Mehmet Yalaz

Selective head cooling with hypothermia suppresses the generation of platelet-activating factor in cerebrospinal fluid of newborn infants with perinatal asphyxia

Hypoxic-ischemic encephalopathy (HIE) remains one of the most important neurologic complications in the newborn. Several experimental and clinical studies have shown that hypothermia is the most effective means known for protecting the brain against hypoxic-ischemic brain damage. Furthermore, recent data have suggested that platelet-activating factor (PAF) could play a pathophysiologically important role in the progression of hypoxic-ischemic brain injury. The aim of the present study was to investigate the role of head cooling combined with minimal hypothermia in short-term outcome of infants with perinatal asphyxia. In addition, we have examined the effect of head cooling combined with minimal hypothermia on PAF concentrations in cerebrospinal fluid (CSF) after hypoxic-ischemic brain injury. The group of asphyxiated infants (Group 1) consisted of 21 full-term (gestational age >37 weeks). These infants were randomized and divided into either a standard therapy group (Group 1a; n=10) or cooling group (Group 1b; n=11). Head cooling combined with minimal hypothermia (rectal temperature 36.5-36 degrees C) was started as soon as practicable after birth. The infants were cooled for 72h and then were rewarmed at 0.5 degrees C/h. The control group (Group 2) consisted of seven full-term infants and none of these infants showed any sign of asphyxia. To measure PAF concentration in CSF, CSF with lumbar puncture was collected into tubes immediately before the cooling (1-3h after birth) and again after 36h. We had no evidence of severe adverse events related to hypothermia. In Group 1a, two infants died after 72h of life; however, all newborn infants in Group 1b survived. Convulsion required treatment in three infants of standard therapy group (1a); none of the infants in Group 1b had clinical seizure activity. Abnormal EEG patterns were found in four infants of Group 1a; no EEG abnormalities were noted in Group 1b (P<0.05). On admission (before cooling), PAF concentration in CSF of asphyxiated infants was found to be significantly higher when compared with that of control (P<0.001). Mean PAF concentration before initiation of the study was similar in the two asphyxiated groups (Group 1a vs. 1b) (P>0.05). Obtained PAF level in CSF after 36h, showed a profound decline in cooling group of infants compared to Group 1a infants (P<0.01). In conclusion, the present study suggests that cerebral cooling with minimal hypothermia started soon after birth has no severe adverse effects during 72-h cooling period and that short-term outcome of infants are encouraging. Our results also support the hypothesis PAF an important mediator in hypoxic-ischemic brain injury and demonstrate that head cooling combined with minimal hypothermia reduces the normal increase in PAF following hypoxic-ischemic brain injury in full-term infants.

Protective Effect of Dietary Supplementation with L-Arginine and L-Carnitine on Hypoxia/Reoxygenation-Induced Necrotizing Enterocolitis in Young Mice

Oxygen-derived free radicals are important components of gastrointestinal injury in necrotizing enterocolitis (NEC). In the present investigation, we examined the protective actions of L-arginine, a nitric oxide synthase substrate, and L-carnitine against hypoxia-reoxygenation (H/R) induced NEC in young mice. Young mice were divided into four groups: group 1 mice were subjected to H/R only; group 2 H/R mice were supplemented with L-arginine in the drinking water (2 g/l) for 7 days; group 3 H/R mice were given L-carnitine solution in water (50 mg/kg p.o.) for 7 days, and group 4 mice served as controls.Hypoxia was induced by placing the mice in a 100% CO2 chamber for 5 min. After hypoxia, the mice were reoxygenated for 10 min with 100% oxygen. We examined the intestinal lesions by light microscopy and measured the intestinal generation of thiobarbituric acid reactive substances (TBARS) and the activities of superoxide dismutase and catalase in the H/R-induced model of NEC. In both L-arginine and L-carnitine groups, the NEC-induced intestinal tissue damage was greatly attenuated, with necrosis limited partially to the mucosa. The tissue TBARS level was significantly higher in group 1 than in any of the other groups (p < 0.001). However, those treated with L-arginine and L-carnitine had TBARS levels similar to those in the control animals. An increased tissue concentration of nitrate, a stable metabolite of nitric oxide, was found in the L-arginine-supplemented group as compared with the control group (p < 0.05). Both superoxide dismutase and catalase activities in the intestine were similar in H/R groups when compared with the intestine of control animals. The present study suggests that oxygen-derived free radicals are involved in the pathogenesis of H/R-induced NEC. This study also shows that dietary supplementation with L-arginine and L-carnitine ameliorates the histological evidence of H/R-induced intestinal injury and significantly decreases lipid peroxidation in H/R-induced bowel injury. Based on these findings, the beneficial effects of L-arginine and L-carnitine in this model may be mediated via mechanisms preventing free radical damage.

Successful caspofungin treatment of multidrug resistant Candida parapsilosis septicaemia in an extremely low birth weight neonate.

Candida septicaemia with multidrug resistance is an uncommon event in preterm neonates. We present an extremely low birth weight infant (gestational age of 27 weeks, birth weight of 980 g) who developed congenital Candida parapsilosis septicaemia. Because the fungus was resistant both to amphotericin B and fluconazole, caspofungin was chosen for therapy. The fungus was successfully eradicated without any clinical or laboratory adverse effects.

Insulin-Like Growth Factor Attenuates Apoptosis and Mucosal Damage in Hypoxia/Reoxygenation-Induced Intestinal Injury

Objective: Necrotizing enterocolitis (NEC) is a potentially lethal disease among premature infants. The aim of the present study was to investigate whether hypoxia-reoxygenation (H/R)-induced intestinal injury was due to increased apoptosis of the intestinal mucosa in young mice and whether pre-treatment of the animals with recombinant human insulin-like growth factor-I (IGF-I), a known anti-apoptotic factor, could protect the intestinal cells from H/R-induced apoptosis or intestinal injury. Study Design: Young mice were divided into three groups: group 1 mice (H/R) were hypoxia-reoxygenation; group 2 mice (H/R + IGF-I) were treated with recombinant human IGF-I by intraperitoneal injection (1 µg/g b.w. once daily) for 7 days, and group 3 mice served as control. Hypoxia was induced by placing young mice in a Plexiglas chamber consisting of 10% oxygen for 60 min. After hypoxia, the young mice were reoxygenated for 10 min with 100% oxygen. Intestinal generation of substances reactive to thiobarbituric acid (TBARS) and active caspase-3 were measured in H/R-induced intestinal injury. Results: Increased numbers of apoptotic cells (apoptotic index) across the villi in young mice subjected to H/R were observed with the TUNEL reaction whereas few apoptotic cells existed in the control animals. In addition, H/R-induced intestinal damage in the H/R + IGF-I group was greatly attenuated, with necrosis limited partially to the mucosa. Tissue-active caspase-3 levels in the H/R group were found to be significantly higher when compared with that of the H/R + IGF-I group of mice and control. However, TBARS concentrations in the intestine were similar in H/R groups when compared to the intestine of control animals. Conclusion: The present study suggests that both necrosis and apoptosis, via mechanisms occurring due to oxygen-derived free radicals and activation of caspase-3, play a role in the pathogenesis of H/R-induced bowel injury. We also show that IGF-I protect intestinal mucosa from necrosis and apoptosis from intestinal H/R injury.

Histological Chorioamnionitis: Effects on Premature Delivery and Neonatal Prognosis

BACKGROUND Chorioamnionitis is closely related to premature birth and has negative effects on neonatal morbidity and mortality. METHODS In this prospective study, 43 mothers who delivered earlier than 35 gestational weeks and their 57 infants were evaluated clinically and with laboratory findings. Placentas and umbilical cords were investigated histopathologically for chorioamnionitis and funisitis. RESULTS The overall frequency of clinical and histological chorioamnionitis (HCA) was 8.3% and 23.2%, respectively. The frequency of HCA was 47.3% and 83.3% in mothers delivered <32 weeks and <30 weeks, respectively. Maternal demographic and clinical findings and also leukocyte and C-reactive protein values were not indicative of HCA. Infants of mothers with HCA had significantly lower Apgar scores together with higher SNAP-PE-II and CRIB scores. These infants had increased mechanical ventilator and surfactant requirements, higher incidences of patent ductus arteriosus, early sepsis, and bronchopulmonary dysplasia, and higher mortality rates. The effect of HCA on neonatal morbidity and mortality was more prominent than the effect of low birthweight and lower gestational age. CONCLUSION Chorioamnionitis not only causes premature deliveries, but is also associated with neonatal complications and increased mortality. Clinical findings and infectious markers in mother or infant do not predict the diagnosis of histological chorioamnionitis. Therefore, placental histopathology may have a role in predicting neonatal outcome in premature deliveries, especially those below 30 weeks.

Mannose-binding lectin gene polymorphism and early neonatal outcome in preterm infants.

Background: Mannose-binding lectin (MBL) as a component of innate immunity plays an important role in preterm infants in whom adaptive immunity is not sufficiently developed. Polymorphisms in immunoregulatory genes influence the response to infection and subsequent inflammation. Infection and inflammation have been implicated in the mechanisms responsible for many of the diseases in the preterm newborns. Objectives: The aim of the study was to investigate the relationship between MBL gene polymorphism and early neonatal outcome in preterm infants. Methods: Codon 54 and 57 polymorphisms in MBL2 gene were genotyped in 99 preterm infants admitted to the Neonatal Intensive Care Unit at Ege University Children’s Hospital. Results: Overall frequencies of sepsis and early-onset sepsis were higher in the group of infants with MBL polymorphism when compared to infants with wild-type MBL genotype (p = 0.008, 0.009, respectively). Maximum Tollner sepsis score in the first 3 days of life was higher for the infants with variant MBL genotype (p = 0.0278). More infants in the variant MBL group had significant patent ductus arteriosus when compared to infants with wild-type MBL (27.8 vs. 9.5% respectively, p = 0.037). Conclusion: MBL gene polymorphism was associated with increased frequency of clinical sepsis particularly with early neonatal sepsis and also with higher Tollner sepsis scores and increased frequency of patent ductus arteriosus in infants. Overall mortality and incidence of culture proven sepsis, respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia and necrotizing enterocolitis were not found to be related to MBL genotype.

Cooling for Newborns with Hypoxic Ischemic Encephalopathy

adverse effects of cooling and ‘early’ indicators of neurodevelopmental outcome. Data Collection and Analysis: Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). Main Results: We included 11 randomized controlled trials in this updated review, comprising 1,505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68–0.83); typical RD –0.15, 95% CI –0.20 to –0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5–10) (8 studies, 1,344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64–0.88), typical RD –0.09 (95% CI –0.13 to –0.04); NNTB 11 (95% CI 8–25) (11 studies, 1,468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63–0.94), typical RD –0.13 (95% CI –0.19 to –0.07); NNTB 8 (95% CI 5–14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. Cochrane Abstract

The efficacy of two different lipid-based amphotericin B in neonatal Candida septicemia

Abstract Background : Fungal sepsis is becoming more frequent in neonatal intensive care units (NICU) and has a high mortality rate due to the invasive nature of the disease and to the insufficiency of low doses and high incidence of renal problems with effective doses of amphotericin B. New generation lipid formulated amphotericin B preparations may be more efficient because they are less toxic to be applied in target doses. However, there is limited experience in neonates and preterm infants.

Molybdenum cofactor deficiency associated with Dandy–Walker complex

Molybdenum cofactor deficiency is a rare and devastating disease leading to intractable seizures in the neonatal period. Severe loss of neocortical neurons, gliosis, and cystic necrosis of cerebral white matter resulting in significant cerebral volume loss are the neuropathological findings. The mechanism of cerebral injury is unknown, but sulphite excess, and sulphate or uric acid deficiencies are possible factors. We present here a new case of Molybdenum cofactor deficiency associated with Dandy-Walker complex with a history of three dead siblings, the latter also having Dandy-Walker malformation. We speculate that severe cerebral volume loss due to the above mentioned mechanisms may lead to an appearance resembling Dandy-Walker malformation.

Association of vitamin D receptor gene polymorphisms and bronchopulmonary dysplasia

Background:Vitamin D and its receptor (VDR) have important roles in perinatal lung development. The aim of this study was to investigate the relationship between VDR gene polymorphism and bronchopulmonary dysplasia (BPD) in preterm infants.Methods:VDR Fok I, Bsm I, Apa I, and Taq I polymorphisms were genotyped using restriction fragment length polymorphism in 109 preterm infants (47 with BPD, 62 without BPD).Results:In univariate analysis, Ff (odds ratio (OR) = 3.937, P = 0.022, 95% confidence interval (CI) = 1.22–12.69) and ff (OR = 5.23, P = 0.004, 95% CI = 1.69–16.23) genotypes of Fok I were associated with the increased risk of BPD; whereas tt genotype of Taq 1 was associated with a protective effect against BPD (OR = 0.30, P = 0.04, 95% CI = 0.09–0.94). In multivariate logistic regression analysis, variant Fok 1 genotype increased risk of BPD (OR = 4.11, 95% CI = 1.08–15.68, P = 0.038) independent of patent ductus arteriosus, sepsis, mechanical ventilation, and surfactant treatment. Taq 1, Bsm 1, and Apa 1 polymorphisms did not have any effect.Conclusion:After adjusting for multiple confounders, VDR Fok 1 polymorphism was associated with the increased frequency of BPD. Further studies are needed to assess the contribution of VDR signaling to the pathogenesis of BPD and to determine if VDR polymorphisms may be suitable for identifying infants at high risk for BPD.