Inhibition of Electrical Activity by Retroviral Infection with Kir2.1 Transgenes Disrupts Electrical Differentiation of Motoneurons

Network-driven spontaneous electrical activity in the chicken spinal cord regulates a variety of developmental processes including neuronal differentiation and formation of neuromuscular structures. In this study we have examined the effect of chronic inhibition of spinal cord activity on motoneuron survival and differentiation. Early spinal cord activity in chick embryos was blocked using an avian replication-competent retroviral vector RCASBP (B) carrying the inward rectifier potassium channel Kir2.1. Chicken embryos were infected with one of the following constructs: RCASBP(B), RCASBP(B)-Kir2.1, or RCASBP(B)-GFP. Infection of chicken embryos at E2 resulted in widespread expression of the viral protein marker p27 gag throughout the spinal cord. Electrophysiological recordings revealed the presence of functional Kir2.1 channels in RCASBP(B)-Kir2.1 but not in RCASBP(B)-infected embryos. Kir2.1 expression significantly reduced the generation of spontaneous motor movements in chicken embryos developing in ovo. Suppression of spontaneous electrical activity was not due to a reduction in the number of surviving motoneurons or the number of synapses in hindlimb muscle tissue. Disruption of the normal pattern of activity in chicken embryos resulted in a significant downregulation in the functional expression of large-conductance Ca2+-dependent K+ channels. Reduction of spinal cord activity also generates a significant acceleration in the inactivation rate of A-type K+ currents without any significant change in current density. Kir2.1 expression did not affect the expression of voltage-gated Na+ channels or cell capacitance. These experiments demonstrate that chronic inhibition of chicken spinal cord activity causes a significant change in the electrical properties of developing motoneurons

Early blood glucose profile and neurodevelopmental outcome at two years in neonatal hypoxic-ischaemic encephalopathy

Background: To examine the blood glucose profile and the relationship between blood glucose levels and neurodevelopmental outcome in term infants with hypoxic-ischaemic encephalopathy. Methods: Blood glucose values within 72 hours of birth were collected from 52 term infants with hypoxic-ischaemic encephalopathy. Hypoglycaemia [ 150 mg/dL (8.3 mmol/L)] were correlated to neurodevelopmental outcome at 24 months of age. Results: Four fifths of the 468 blood samples were in the normoglycaemic range (392/468:83.8%). Of the remaining 76 samples, 51.3% were in the hypoglycaemic range and (48.7%) were hyperglycaemic. A quarter of the hypoglycaemic samples (28.2%:11/39) and a third of the hyperglycaemic samples (32.4%:12/37) were recorded within the first 30 minutes of life. Mean (SD) blood glucose values did not differ between infants with normal and abnormal outcomes [4.89(2.28) mmol/L and 5.02(2.35) mmol/L, p value = 0.15] respectively. In term infants with hypoxic-ischaemic encephalopathy, early hypoglycaemia (between 0-6 hours of life) was associated with adverse outcome at 24 months of age [OR = 5.8, CI = 1.04-32)]. On multivariate analysis to adjust for grade of HIE this association was not statistically significant. Late hypoglycaemia (6-72 hours of life) was not associated with abnormal outcome [OR = 0.22, CI (0.04-1.14)]. The occurrence of hyperglycaemia was not associated with adverse outcome. Conclusion: During the first 72 hours of life, blood glucose profile in infants with hypoxic-ischaemic encephalopathy varies widely despite a management protocol. Early hypoglycaemia (0-6 hours of life) was associated with severe HIE, and thereby; adverse outcome

Current concepts of polymicrogyria

Polymicrogyria is one of the most common malformations of cortical development. It has been known for many years and its clinical and MRI manifestations are well described. Recent advances in imaging, however, have revealed that polymicrogyria has many different appearances on MR imaging, suggesting that is may be a more heterogeneous malformation than previously suspected. The clinical and imaging heterogeneity of polymicrogyria is explored in this review

p21 as a Transcriptional Co-Repressor of S-Phase and Mitotic Control Genes

It has been previously described that p21 functions not only as a CDK inhibitor but also as a transcriptional co-repressor in some systems. To investigate the roles of p21 in transcriptional control, we studied the gene expression changes in two human cell systems. Using a human leukemia cell line (K562) with inducible p21 expression and human primary keratinocytes with adenoviral-mediated p21 expression, we carried out microarray-based gene expression profiling. We found that p21 rapidly and strongly repressed the mRNA levels of a number of genes involved in cell cycle and mitosis. One of the most strongly down-regulated genes was CCNE2 (cyclin E2 gene). Mutational analysis in K562 cells showed that the N-terminal region of p21 is required for repression of gene expression of CCNE2 and other genes. Chromatin immunoprecipitation assays indicated that p21 was bound to human CCNE2 and other p21-repressed genes gene in the vicinity of the transcription start site. Moreover, p21 repressed human CCNE2 promoter-luciferase constructs in K562 cells. Bioinformatic analysis revealed that the CDE motif is present in most of the promoters of the p21-regulated genes. Altogether, the results suggest that p21 exerts a repressive effect on a relevant number of genes controlling S phase and mitosis. Thus, p21 activity as inhibitor of cell cycle progression would be mediated not only by the inhibition of CDKs but also by the transcriptional down-regulation of key genes

Clinical characteristics and complications of rotavirus gastroenteritis in children in east London: A retrospective case-control study.

BACKGROUND: Rotavirus is the leading cause of acute gastroenteritis in children and is associated with neurological complications such as seizures and encephalopathy. The aim of this study was to investigate the presentation and complications of rotavirus compared to non-rotavirus gastroenteritis in UK children. METHODS: This was a retrospective, case-control, hospital-based study conducted at three sites in east London, UK. Cases were children aged 1 month to 16 years diagnosed with acute gastroenteritis between 1 June 2011 and 31 December 2013, in whom stool virology investigations confirmed presence of rotavirus by PCR. They were matched by age, gender and month of presentation to controls with rotavirus-negative gastroenteritis. RESULTS: Data were collected from 116 children (50 cases and 66 controls). Children with rotavirus gastroenteritis tended to present more frequently with metabolic acidosis (pH 7.30 vs 7.37, P = 0.011) and fever (74% versus 46%; P = 0.005) and were more likely to require hospitalisation compared to children with non-rotavirus gastroenteritis (93% versus 73%; P = 0.019). Neurological complications were the most common extra-intestinal manifestations, but did not differ significantly between children with rotavirus-positive gastroenteritis (RPG) and rotavirus-negative gastroenteritis (RNG) (24% versus 15%, respectively; P = 0.24). Encephalopathy occurred only in children with rotavirus infection (n = 3, 6%). CONCLUSION: Rotavirus causes longer and more severe disease compared to other viral pathogens. Seizures and milder neurological signs were surprisingly common and associated with multiple pathogens, but encephalopathy occurred only in children with rotavirus gastroenteritis. Rotavirus vaccination may reduce seizures and presentation to hospital, but vaccines against other pathogens causing gastroenteritis are required.AJP receives funding from the Wellcome Trust (grant 108065/Z/15/Z)

Lack of Prominent Cognitive Regression in the Long-term Outcome of Patients Having Electrical Status Epilepticus During Sleep With Different Types of Epilepsy Syndromes

The purpose was to document 4 patients with different epilepsy syndromes, showing electrical status epilepticus during sleep (ESES), without marked cognitive and behavioral regression in the long-term follow-up. The mean age at onset of seizures was 8 years. Absences, myoclonic, focal motor, or generalized tonic - clonic seizures and drop attacks were the prominent seizure types. The neurological examination and neuroimaging findings revealed no abnormality. Focal epileptiform electroencephalographic (EEG) activity was seen in 3 cases, whereas generalized photosensitive epileptic discharges were detected in 1 patient with juvenile myoclonic epilepsy. Neuropsychological evaluations of all cases were within the normal range, and deterioration in mental status was not observed during their mean follow-up duration of 14 years. Our data support the view that ESES can emerge along with different types of childhood epilepsy syndromes, including idiopathic generalized epilepsies, and may not always be a poor prognostic factor