RESUMEN
BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is associated with neurological symptoms, including autism spectrum disorder. Tuberous sclerosis complex is caused by pathogenic germline mutations of either the TSC1 or TSC2 gene, but somatic mutations were identified in both genes, and the combined effects of TSC1 and TSC2 mutations have been unknown. METHODS: The present study investigated social behaviors by the social interaction test and three-chambered sociability tests, effects of rapamycin treatment, and gene expression profiles with a gene expression microarray in Tsc1 and Tsc2 double heterozygous mutant (TscD+/-) mice. RESULTS: TscD+/- mice exhibited impairments in social behaviors, and the severity of impairments was similar to Tsc2+/- mice rather than Tsc1+/- mice. Impairments in social behaviors were rescued by rapamycin treatment in all mutant mice. Gene expression profiles in the brain were greatly altered in TscD+/- mice more than in Tsc1+/- and Tsc2+/- mice. The gene expression changes compared with wild type (WT) mice were similar between TscD+/- and Tsc2+/- mice, and the overlapping genes whose expression was altered in mutant mice compared with WT mice were enriched in the neoplasm- and inflammation-related canonical pathways. The "signal transducer and activator of transcription 3, interferon regulatory factor 1, interferon regulatory factor 4, interleukin-2R α chain, and interferon-γ" signaling pathway, which is initiated from signal transducer and activator of transcription 4 and PDZ and LIM domain protein 2, was associated with impairments in social behaviors in all mutant mice. LIMITATIONS: It is unclear whether the signaling pathway also plays a critical role in autism spectrum disorders not caused by Tsc1 and Tsc2 mutations. CONCLUSIONS: These findings suggest that TSC1 and TSC2 double mutations cause autistic behaviors similarly to TSC2 mutations, although significant changes in gene expression were attributable to the double mutations. These findings contribute to the knowledge of genotype-phenotype correlations in TSC and suggest that mutations in both the TSC1 and TSC2 genes act in concert to cause neurological symptoms, including autism spectrum disorder.
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Trastorno del Espectro Autista , Esclerosis Tuberosa , Ratones , Animales , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/patología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Mutación , SirolimusRESUMEN
AIM: To develop standardized diagnostic criteria for 'infection-triggered encephalopathy syndrome (ITES)' and five specific clinical syndromes of ITES. METHOD: The draft definitions were based on existing criteria, standardized, and discussed by a panel of international experts using nominal group technique over 18 months to achieve consensus. All criteria use the same format: (1) presence of infection/fever; (2) clinical features including encephalopathy; (3) neuroradiological features on magnetic resonance imaging; (4) exclusion of other causes. RESULTS: We first highlighted differences between ITES and infectious and autoimmune encephalitis, which is the most important differential diagnosis. Consensus was achieved to define five specific ITESs: acute encephalopathy with biphasic seizures and late reduced diffusion; acute necrotizing encephalopathy; mild encephalopathy with a reversible splenial lesion; acute fulminant cerebral oedema; and acute shock with encephalopathy and multiorgan failure. Two further conditions that are currently classified as epilepsy syndromes but have similar features to ITES, namely febrile infection-related epilepsy syndrome and hemiconvulsion-hemiplegia-epilepsy syndrome, are also discussed. INTERPRETATION: The consensus definition is expected to improve awareness of this disease concept, provide diagnostic framework, and facilitate future international research and clinical trials.
RESUMEN
New clinical issues have been raised through an interval of 7 years from the previous version (2016). In this study, we update the "Clinical Practice Guidelines for tuberous sclerosis complex-associated renal angiomyolipoma" as a 2023 version under guidance by the Japanese Urological Association. The present guidelines were cooperatively prepared by the Japanese Urological Association and Japanese Society of Tuberous Sclerosis Complex; committee members belonging to one of the two societies or specializing in the treatment of this disease were selected to prepare the guidelines in accordance with the "Guidance for preparing treatment guidelines" published by Minds (2020 version). The "Introduction" consisted of four sections, "Background Questions (BQ)" consisted of four sections, "Clinical Questions (CQ)" consisted of three sections, and "Future Questions (FQ)" consisted of three sections (total: 14 sections). Concerning CQ, an agreement was confirmed through voting by the committee members based on the direction and strength of recommendation, accuracy of evidence, and recommendation comments. The present guidelines were updated based on the current evidence. We hope that the guidelines will provide guiding principles for the treatment of tuberous sclerosis complex-associated renal angiomyolipoma to many urologists, becoming a foundation for subsequent updating.
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Angiomiolipoma , Neoplasias Renales , Esclerosis Tuberosa , Humanos , Angiomiolipoma/complicaciones , Angiomiolipoma/terapia , Neoplasias Renales/tratamiento farmacológico , Esclerosis Tuberosa/terapia , Esclerosis Tuberosa/tratamiento farmacológicoRESUMEN
Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a severe syndrome of acute encephalopathy that affects infants and young children. AESD is a polygenic disorder preceded by common viral infections with high fever. We conducted an association study of human leukocyte antigen (HLA) regions with AESD using HLA imputation. SNP genotyping was performed on 254 Japanese patients with AESD and 799 healthy controls. We conducted 3-field HLA imputation for 14 HLA genes based on Japanese-specific references using data from our previous genome-wide association study. After quality control, 208 patients and 737 controls were included in the analysis of HLA alleles. We then compared the carrier frequencies of HLA alleles and haplotypes between the patients and controls. HLA-DPB1*04:01:01 showed a significant association with AESD, exerting a protective effect against the disease (p = 0.0053, pcorrected = 0.042, odds ratio = 0.43, 95% confidence interval = 0.21-0.80). The allele frequency of HLA-DPB1*04:01:01 was lower in East Asians than in Caucasians, which may partially account for the higher incidence of AESD in the Japanese population. The present results demonstrate the importance of fine-mapping of the HLA region to investigate disease susceptibilities and elucidate the pathogenesis of AESD.
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Encefalopatías , Estudio de Asociación del Genoma Completo , Niño , Preescolar , Cadenas beta de HLA-DP/genética , Antígenos de Histocompatibilidad Clase II , Humanos , Lactante , Convulsiones/patologíaRESUMEN
The mammalian target of the rapamycin (mTOR) system plays multiple, important roles in the brain, regulating both morphology, such as cellular size, shape, and position, and function, such as learning, memory, and social interaction. Tuberous sclerosis complex (TSC) is a congenital disorder caused by a defective suppressor of the mTOR system, the TSC1/TSC2 complex. Almost all brain symptoms of TSC are manifestations of an excessive activity of the mTOR system. Many children with TSC are afflicted by intractable epilepsy, intellectual disability, and/or autism. In the brains of infants with TSC, a vicious cycle of epileptic encephalopathy is formed by mTOR hyperactivity, abnormal synaptic structure/function, and excessive epileptic discharges, further worsening epilepsy and intellectual/behavioral disorders. Molecular target therapy with mTOR inhibitors has recently been proved to be efficacious for epilepsy in human TSC patients, and for autism in TSC model mice, indicating the possibility for pharmacological treatment of developmental synaptic disorders.
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Encéfalo/metabolismo , Esclerosis Tuberosa/diagnóstico , Esclerosis Tuberosa/etiología , Animales , Encéfalo/patología , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Epilepsia/diagnóstico , Epilepsia/etiología , Predisposición Genética a la Enfermedad , Humanos , Evaluación de Síntomas , Serina-Treonina Quinasas TOR/metabolismo , Esclerosis Tuberosa/metabolismo , Esclerosis Tuberosa/terapia , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genéticaRESUMEN
BACKGROUND: Human cytomegalovirus (HCMV) causes asymptomatic infections, but also causes congenital infections when women were infected with HCMV during pregnancy, and life-threatening diseases in immunocompromised patients. To better understand the mechanism of the neutralization activity against HCMV, the association of HCMV NT antibody titers was assessed with the antibody titers against each glycoprotein complex (gc) of HCMV. METHODS: Sera collected from 78 healthy adult volunteers were used. HCMV Merlin strain and HCMV clinical isolate strain 1612 were used in the NT assay with the plaque reduction assay, in which both the MRC-5 fibroblasts cells and the RPE-1 epithelial cells were used. Glycoprotein complex of gB, gH/gL complexes (gH/gL/gO and gH/gL/UL128-131A [PC]) and gM/gN were selected as target glycoproteins. 293FT cells expressed with gB, gM/gN, gH/gL/gO, or PC, were prepared and used for the measurement of the antibody titers against each gc in an indirect immunofluorescence assay (IIFA). The correlation between the IIFA titers to each gc and the HCMV-NT titers was evaluated. RESULTS: There were no significant correlations between gB-specific IIFA titers and the HCMV-NT titers in epithelial cells or between gM/gN complex-specific IIFA titers and the HCMV-NT titers. On the other hand, there was a statistically significant positive correlation between the IIFA titers to gH/gL complexes and HCMV-NT titers. CONCLUSIONS: The data suggest that the gH/gL complexes might be the major target to induce NT activity against HCMV.
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Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Citomegalovirus/inmunología , Inmunoglobulina G/sangre , Proteínas del Envoltorio Viral/inmunología , Adulto , Línea Celular , Citomegalovirus/genética , Femenino , Fibroblastos/virología , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: Reversible myelin vacuolization is associated with variable conditions including mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), which is characterized by mildly impaired consciousness and transient splenial lesion. Familial and/or recurrent cases with a clinical diagnosis of MERS suggest the presence of genetic factors. METHODS: We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations. Whole-exome sequencing was performed in family members. RESULTS: Eight rare nonsynonymous single-nucleotide variants shared by all patients were identified. By filtering genes expressed in the corpus callosum, we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene. We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort comprised of 33 sporadic cases with MERS and 3 cases in another family with extensive myelin vacuolization, and identified the same heterozygous c.1208A>G in all affected members in the second family. Luciferase assay revealed that transcriptional activity of the N-terminal region of MYRF was significantly diminished by introducing the c.1208A>G variant. INTERPRETATION: MYRF is a transcriptional regulator that is necessary for oligodendrocyte differentiation and myelin maintenance. Functional defects of MYRF are likely to be causally associated with encephalopathy with extensive myelin vacuolization. We propose the term "MYRF-related mild encephalopathy with reversible myelin vacuolization." Our findings provide a new perspective on the pathogenesis of myelin vacuolization. Ann Neurol 2018;83:98-106.
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Encefalopatías/genética , Proteínas de la Membrana/genética , Vaina de Mielina/patología , Factores de Transcripción/genética , Adolescente , Adulto , Encefalopatías/diagnóstico por imagen , Encefalopatías/patología , Niño , Preescolar , Estudios de Cohortes , Cuerpo Calloso/metabolismo , Progresión de la Enfermedad , Electroencefalografía , Exoma/genética , Familia , Humanos , Imagen por Resonancia Magnética , Masculino , Linaje , Polimorfismo de Nucleótido Simple/genética , Vacuolas/patología , Adulto JovenRESUMEN
Rotavirus vaccines have been available in Japan since 2011. This study conducted to monitor the trend of group A rotavirus (RVA) genotypes 3 years after vaccine introduction. A total of, 539 fecal samples were collected from children with acute gastroenteritis in six regions during July 2014-June 2015. Among them, 178 samples (33.0%) were positive for RVA. The most predominant genotype was G1P[8] (35.9%) followed by G2P[4] (26.4%), G9P[8] (21.3%), G3P[8] (4.5%), and G3P[9] (4.5%). The detection rate of G2P[4] was increased soon after vaccine introduction. Sequence analyses of VP7 and VP4 genes of the representative G2P[4] strains were found to be clustered in sub-lineage IVa of lineage IV. It is noteworthy that one amino acid substitution in the antigenic epitope (Q114P) of VP4 gene was found in representative G2P[4] strains of the current study. However, it is unclear whether the change in antigenic epitope is due to the effect of vaccination or due to natural variation, warranting further continuous monitoring of rotavirus evolution after vaccine introduction.
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Gastroenteritis/epidemiología , Gastroenteritis/virología , Genotipo , Infecciones por Rotavirus/epidemiología , Infecciones por Rotavirus/virología , Rotavirus/clasificación , Rotavirus/aislamiento & purificación , Sustitución de Aminoácidos , Antígenos Virales/genética , Proteínas de la Cápside/genética , Niño , Preescolar , Análisis por Conglomerados , Enfermedades Transmisibles Emergentes/epidemiología , Enfermedades Transmisibles Emergentes/virología , Epítopos/genética , Heces/virología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Japón/epidemiología , Masculino , Epidemiología Molecular , Rotavirus/genética , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/inmunología , Análisis de Secuencia de ADN , Homología de SecuenciaRESUMEN
Background: Antiviral-resistant herpes simplex virus type 1 (HSV-1) has been recognized as an emerging clinical problem among patients undergoing hematopoietic stem cell transplantation (HSCT). Methods: A prospective observational study was conducted at a hematological center over a 2-year period. Oropharyngeal swab samples were serially collected each week from 1 week before and up to 100 days after HSCT and were tested for virus isolation. The HSV-1 isolates were tested for sensitivity to acyclovir (ACV). The prognosis of patients with ACV-resistant (ACVr) HSV-1 and the genetic background of the ACVr HSV-1 isolates were assessed. Results: Herpes simplex virus type 1 was isolated in 39 of 268 (15%) HSCT patients within 100 days after transplantation. Acyclovir-resistant HSV-1 emerged in 11 of these 39 patients (28%). The 100-day death rates of HSCT patients without HSV-1 shedding, those with only ACV-sensitive HSV-1 shedding, and those with ACVr HSV-1 shedding were 31%, 39%, and 64%, respectively. Patients with HSV-1, including ACVr HSV-1, shedding showed a significantly higher mortality rate. Relapsed malignancies were a significant risk factor for the emergence of ACVr HSV-1. Acyclovir resistance was attributable to viral thymidine kinase and DNA polymerase mutations in 6 and 5 patients, respectively. Conclusions: Herpes simplex virus type 1, including ACVr HSV-1, shedding was associated with poorer outcome in HSCT patients, even if HSV disease did not always occur. Patients with relapsed malignancies were at especially high risk for the emergence of ACVr HSV-1.
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Aciclovir/uso terapéutico , Antivirales/uso terapéutico , Farmacorresistencia Viral , Trasplante de Células Madre Hematopoyéticas/mortalidad , Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 1/efectos de los fármacos , Adolescente , Adulto , Anciano , ADN Polimerasa Dirigida por ADN/genética , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Herpes Simple/virología , Herpesvirus Humano 1/aislamiento & purificación , Humanos , Japón , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Análisis Multivariante , Complicaciones Posoperatorias/virología , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Recurrencia , Tasa de Supervivencia , Timidina Quinasa/genética , Adulto JovenRESUMEN
Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders accompanied by intractable epilepsies, i.e. West syndrome or atypical Rett syndrome. Here we report generation of the Cdkl5 knockout mouse and show that CDKL5 controls postsynaptic localization of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the hippocampus and regulates seizure susceptibility. Cdkl5 -/Y mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA. In concordance with this result, electrophysiological analysis in the hippocampal CA1 region disclosed an increased ratio of NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) and a significantly larger decay time constant of NMDA receptor-mediated EPSCs (NMDA-EPSCs) as well as a stronger inhibition of the NMDA-EPSCs by the GluN2B-selective antagonist ifenprodil in Cdkl5 -/Y mice. Subcellular fractionation of the hippocampus from Cdkl5 -/Y mice revealed a significant increase of GluN2B and SAP102 in the PSD (postsynaptic density)-1T fraction, without changes in the S1 (post-nuclear) fraction or mRNA transcripts, indicating an intracellular distribution shift of these proteins to the PSD. Immunoelectron microscopic analysis of the hippocampal CA1 region further confirmed postsynaptic overaccumulation of GluN2B and SAP102 in Cdkl5 -/Y mice. Furthermore, ifenprodil abrogated the NMDA-induced hyperexcitability in Cdkl5 -/Y mice, suggesting that upregulation of GluN2B accounts for the enhanced seizure susceptibility. These data indicate that CDKL5 plays an important role in controlling postsynaptic localization of the GluN2B-SAP102 complex in the hippocampus and thereby regulates seizure susceptibility, and that aberrant NMDA receptor-mediated synaptic transmission underlies the pathological mechanisms of the CDKL5 loss-of-function.
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Hipocampo/metabolismo , Densidad Postsináptica/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsiones/metabolismo , Animales , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Guanilato-Quinasas/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ácido Kaínico , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , N-Metilaspartato , Piperidinas/farmacología , Densidad Postsináptica/efectos de los fármacos , Densidad Postsináptica/patología , Proteínas Serina-Treonina Quinasas/genética , ARN Mensajero/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Convulsiones/patología , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: Group A rotavirus (RVA) vaccines have been introduced in Japan since 2011. To investigate the molecular epidemiological traits of RVA during the transitional period of rotavirus vaccine implementation in Japan, this study was undertaken by following up three-decade long surveillance conducted in the same regions. METHODS: RVA were screened and genotyped by RT-PCR from diarrheal samples collected from non-hospitalized patients in six localities (Hokkaido, Tokyo, Shizuoka, Osaka, Kyoto, and Saga) during 2011 - 2014. Selected samples were sequenced to elucidate the evolutionary trend. RESULTS: Among 1858 specimens, the detection rate of RVA declined to 4.0% in 2013 - 2014 from 17.9% in 2011 - 2012 and 22.1% in 2012 - 2013. G1P[8] was the most predominant genotype in the first two years accounting for more than half, and G9P[8] showed the highest detection rate as 35.0% in the last year. Interestingly, the proportional rate of G2 strains in the studied period increased from 0% to 25%. VP6 genotyping revealed that DS-1 like reassortant G1P[8] strains were detected all over Japan and their prevalence fluctuated greatly from 35.0% to 89.5%. Sequence analysis of VP6 showed that strains in the current strains were closely related but distinct from the original reference strains, namely Wa and DS-1. CONCLUSIONS: The detection rates of RVA, their GP combinations, prevalence of reassortant strains varied greatly after the introduction of rotavirus vaccines in Japan. Continuous monitoring is warranted to refine future vaccine strategy.
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Epidemiología Molecular , Infecciones por Rotavirus , Rotavirus/genética , Niño , Genotipo , Humanos , Japón , Filogenia , Rotavirus/aislamiento & purificación , Vacunas contra RotavirusRESUMEN
Niemann-Pick disease type C (NPC) is a cholesterol storage disease caused by defective cellular cholesterol transportation. The onset and progression of NPC are variable, and autopsy findings have mainly been reported for the adult and juvenile forms of this disease. Here we report the clinical and pathological findings from a 9-year-old female patient with the late infantile form of NPC due to NPC1 gene mutation. She had notable splenomegaly at 4 months of age. She lost the ability to speak at 18 months of age. She learned to walk, but often fell and could no longer walk after 30 months. At 3 years of age, she was diagnosed with NPC. Sequence analysis of the NPC1 gene revealed compound heterozygous mutation of T2108C (F703S) and C2348G (S813X) (both novel). Thereafter, the patient suffered repeated respiratory infections and died of respiratory failure at 9 years of age. Pathological findings included cerebral atrophy (particularly of white matter), severe demyelination, and the loss of neurons from the cerebrum and from the nuclei of the brain stem. Remnant neuronal cells and microglia in the cerebrum, cerebellum, and brain stem had become swollen and foamy. Neurons of the hippocampal CA1 and Purkinje cells were relatively spared, and senile plaques and axonal spheroids were not present. Foamy cells were also observed in other organs, especially the spleen and bone marrow. The F703S mutation in this patient was localized in a sterol-sensing domain (SSD). Severe neurological phenotypes have been previously reported in patients with missense mutations in an SSD. It is considered that the combination of a nonsense mutation and missense mutation in an SSD was responsible for the severe neurological phenotype of our present patient. While pathological findings of adult/juvenile forms of NPC have included swollen neurons and glia, neuronal cell loss, and NFTs, demyelination may be a predominant finding in the infantile form of NPC.
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Encéfalo/patología , Enfermedades Desmielinizantes/patología , Enfermedad de Niemann-Pick Tipo C/patología , Niño , Femenino , HumanosRESUMEN
Cosavirus is a recently established genus in the family Picornaviridae. The present study investigated the prevalence and genetic diversity of cosaviruses in stool samples collected from piglets and pigs with and without diarrhea in Thailand and Japan. It was observed that the cosavirus-positive rate in Thailand was higher than in Japan (55.4 % vs. 18.9 %). Phylogenetic analysis of a portion of the 5' untranslated region showed that porcine cosavirus strains clustered together in the same branch with members of the species Cosavirus A. These strains showed 97.0 to 100 % nucleotide sequence identity to each other. The virus concentration of cosavirus was very low compared with that detected in a infant with diarrhea. These results demonstrated that cosaviruses were circulating in the swine populations of both countries during the study term; however, it remains unclear whether the virus causes diarrhea in piglets and pigs.
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Diarrea/virología , Infecciones por Picornaviridae/veterinaria , Picornaviridae/aislamiento & purificación , Animales , Heces/virología , Japón/epidemiología , Datos de Secuencia Molecular , Filogenia , Picornaviridae/clasificación , Picornaviridae/genética , Infecciones por Picornaviridae/epidemiología , Infecciones por Picornaviridae/virología , Porcinos , Enfermedades de los Porcinos/epidemiología , Enfermedades de los Porcinos/virología , Tailandia/epidemiologíaRESUMEN
Most childhood cases of acute necrotizing encephalopathy (ANE) involve neither family history nor recurrence. ANE occasionally occurs, however, as a familial disorder or recurs in Caucasian patients. A mutation of RAN-binding protein 2 (RANBP2) has been discovered in more than one half of familial or recurrent ANE patients. In contrast, there has been no report of this mutation in East Asia. Here, we report the first sibling cases of typical ANE in Japan, with poor outcome. DNA analysis of genes associated with ANE or other encephalopathies, including RANBP2 and carnitine palmitoyl transferase II (CPT2), indicated neither mutations nor disease-related polymorphisms. On literature review, recurrent or familial ANE without the RANBP2 mutation has a more severe outcome and greater predilection for male sex than that with the RANBP2 mutation. This suggests that there are unknown gene mutations linked to ANE.
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Encefalopatías/genética , Encéfalo/diagnóstico por imagen , ADN/genética , Chaperonas Moleculares/genética , Mutación , Proteínas de Complejo Poro Nuclear/genética , Hermanos , Enfermedad Aguda , Encefalopatías/diagnóstico , Encefalopatías/metabolismo , Análisis Mutacional de ADN , Resultado Fatal , Humanos , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Chaperonas Moleculares/metabolismo , Proteínas de Complejo Poro Nuclear/metabolismoRESUMEN
Neonatal hypoxic-ischemic encephalopathy (HIE) remains a serious burden in neonatal care. Hypothermia provides a good outcome in some babies with HIE. Here, we investigated the biological mechanisms of its neuroprotective effect and sought for a new therapeutic target. We made neonatal HIE rats and subjected some of them to hypothermia at 28°C for 3 hours. We pathologically confirmed the efficacy of hypothermia against the neonatal HIE brain. To clarify the molecular mechanism of hypothermia's efficacy, we analyzed mRNA expression, immunoassay, and pathology in the brain with or without HIE and/or hypothermia. We selected from these analyses 12 molecules with possible neuroprotective effects. After identification of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) as a therapeutic target candidate, we examined the efficacy of an anti-LOX-1 neutralizing antibody in neonatal HIE rats. Administration of an anti-LOX-1 neutralizing antibody reduced infarction area, brain edema, and apoptotic cell death to a degree comparable with hypothermia. Protection from those pathological conditions was considered part of the therapeutic mechanism of hypothermia. The efficacy of administering anti-LOX-1 neutralizing antibody was similar to that of hypothermia. LOX-1 is a promising therapeutic target in neonatal HIE, and the inhibition of LOX-1 may become a novel treatment for babies who have experienced asphyxia.
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Anticuerpos Neutralizantes/farmacología , Infarto Encefálico/tratamiento farmacológico , Enfermedades del Recién Nacido/tratamiento farmacológico , Receptores Depuradores de Clase E/antagonistas & inhibidores , Animales , Animales Recién Nacidos , Infarto Encefálico/metabolismo , Infarto Encefálico/prevención & control , Humanos , Hipotermia Inducida , Recién Nacido , Enfermedades del Recién Nacido/metabolismo , Enfermedades del Recién Nacido/patología , Ratas , Ratas Sprague-Dawley , Receptores Depuradores de Clase E/metabolismoRESUMEN
Genetic variability makes influenza virus to escape the immunity and causes yearly epidemics. Monitoring those changes is necessary for vaccine selection. In addition, H3N2 viruses were considered to be seeded from Southeast Asia before spreading globally. This study described the molecular epidemiology of influenza A during the post-pandemic season 2010-2011 in Vietnam. Nasopharyngeal samples were collected from children with respiratory infections at Children's Hospital 2, Ho Chi Minh City. The HA, NA, M genes were amplified, sequenced and analyzed. Thirty-five of 1,082 (3.2%) patients were positive for influenza A, including 14 pandemic H1N1 2009 (H1N1pdm09) and 21 H3N2 infections. H3N2 was dominant in the rainy season (May-October 2010) while H1N1pdm09 was dominant in the dry season (November 2010-April 2011). Phylogenetic analysis showed that Vietnamese H1N1pdm09 sequences in 2010-2011 formed the distinct cluster, with other contemporary Asian and 2012-American sequences, suggesting a possible common ancestor. All were oseltamivir-sensitive except two strains carrying S247N and D199N in NA which reduced the neuraminidase inhibitor susceptibility. The Vietnamese H3N2 viruses in mid-2010 belonged to the emerging subclade Perth10/2010, which then spread worldwide in 2011. The Vietnamese influenza viruses were well matched with the Southern Hemisphere vaccine formulation. Mutations at antigenic sites were also identified in these viruses. Surveillance of influenza viruses in tropical countries is important not only for development of their prevention and control strategies but also for earlier identification of the newly emerged strains that may be selected for future vaccine.
Asunto(s)
Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H3N2 del Virus de la Influenza A/genética , Gripe Humana/epidemiología , Gripe Humana/virología , Adolescente , Antivirales/farmacología , Antivirales/uso terapéutico , Niño , Preescolar , Femenino , Genes Virales , Hospitalización , Humanos , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , Masculino , Epidemiología Molecular , Filogenia , Estaciones del Año , Análisis de Secuencia de ADN , Factores de Tiempo , Vietnam/epidemiologíaRESUMEN
Acute gastroenteritis continues to be a major public health problem worldwide. A wide variety of viruses associated with diarrhea disease is being reported continually. This study investigated the epidemiological situation of viruses that cause diarrhea in Japanese pediatric patients. This study enrolled a total of 2,381 fecal specimens collected between 2009 and 2013 from Japanese children with acute gastroenteritis. There is currently a 70.4% prevalence of viruses causing diarrhea among these Japanese pediatric outpatients. Norovirus was detected in 39.3% of the patients, whereas the prevalence of rotavirus, human parechovirus, enterovirus, adenovirus, sapovirus, astrovirus, and Aichi virus was 20.1, 6.6, 6.1, 5.6, 4.8, 2.3, and 0.1%, respectively. Co-infections were observed at the prevalence rates of 13.4 and 0.5% for double infections and triple infections, respectively. Mixed viral infections were found commonly in Japanese outpatients, and the norovirus seemed to play a major role in co-infections. Viral diarrhea cases were detected mostly in children younger than 3 years of age. The norovirus and rotavirus can be detected throughout the year, with a peak during the cold and dry seasons, whereas other common viruses are found during no specific season. Surveillance data revealed that a wide variety of viruses has caused diarrhea to circulate currently in Japanese pediatric outpatients, with very high detection rates; and norovirus and rotavirus are the most important pathogens. The data obtained from this study are valuable for compiling the overall picture of several viruses that causes diarrhea and associates with acute gastroenteritis in the Japanese pediatric population.
Asunto(s)
Diarrea/epidemiología , Diarrea/virología , Gastroenteritis/epidemiología , Gastroenteritis/virología , Factores de Edad , Preescolar , Coinfección , Heces/virología , Femenino , Humanos , Lactante , Recién Nacido , Japón/epidemiología , Masculino , Pacientes Ambulatorios , Prevalencia , Estaciones del Año , Virus/clasificación , Virus/genéticaRESUMEN
INTRODUCTION: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common subtype of infectious pediatric encephalopathy in Japan. It is sometimes difficult to make an early diagnosis of AESD; excitotoxicity is postulated to be the pathogenesis based on elevated glutamine (Gln) and glutamate (Glu) complex (Glx = Glu + Gln) observed on MR spectroscopy. It is uncertain whether Gln or Glu contributes to the elevated Glx, or whether MR spectroscopy is useful for an early diagnosis. METHODS: Five Japanese patients with AESD (three boys and two girls, 1 year of age) were enrolled in this study. MR spectroscopy was acquired from the frontal white matter (repetition time (TR) of 5000 ms, echo time (TE) of 30 ms) with a 1.5- or 3.0-T scanner. MR spectroscopy was performed four times for two patients, three times for one patient, and two times for two patients. Quantification of Glu and Gln was performed using LCModel. RESULTS: Glu was elevated in three of four studies on days 1-4 and became normal or low afterward. Gln was normal in three studies on days 1-2, elevated in all seven studies on days 4-12, and became normal or low afterward. CONCLUSION: These findings suggest that MR spectroscopy may be useful for an early diagnosis. Acute Glu elevation changes to subacute Gln elevation, suggesting that a disrupted Glu-Gln cycle may play an important role.
Asunto(s)
Epilepsia Tónico-Clónica/metabolismo , Lóbulo Frontal/metabolismo , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Sustancia Blanca/metabolismo , Biomarcadores/sangre , Epilepsia Tónico-Clónica/patología , Femenino , Lóbulo Frontal/patología , Humanos , Recién Nacido , Masculino , Tasa de Depuración Metabólica , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución Tisular , Sustancia Blanca/patologíaRESUMEN
BACKGROUND: Early identification of the etiology of infection is beneficial. Most infections are treated as outpatients. However, facilities for rapid diagnosis are not available in clinic settings. METHODS: We applied Immunochromatography (IC) and Loop-mediated Isothermal Amplification (LAMP) methods to rapidly diagnose pathogens among 31 children with respiratory infection and 12 with gastroenteritis at a clinic in Saitama prefecture, Japan. Pathogens were then screened by multiplex conventional and real-time PCRs and bacterial culture. RESULTS: Respiratory pathogens were found in 64.5%. Despite the narrow spectrum, rapid tests identified pathogens in 28.6% of cases with a high agreement rate of 89.3% with PCR. Gastroenteritis pathogens were found in 66.7%. E. coli was positive in 3 cases and all were negative for verotoxin by LAMP. The agreement rate of IC and PCR assay was high, 100%. CONCLUSIONS: IC and LAMP are reliable and suitable methods in limited-resource settings for early pathogenic identification, which will help appropriate management, avoid unnecessary intervention, and cost saving.