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Cognitive deficits are the core feature of schizophrenia and effective treatment strategies are still missing. Previous studies have reported that fisetin promotes long-term potentiation (LTP) and cognitive function in normal rodents and other model animals of neurological diseases. The aim of this study was to assess the effect of fisetin on synaptic plasticity and cognitive deficits caused by a brief disruption of N-methyl-D-aspartate receptors (NMDARs) with dizocilpine (MK-801) during early development in rats. The cognitive performance was examined by the Morris water maze task and a fear conditioning test. Hippocampal synaptic plasticity was investigated by field potential recording. The expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) and cognition-related proteins was measured by western blotting. We found that intraperitoneal administration of fisetin rescued hippocampus-dependent spatial and contextual fear memory in MK-801 rats. In parallel with these behavioral results, fisetin treatment in MK-801 rats reversed the impairment of hippocampal LTP. At the molecular level, fisetin treatment selectively increased the phosphorylation and surface expression of AMPA receptor subunit 1 (GluA1) in MK-801-treated rats. Moreover, fisetin restored the phosphorylation levels of calcium-calmodulin-dependent kinaseII (CaMKII), cAMP response element-binding protein (CREB), and the extracellular signal-regulated kinase (ERK1/2) in MK-801-treated rats. Collectively, our findings demonstrate that fisetin treatment can reverse the deficits of hippocampal synaptic plasticity and memory in a male rat model of schizophrenia by restoring the phosphorylation and surface expression of AMPAR GluA1 subunit, suggesting fisetin as a promising therapeutic candidate for schizophrenia-associated cognitive deficits.
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Cognição/efeitos dos fármacos , Flavonóis/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Receptores de AMPA/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Sinapses/efeitos dos fármacos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Medo/psicologia , Injeções Intraperitoneais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Psicologia do EsquizofrênicoRESUMO
BACKGROUND: An increasing number of techniques have been used for prenatal diagnosis of genetic abnormalities. Our initial objective was to explore the value of the BACs-on-Beads (BoBs) assay for the prenatal diagnosis of aneuploidies and microdeletion/microduplication syndromes in Quanzhou, Southeast China. METHODS: A total of 1409 pregnant women with high-risk factors for chromosomal abnormalities admitted to Quanzhou Women's and Children's Hospital were enrolled in this study. BoBs assays and karyotype analyses were conducted for all subjects. Subsequently, chromosome microarray analysis (CMA) or fluorescence in situ hybridization (FISH) was performed to validate the findings. RESULTS: In this study, karyotype analysis and BoBs assay failed in 4 cases, and 2 cases, respectively. A total of 1403 cases were successfully analyzed, with success rates of 99.72% (1405/1409) and 99.85% (1407/1409) for karyotype analysis and Bobs assay, respectively. BoBs assay rapidly detected chromosomal aneuploidies in line with the karyotyping data. Additionally, 23 cases of microdeletions/microduplications were detected by BoBs assay but missed by karyotyping, including 22q11.2 microdeletions/microduplications, 5p15.32p15.33 microdeletion, Xp22.31 microdeletions/microduplications, Xq27.3 microdeletion, and Yp11.2 and Yq11.22q11.222 microduplication. In comparison with karyotyping, fewer mosaicisms were identified by BoBs assay. A high detection rate of chromosomal abnormalities was observed in the high-risk group during noninvasive prenatal testing (NIPT) (41.72%) and the abnormal ultrasound group (13.43%). CONCLUSIONS: BoBs assay can be used for the rapid and efficient prenatal diagnosis of common aneuploidies and microdeletion/microduplication syndromes. Moreover, the combined use of BoBs assay and karyotyping in prenatal diagnosis may allow for a more effective detection of chromosomal abnormalities.
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Aberrações Cromossômicas/embriologia , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Diagnóstico Pré-Natal/métodos , Adulto , China , Feminino , Idade Gestacional , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , GravidezRESUMO
BACKGROUND: Microglial polarization and the subsequent neuroinflammatory response are contributing factors for traumatic brain injury (TBI)-induced secondary injury. High mobile group box 1 (HMGB1) mediates the activation of the NF-κB pathway, and it is considered to be pivotal in the late neuroinflammatory response. Activation of the HMGB1/NF-κB pathway is closely related to HMGB1 acetylation, which is regulated by the sirtuin (SIRT) family of proteins. Omega-3 polyunsaturated fatty acids (ω-3 PUFA) are known to have antioxidative and anti-inflammatory effects. We previously demonstrated that ω-3 PUFA inhibited TBI-induced microglial activation and the subsequent neuroinflammatory response by regulating the HMGB1/NF-κB signaling pathway. However, no studies have elucidated if ω-3 PUFA affects the HMGB1/NF-κB pathway in a HMGB1 deacetylation of dependent SIRT1 manner, thus regulating microglial polarization and the subsequent neuroinflammatory response. METHODS: The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, rotarod test, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and HMGB1, were used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1/NF-κB signaling pathway activation to evaluate the effects of ω-3 PUFA supplementation. The impact of SIRT1 deacetylase activity on HMGB1 acetylation and the interaction between HMGB1 and SIRT1 were assessed to evaluate anti-inflammation effects of ω-3 PUFAs, and also, whether these effects were dependent on a SIRT1-HMGB1/NF-κB axis to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI. RESULTS: The results of our study showed that ω-3 PUFA supplementation promoted a shift from the M1 microglial phenotype to the M2 microglial phenotype and inhibited microglial activation, thus reducing TBI-induced inflammatory factors. In addition, ω-3 PUFA-mediated downregulation of HMGB1 acetylation and its extracellular secretion was found to be likely due to increased SIRT1 activity. We also found that treatment with ω-3 PUFA inhibited HMGB1 acetylation and induced direct interactions between SIRT1 and HMGB1 by elevating SIRT1 activity following TBI. These events lead to inhibition of HMGB1 nucleocytoplasmic translocation/extracellular secretion and alleviated HMGB1-mediated activation of the NF-κB pathway following TBI-induced microglial activation, thus inhibiting the subsequent inflammatory response. CONCLUSIONS: The results of this study suggest that ω-3 PUFA supplementation attenuates the inflammatory response by modulating microglial polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway, leading to neuroprotective effects following experimental traumatic brain injury.
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Lesões Encefálicas Traumáticas/complicações , Polaridade Celular/fisiologia , Ácidos Graxos Ômega-3 , Inflamação/tratamento farmacológico , Inflamação/etiologia , Transdução de Sinais/fisiologia , Sirtuína 1/metabolismo , Animais , Barreira Hematoencefálica/fisiopatologia , Lesões Encefálicas Traumáticas/patologia , Permeabilidade Capilar/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Proteína HMGB1/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Atividade Motora/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Exame Neurológico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Microglial activation and the subsequent inflammatory response in the central nervous system play important roles in secondary damage after traumatic brain injury (TBI). High-mobility group box 1 (HMGB1) protein, an important mediator in late inflammatory responses, interacts with transmembrane receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) to activate downstream signaling pathways, such as the nuclear factor (NF)-κB signaling pathway, leading to a cascade amplification of inflammatory responses, which are related to neuronal damage after TBI. Omega-3 polyunsaturated fatty acid (ω-3 PUFA) is a commonly used clinical immunonutrient, which has antioxidative and anti-inflammatory effects. However, the effects of ω-3 PUFA on HMGB1 expression and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway are not clear. METHODS: The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglial activation in lesioned sites and protein markers for proinflammatory, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, interferon (IFN)-γ, and HMGB1 were used to evaluate neuroinflammatory responses and anti-inflammation effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway to evaluate the effects of ω-3 PUFA supplementation and gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI. RESULTS: It was found that ω-3 PUFA supplementation inhibited TBI-induced microglial activation and expression of inflammatory factors (TNF-α, IL-1ß, IL-6, and IFN-γ), reduced brain edema, decreased neuronal apoptosis, and improved neurological functions after TBI. We further demonstrated that ω-3 PUFA supplementation inhibited HMGB1 nuclear translocation and secretion and decreased expression of HMGB1 in neurons and microglia in the lesioned areas. Moreover, ω-3 PUFA supplementation inhibited microglial activation and the subsequent inflammatory response by regulating HMGB1 and the TLR4/NF-κB signaling pathway. CONCLUSIONS: The results of this study suggest that microglial activation and the subsequent neuroinflammatory response as well as the related HMGB1/TLR4/NF-κB signaling pathway play essential roles in secondary injury after TBI. Furthermore, ω-3 PUFA supplementation inhibited TBI-induced microglial activation and the subsequent inflammatory response by regulating HMGB1 nuclear translocation and secretion and also HMGB1-mediated activation of the TLR4/NF-κB signaling pathway, leading to neuroprotective effects.
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Lesões Encefálicas Traumáticas/patologia , Encefalite/dietoterapia , Ácidos Graxos Ômega-3/administração & dosagem , Proteína HMGB1/metabolismo , Microglia/efeitos dos fármacos , Neuroprostanos/administração & dosagem , Animais , Edema Encefálico/etiologia , Lesões Encefálicas Traumáticas/complicações , Proteínas de Ligação ao Cálcio/metabolismo , Córtex Cerebral/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalite/etiologia , Encefalite/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/patologia , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Fatores de TempoRESUMO
BACKGROUND: Limited research has been conducted regarding the elucidation of genotype-phenotype correlations within the 20q13.33 region. The genotype-phenotype association of 20q13.33 microdeletion remains inadequately understood. In the present study, two novel cases of 20q13.33 microdeletion were introduced, with the objective of enhancing understanding of the genotype-phenotype relationship. METHODS: Two unrelated patients with various abnormal clinical phenotypes from Fujian province Southeast China were enrolled in the present study. Karyotype analysis and chromosomal microarray analysis (CMA) were performed to investigate chromosomal abnormalities and copy number variants. RESULTS: The results of high-resolution G-banding karyotype analysis elicited a 46,XY,der(20)add(20)(q13.3) in Patient 1. This patient exhibited various clinical manifestations, such as global developmental delay, intellectual disability, seizures, and other congenital diseases. Subsequently, a 1.0-Mb deletion was identified in the 20q13.33 region alongside a 5.2-Mb duplication in the 14q32.31q32.33 region. In Patient 2, CMA results revealed a 1.8-Mb deletion in the 20q13.33 region with a 4.8-Mb duplication of 17q25.3. The patient exhibited additional abnormal clinical features, including micropenis, congenital heart disease, and a distinctive crying pattern characterized by a crooked mouth. CONCLUSION: In the present study, for the first time, an investigation was conducted into two novel cases of 20q13.33 microdeletion with microduplications in the 17q25.3 and 14q32.31q32.33 regions in the Chinese population. The presence of micropenis may be attributed to the 20q13.33 microdeletion, potentially expanding the phenotypic spectrum associated with this deletion.
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Estruturas Cromossômicas , Doenças dos Genitais Masculinos , Deficiência Intelectual , Pênis/anormalidades , Criança , Humanos , Deficiência Intelectual/genética , Cariotipagem , CariótipoRESUMO
Few existing reports have investigated the copy number variants (CNVs) in fetuses with central nervous system (CNS) anomalies. To gain further insights into the genotype-phenotype relationship, we conducted chromosomal microarray analysis (CMA) to reveal the pathogenic CNVs (pCNVs) that were associated with fetal CNS anomalies. We enrolled 5,460 pregnant women with different high-risk factors who had undergone CMA. Among them, 57 subjects with fetal CNS anomalies were recruited. Of the subjects with fetal CNS anomalies, 23 were given amniocentesis, which involved karyotype analysis and CMA to detect chromosomal abnormalities. The other 34 cases only underwent CMA detection using fetal abortive tissue. In this study, we identified five cases of chromosome aneuploid and nine cases of pCNVs in the fetuses, with a chromosomal aberration detection rate of 24.56% (14/57). In the 23 cases that were given both karyotype and CMA analysis, one case with trisomy 18 was detected by karyotyping. Moreover, CMA revealed a further three cases of pCNVs, including the 1p36.33p36.31, 7q11.23, and 1q21.1q21.2 microdeletions, with a 13.04% (3/23) increase in CMA yield over the karyotype analysis. Additionally, three cases of trisomy 13, one case of trisomy 21, and six cases of pCNVs were detected in the other 34 fetuses where only CMA was performed. Furthermore, a higher chromosomal aberration detection rate was observed in the extra CNS anomaly group than in the isolated CNS anomaly group (40.91% vs 14.29%). In conclude, several pathogenic CNVs were identified in the fetuses with CNS anomalies using CMA. Among the detected CNVs, ZIC2, GNB1, and NSUN5 may be the candidate genes that responsible for fetal CNS anomalies. Our findings provides an additional reference for genetic counseling regarding fetal CNS anomalies and offers further insight into the genotype-phenotype relationship.
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Doenças do Sistema Nervoso Central , Malformações do Sistema Nervoso , Gravidez , Feminino , Humanos , Estudos Retrospectivos , Diagnóstico Pré-Natal , Aberrações Cromossômicas , Cariotipagem , Análise em Microsséries , Feto/anormalidades , Cariótipo , Variações do Número de Cópias de DNA/genéticaRESUMO
BACKGROUND: Rare and novel variants of HBA1/2 and HBB genes resulting in thalassemia and hemoglobin (Hb) variants have been increasingly identified. Our goal was to identify two rare Hb variants in Chinese population using third-generation sequencing (TGS) technology. METHODS: Enrolled in this study were two Chinese families from Fujian Province. Hematological screening was conducted using routine blood analysis and Hb capillary electrophoresis analysis. Routine thalassemia gene testing was carried out to detect the common mutations of α- and ß-thalassemia in Chinese population. Rare or novel α- and ß-globin gene variants were further investigated by TGS. RESULTS: The proband of family 1 was a female aged 32, with decreased levels of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), Hb A2, and abnormal Hb bands in zone 5 and zone 12. No common thalassemia mutations were detected by routine thalassemia analysis, while a rare α-globin gene variant Hb Jilin [α139(HC1)Lys>Gln (AAA>CAA); HBA2:c.418A>C] was identified by TGS. Subsequent pedigree analysis showed that the proband's son also harbored the Hb Jilin variant with slightly low levels of MCH, Hb A2, and abnormal Hb bands. The proband of family 2 was a male at 41 years of age, exhibiting normal MCV and MCH, but a low level of Hb A2 and an abnormal Hb band in zone 12 without any common α- and ß-thalassemia mutations. The subsequent TGS detection demonstrated a rare Hb Beijing [α16(A14)Lys>Asn (AAG>AAT); HBA2:c.51G>T] variant in HBA2 gene. CONCLUSION: In this study, for the first time, we present two rare Hb variants of Hb Jilin and Hb Beijing in Fujian Province, Southeast China, using TGS technology.
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Talassemia , Talassemia beta , Humanos , Masculino , Feminino , Talassemia beta/genética , Talassemia/genética , Mutação , Índices de Eritrócitos , China/epidemiologiaRESUMO
BACKGROUND: Causative mutations of PBX1 are associated with congenital abnormalities of the kidney and urinary tract (CAKUT), often accompanied by hearing loss, abnormal ear morphology, or developmental delay. The aim of the present investigation was to introduce a novel variant in the PBX1 gene identified in a Chinese family, leading to recurrent neonatal mortality. METHODS: A pregnant woman (gravida 5, para 0), who had experienced recurrent neonatal deaths, sought genetic etiology diagnosis. Whole exome sequencing (WES) was conducted to identify sequence variants and copy number variants in the fetus presenting with posterior nuchal cystic hygroma and fetal hydrops. RESULTS: A novel NM_002585.4:c.694G>C(p.D232H) in PBX1 was identified in the fetus through trio whole exome sequencing (WES), revealing a paternal mosaic PBX1 variant in blood at 11.54% (6/52 variants reads). Subsequent parental Sanger sequencing confirmed the variant detected by WES. Ultimately, the variant was classified as likely pathogenic, leading the family to elect pregnancy termination at 17 weeks gestation. CONCLUSION: The novel variant in the PBX1 gene appears to be a significant factor contributing to recurrent neonatal deaths in the Chinese family. Such findings expand the spectrum of PBX1 gene variants and provide valuable perinatal guidance for diagnosing fetuses with PBX1 mutations.
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Sequenciamento do Exoma , Fator de Transcrição 1 de Leucemia de Células Pré-B , Humanos , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Sequenciamento do Exoma/métodos , Feminino , Gravidez , Recém-Nascido , Morte Perinatal , Masculino , Povo Asiático/genética , Mutação/genética , China , Adulto , Linhagem , População do Leste AsiáticoRESUMO
Hemoglobin (Hb) Lepore is a rare deletional δß-thalassemia caused by the fusion between delta-beta genes, and cannot be identified by traditional thaltassemia gene testing technology. The aim of this study was to conduct molecular diagnosis and clinical analysis of Hb Lepore in four unrelated Chinese families using third generation sequencing. Decreased levels of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and an abnormal Hb band were observed in the probands of the four families. However, no common α and ß-thalassemia variants were detected in the enrolled families using polymerase chain reaction-reverse dot blot hybridization based traditional thalassemia gene testing. Further third-generation sequencing revealed similar Hb Lepore-Boston-Washington variants in all the patients, which were resulted from partial coverage of the HBB and HBD globin genes, leading to the formation of a delta-beta fusion gene. Specific gap-PCR and Sanger sequencing confirmed that all the patients carried a similar Hb Lepore-Boston-Washington heterozygote. In addition, decreased levels of MCH and Hb A2 were observed in the proband's wife of family 2, an extremely rare variant of Hb Nanchang (GGT > AGT) (HBA2:c.46G > A) was identified by third-generation sequencing and further confirmed by Sanger sequencing. This present study was the first to report the similar Hb Lepore-Boston-Washington in Chinese population. By combining the utilization of Hb capillary electrophoresis and third-generation sequencing, the screening and diagnosis of Hb Lepore can be effectively enhanced.
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Povo Asiático , Hemoglobinas Anormais , Adulto , Feminino , Humanos , Masculino , Povo Asiático/genética , Globinas beta/genética , Talassemia beta/genética , Talassemia beta/diagnóstico , Talassemia beta/sangue , China , População do Leste Asiático , Hemoglobinas Anormais/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , LinhagemRESUMO
Sarcopenia has been recognized as an emerging complication of type 2 diabetes mellitus (T2DM). Currently, the pathogenesis of T2DM-related sarcopenia remains unclear. The aim of this study was to investigate the molecular mechanisms and potential therapeutic targets for T2DM-related sarcopenia. In this study, a T2DM-related sarcopenia mouse model was established using db/db mice. Proteins extracted from the gastrocnemius muscles of db/db mice and littermate control db/m mice were analyzed by a 4D label-free quantitative proteomics approach. A total of 131 upregulated and 68 downregulated proteins were identified as differentially expressed proteins (DEPs). Bioinformatics analysis revealed that DEPs were significantly enriched in lipid metabolism. Protein-protein interaction network analysis revealed that six hub proteins, including ACOX1, CPT2, ECI2, ACADVL, ACADL, and ECH1, were involved in the fatty acid oxidation. The hub protein-transcription factor-miRNA network was also constructed using the NetworkAnalyst tool. Finally, the hub proteins were validated by Western blotting and immunohistochemistry and further confirmed to be significantly negatively correlated with muscle mass and grip strength. Our study suggested that lipid metabolism, especially excessive fatty acid oxidation, may be a crucial contributor to the progression of T2DM-related sarcopenia and a common cause of the inter-relationship between T2DM and sarcopenia. Targeting lipid metabolism may be a promising therapeutic strategy for T2DM-related sarcopenia.
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Objective: Accumulating evidence has indicated that neurodevelopmental defects may underlie the pathophysiology of bipolar disorder (BD). Insulin-like growth factors (IGFs) are a family of neurotrophic factors that are essential for the survival and development of neurons. The present study aims to investigate whether IGF-2 signaling is implicated in the pathophysiological processes of BD. Method: 50 healthy controls and 78 patients with BD, including 23 patients who diagnosed acute depressive episode and 55 patients who diagnosed acute manic episode, were recruited in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) and the Young Mania Rating Scale (YMRS) were used to assess the severity of the depressive and manic symptoms, respectively. The serum IGF-2 level was determined by an enzyme-linked immunosorbent assay (ELISA). The Kolmogorov-Smirnov and Mann-Whitney U tests were used for between-group comparisons and spearman analysis was used to analyze correlations. Results: Patients with BD had lower serum IGF-2 levels (66.08 ± 21.22 ng/ml) when compared to healthy controls (88.72 ± 31.55 ng/ml). BD patients were divided into manic episode and depressive episode subgroups. We found that serum IGF-2 levels were reduced in both the mania and depression subgroups (mania: 67.19 ± 21.52 ng/ml, depression: 63.43 ± 20.67 ng/ml; P < 0.001), while no significant difference was observed between two groups (P > 0.05). Spearman correlation analyses revealed that the levels of serum IGF-2 were negatively correlated with the YMRS scores in BD patients (r = -0.522, P < 0.001). Furthermore, IGF-2 was found to be an independent contributor to the severity of symptoms in patients with manic episodes (B = -0.610, t = -5.299, P < 0.001). Conclusion: Lower serum IGF-2 levels were found in BD patients and correlated with the severity of the manic symptoms in these patients during manic episodes. These results suggest that reduced IGF-2 levels might be involved in the pathophysiology of BD, and serum IGF-2 could be a peripheral biomarker for the evaluation of the severity of manic symptoms in BD patients.
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Objective: The aim of this study is to investigate the clinical value of radiomics based on non-enhanced head CT in the prediction of hemorrhage transformation in acute ischemic stroke (AIS). Materials and methods: A total of 140 patients diagnosed with AIS from January 2015 to August 2022 were enrolled. Radiomic features from infarcted areas on non-enhanced CT images were extracted using ITK-SNAP. The max-relevance and min-redundancy (mRMR) and the least absolute shrinkage and selection operator (LASSO) were used to select features. The radiomics signature was then constructed by multiple logistic regressions. The clinicoradiomics nomogram was constructed by combining radiomics signature and clinical characteristics. All predictive models were constructed in the training group, and these were verified in the validation group. All models were evaluated with the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). Results: Of the 140 patients, 59 experienced hemorrhagic transformation, while 81 remained stable. The radiomics signature was constructed by 10 radiomics features. The clinicoradiomics nomogram was constructed by combining radiomics signature and atrial fibrillation. The area under the ROC curve (AUCs) of the clinical model, radiomics signature, and clinicoradiomics nomogram for predicting hemorrhagic transformation in the training group were 0.64, 0.86, and 0.86, respectively. The AUCs of the clinical model, radiomics signature, and clinicoradiomics nomogram for predicting hemorrhagic transformation in the validation group were 0.63, 0.90, and 0.90, respectively. The DCA curves showed that the radiomics signature performed well as well as the clinicoradiomics nomogram. The DCA curve showed that the clinical application value of the radiomics signature is similar to that of the clinicoradiomics nomogram. Conclusion: The radiomics signature, constructed without incorporating clinical characteristics, can independently and effectively predict hemorrhagic transformation in AIS patients.
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[This corrects the article DOI: 10.3389/fpsyt.2024.1354999.].
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Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated primary inflammatory myelinopathy of the central nervous system that primarily affects the optic nerve and spinal cord. The aquaporin 4 antibody (AQP4-Ab) is a specific autoantibody marker for NMOSD. Most patients with NMOSD are seropositive for AQP4-Ab, thus aiding physicians in identifying ways to treat NMOSD. AQP4-Ab has been tested in many clinical and laboratory studies, demonstrating effectiveness in diagnosing NMOSD. Recently, novel assays have been developed for the rapid and accurate detection of AQP4-Ab, providing further guidance for the diagnosis and treatment of NMOSD. This article summarizes the importance of rapid and accurate diagnosis for treating NMOSD based on a review of the latest relevant literature. We discussed current challenges and methods for improvement to offer new ideas for exploring rapid and accurate AQP4-Ab detection methods, aiming for early diagnosis of NMOSD.
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BACKGROUND: Isolated terminal 4q35.2 microdeletion is an extremely rare copy number variant affecting people all over the world. To date, researchers still have controversial opinions and results on its pathogenicity. Here, we aim to present a Chinese pediatric patient with terminal 4q35.2 microdeletion and use this case to clarify the underlying genotype-phenotype correlation. METHODS: A 17-year-old boy from Quanzhou, South China, was recruited as the main subject in this study. Karyotype and single-nucleotide polymorphism (SNP) based microarray analysis were carried out to detect chromosomal abnormalities and copy number variants in this family. Trio whole exome sequencing (Trio-WES) was performed to investigate the potential pathogenic variant in this family. RESULTS: During observation, we identified abnormal clinical phenotypes including upper eyelid ptosis, motor developmental delay, abnormal posturing, abnormality of coordination, attention deficit hyperactivity disorder, and involuntary movements in the patient. SNP array analysis results confirmed a case of 2.0 Mb 4q35.2 microdeletion and parental SNP array verification results indicated that the terminal 4q35.2 microdeletion was inherited from his mother. No copy number variants were detected in his father. In addition, the trio-WES results demonstrated none of pathogenic or likely pathogenic variants in the patient. CONCLUSIONS: This study brings a novel analysis of a case of 2.0 Mb terminal 4q35.2 microdeletion affecting a Chinese individual. In addition, additional clinical symptoms such as upper eyelid ptosis and involuntary movements were first reported to affect a patient with terminal 4q35.2 microdeletion, which may broaden the phenotype spectrum of the condition.
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The neurovascular unit (NVU) is composed of neurons, glial cells, and blood vessels. NVU dysfunction involves the processes of neuroinflammation, and microcirculatory disturbances, as well as neuronal injury after traumatic brain injury (TBI). Traditional anti-inflammatory drugs have limited efficacy in improving the prognosis of TBI. Thus, treatments that target NVU dysfunction may provide a breakthrough. A large number of clinical studies have shown that the nutritional status of patients with TBI was closely related to their conditions and prognoses. Nutrient complexes and complementary therapies for the treatment of TBI are therefore being implemented in many preclinical studies. Importantly, the mechanism of action for this treatment may be related to repair of NVU dysfunction by ensuring adequate omega-3 fatty acids, curcumin, resveratrol, apigenin, vitamins, and minerals. These nutritional supplements hold promise for translation to clinical therapy. In addition, dietary habits also play an important role in the rehabilitation of TBI. Poor dietary habits may worsen the pathology and prognosis of TBI. Adjusting dietary habits, especially with a ketogenic diet, may improve outcomes in patients with TBI. This article discusses the impact of clinical nutrition on NVU dysfunction after TBI, focusing on nutritional complexes and dietary habits.
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Lesões Encefálicas Traumáticas , Estado Nutricional , Humanos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Suplementos Nutricionais , Microcirculação , Vitaminas/uso terapêutico , Comportamento AlimentarRESUMO
BACKGROUND: Pathogenic PAK1 variants were described to be causative of neurodevelopmental disorder with macrocephaly, seizures, and speech delay. Herein, we present a de novo PAK1 variant combine with a de novo terminal 1q microdeletion in a Chinese pediatric patient, aiming to provide more insights into the underlying genotype-phenotype relationship. METHODS: Enrolled in this study was a 6-year-old girl with clinical features of global developmental delay, severe intellectual disability, speech delay, and seizures from Quanzhou region of China. Karyotype and chromosomal microarray analysis (CMA) were performed to detect chromosome abnormalities in this family. Whole exome sequencing (WES) was performed to investigate additional genetic variants in this family. RESULTS: No chromosomal abnormalities were elicited from the entire family by karyotype analysis. Further familial CMA results revealed that the patient had a de novo 2.7-Mb microdeletion (arr[GRCh37] 1q44(246,454,321_249,224,684) × 1]) in 1q44 region, which contains 14 OMIM genes, but did not overlap the reported smallest region of overlap (SRO) responsible for the clinical features in 1q43q44 deletion syndrome. In addition, WES result demonstrated a de novo NM_002576: c.251C > G (p.T84R) variant in PAK1 gene in the patient, which was interpreted as a likely pathogenic variant. CONCLUSION: In this study, we identify a novel PAK1 variant associated with a terminal 1q microdeletion in a patient with neurodevelopmental disorder. In addition, we believe that the main clinical features may ascribe to the pathogenic variant in PAK1 gene in the patient.
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Deficiência Intelectual , Transtornos do Desenvolvimento da Linguagem , Humanos , Aberrações Cromossômicas , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Quinases Ativadas por p21/genética , Fenótipo , Convulsões/genética , ChinaRESUMO
BACKGROUND: Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X-linked dominant, lethal male disorder caused by mutations to the NSDHL (NAD(P)H steroid dehydrogenase-like protein) gene. It primarily exhibits strictly unilateral congenital hemidysplasia with ichthyosiform erythroderma and ipsilateral limb defects in female individuals. METHODS: A Chinese couple suffering from recurrent spontaneous abortion in male fetuses was enrolled in this study. Chromosomal microarray analysis and whole-exome sequencing were performed for genetic etiological diagnosis. RESULTS: A 33-year-old pregnant woman with recurrent spontaneous abortion was experiencing her third pregnancy with a male embryo. In this pregnancy, a miscarriage occurred at a gestational age of 10+6 weeks with no copy number variants. However, a novel mutation c.790-6C>T in the NSDHL gene was observed in the fetus through whole-exome sequencing (WES). Parental verification indicated that the NSDHL gene variant was inherited from the mother. Additionally, the variant in the NSDHL gene was absent in her subsequent pregnancy with a female fetus. CONCLUSION: In this study, we detected c.790-6C>T, a novel variant in the NSDHL gene that results in recurrent miscarriage in males. Our study may broaden the scope of research on the NSDHL gene in CHILD syndrome and strengthens the application value of WES for the genetic etiological identification of recurrent miscarriage.
Assuntos
Anormalidades Múltiplas , Aborto Habitual , Nevo , Neoplasias Cutâneas , Adulto , Feminino , Humanos , Lactente , Masculino , Gravidez , 3-Hidroxiesteroide Desidrogenases/genética , Anormalidades Múltiplas/genética , Sequenciamento do Exoma , Mutação , Nevo/genética , Evolução Fatal , Resultado da GravidezRESUMO
CONTEXT.: Identification of rare thalassemia variants requires a combination of multiple diagnostic technologies. OBJECTIVE.: To investigate a new approach of comprehensive analysis of thalassemia alleles based on third-generation sequencing (TGS) for identification of α- and ß-globin gene variants. DESIGN.: Enrolled in this study were 70 suspected carriers of rare thalassemia variants. Routine gap-polymerase chain reaction and DNA sequencing were used to detect rare thalassemia variants, and TGS technology was performed to identify α- and ß-globin gene variants. RESULTS.: Twenty-three cases that carried rare variants in α- and ß-globin genes were identified by the routine detection methods. TGS technology yielded a 7.14% (5 of 70) increment of rare α- and ß-globin gene variants as compared with the routine methods. Among them, the rare deletional genotype of -THAI was the most common variant. In addition, rare variants of CD15 (G>A) (HBA2:c.46G>A), CD117/118(+TCA) (HBA1:c.354_355insTCA), and ß-thalassemia 3.5-kilobase gene deletion were first identified in Fujian Province, China; to the best of our knowledge, this is the second report in the Chinese population. Moreover, HBA1:c.-24C>G, IVS-II-55 (G>T) (HBA1:c.300+55G>T) and hemoglobin (Hb) Maranon (HBA2:c.94A>G) were first identified in the Chinese population. We also identified rare Hb variants of HbC, HbG-Honolulu, Hb Miyashiro, and HbG-Coushatta in this study. CONCLUSIONS.: TGS technology can effectively and accurately detect deletional and nondeletional thalassemia variants simultaneously in one experiment. Our study also demonstrated the application value of TGS-based comprehensive analysis of thalassemia alleles in the detection of rare thalassemia gene variants.
Assuntos
alfa-Globinas , Talassemia alfa , Globinas beta , Humanos , Alelos , Talassemia alfa/diagnóstico , Talassemia alfa/genética , Talassemia alfa/epidemiologia , Globinas beta/genética , População do Leste Asiático , Genótipo , Hemoglobinas Glicadas , Mutação , alfa-Globinas/genéticaRESUMO
BACKGROUND: Pathogenic mutations in EVC or EVC2 gene can lead to Ellis-van Creveld (EvC) syndrome, which is a rare autosomal recessive skeletal dysplasia disorder. This study aimed to determine pathogenic gene variations associated with EvC syndrome in fetuses showing ultrasound anomalies. METHODS: A 32-year-old pregnant woman from Quanzhou, China was investigated. In her pregnancy examination, the fetus exhibited multiple fetal malformations, including a narrow thorax, short limbs, postaxial polydactyly, cardiac malformations, and separation of double renal pelvis. Karyotype, chromosomal microarray analysis and whole exome sequencing were performed for prenatal genetic etiology analysis. RESULTS: Chromosome abnormalities and copy number variants were not observed in the fetus using karyotype and chromosomal microarray analysis. Using whole exome sequencing, two compound heterozygous variants NM_147127.5:c.[2484G>A(p.Trp828Ter)];[871-2_894del] in EVC2 gene were identified in the fetus as pathogenic variants inherited from parents. CONCLUSIONS: The study is the first to identify two rare compound variants in EVC2 gene in a Chinese family using whole exome sequencing. The application of whole-exome sequencing would be helpful in fetal etiological diagnosis with ultrasound anomalies.