Randomized placebo-controlled crossover trial of memantine in children with epileptic encephalopathy.

Memantine is an N-methyl-D-aspartate receptor antagonist, approved for dementia treatment. There is limited evidence of memantine showing benefit for paediatric neurodevelopmental phenotypes, but no randomized placebo-controlled trials in children with developmental and epileptic encephalopathy. In this randomized double-blind placebo-controlled crossover trial (Trial registration: https://clinicaltrials.gov/ct2/show/NCT03779672), patients with developmental and epileptic encephalopathy received memantine and placebo, each for a 6-week period separated by a 2-week washout phase. Electroencephalography, seizure diary, patient caregivers' global impression, serum inflammatory markers and neuropsychological evaluation were performed at baseline and after each treatment phase. The primary outcome measure was classification as a 'responder', defined as ≥2 of: >50% seizure frequency reduction, electroencephalography improvement, caregiver clinical impression improvement or clear neuropsychological testing improvement. Thirty-one patients (13 females) enrolled. Two patients withdrew prior to initiating medication and two (twins) had to be removed from analysis. Of the remaining 27 patients, nine (33%) were classified as responders to memantine versus two (7%) in the placebo group (P < 0.02). Electroencephalography improvement was seen in eight patients on memantine compared to two on placebo (P < 0.04). Seizure improvement was observed in eight patients on memantine and two on placebo (P < 0.04). Caregivers reported overall clinical improvement in 10 patients on memantine compared to seven on placebo (not significant). Statistical analysis of neuropsychological evaluation suggested improvements in symptoms of attention-deficit hyperactivity disorder and autism. Memantine is a safe and effective treatment for children with developmental and epileptic encephalopathy, having the potential to improve both seizure control and cognitive function.

Nodal is required to maintain the uterine environment in an anti-inflammatory state during pregnancy†.

Preterm birth remains the major cause of perinatal mortality and morbidity worldwide, affecting up to 12% of pregnancies and accounting for ~75% of neonatal deaths. However, the mechanisms and causes that underlie it are still largely unknown. One of the major causes of preterm birth is infection or inflammation within the maternal-fetal interface. Our lab has previously shown that a uterine specific deletion of Nodal results in mutant females delivering 2 days prior to term demonstrating an important role for this factor in the maintenance of pregnancy. Here, we have addressed the function of Nodal in the uterus during pregnancy. We demonstrate that Nodal heterozygous mice have an increase in basal levels of pro-inflammatory cytokines IL-1ß, IL-6, IL-12p, TNF-α, and IFN-γ as well as an increase in the number of macrophages in response to the inflammatory agent, lipopolysaccharide (LPS). Using bone marrow-derived macrophages, we demonstrated that pretreatment with recombinant Nodal reduces pro-inflammatory gene expression when these cells are challenged with LPS. Our results demonstrate that Nodal is required to maintain the uterine environment in an anti-inflammatory state by preventing proinflammatory cytokine expression.

Protective Effects of Interleukin-1 Blockade on Group B Streptococcus-Induced Chorioamnionitis and Subsequent Neurobehavioral Impairments of the Offspring.

Group B Streptococcus (GBS) is one of the most common bacteria isolated in human chorioamnionitis. Placental infection due to GBS is a major risk factor for fetal organ injuries, preterm birth, perinatal morbidity and mortality, and life-long multiorgan morbidities. Preclinical and clinical studies have shown that GBS-induced infection drives polymorphonuclear (PMN) cell infiltration within the placenta, the hallmark of human chorioamnionitis. In preclinical and clinical studies, the upregulation of interleukin(IL)-1ß in the placenta and maternal/fetal blood was associated with a high risk of neurodevelopmental impairments in the progeny. We hypothesized that targeted IL-1 blockade administered to the dam alleviates GBS-induced chorioamnionitis and the downstream fetal inflammatory response syndrome (FIRS). IL-1 receptor antagonist (IL-1Ra) improved the gestational weight gain of GBS-infected dams and did not worsen the infectious manifestations. IL-1Ra reduced the IL-1ß titer in the maternal sera of GBS-infected dams. IL-1Ra decreased the levels of IL-1ß, IL-6, chemokine (C-X-C motif) ligand 1 (CXCL1), and polymorphonuclear (PMN) infiltration in GBS-infected placenta. IL-1Ra treatment reduced the IL-1ß titer in the fetal sera of GBS-exposed fetuses. IL-1 blockade also alleviated GBS-induced FIRS and subsequent neurobehavioral impairments of the offspring without worsening the outcome of GBS infection. Altogether, these results showed that IL-1 plays a key role in the physiopathology of live GBS-induced chorioamnionitis and consequent neurobehavioral impairments.

C-section of Preclinical Animal Model of Chorioamnionitis Triggered by Group B Streptococcus (GBS).

Group B Streptococcus (GBS) is one of the most common bacteria isolated during human pregnancy. It is a leading cause of placental infection/inflammation, termed chorioamnionitis. Chorioamnionitis exposes the developing fetus to a high risk of organ injuries, perinatal morbidity, and mortality, as well as life-long neurobehavioral impairments and other non-neurological developmental issues. The two most frequent subtypes of GBS isolates from maternal and fetal tissues are serotypes Ia (13%-23%) and III (25%-53%). Our lab has developed and characterized a rat model of GBS-induced chorioamnionitis to study subsequent impacts on the central nervous system of the developing fetus and to understand underlying mechanistic aspects. This article presents the design as well as uses of the preclinical rat model, which closely reproduces the hallmark of GBS-induced chorioamnionitis in humans. This article aims to help scientists reproduce the experimental design as well as to provide support through examples of troubleshooting. The present model may also contribute to potential discoveries through uncovering causes, mechanisms, and novel therapeutic avenues, which remain unsettled in many developmental impairments arising from chorioamnionitis. Furthermore, the use of this model may be extended to the studies of perinatal non-neurological common and severe morbidities affecting, for instance, the retina, bowel, lung, and kidney. The main interest of this research is in the field of GBS-induced fetal neurodevelopmental impairments such as cerebral palsy (CP), attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). The rationale supporting this model is presented in this article, followed by procedures and results.

Evidence of a gene-environment interaction of NODAL variants and inflammation in preterm birth.

OBJECTIVE: NODAL has been implicated in timing of parturition and immune regulation. We investigated the relationship between NODAL polymorphisms, infection/inflammation, and preterm birth. STUDY DESIGN: For this secondary analysis, 613 women (189 preterm and 424 term) from the Montreal Prematurity Study were genotyped for NODAL polymorphisms and assessed for bacterial vaginosis and placental inflammation. RESULT: NODAL polymorphisms were not associated with preterm birth. However, the rs2231947(C>T) variant allele was associated with increased risk for preterm birth among women with bacterial vaginosis (odds ratio: 2.76, 95% confidence interval: 1.12-6.85). Among women without placental inflammation, the rs1904589(A>G) variant allele was associated with increased risk of preterm birth (odds ratio: 1.31, 95% confidence interval: 1.02-1.70). Among women with placental inflammation, the rs10999338(C>T) variant allele was associated with reduced risk of preterm birth (odds ratio: 0.50, 95% confidence interval: 0.29-0.87). CONCLUSION: The effect of NODAL polymorphisms on preterm birth depends on maternal infection/inflammation status.