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Influenza A virus (IAV) infection causes acute and often lethal inflammation in the lung. The role of macrophages in this adverse inflammation is partially understood. The surfactant protein A receptor 210 (SP-R210) consists of two isoforms, a long (L) SP-R210 L and a short (S) SP-R210 S isoform encoded by alternative splicing of the myosin 18A gene. We reported that disruption of SP-R210 L enhances cytosolic and endosomal antiviral response pathways. Here, we report that SP-R210 L antagonizes type I interferon β (IFNβ), as depletion of SP-R210 L potentiates IFNβ secretion. SP-R210 antibodies enhance and attenuate IFNβ secretion in SP-R210 L replete and deficient macrophages, respectively, indicating that SP-R210 isoform stoichiometry alters macrophage function intrinsically. This reciprocal response is coupled to unopposed and restricted expression of viral genes in control and SP-R210 L -deficient macrophages, respectively. Human monocytic cells with sub-stoichiometric expression of SP-R210 L resist IAV infection, whereas alveolar macrophages with increased abundance of SP-R210 L permit viral gene expression similar to murine macrophages. Uptake and membrane binding studies show that lack of SP-R210 isoforms does not impair IAV binding and internalization. Lack of SP-R210 L , however, results in macropinocytic retention of the virus that depends on both SP-R210 S and interferon-inducible transmembrane protein-3 (IFITM3). Mass spectrometry and Western blot analyses indicate that SP-R210 isoforms modulate differential recruitment of the Rho-family GTPase RAC1 and guanine nucleotide exchange factors. Our study suggests that SP-R210 isoforms modulate RAC-dependent macropinosomal sorting of IAV to discrete endosomal and lysosomal compartments that either permit or prevent endolysosomal escape and inflammatory sensing of viral genomes in macrophages. [ABSTRACT FROM AUTHOR]

Macrophages play an important role in maintaining tissue homeostasis, from regulating the inflammatory response to pathogens to resolving inflammation and aiding tissue repair. The surfactant protein A (SP-A) receptor SP-R210 (MYO18A) has been shown to affect basal and inflammatory macrophage states. Specifically, disruption of the longer splice isoform SP-R210 L /MYO18Aα renders macrophages hyper-inflammatory, although the mechanism by which this occurs is not well understood. We asked whether disruption of the L isoform led to the hyper-inflammatory state via alteration of global genomic responses. RNA sequencing analysis of L isoform-deficient macrophages (SP-R210 L (DN)) revealed basal and influenza-induced upregulation of genes associated with inflammatory pathways, such as TLR, RIG-I, NOD, and cytoplasmic DNA signaling, whereas knockout of both SP-R210 isoforms (L and S) only resulted in increased RIG-I and NOD signaling. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis showed increased genome-wide deposition of the pioneer transcription factor PU.1 in SP-R210 L (DN) cells, with increased representation around genes relevant to inflammatory pathways. Additional ChIP-seq analysis of histone H3 methylation marks showed decreases in both repressive H3K9me3 and H3K27me3 marks with a commensurate increase in transcriptionally active (H3K4me3) histone marks in the L isoform deficient macrophages. Influenza A virus (IAV) infection, known to stimulate a wide array of anti-viral responses, caused a differential redistribution of PU.1 binding between proximal promoter and distal sites and decoupling from Toll-like receptor regulated gene promoters in SP-R210 L (DN) cells. These finding suggest that the inflammatory differences seen in SP-R210 L -deficient macrophages are a result of transcriptional differences that are mediated by epigenetic changes brought about by differential expression of the SP-R210 isoforms. This provides an avenue to explore how the signaling pathways downstream of the receptor and the ligands can modulate the macrophage inflammatory response. [ABSTRACT FROM AUTHOR]

Background The cause of infantile-onset epilepsy is complex and is not easily recognized clinically, particularly in paediatric patients who present with non-specific neurological signs, no radiological abnormalities and no metabolic changes. Case We report a case of infantile-onset epilepsy in a 10-month-old Chinese girl who presented with non-specific neurological signs, no radiological abnormalities and no biochemical disturbances. She first presented at birth with twitching movements and convulsions of an unknown aetiology. Ambulatory EEG showed epileptic rhythmic activities, the presence of asynchrony and runs of sharp waves over the right parietal and central areas. Given the non-specific neurological features and negative structural and biochemical findings, we applied clinical whole-exome sequencing (WES) to determine the underlying aetiology. WES revealed a novel heterozygous missense pathogenic variant, GNAO1 :NM_020988.2:c.118G > A; NP_066268.1:p.Gly40Arg. A genetic analysis of the family confirmed the variant identified is a de novo mutation. Conclusions Clinical WES can streamline genetic analysis and sort out pathogenic genes in an unbiased approach. GNAO1 is a disease-causing gene for the autosomal dominant form of early infantile epileptic encephalopathy. The novel pathogenic variant identified in this case should contribute to our understanding of the expanding spectrum of infantile-onset epilepsy. [ABSTRACT FROM AUTHOR]

Abstract: This study investigated the prescribing patterns of antiepileptic drugs, especially the uptake of newer drugs, among children and adolescents in Hong Kong. Data were retrieved from the Clinical Data Analysis and Reporting System. Children aged 0-19 years who received at least one prescription of anticonvulsants were selected. The study period extended from April 1, 2005 to March 31, 2009. The overall prevalence of anticonvulsants prescribing was 2.23/1000 children in 2005. A slight but steady decline in anticonvulsants prevalence was observed throughout the study period. Valproic acid was the most frequently prescribed drug, followed by carbamazepine and benzodiazepine derivatives. The use of newer anticonvulsants rose significantly, by 26.9%. The use of valproic acid remained unchanged, whereas the use of carbamazepine declined by 20%. Among newer drugs, the use of levetiracetam increased fourfold, and that of oxcarbazepine increased 15-fold. In the youngest age group, phenobarbital was the second most frequently used drug. A significant increase in lamotrigine prescriptions was not observed among adolescents. The persistent increase in using newer antiepileptic drugs implies not only an increase in drug expenditure. It also reflects the need to assess cost-effectiveness in terms of long-term outcomes, quality of life, and health economic outcomes. [Copyright &y& Elsevier]