth . The target temperature should be 33 ° to 34 ° C and duration of cooling should be 72 hours , as per the published trials . Rewarming should be slow , at 0.5 ° C per hour . Infants should have serial neurological examinations during and at the end of cooling and at discharge . Multiorgan function should be supported and hypocarbia should be avoided during ventilator therapy . If available , the amplitude integrated EEG should be obtained prior to cooling and following rewarming . All infants should have magnetic resonance brain imaging studies within 1 to 2 weeks of age . Information from the neurological examination , aEEG and MRI studies will be helpful in discussing prognosis with parents . All infants should be followed for a minimum of 18 months to evaluate growth parameters and neurodevelopment al outcome BACK 
    Output:
    
Tertiary brain injury describes the long-term effect of HIE on brain development including sensitization of the immune system to inflammation and low endogenous trophical factors , effecting on oligodendrocyte maturation , myelination and repair [ 3 ] .