Regulatory T cells ameliorate intrauterine growth retardation in a transgenic rat model for preeclampsia

Preeclampsia is a multisystemic syndrome during pregnancy that is often associated with intrauterine growth retardation. Immunologic dysregulation, involving T cells, is implicated in the pathogenesis. The aim of this study was to evaluate the effect of upregulating regulatory T cells in an established transgenic rat model for preeclampsia. Application of superagonistic monoclonal antibody for CD28 has been shown to effectively upregulate regulatory T cells. In the first protocol (treatment protocol), we applied 1 mg of CD28 superagonist or control antibody on days 11 and 15 of pregnancy. In the second protocol (prevention protocol), the superagonist or control antibody was applied on days 1, 5, and 9. Superagonist increased regulatory T cells in circulation and placenta from 8.49+/-2.09% of CD4-positive T cells to 23.50+/-3.05% and from 3.85+/-1.45% to 23.27+/-7.64%, respectively. Blood pressure and albuminuria (30.6+/-15.1 versus 14.6+/-5.5 mg/d) were similar in the superagonist or control antibody-treated preeclamptic group for both protocols. Rats treated with CD28 superagonist showed increased pup weights in the prevention protocol (2.66+/-0.03 versus 2.37+/-0.05 g) and in the treatment protocol (3.04+/-0.04 versus 2.54+/-0.1 g). Intrauterine growth retardation, calculated by brain:liver weight ratio, was also decreased by the superagonist in both protocols. Further analysis of brain development revealed a 20% increase in brain volume by the superagonist. Induction of regulatory T cells in the circulation and the uteroplacental unit in an established preeclamptic rat model had no influence on maternal hypertension and proteinuria. However, it substantially improved fetal outcome by ameliorating intrauterine growth retardation

Elevated nerve growth factor and neurotrophin-3 levels in cerebrospinal fluid of children with hydrocephalus

BACKGROUND: Elevated intracranial pressure (ICP) resulting from impaired drainage of cerebrospinal fluid (CSF) causes hydrocephalus with damage to the central nervous system. Clinical symptoms of elevated intracranial pressure (ICP) in infants may be difficult to diagnose, leading to delayed treatment by shunt placement. Until now, no biochemical marker of elevated ICP has been available for clinical diagnosis and monitoring. In experimental animal models, nerve growth factor (NGF) and neurotrophin-3 (NT-3) have been shown to be produced by glial cells as an adaptive response to hypoxia. We investigated whether concentrations of NGF and NT-3 are increased in the CSF of children with hydrocephalus. METHODS: NGF was determined in CSF samples collected from 42 hydrocephalic children on 65 occasions (taps or shunt placement surgery). CSF samples obtained by lumbar puncture from 22 children with suspected, but unconfirmed bacterial infection served as controls. Analysis was performed using ELISA techniques. RESULTS: NGF concentrations in hydrocephalic children were over 50-fold increased compared to controls (median 225 vs 4 pg/mL, p < 0.0001). NT-3 was detectable (> 1 pg/mL) in 14/31 hydrocephalus samples at 2–51 pg/mL but in none of 11 control samples (p = 0.007). CONCLUSION: NGF and NT-3 concentrations are increased in children with hydrocephalus. This may represent an adaptive response of the brain to elevated ICP

Early inhaled budesonide for the prevention of bronchopulmonary dysplasia

BACKGROUND Systemic glucocorticoids reduce the incidence of bronchopulmonary dysplasia among extremely preterm infants, but they may compromise brain development. The effects of inhaled glucocorticoids on outcomes in these infants are unclear. METHODS We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to early (within 24 hours after birth) inhaled budesonide or placebo until they no longer required oxygen and positive-pressure support or until they reached a postmenstrual age of 32 weeks 0 days. The primary outcome was death or bronchopulmonary dysplasia, confirmed by means of standardized oxygen-saturation monitoring, at a postmenstrual age of 36 weeks. RESULTS A total of 175 of 437 infants assigned to budesonide for whom adequate data were available (40.0%), as compared with 194 of 419 infants assigned to placebo for whom adequate data were available (46.3%), died or had bronchopulmonary dysplasia (relative risk, stratified according to gestational age, 0.86; 95% confidence interval [CI], 0.75 to 1.00; P = 0.05). The incidence of bronchopulmonary dysplasia was 27.8% in the budesonide group versus 38.0% in the placebo group (relative risk, stratified according to gestational age, 0.74; 95% CI, 0.60 to 0.91; P = 0.004); death occurred in 16.9% and 13.6% of the patients, respectively (relative risk, stratified according to gestational age, 1.24; 95% CI, 0.91 to 1.69; P = 0.17). The proportion of infants who required surgical closure of a patent ductus arteriosus was lower in the budesonide group than in the placebo group (relative risk, stratified according to gestational age, 0.55; 95% CI, 0.36 to 0.83; P = 0.004), as was the proportion of infants who required reintubation (relative risk, stratified according to gestational age, 0.58; 95% CI, 0.35 to 0.96; P = 0.03). Rates of other neonatal illnesses and adverse events were similar in the two groups. CONCLUSIONS Among extremely preterm infants, the incidence of bronchopulmonary dysplasia was lower among those who received early inhaled budesonide than among those who received placebo, but the advantage may have been gained at the expense of increased mortality

Incidence and risk factors of cerebral sinovenous thrombosis in infants.

Developmental Medicine &amp; Child Neurology published by John Wiley &amp; Sons Ltd on behalf of Mac Keith Press. Aim: To describe the incidence of term and preterm neonatal cerebral sinovenous thrombosis (CSVT) and identify perinatal risk factors. Method: This was a national capture-recapture calculation-corrected surveillance and nested case–control study. Infants born preterm and at term with magnetic resonance imaging-confirmed neonatal CSVT were identified by surveillance in all paediatric hospitals in Germany (2015–2017). Incidence was corrected for underreporting using a capture-recapture method in one federal state and then extrapolated nationwide. We reviewed PubMed for comparisons with previously reported incidence estimators. We used a population-based perinatal database for quality assurance to select four controls per case and applied univariate and multivariable regression for risk factor analysis. Results: Fifty-one newborn infants (34 males, 17 females; 14 born preterm) with neonatal CSVT were reported in the 3-year period. The incidence of term and preterm neonatal CSVT was 6.6 (95% confidence interval [CI] 4.4–8.7) per 100&nbsp;000 live births. Median age at time of confirmation of the diagnosis was 9.95 days (range 0–39d). In the univariate analysis, male sex, preterm birth, hypoxia and related indicators (umbilical artery pH &lt;7.1; 5-minute Apgar score &lt;7; intubation/mask ventilation; perinatal asphyxia), operative vaginal delivery, emergency Caesarean section, and pathological fetal Doppler sonography were associated (p&lt;0.05) with neonatal CSVT. Multivariable regression yielded hypoxia (odds ratio=20.3; 95% CI 8.1–50.8) as the independent risk factor. Interpretation: Incidence of neonatal CSVT was within the range of other population-based studies. The results suggest that hypoxia is an important perinatal risk factor for the aetiology of neonatal CSVT

Risk factors for perinatal arterial ischaemic stroke: A large case–control study.

Aim: To identify maternal, obstetric, and neonatal risk factors related to perinatal arterial ischaemic stroke (PAIS) diagnosed within 28&nbsp;days after birth and to understand the underlying pathophysiology. Method: For case and control ascertainment, we used active surveillance in 345 paediatric hospitals and a population-based perinatal database for quality assurance of hospital care. We analysed complete cases of PAIS using logistic regression. Multivariate analysis was guided by a directed acyclic graph. Results: After exclusion of records with missing data, we analysed 134 individuals with PAIS and 576 comparison individuals. In univariate analysis, male sex, preterm birth (&lt;37wk gestational age), small for gestational age (SGA), low umbilical artery pH (&lt;7.1), low 5-minute-Apgar score (&lt;7), multiple pregnancies, hypoxia, intubation/mask ventilation, nulliparity, Caesarean section, vaginal-operative delivery, chorioamnionitis, and oligohydramnios were associated with an increased risk. Mutual adjustment yielded male sex (odds ratio [OR] 1.81; 95% confidence interval [CI] 1.20–2.73), multiple birth (OR 3.22; 95% CI 1.21–8.58), chorioamnionitis (OR 9.89; 95% CI 2.88–33.94), preterm birth (OR 1.86; 95% CI 1.01–3.43), and SGA (OR 3.05; 95% CI 1.76–5.28) as independent risk factors. Interpretation: We confirmed the increased risk in males and the role of chorioamnionitis and SGA for PAIS, pointing to the importance of inflammatory processes and fetal–placental insufficiency. Multiple birth and preterm birth were additional risk factors. What this paper adds: Chorioamnionitis and small for gestational age (SGA) precede perinatal arterial ischaemic stroke (PAIS). Chorioamnionitis and SGA are independent risk factors for PAIS. Inflammatory processes and fetal–placental insufficiency are the likely underlying mechanisms. Multiple birth and preterm birth are additional risk factors

Supplementary Material for: Sildenafil Enhances Quantity of Immature Neurons and Promotes Functional Recovery in the Developing Ischemic Mouse Brain

<p><b><i>Background:</i></b> Hypoxic-ischemic (HI) injury to the developing brain occurs in 1 out of 1,000 live births and remains a major cause of significant morbidity and mortality. A large number of survivors suffer from long-term sequelae including seizures and neurological deficits. However, the pathophysiological mechanisms of recovery after HI insult are not clearly understood, and preventive measures or clinical treatments are nonexistent or not sufficiently effective in the clinical setting. Sildenafil as a specific phosphodiesterase 5 inhibitor leads to increased levels of the second messenger cyclic guanosine monophosphate (cGMP) and promotes functional recovery and neurogenesis after ischemic injury to the adult brain. <b><i>Objective:</i></b> Here, we investigated the effect of sildenafil treatment on activation of intracellular signaling pathways, histological and neurogenic response including functional recovery after an ischemic insult to the developing brain. <b><i>Design/Methods:</i></b> Nine-day-old C57BL/6 mice were subjected either to sham operation or underwent ligation of the right common carotid artery followed by hypoxia (8%) for 60 min. Animals were either administered sildenafil (10 mg/kg, i.p.) or vehicle 2 h after hypoxia. A subgroup of animals received multiple injections of 10 mg/kg daily on 5 consecutive days. Pups were either perfusion fixed at postnatal days 14 or 47 for immunohistochemical analysis, or brains were dissected 2, 6, 12, and 24 h after the end of hypoxia and analyzed for cGMP, pAkt, pGSK-3β, and β-catenin by means of ELISA or immunoblotting. In addition, behavioral studies using the wire hang test and elevated plus maze were conducted 21 and 38 days after HI injury. <b><i>Results:</i></b> Based on cresyl violet staining, single or multiple sildenafil injections did not reveal any differences in injury scoring compared to sham animals. However, cerebral levels of cGMP were altered after sildenafil therapy. Treatment significantly increased numbers of immature neurons, as indicated by doublecortin immunoreactivity in the ipsilateral subventricular zone and striatum. In addition, animals treated with sildenafil after HI insult demonstrated improved functional recovery. pAkt, pGSK-3β, and β-catenin levels vary after HI injury but additional sildenafil treatment had no impact on protein expression compared to the level of sham controls. <b><i>Conclusions:</i></b> Here, we report that treatment with sildenafil after HI insult did not improve histological brain injury scores. Nevertheless, our results suggest involvement of the cGMP and PI3K/Akt/GSK-3β signaling pathway with promotion of a neurogenic response and reduction of neurological deficits. In summary, sildenafil may have a role in promoting recovery from HI injury in the developing brain.</p

Diagnosis and treatment of Guillain-Barré Syndrome in childhood and adolescence: An evidence- and consensus-based guideline

This evidence- and consensus-based practical guideline for the diagnosis and treatment of Guillain-Barré Syndrome (GBS) in childhood and adolescence has been developed by a group of delegates from relevant specialist societies and organisations; it is the result of an initiative by the German-Speaking Society of Neuropediatrics (GNP), and is supported by the Association of Scientific Medical Societies (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften). A systematic analysis of the literature revealed that only a few adequately-controlled studies exist for this particular age group, while none carries a low risk of bias. For this reason, the diagnostic and therapeutic recommendations largely rely on findings in adult patients with GBS, for which there are a higher number of suitable studies available. Consensus was established using a written, multi-step Delphi process. A high level of consensus could be reached for the crucial steps in diagnosis and treatment. We recommend basing the diagnostic approach on the clinical criteria of GBS and deriving support from CSF and electrophysiological findings. Repetition of invasive procedures that yield ambiguous results is only recommended if the diagnosis cannot be ascertained from the other criteria. For severe or persistently-progressive GBS treatment with intravenous immunoglobulin (IVIG) is recommended, whereas in cases of IVIG intolerance or inefficacy we recommended treatment with plasmapheresis. Corticosteroids are ineffective for GBS but can be considered when acute onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) is suspected due to a prolonged disease course. The full German version of the Guideline is available on the AWMF website (https://www.awmf.org/leitlinien/detail/ll/022-008.html)