Peroxisome proliferator-activated receptor-γ agonist pioglitazone reduces the development of necrotizing enterocolitis in a neonatal preterm rat model.

BACKGROUND: Factors affecting innate immunity and acting as inflammatory regulators, such as the nuclear peroxisome proliferator-activated receptors (PPAR) could be crucial in the pathogenesis of necrotizing enterocolitis (NEC). We hypothesized that the PPARγ agonist pioglitazone (PIO) might be effective in preventing the development of NEC and/or reducing its severity. METHODS: We studied preterm rats in which NEC was induced using the hypoxia-hypothermia model. The treatment group (TG; n = 30) received enteral PIO (10 mg/kg/d) for 72 h and the control group (CG; n = 30) did not. Animals were sacrificed 96 h after birth. NEC was diagnosed evaluating histological ileum changes, and mRNA levels of IL-4, IL-12, IL-6, IL-10, INF-γ, and TNF-α cytokines were measured. RESULTS: NEC occurrence was higher in the CG (18/30; 60%) than in the TG (5/30; 16.7%) and was more severe. Proinflammatory IL-12 and INF-γ mRNA levels were significantly lower in the TG than in the CG; conversely, the anti-inflammatory IL-4 mRNA level was significantly higher in the TG than in the CG. CONCLUSION: Our results demonstrate for the first time that PIO is effective in reducing the incidence and severity of NEC and in decreasing renal injuries in a preterm rat model.

Change of Cerebral Oxygenation during Surfactant Treatment in Preterm Infants: "LISA" versus "InSurE" Procedures.

Objectives The aim of the study was to compare the effects on cerebral oxygenation in preterm infants of two different procedures for surfactant administration: the LISA (low-invasive method of surfactant administration) and the InSurE (Intubation, SURfactant administration, Extubation). Study Design Twenty premature infants with respiratory distress syndrome were assigned to receive surfactant either by "LISA" (n = 10) or "InSurE" (n = 10) procedure. Patients were continuously studied by near-infrared spectroscopy (NIRS) for the measurement of cerebral regional oxygenation (rSO2C) and calculation of cerebral fractional oxygen extraction rate (cFTOE), and NIRS data were recorded 30 minutes before (T0) surfactant administration, during the procedure (Tproc), and 30 (T1), 60 (T2T2), and 120 minutes (T3) afterward. Cerebral blood flow velocity (CBFV) was studied in the anterior cerebral artery at T0, T1, and T3. Results SpO2 significantly decreased at Tproc in comparison with T0, T1, T2, and T3 and the decrease was higher in the LISA than in the InSurE group. rSO2C was lower at tproc and T3 in the LISA than in the InSurE group. cFTOE was higher at tproc, t2, and t3 in the LISA group than in the InSurE group. CBFV did not change during the study periods in both groups. Conclusions The LISA and InSurE procedures transiently decreased rSO2C in our population, and the decrease was higher in the LISA group. Consistently, there was a contemporary increase in cFTOE that was higher in the LISA than in the InSurE group, suggesting that it represents a compensatory mechanism.

Broad-spectrum light versus blue light for phototherapy in neonatal hyperbilirubinemia: a randomized controlled trial.

Phototherapy is standard care for treatment of neonatal hyperbilirubinemia. Our aim was to compare the effectiveness of broad-spectrum light (BSL) to that of blue light emitting diodes (LED) phototherapy for the treatment of jaundiced late preterm and term infants. Infants with gestational age from 35(+0) to 41(+6) weeks of gestation and nonhemolytic hyperbilirubinemia were randomized to treatment with BSL phototherapy or blue LED phototherapy. A total of 20 infants were included in the blue LED phototherapy group and 20 in the BSL phototherapy group. The duration of phototherapy was lower in the BSL than in the blue LED phototherapy group (15.8 ± 4.9 vs. 20.6 ± 6.0 hours; p = 0.009), and infants in the former group had a lower probability (p = 0.015) of remaining in phototherapy than infants in the latter. We concluded that BSL phototherapy is more effective than blue LED phototherapy for the treatment of hyperbilirubinemia in late preterm and term infants. Our data suggest that these results are not due to the different irradiance of the two phototherapy systems, but probably depend on their different peak light emissions.

Early fresh-frozen plasma transfusion decreases the risk of retinopathy of prematurity.

BACKGROUND: Insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) play a main role in the pathogenesis of retinopathy of prematurity (ROP). Fresh-frozen plasma (FFP) from adult donors may be an actual source of IGF-1 and IGFBP-3 because it contains higher concentrations. The objective was to evaluate whether FFP transfusions can decrease the occurrence of ROP in a cohort of preterm infants. STUDY DESIGN AND METHODS: We retrospectively analyzed data from 218 infants with gestational age of less than 29 weeks who either received FFP or did not and correlated this procedure to the development of any grade of ROP. RESULTS: Logistic regression analysis demonstrated that two or more transfusions of FFP was effective in decreasing the risk of development of any grade of ROP (relative risk, 0.46; 95% confidence interval, 0.23-0.93). Other factors that affected the risk of ROP were gestational age, birthweight, antenatal steroid treatment, FiO2 of at least 0.40, mechanical ventilation, and sepsis. CONCLUSIONS: We found that two or more transfusions of FFP in the first week of life decrease the risk of developing any grade of ROP in preterm infants with gestational age of less than 29 weeks.

Neonatal respiratory support strategies in the intensive care unit: an Italian survey.

We carried out a survey of current practices of neonatal respiratory support in neonatal intensive care units (NICUs) in Italy with the aim of comparing the current reality with evidence from the literature. We sent a questionnaire by email to the 103 level III neonatal units in Italy. There was a 61 % (73/120) response rate to the questionnaire. We found that synchronized intermittent positive pressure ventilation is mostly used in infants in the acute phase of respiratory distress syndrome (RDS), while the majority of the units prefer volume-targeted ventilation for those in the weaning phase. Nasal continuous positive airway pressure is the most commonly used non-invasive mode of respiratory support, both in the acute and post-extubation phase of RDS. Surfactant is mainly given as rescue treatment. Infants receive caffeine before extubation and analgesia under mechanical ventilation, while post-natal steroids are given after the first week of life in the majority of the units. In conclusion, respiratory support strategies in Italian NICUs are frequently evidence-based. However, since there are areas where this does not occur, we suggest that focused interventions take place on these areas to help improve clinical practice and increase their adherence to evidence-based medical criteria.

Successful treatment with a low-dose cisplatin--etoposide regimen for patients with diencephalic syndrome.

Diencephalic syndrome (DS) is a rare but rapidly fatal condition, usually occurring during the first year of life, as a result of a hypothalamic/chiasmatic tumor. The purpose of this study was to induce an objective tumor response and to achieve rapid weight recovery by using ten three-day courses of reduced-dose cisplatin-etoposide. Between 2004 and 2009, eight pediatric patients with DS as a result of an hypothalamic tumor and with a median age at diagnosis of 6.5 months (range 4-60 months) received 10 monthly courses of cisplatin (25 mg/m(2)/day on days 1-3) and etoposide (100 mg/m(2)/day on days 1-3). Under chemotherapy, rapid weight recovery was observed for all patients; tumor response was observed for six (75 %; partial response in four and minimum response in two). The other two had stable disease at completion of treatment. Mean time to weight recovery was 6 months (range 5-7 months) for pilomyxoid astrocytoma patients, and 3.3 months (range 3-4 months) for those with pilocytic astrocytoma. For DS patients who received nutritional support (enteral or parenteral nutrition) the mean time for weight recovery was 5 months (range 3-7 months) whereas children who were able to orally ingest a high-energy diet had a mean time for weight recovery of 8.66 months (range 3-19 months). After follow-up ranging from 22 to 89 months (median 38 months) all patients are alive. A low-dose cisplatin-etoposide regimen is highly effective regarding tumor response and treatment of DS symptoms/cachexia without causing significant side-effects.

Metabolomic profile of term infants of gestational diabetic mothers.

OBJECTIVE: Maternal diabetes increases the risk of perinatal mortality and morbidity, but the maintenance of antenatal normal glucose serum prevents the majority of neonatal complications. The aim of our study is to compare the metabolomic profile of infants of gestational diabetic mothers (IGDMs) to that of infants of healthy mothers to evaluate if differences remain despite a strict control of gestational diabetes. METHODS: We performed the metabolomics study in cord serum sampled from 30 term IGDMs and 40 controls recording the occurrence of the most frequent complications in IGDMs. RESULTS: We demonstrated that IGDMs have lower level of glucose and higher level of pyruvate, histidine, alanine, valine, methionine, arginine, lysine, hypoxanthine, lipoprotein and lipid than controls, but we did not find any clinical differences. CONCLUSIONS: Our results suggest that prolonged fetal exposure to hyperglycemia during pregnancy can change neonatal metabolomic profile at birth without affecting the clinical course.

Continuous subcutaneous infusion of protein C concentrate using an insulin pump in a newborn with congenital protein C deficiency.

We describe the case of a newborn presenting with multicystic encephalomalacy, hydrocephalus and bilateral hemovitreous. An underlying coagulation disorder was suspected and laboratory tests revealed severe protein C deficiency. At 25 days of life, after the appearance of purpura fulminans, replacement therapy with intravenous protein C concentrate (Ceprotin; Baxter, Vienna, Austria) was started.Due to difficulties in getting peripheral venous access and to repeated loss of the venous access, continuous subcutaneous infusion of protein C was started with an insulin pump (VEO 754; Medtronic, Minneapolis, Minnesota, USA), normally adopted in patients with type 1 diabetes mellitus. Protein C values increased into the normal range and the resolution of the purpuric skin lesion was achieved. Chronic prophylaxis with low-molecular-weight heparin failed and, due to cutaneous and cerebral recrudescence, replacement therapy with the pump was started again. The insulin pump allowed us to reduce the number of injections per day and to deal with the difficulties in getting peripheral venous access, permitting medical and paramedical staff an easier management of the therapy. The dosing schedule could be easily adapted with the insulin pump and the continuous subcutaneous administration of small amounts of protein C concentrate prevented fluctuation in trough levels of protein C. This is the first reported case of a novel, successful use of an insulin pump in an extremely rare disease, to administer a drug different from insulin, which needs to be further analyzed, underlining the importance of a multidisciplinary team approach in order to provide effective and efficient care in high-complexity diseases.

Short term outcome of term newborns with unexpected umbilical cord arterial pH between 7.000 and 7.100.

BACKGROUND: The relationship between cord arterial pH (CA-pH) > 7.000 and the neonatal outcome is not clear. AIMS: To evaluate if asymptomatic infants born with unexpected cord arterial pH (CA-pH) between 7.000 and 7.100 develop clinical, biochemical, and instrumental signs of hypoxic cerebral, renal, and heart failure more frequently than symptomatic infants. STUDY DESIGN: Term infants with CA-pH of 7.000-7.100 and appropriate birth weight were prospectively and consecutively enrolled and classified as asymptomatic, when they had no resuscitation, early respiratory distress or early abnormal neurologic signs, and symptomatic infants. Clinical, biochemical, and instrumental signs of hypoxic cerebral, renal, and heart failure were evaluated in the two groups. RESULTS: A total of 53 infants were enrolled. Twenty-eight (53%) were asymptomatic. CA-pH was similar in both the groups, while the cTnI serum concentration in the first day of life and the occurrence of poor feeding were higher in the symptomatic than in asymptomatic infants. An arterial lactate level of ≥ 4.1 mmol/l measured in the first hour of life was an independent risk factor for the development of a symptomatic course. CONCLUSIONS: In our population the majority of infants born with a CA-pH between 7.000 and 7.100 were asymptomatic and would not have needed immediate admission to the neonatal care unit. Symptomatic infants showed a higher occurrence of subclinical heart injury and poor feeding.

Expression of ß-adrenergic receptors in pediatric malignant brain tumors.

ß-adrenergic receptors (ß-ARs) are G protein-coupled receptors that activate signal transduction pathways involved in angiogenesis, resulting in enhanced tumor vascularization and more aggressive growth. In this study, we evaluated the expression of ß-ARs in a population of 12 children affected by malignant primary brain tumors. We found a significant expression of ß1- and ß2-ARs in all 12 samples as well as the 3 cell lines tested (U87MG, T98G and DAOY). The mean absolute ß1-AR mRNA level standardized to GAPDH was 5.81 (range, -7.91 to 11.29) for brain tumors and 8.59 (range, 6.046 to 12.59) for cell lines (U87MG, DAOY and T98G), respectively. The mean absolute ß2-AR mRNA level was 4.74 (range, -9.30 to 8.45) for tumor specimens and 7.64 (range, 5.85 to 8.88) for cell lines. These real-time quantitative (qRT)-PCR expression data were confirmed by immunohistochemical analysis. Our study evaluated the presence of ß1- and ß2-ARs in malignant pediatric brain tumors and brain tumor cell lines.

Prevention of flare recurrences in childhood-refractory chronic uveitis: an open-label comparative study of adalimumab versus infliximab.

OBJECTIVE: To compare the efficacy and safety of adalimumab versus infliximab in an open-label prospective, comparative, multicenter cohort study of childhood noninfectious chronic uveitis. METHODS: Thirty-three patients (22 females, 11 males, median age 9.17 years) with refractory, vision-threatening, noninfectious active uveitis were enrolled, and received for at least 1 year infliximab (5 mg/kg at weeks 0, 2, and 6, and then every 6-8 weeks) or adalimumab (24 mg/m2 every 2 weeks). The primary outcome was to assess, once remission was achieved, the time of a first relapse. Time to remission, time to steroid discontinuation, and the number of relapses were also considered. RESULTS: Sixteen children (12 with juvenile idiopathic arthritis [JIA], 3 with idiopathic uveitis, and 1 with Behçet's disease) were recruited in the adalimumab cohort and 17 children (10 with JIA, 5 with idiopathic uveitis, 1 with early-onset sarcoidosis, and 1 with Behçet's disease) were recruited in the infliximab group. Cox regression analysis did not show statistically significant differences between the two groups with regard to time to achieve remission and time to steroid discontinuation, whereas a higher probability of uveitis remission on adalimumab during the time of treatment was shown (Mantel-Cox χ2=6.83, P<0.001). At 40 months of followup, 9 (60%) of 15 children receiving adalimumab compared to 3 (18.8%) of 16 children receiving infliximab were still in remission on therapy (P<0.02). CONCLUSION: Even if limited to a relatively small group, our study suggests that over 3 years of treatment, adalimumab is more efficacious than infliximab in maintaining remission of chronic childhood uveitis.

Current therapeutic approaches to autoimmune chronic uveitis in children.

Uveitis is an inflammatory disorder involving inflammation of the uveal tract. It is classified as anterior, intermediate, posterior or panuveitis, depending on the part of eye affected by the inflammatory process. In children, non-infectious, chronic uveitis is a relatively uncommon but serious disease, with the potential for significant long-term complications and possible blindness. Although frequently associated with an underlying systemic disease, e.g. juvenile idiopathic arthritis (JIA), a significant number of cases in children show no associated signs or symptoms, and are labelled as idiopathic. Taking into account this evidence, an anti-inflammatory therapy based on an immuno-modulatory approach seems a reasonable strategy for non-infectious chronic uveitis, in children as well as in adults. Due to a lack of controlled studies regarding uveitis in children, immunosuppressive drugs are supported only at evidence level III. The aim of this review is to report currently available medical strategies for treatment of childhood sight-threatening chronic uveitis; in addition, a step-by-step approach to the use of immunosuppressants in this context is suggested.