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Purpose: The TRAK1 gene is mapped to chromosome 3p22.1 and encodes trafficking protein kinesin binding 1. The aim of this study was to investigate the genotype-phenotype of TRAK1-associated epilepsy. Methods: Trio-based whole-exome sequencing was performed on a cohort of 98 patients with epilepsy of unknown etiologies. Protein modeling and the VarCards database were used to predict the damaging effects of the variants. Detailed neurological phenotypes of all patients with epilepsy having TRAK1 variants were analyzed to assess the genotype-phenotype correlations. Results: A novel TRAK1 compound heterozygous variant comprising variant c.835C > T, p.Arg279Cys and variant c.2560A > C, p.Lys854Gln was identified in one pediatric patient. Protein modeling and VarCards database analyses revealed that the variants were damaging. The patient received a diagnosis of early infantile epileptic spasms with a developmental disorder; he became seizure-free through valproate and adrenocorticotropic hormone treatment. Further results for six variants in 12 patients with epilepsy indicated that biallelic TRAK1 variants (including homozygous or compound heterozygous variants) were associated with epilepsy with developmental disorders. Among these patients, eight (67%) had epileptic spasms and seven (58%) were intractable to anti-seizure medicines. Moreover, eight patients experienced refractory status epilepticus, of which seven (88%) died in early life. To our knowledge, this is the first reported case of epilepsy caused by TRAK1 compound heterozygous variants. Conclusion: Biallelic TRAK1 variants can cause epilepsy and developmental disorders. In these patients, seizures progress to status epilepticus, suggesting a high risk for poor outcomes and the requirement of early treatment.
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BACKGROUND: Guillain-Barré syndrome (GBS), as the most common cause of acute flaccid paralysis worldwide, is considered a part of a clinical spectrum in which discrete, complete, or incomplete forms of GBS and overlapping syndromes lie on the basis of their clinical features. The term overlapping Miller Fisher syndrome (MFS)/GBS is used when patients with MFS also suffer from progressive motor weakness of the limbs. Anti-ganglioside GQ1b has been specifically associated with MFS and ophthalmoplegia. CASE DESCRIPTION: Here, we report a Chinese girl who was diagnosed with overlapping MFS/GBS showing acute flaccid paralysis of all four limbs, sensory symptoms, cranial nerve dysfunction, autonomic involvement, ophthalmoplegia, and ataxia. She had high serum and cerebrospinal fluid titres of monospecific anti-GM4 IgG antibody instead of anti-GQ1b antibody in the acute phase. CONCLUSION: Anti-GM4 antibodies usually coexist with other antiganglioside antibodies, leading to missed diagnoses. The findings of the present study show that antibodies to ganglioside GM4 may in overlapping MFS/GBS as the lone immunological factors.
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Enfermedades Virales del Sistema Nervioso Central , Síndrome de Guillain-Barré , Síndrome de Miller Fisher , Mielitis , Enfermedades Neuromusculares , Oftalmoplejía , Femenino , Humanos , China , Gangliósidos , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Miller Fisher/diagnóstico , Oftalmoplejía/diagnóstico , PreescolarRESUMEN
BACKGROUND: The etiology of unexplained epilepsy in most patients remains unclear. Variants of FRMPD4 are suggested to be associated with neurodevelopmental disorders. Therefore, we screened for disease-causing FRMPD4 variants in patients with epilepsy. METHODS: Trios-based whole-exome sequencing was conducted on a cohort of 85 patients with unexplained epilepsy, their parents, and extended family members. Additional cases with FRMPD4 variants were identified from the China Epilepsy Gene Matching Platform V.1.0. The frequency of variants was analyzed, and their subregional effects were predicted using in silico tools. The genotype-phenotype correlation of the newly defined causative genes and protein stability were analyzed using I-Mutant V.3.0 and Grantham scores. RESULTS: Two novel missense variants of FRMPD4 were identified in two families. Using the gene matching platform, we identified three additional novel missense variants. These variants presented at low or no allele frequencies in the gnomAD database. All the variants were located outside the three FRMPD4 main domains (WW, PDZ, and FERM). In silico analyses revealed that the variants were damaging and were predicted to be the least stable. All patients eventually became seizure-free. Eight of the 21 patients with FRMPD4 variants had epilepsy, of which five (63%) had missense variants located outside the domains, two had deletions involving exon 2, and one had a frameshift variant located outside the domains. Patients with epilepsy caused by missense variants were often free of intellectual disabilities (4/5), whereas patients with epilepsy caused by truncated variants had intellectual disabilities and structural brain abnormalities (3/3). CONCLUSIONS: The FRMPD4 gene is potentially associated with epilepsy. The genotype-phenotype correlation of FRMPD4 variants indicated that differences in variant types and locations of FRMPD4 may explain their phenotypic variation.
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Epilepsia , Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Epilepsia/genética , Mutación del Sistema de Lectura , Mutación Missense , Frecuencia de los GenesRESUMEN
OBJECTIVE: Bone metabolism can be influenced by a range of factors. We selected children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and lifestyles similar to those of healthy children to control for the confounding factors that may influence bone metabolism. We aimed to identify the specific effects of epilepsy and/or anti-seizure medications (ASMs) on bone metabolism. METHODS: Patients with SeLECTS were divided into an untreated group and a monotherapy group, and the third group was a healthy control group. We determined the levels of various biochemical markers of bone metabolism, including procollagen type I nitrogenous propeptide (PINP), alkaline phosphatase (ALP), osteocalcin (OC), collagen type I cross-linked C-telopeptide (CTX), calcium, magnesium, phosphorus, parathyroid hormone (PTH), and vitamin D3 (VD3 ). RESULTS: A total of 1487 patients (from 19 centers) were diagnosed with SeLECTS; 1032 were analyzed, including 117 patients who did not receive any ASMs (untreated group), 643 patients who received only one ASM (monotherapy group), and 272 children in the healthy control group. Except for VD3 , other bone metabolism of the three groups were different (p < .001). Bone metabolism was significantly lower in the untreated group than the healthy control group (p < .05). There were significant differences between the monotherapy and healthy control group in the level of many markers. However, when comparing the monotherapy and untreated groups, the results were different; oxcarbazepine, levetiracetam, and topiramate had no significant effect on bone metabolism. Phosphorus and magnesium were significantly lower in the valproic acid group than the untreated group (adjusted p < .05, Cliff's delta .282-.768). CTX was significantly higher in the lamotrigine group than in the untreated group (adjusted p = .012, Cliff's delta = .316). SIGNIFICANCE: Epilepsy can affect many aspects of bone metabolism. After controlling epilepsy and other confounders that affect bone metabolism, we found that the effects of ASMs on bone metabolism differed. Oxcarbazepine, levetiracetam, and topiramate did not affect bone metabolism, and lamotrigine corrected some of the abnormal markers of bone metabolism in patients with epilepsy.
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CANDOR (NCT03158688) is a phase 3, randomized, open-label trial comparing carfilzomib, daratumumab, and dexamethasone (KdD) vs carfilzomib and dexamethasone (Kd) in adults with relapsed/refectory multiple myeloma (RRMM) with 1 to 3 prior therapies. The CANDOR study met its primary end point of progression-free survival (PFS) in the primary analysis. Here, we report the final analysis of the study, including secondary end points and subgroup analyses thereof. The median follow-up was 50 months. Patients treated with KdD had higher minimal residual disease-negative (MRD-) achievement rates (28% vs 9%; odds ratio [OR], 4.22; 95% confidence interval [95% CI], 2.28-7.83) and MRD- complete response rates (22% vs 8%; OR, 3.55; 95% CI, 1.83-6.88) than those treated with Kd. Median PFS was 28.4 months for KdD vs 15.2 months for Kd (hazard ratio [HR], 0.64; 95% CI, 0.49-0.83). Median overall survival (OS) for KdD was 50.8 months vs 43.6 months for Kd (HR, 0.78 [0.60-1.03]; P = .042). Trends toward improved OS occurred in predefined subgroups, including patients refractory to lenalidomide (KdD, not reached vs Kd, 38.2 months; HR, 0.69 [0.43-1.11]) and refractory to proteasome inhibitor (KdD, 43.2 months vs Kd, 30.0 months; HR, 0.70 [0.45-1.09]), and there was significant improvement in patients with high-risk cytogenetics (KdD, 34.3 months vs Kd: 17.1 months; HR, 0.52 [0.29-0.94]). No new safety signals were identified. In summary, the final analysis of CANDOR confirmed the PFS benefit and showed a trend in OS benefit with KdD vs Kd. These findings reinforce KdD as a standard of care for RRMM, especially in clinically relevant patient subgroups. This trial was registered at www.clinicaltrials.gov as #NCT03158688.
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Protocolos de Quimioterapia Combinada Antineoplásica , Mieloma Múltiple , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/uso terapéuticoRESUMEN
Epilepsy is a common chronic neurological disorder characterized by widespread neuronal death. The purpose of this study was to investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) m6A methylation in epilepsy. To create epileptic models, the rats were given Lithium chloride and pilocarpine, and isolated primary rat hippocampal neurons were cultured in an Mg2+ -free medium. The frequency of seizures was recorded in the epilepsy group of rats. The functional tests included TUNEL, MTT, and flow cytometry. Mechanistically, RNA degradation assay, RNA immunoprecipitation, and methylated RNA immunoprecipitation were performed. In epileptic models, Nrf2 and fat mass and obesity-associated (FTO) levels were downregulated, whereas YT521-B homology (YTH) domain family protein 2 (YTHDF2) was upregulated. Additionally, in epileptic models, there was a rise in the m6A methylation level of Nrf2 mRNA. Overexpressing FTO increased cell viability and reduced apoptosis, but Nrf2 interference reversed these effects. Meanwhile, FTO overexpression decreased the m6A methylation of Nrf2 mRNA. Moreover, YTHDF2 bound to Nrf2 mRNA and decreased its stability. Furthermore, FTO overexpression reduced seizure frequency in rats and inhibited hippocampal neuron apoptosis via lowering the m6A methylation level of Nrf2 mRNA. Overexpressing FTO reduced m6A methylation of Nrf2 mRNA, increased cell viability, suppressed apoptosis, and slowed the progression of epileptic diseases, which is linked to YTHDF2 binding to m6A-modified Nrf2 and promoting its degradation, as well as downregulating Nrf2 expression in hippocampal neurons.
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Epilepsia , Factor 2 Relacionado con NF-E2 , Ratas , Animales , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Regulación hacia Abajo , Epilepsia/metabolismo , ARN/efectos adversos , ARN/metabolismo , ARN Mensajero/metabolismo , Convulsiones/metabolismo , Neuronas/metabolismo , Hipocampo/metabolismoRESUMEN
PURPOSE: Genotype-phenotypic correlation of KCNH1 variant remains elusive. This study aimed to expand the phenotypic spectrum of KCNH1 and explore the correlations between epilepsy and molecular sub-regional locations. METHODS: We performed whole-exome sequencing in a cohort of 98 patients with familiar febrile seizure (FS) or epilepsy with unexplained etiologies. The damaging effects of variants were predicted by protein modeling and multiple in silico tools. All reported patients with KCNH1 pathogenic variants with detailed neurological phenotypes were analyzed to evaluate the genotype-phenotype correlation. RESULTS: Two novel KCNH1 variants were identified in three cases, including two patients with FS with inherited variant (p.Ile113Thr) and one boy with epilepsy with de novo variant (p.Arg357Trp). Variant Ile113Thr was located within the eag domain, and variant p.Arg357Trp was located in transmembrane domain 4 of KCNH1, respectively. Two patients experienced refractory status epilepticus (SE), of which one patient died of acute encephalopathy induced by SE. Further analysis of 30 variants in 51 patients demonstrated that de novo variants were associated with epileptic encephalopathy, while mosaic/somatic or germline variants cause isolated epilepsy/FS. All hotspot variants associated with epileptic encephalopathy clustered in transmembrane domain (S4 and S6), while those with isolated epilepsy/seizures or TBS/ZLS without epilepsy were scattered in the KCNH1. CONCLUSIONS: We found two novel missense variants of KCNH1 in three individuals with isolated FS/epilepsy. Variants in the KCNH1 cause a spectrum of epileptic disorders ranging from a benign form of genetic isolated epilepsy/FS to intractable form of epileptic encephalopathy. The genotypes and variant locations help explaining the phenotypic variation of patients with KCNH1 variant.
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Encefalopatías , Epilepsia Generalizada , Epilepsia , Convulsiones Febriles , Humanos , Epilepsia/genética , Mutación Missense/genética , Genotipo , Fenotipo , Canales de Potasio Éter-A-Go-Go/genéticaRESUMEN
Background: Anti-Contactin-associated protein-like 2 (CASPR2) antibody-associated encephalitis is a rare group of autoimmune diseases that causes extensive damage to the central and/or peripheral nervous system. Case presentation: Here, we reported a case of anti-CASPR2 antibody-associated encephalitis in a 12-year-old male patient with symptoms of headache, consciousness disturbance, mental abnormalities, urinary incontinence, fasciculations in the extremity muscles, and involuntary movements. The testing for autoimmune encephalitis-associated antibodies showed that CASPR2-associated antibodies were positive, and electroencephalography showed diffuse slow waves. No tumor was found after screening for malignancies. The child's status significantly improved after receiving immunotherapy with intravenous methylprednisolone and immunoglobulin. Conclusions: Anti-CASPR2 antibody-associated encephalitis has been rarely reported in children. It has a complex clinical presentation and a low incidence of tumor. Most pediatric patients have a favorable prognosis and relapse is uncommon.
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A boy, aged 1 year and 7 months, was hospitalized due to weakness in both lower limbs and blepharoptosis, which showed progressive aggravation and developed into irregular breathing. Neurological examinations showed lethargy, blepharoptosis, grade 4 muscle strength of both upper limbs, grade 3 muscle strength of both lower limbs, and disappearance of tendon reflex. Laboratory tests revealed albuminocytological dissociation in cerebrospinal fluid, disappearance of H reflex, and positive serum anti-GD1b IgG. The boy was finally diagnosed with Guillain-Barré syndrome (GBS) overlapping with Miller-Fisher syndrome and Bickerstaff brainstem encephalitis. He recovered and was discharged after treatment including immunoglobulin, plasma exchange, and respiratory support. The GBS overlap syndromes in children have strong clinical heterogeneity due to the injury of both peripheral nerve and brainstem, among which anti-GD1b antibody-related GBS overlap syndromes have special clinical manifestations and complex neuroelectrophysiological changes and are thus difficult to diagnose. Nerve conduction velocity tests, especially H reflex test, should be performed for children with weakness in both lower limbs and blepharoptosis.
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Blefaroptosis , Encefalitis , Síndrome de Guillain-Barré , Síndrome de Miller Fisher , Niño , Humanos , Extremidad Inferior , MasculinoRESUMEN
BACKGROUND: Autoimmune encephalitis (AE) is a group of immune-mediated brain diseases. However, new diagnostic criteria for AE in children indicate that partial pediatric patients with AE may be diagnosed without evidence of positive autoantibodies. Therefore, the clinical characteristics and prognosis of children with antibody-negative but probable AE require further investigation. METHODS: Forty-one children with AE admitted to our hospital from April 2014 to January 2021 were retrospectively enrolled in this study. Children were divided into two groups according to positive or negative antibody tests. Clinical characteristics, cerebrospinal fluid, video electroencephalography, brain magnetic resonance imaging, and prognosis were analyzed, and the correlation between modified Rankin scale (mRS) and neutrophil-to-lymphocyte ratio (NLR) was examined. RESULTS: Of 41 children, 16 cases tested positive for autoantibodies. The main features were psychiatric symptoms, cognitive disturbances, speech disturbances, movement disorders, and seizures. All the children were given a combination of intravenous methylprednisolone pulses with intravenous immunoglobulin therapy; 26 cases (63%) had a good outcome, and 15 cases (37%) had a poor outcome. Antibody-positive and antibody-negative but probable AE were analyzed by univariate analysis and showed lower lymphocyte counts and higher NLR and mRS scores in the antibody-negative group (P < 0.05). The Spearman rank correlation analysis showed a positive correlation between NLR level and mRS scores (P < 0.05). CONCLUSIONS: Antibody-negative but possible AE is frequent in children who may have a more severe neurological impairment and higher NLR than antibody-positive AE. Aggressive immunotherapy in antibody-negative AE is essential to achieve a good prognosis.
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Encefalitis , Enfermedad de Hashimoto , Autoanticuerpos/líquido cefalorraquídeo , Niño , Encefalitis/diagnóstico , Encefalitis/terapia , Enfermedad de Hashimoto/diagnóstico , Enfermedad de Hashimoto/terapia , Humanos , Pronóstico , Estudios RetrospectivosRESUMEN
A boy, aged 5 years, attended the hospital due to progressive psychomotor regression for 2.5 years. Motor function regression was the main manifestation in the early stage, and brain MRI and whole-exome sequencing (WES) of the family showed no abnormalities. After the age of 4 years and 9 months, the boy developed cognitive function regression, and brain MRI showed cerebellar atrophy. The reanalysis of WES results revealed a compound heterozygous mutation, [NM_000520, c.784C>T(p.His262Tyr]), c.1412C>T(p.Pro471Leu)], in the HEXA gene. The enzyme activity detection showed a significant reduction in the level of ß-hexosaminidase encoded by this gene. The boy was diagnosed with juvenile Tay-Sachs disease (TSD). TSD has strong clinical heterogeneity, and cerebellar atrophy may be an important clue for the diagnosis of juvenile TSD. The reanalysis of genetic data when appropriate based on disease evolution may improve the positive rate of WES.
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Enfermedad de Tay-Sachs , Atrofia , Humanos , Imagen por Resonancia Magnética , Masculino , Mutación , Enfermedad de Tay-Sachs/diagnóstico , Enfermedad de Tay-Sachs/genéticaRESUMEN
BACKGROUND: Mutations in PIGN, resulting in a glycosylphosphatidylinositol (GPI) anchor deficiency, typically leads to multiple congenital anomalies-hypotonia-seizures syndrome. However, the link between PIGN and epilepsy or paroxysmal non-kinesigenic dyskinesia (PNKD) is not well-described. This study reported a patient with PIGN mutation leading to developmental and epileptic encephalopathy and PNKD, to expand upon the genotype-phenotype correlation of PIGN. CASE PRESENTATION: During the first 10 days of life, a girl exhibited paroxysmal staring episodes with durations that ranged from several minutes to hours. These episodes occurred 2-5 times daily and always occurred during wakefulness. Ictal electroencephalography revealed no abnormalities, and PNKD was diagnosed. The patient also exhibited severely delayed psychomotor development and generalized seizures at the age of 4 months. Results of brain magnetic resonance imaging and metabolic screenings were normal, but trio-based whole-exome sequencing identified two novel compound heterozygous PIGN mutations (NM_176787; c.163C > T [p.R55 > X] and c.283C > T [p.R95W]). Flow cytometry analysis of the patient's granulocytes revealed dramatically reduced expression of GPI-anchored proteins. This indicated that the mutations compromised GPI functions. The patient got seizure-free for 1 year, and her dyskinesia episodes reduced significantly (1-2 times/month) after treatment with levetiracetam (600 mg/day) and clonazepam (1.5 mg/day). No progress was observed with respect to psychomotor development; however, no craniofacial dysmorphic features, cleft lip/palate, brachytelephalangy with nail hypoplasia, and internal malformations have been observed until now (6 years of age). CONCLUSION: This is the first study to document developmental and epileptic encephalopathy with PNKD in a human with PIGN mutations. This report expanded our understanding of the genotype-phenotype correlation of PIGN, and PIGN may be considered a potentially relevant gene when investigating cases of epilepsy or PNKD.
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Labio Leporino , Fisura del Paladar , Discinesias , Epilepsia , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Femenino , Glicosilfosfatidilinositoles/deficiencia , Humanos , Mutación , Fosfotransferasas/genética , ConvulsionesRESUMEN
Vagus nerve stimulation (VNS) is a safe and effective therapy for pediatric patients with drug-resistant epilepsy (DRE). However, in children with DRE, the effects of VNS on autistic behaviors remain controversial. We retrospectively collected data from 10 children with DRE who underwent VNS implantation and regular parameter regulation in three pediatric epilepsy centers, and completed the behavioral assessments, including the autistic behavior checklist and the child behavior checklist, at follow-ups 1 (mean 2.16 years) and 2 (mean 2.98 years). The 10 children maintained stable seizure control between the two follow-ups. Their autistic behaviors, especially in language, social and self-help, were reduced at follow-up 2 compared to follow-up 1 (p = 0.01, p = 0.01, respectively). Moreover, these improvements were not associated with their seizure control, whether it was positive or negative. These results suggested that the VNS had a positive effect on autistic behaviors, which provided a preliminary clinical basis that VNS may benefit to younger children with DRE comorbidity autism spectrum disorder (ASD).
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Because of the continuous rise of foodborne illnesses caused by the consumption of raw fruits and vegetables, effective post-harvest anti-microbial strategies are necessary. The aim of this study was to evaluate the anti-microbial efficacy of ozone (O3) against two common causes of fresh produce contamination, the Gram-negative Escherichia coli O157:H7 and Gram-positive Listeria monocytogenes, and to relate its effects to potential mechanisms of xenobiosis by transcriptional network modeling. The study on non-host tomato environment correlated the dose × time aspects of xenobiosis by examining the correlation between bacterial survival in terms of log-reduction and defense responses at the level of gene expression. In E. coli, low (1 µg O3/g of fruit) and moderate (2 µg O3/g of fruit) doses caused insignificant reduction in survival, while high dose (3 µg/g of fruit) caused significant reduction in survival in a time-dependent manner. In L. monocytogenes, moderate dose caused significant reduction even with short-duration exposure. Distinct responses to O3 xenobiosis between E. coli and L. monocytogenes are likely related to differences in membrane and cytoplasmic structure and components. Transcriptome profiling by RNA-Seq showed that primary defenses in E. coli were attenuated after exposure to a low dose, while the responses at moderate dose were characterized by massive upregulation of pathogenesis and stress-related genes, which implied the activation of defense responses. More genes were downregulated during the first hour at high dose, with a large number of such genes getting significantly upregulated after 2 hr and 3 hr. This trend suggests that prolonged exposure led to potential adaptation. In contrast, massive downregulation of genes was observed in L. monocytogenes regardless of dose and exposure duration, implying a mechanism of defense distinct from that of E. coli. The nature of bacterial responses revealed by this study should guide the selection of xenobiotic agents for eliminating bacterial contamination on fresh produce without overlooking the potential risks of adaptation.
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Antibacterianos/farmacología , Escherichia coli O157/efectos de los fármacos , Enfermedades Transmitidas por los Alimentos/prevención & control , Listeria monocytogenes/efectos de los fármacos , Ozono/farmacología , Solanum lycopersicum/microbiología , Carga Bacteriana/efectos de los fármacos , Microbiología de Alimentos , Enfermedades Transmitidas por los Alimentos/microbiología , Frutas/microbiología , Perfilación de la Expresión Génica , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Viabilidad Microbiana/efectos de los fármacos , Prueba de Estudio Conceptual , ARN Bacteriano/genética , RNA-Seq , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , Verduras/microbiologíaRESUMEN
Objective: Intractable epilepsy and uncontrolled seizures could affect cardiac function and the autonomic nerve system with a negative impact on children's growth. The aim of this study was to investigate the variability and complexity of cardiac autonomic function in pre-school children with pediatric intractable epilepsy (PIE). Methods: Twenty four-hour Holter electrocardiograms (ECGs) from 93 patients and 46 healthy control subjects aged 3-6 years were analyzed by the methods of traditional heart rate variability (HRV), multiscale entropy (MSE), and Kurths-Wessel symbolization entropy (KWSE). Receiver operating characteristic (ROC) curve analysis was used to estimate the overall discrimination ability. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) models were also analyzed. Results: Pre-school children with PIE had significantly lower HRV measurements than healthy controls in time (Mean_RR, SDRR, RMSSD, pNN50) and frequency (VLF, LF, HF, LF/HF, TP) domains. For the MSE analysis, area 1_5 in awake state was lower, and areas 6_15 and 6_20 in sleep state were higher in PIE with a significant statistical difference. KWSE in the PIE group was also inferior to that in healthy controls. In ROC curve analysis, pNN50 had the greatest discriminatory power for PIE. Based on both NRI and IDI models, the combination of MSE indices (wake: area1_5 and sleep: area6_20) and KWSE (m = 2, τ = 1, α = 0.16) with traditional HRV measures had greater discriminatory power than any of the single HRV measures. Significance: Impaired HRV and complexity were found in pre-school children with PIE. HRV, MSE, and KWSE could discriminate patients with PIE from subjects with normal cardiac complexity. These findings suggested that the MSE and KWSE methods may be helpful for assessing and understanding heart rate dynamics in younger children with epilepsy.
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Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome (ROHHADS) is a rare multi-system disease, and delayed diagnosis and treatment may lead to catastrophic cardiopulmonary complications. As far as we know, no patient with ROHHADS has been reported in China, and this article reports a child with ROHHADS to improve the awareness of this disease among clinicians. A girl, aged 3 years, had the clinical manifestations of rapid weight gain, fever, disturbance of consciousness, and convulsion. The physical examination showed a body weight of 20 kg, somnolence, irregular breathing, and stiff neck. She had increased blood levels of prolactin and follicle-stimulating hormone and hyponatremia. The lumbar puncture showed an increased intracranial pressure. The brain MRI and magnetic resonance venography showed symmetrical lesions in the periventricular region and venous thrombosis in the right transverse sinus and the superior sagittal sinus. The sleep monitoring showed hypopnea. The girl was finally diagnosed with ROHHADS and intracranial venous thrombosis. She recovered after symptomatic treatment including decreasing intracranial pressure, anticoagulation, and respiratory support. The possibility of ROHHADS should be considered for patients with unexplained obesity, fever, and hypoventilation, with or without central nervous system symptoms. Early diagnosis and standardized follow-up can improve the prognosis of children with ROHHADS.
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Estado de Conciencia , Enfermedades Hipotalámicas , Niño , Preescolar , China , Femenino , Humanos , Hipoventilación , ObesidadRESUMEN
Aspergillus flavus is a saprophytic cosmopolitan fungus, capable of infecting crops both pre- and post-harvest and exploiting different secondary metabolites, including aflatoxins. Aflatoxins are known carcinogens to animals and humans, but display no clear effect in host plants such as maize. In a previous study, we mined the genome of A. flavus to identify secondary metabolite clusters putatively involving the pathogenesis process in maize. We now focus on cluster 32, encoding for fungal effectors such as salicylate hydroxylase (SalOH), and necrosis- and ethylene-inducing proteins (npp1 domain protein) whose expression is triggered upon kernel contact. In order to understand the role of this genetic cluster in maize kernel infection, mutants of A. flavus, impaired or enhanced in specific functions (e.g., cluster 32 overexpression), were studied for their ability to cause disease. Within this frame, we conducted histological and histochemical experiments to verify the expression of specific genes within the cluster (e.g., SalOH, npp1), the production of salicylate, and the presence of its dehydroxylated form. Results suggest that the initial phase of fungal infection (2 days) of the living tissues of maize kernels (e.g., aleuron) coincides with a significant increase of fungal effectors such as SalOH and Npp1 that appear to be instrumental in eluding host defences and colonising the starch-enriched tissues, and therefore suggest a role of cluster 32 to the onset of infection.
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Aspergillus flavus/patogenicidad , Redes y Vías Metabólicas/genética , Familia de Multigenes , Zea mays/microbiología , Aflatoxinas/genética , Aflatoxinas/metabolismo , Aspergilosis/genética , Aspergilosis/metabolismo , Aspergillus flavus/genética , Aspergillus flavus/fisiología , Catecoles/metabolismo , Productos Agrícolas/genética , Productos Agrícolas/metabolismo , Productos Agrícolas/microbiología , Resistencia a la Enfermedad/genética , Regulación de la Expresión Génica de las Plantas , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Organismos Modificados Genéticamente , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/microbiología , Quercetina/metabolismo , Ácido Salicílico/metabolismo , Semillas , Zea mays/genética , Zea mays/metabolismoRESUMEN
Escherichia coli serotype O157:H7 is one of the major agents of pathogen outbreaks associated with fresh fruits and vegetables. Gaseous chlorine dioxide (ClO2) has been reported to be an effective intervention to eliminate bacterial contamination on fresh produce. Although remarkable positive effects of low doses of ClO2 have been reported, the genetic regulatory machinery coordinating the mechanisms of xenobiotic effects and the potential bacterial adaptation remained unclear. This study examined the temporal transcriptome profiles of E. coli O157:H7 during exposure to different doses of ClO2 in order to elucidate the genetic mechanisms underlying bacterial survival under such harsh conditions. Dosages of 1 µg, 5 µg, and 10 µg ClO2 per gram of tomato fruits cause different effects with dose-by-time dynamics. The first hour of exposure to 1 µg and 5 µg ClO2 caused only partial killing with significant growth reduction starting at the second hour, and without further significant reduction at the third hour. However, 10 µg ClO2 exposure led to massive bacterial cell death at 1 h with further increase in cell death at 2 and 3 h. The first hour exposure to 1 µg ClO2 caused activation of primary defense and survival mechanisms. However, the defense response was attenuated during the second and third hours. Upon treatment with 5 µg ClO2, the transcriptional networks showed massive downregulation of pathogenesis and stress response genes at the first hour of exposure, with decreasing number of differentially expressed genes at the second and third hours. In contrast, more genes were further downregulated with exposure to 10 µg ClO2 at the first hour, with the number of both upregulated and downregulated genes significantly decreasing at the second hour. A total of 810 genes were uniquely upregulated at the third hour at 10 µg ClO2, suggesting that the potency of xenobiotic effects had led to potential adaptation. This study provides important knowledge on the possible selection of target molecules for eliminating bacterial contamination on fresh produce without overlooking potential risks of adaptation.
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BACKGROUND: Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children, accounting for up to 23% of pediatric epilepsy. The pathogenesis of BECTS is unknown, but it is thought that genetic factors play a role in susceptibility to the disease. METHODS: To investigate the role of common genetic variants in BECTS pathogenesis, a 2-stage genome-wide association study (GWAS) was performed in 1,800 Chinese Han BECTS patients, and 7,090 healthy controls. Genetic findings were used in a Mendelian Randomization study in the UK Biobank dataset to investigate the potential role of smoking in BECTS. FINDINGS: Definitive evidence of a role for common-variant heritability was demonstrated, with heritability of BECTS of >10% observed even with conservative disease prevalence assumptions. Although no individual locus achieved genome-wide significance, twelve loci achieved suggestive evidence of association (5 × 10-8