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Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel NaV1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that NaV1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)] and compared them with neurons from an epileptic encephalopathy (EE) patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower NaV1.2 protein levels. In neurons with the frameshift variant, NaV1.2 mRNA and protein levels were reduced by ~ 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying NaV1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced NaV1.2 levels. In contrast, epilepsy neurons displayed no change in NaV1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced NaV1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to NaV1.2 dysfunction and can guide further investigations.
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Epilepsia , Discapacidad Intelectual , Epilepsia/genética , Discapacidad Intelectual/genética , Canal de Sodio Activado por Voltaje NAV1.2/genética , Canal de Sodio Activado por Voltaje NAV1.2/metabolismo , Neuronas/metabolismo , Convulsiones , Sodio/metabolismo , Canales de Sodio/genética , HumanosRESUMEN
BACKGROUND: The efficacy of antibody-targeted therapy of solid cancers is limited by the lack of consistent tumour-associated antigen expression. However, tumour-associated antigens shared with non-malignant cells may still be targeted using conditionally activated-antibodies, or by chimeric antigen receptor (CAR) T cells or CAR NK cells activated either by the tumour microenvironment or following 'unlocking' via multiple antigen-recognition. In this study, we have focused on tissue factor (TF; CD142), a type I membrane protein present on a range of solid tumours as a basis for future development of conditionally-activated BiTE or CAR T cells. TF is frequently upregulated on multiple solid tumours providing a selective advantage for growth, immune evasion and metastasis, as well as contributing to the pathology of thrombosis via the extrinsic coagulation pathway. METHODS: Two well-characterised anti-TF monoclonal antibodies (mAb) were cloned into expression or transposon vectors to produce single chain (scFv) BiTE for assessment as CAR and CD28-CD3-based CAR or CD3-based BiTE. The affinities of both scFv formats for TF were determined by surface plasmon resonance. Jurkat cell line-based assays were used to confirm the activity of the BiTE or CAR constructs. RESULTS: The anti-TF mAb hATR-5 and TF8-5G9 mAb were shown to maintain their nanomolar affinities following conversion into a single chain (scFv) format and could be utilised as CD28-CD3-based CAR or CD3-based BiTE format. CONCLUSION: Because of the broad expression of TF on a range of solid cancers, anti-TF antibody formats provide a useful addition for the development of conditionally activated biologics for antibody and cellular-based therapy.
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Receptores Quiméricos de Antígenos , Linfocitos T , Tromboplastina , Humanos , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Tromboplastina/inmunología , Tromboplastina/metabolismo , Linfocitos T/inmunología , Inmunoterapia Adoptiva/métodos , Anticuerpos de Cadena Única/inmunología , Anticuerpos de Cadena Única/genética , Neoplasias/inmunología , Neoplasias/terapia , Células JurkatRESUMEN
INTRODUCTION: Identification of acute funisitis, a sign of foetal inflammatory response (FIR), is crucial as their presence is associated with ominous neonatal outcomes. Recommendation on which part of umbilical cord should be sampled to facilitate optimal identification of acute funisitis is limited. METHODS: This is a retrospective cross-sectional study over a seven-month duration recruiting all patients with clinical suspicion of chorioamnionitis and/or maternal intrapartum pyrexia. The distribution and the degree of cord inflammation were assessed. The cases were also evaluated for maternal inflammatory response (MIR) and chorionic vasculitis (CV). RESULTS: Of the 191 placentas, 88 (46.1%) had some degree of cord inflammation. Forty-nine (55.7%) had a differential in cord inflammation, with distal cord section (n = 38) demonstrating significant greater inflammation than that of proximal cord section (n = 11) (p<0.001). There were 20 cases with phlebitis only and 8 cases demonstrated arteritis only in either proximal or distal cord sections. Increasing magnitude of cord inflammation was significantly associated with increasing severity of MIR and the rate of CV (p<0.001). CV was observed in 25 (24.3%) cases showing absence of cord inflammation, while 12 (13.6%) cases with cord FIR demonstrated no CV. DISCUSSION: Inflammatory reaction can occur variably throughout the length of the umbilical cord and chorionic plate vessels, with greater inflammation seen in the distal cord section. We affirm the current Amsterdam recommendation of submitting at least two cross sections of the cord representing proximal and distal sites and two sections from placental parenchyma to facilitate the identification of FIR.
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Corioamnionitis , Cordón Umbilical , Humanos , Corioamnionitis/patología , Corioamnionitis/diagnóstico , Femenino , Embarazo , Estudios Retrospectivos , Estudios Transversales , Cordón Umbilical/patología , Adulto , Inflamación/patología , Placenta/patologíaRESUMEN
No abstract available.
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Teratoma , Humanos , Teratoma/patología , Teratoma/congénito , Teratoma/diagnóstico , Femenino , Embarazo , Neoplasias Faciales/patología , Neoplasias Faciales/congénito , Neoplasias de la Boca/patología , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/congénito , AdultoRESUMEN
No abstract available.
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No abstract available.
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Eosinofilia , Enfermedades Placentarias , Vasculitis , Femenino , Humanos , Linfocitos T , CorionRESUMEN
INTRODUCTION: Lymphangiomatous polyp of the tonsil is generally accepted as a hamartomatous lesion. Its differential diagnosis includes fibroepithelial polyp, squamous papilloma, angiofibroma, haemangioma, arteriovenous malformation, hamartoma and lymphangioma. CASE REPORT: A 33-year-old man presented with 2 months history of feeling of foreign body sensation in the throat. Examination revealed a nodular red coloured polyp on the left tonsil. Histologically, the polyp was covered by squamous epithelium and is composed of numerous vascular channels containing lymphocytes and eosinophilic material, in a fibrous stroma. Immunohistochemically, the endothelial cells were positive toward CD31 and D2-40. DISCUSSION: The characteristic histological features of a lymphangiomatous polyp are benign vascular proliferation with variable fibrous, adipose and lymphoid stromal components. Nested intraepithelial epidermotropism of lymphocytes can be observed. The vascular channels are typically thin-walled and contain eosinophilic proteinaceous material and lymphocytes. There is no reported incidence of recurrent or malignant transformation.
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Carcinoma de Células Escamosas , Hamartoma , Masculino , Humanos , Adulto , Tonsila Palatina , Globo Faríngeo , Células Endoteliales , Diagnóstico DiferencialRESUMEN
INTRODUCTION: Hydatidiform mole is one of the gestational trophoblastic disease and comprises complete (CM) and partial moles (PM), which carries a risk of developing persistence disease, invasive mole or choriocarcinoma. MicroRNAs (miRNAs) have been discovered in various tissues, including neoplastic tissues. Its role in the pathogenesis of molar pregnancy or as biomarkers are still largely uncertain. The aim of this study is to identify the differentially expressed miRNAs in CM and PM. MATERIALS AND METHODS: Using next-generation sequencing, the miRNAs profiles of CM (n=3) and PM (n=3) moles, including placenta of non-molar abortus (n=3) as control were determined. The differentially expressed miRNAs between each group were analysed. Subsequently, bioinformatics analysis using miRDB and Targetscan was utilised to predict target genes. RESULTS: We found 10 differentially expressed miRNAs in CMs and PMs, compared to NMAs, namely miR- 518a-5p, miR-423-3p, miR-503-5p, miR-302a-3p, and miR-1323. The other 5 miRNAs were novel, not listed in the known database. The 3 differentially expressed miRNAs in CMs were predicted to commonly target ZTBT46 and FAM73B mRNAs. DISCUSSION: miR-518 was consistently observed to be downregulated in CM versus PM, and CM versus NMA. Further bioinformatic analysis to provide insight into the possible role of these miRNAs in the pathogenesis of HMs, progression of disease and as potential diagnostic biomarkers as well as therapeutic targets for HMs is needed.
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Coriocarcinoma , Mola Hidatiforme , MicroARNs , Topos , Embarazo , Femenino , Humanos , Animales , Topos/genética , Mola Hidatiforme/genética , MicroARNs/genética , Biomarcadores , Perfilación de la Expresión GénicaRESUMEN
AIMS: To determine the prevalence of neovascularity in the supraspinatus tendon of patients presenting with clinically painful unilateral rotator cuff tendinopathy (RCT) using conventional colour Doppler ultrasound (CDU), power Doppler ultrasound (PDU), and superb microvascular imaging (SMI). The association between Doppler findings and clinical scores was also assessed. METHODS: The bilateral supraspinatus of consecutive patients presented with unilateral RCT clinically were evaluated with grey-scale ultrasound (tendon thickening, heterogeneous echotexture, and hypoechogenicity), CDU, PDU, and SMI. The prevalence of neovascularity and grey-scale changes on duplex imaging techniques were analysed. The relationship between neovascularity on CDU, PDU, SMI, and pain/disability as determined using a visual analogue scale (VAS) and the Oxford Shoulder Score (OSS) were assessed. RESULTS: Fifty-nine patients (mean age 53 years, 39 women) were recruited. Of the symptomatic supraspinatus tendons, 42.4% (25/59) demonstrated neovascularity on SMI, compared to 6.8% (4/59) on PDU and 5.1% (3/59) on CDU. Of the asymptomatic supraspinatus tendons, 5.1% (3/59) depicted neovascularity on SMI but not on conventional Doppler techniques. SMI showed a significant correlation with the VAS (r2 = 0.560, p<0.001) and OSS (r2 = 0.62, p<0.001). PDU weakly correlated with the VAS and OSS (r2 = 0.312, p=0.016; r2 = 0.260, p=0.047, respectively) while CDU did not show a significant relationship. CONCLUSION: SMI is superior in demonstrating neovascularity and shows better correlation with pain and functional deficit compared to conventional Doppler in patients with painful RCT. SMI also showed vascularity to a lesser degree in the asymptomatic tendon. Further large-scale studies are needed to prove the diagnostic value of SMI in the assessment of RCT.
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Manguito de los Rotadores , Tendinopatía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/diagnóstico por imagen , Neovascularización Patológica/epidemiología , Dolor , Prevalencia , Manguito de los Rotadores/diagnóstico por imagen , Tendinopatía/diagnóstico por imagen , Tendinopatía/epidemiología , Ultrasonografía Doppler en ColorRESUMEN
In mobile communication systems, congestion is related to high-traffic events (HTEs) that occur in the coverage areas of base stations. Understanding, recognizing, and predicting these HTEs and researching their occurrence rules provides theoretical and decision-making support for preventing system congestion. Communication sectors are regarded as nodes, and if HTEs occur synchronously among sectors, then the corresponding nodes are connected. The total number of synchronous HTEs determines the edge weights. The mobile-communication spatiotemporal data are mapped to a weighted network, with the occurrence locations of HTEs as the basic elements. Network analysis provides a structure for representing the interaction of HTEs. By analyzing the topological features of the event synchronization network, the associations among the occurrence times of HTEs can be mined. We find that the event synchronization network is a small-world network, the cumulative strength distribution is exponential, and the edge weight obeys a power law. Moreover, the node clustering coefficient is negatively correlated with the node degree. A congestion coefficient based on several topological parameters is proposed, and the system congestion is visualized. The congestion coefficient contains information about the synchronous occurrence of HTEs between a sector and its neighbors and information about the synchronous occurrence of HTEs among its neighbors. For the mobile communication system considered in this study, the congestion coefficient of a large number of sectors is small and the risk of system congestion is low.
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ComunicaciónRESUMEN
1. The objective of this study was to investigate the evolution of SCNN1B and AHCYL1 proteins among 10 domestic avian and mammalian animal species, to uncover the expression patterns of SCNN1B and AHCYL1 genes in ducks, identify the genetic variants of the SCNN1B and AHCYL1 genes and analyse their effects on eggshell quality.2. Expression profiles of the SCNN1B and AHCYL1 genes in Sansui female ducks were determined using real-time fluorescence quantitative PCR to identify SNPs. The duck SCNN1B and AHCYL1 genes were amplified to identify SNPs. A total of 502 Sansui female ducks were genotyped by sequencing, and the associations between the mRNA expression/SNP genotypes and 6 eggshell quality indices were analysed using PASW Statistics 18.0.3. The results showed that the SCNN1B and AHCYL1 proteins are highly conserved in different mammalian or domestic animals, especially the AHCYL1 protein. The SCNN1B and AHCYL1 genes were widely expressed in different tissues of male and female ducks, and expression level in the uterus was greater than in other tissues. The expression of SCNN1B and AHCYL1 during the oviposition cycle indicated that expression levels were related to the eggshell mineralisation stage.4. The mRNA expression levels of the uterine SCNN1B and AHCYL1 genes were positively correlated with eggshell strength (ESS), percentage (ESP) and weight (ESW) (P < 0.05), respectively. Ten novel SNPs in SCNN1B and AHCYL1 genes from Chinese domestic laying ducks were identified through PCR amplicon sequencing.5. Genetic association analysis indicated g.797509 C > T, g.797573 C > T and g.797834 C > T in SCNN1B gene and g.169244 T > A, g.169265 T > C and g.175311 T > C in AHCYL1 gene had a significant effect on eggshell quality. Correlation analysis between the SNP genotype and SCNN1B and AHCYL1 genes expression in the uterus showed that the genotypes of g.797509 C > T, g.797573 C > T, g.797834 C > T, g.169244 T > A and g.175311 T > C sites affected the expression of SCNN1B and AHCYL1 genes in utero (P < 0.05).6. The study indicated SCNN1B and AHCYL1 as candidate genes to improve eggshell traits in ducks.
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Patos , Cáscara de Huevo , Animales , Pollos/genética , China , Patos/genética , Femenino , Masculino , Mamíferos/genética , Óvulo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Objective: To explore the application value of personalized three-dimensional (3D) printed protective cap in brain protection after decompressive craniectomy (DC). Methods: Fourty-five patients who underwent DC from January 2021 to October 2021 were selected, including 26 males and 19 females, aged 5-73 (50±13) years old. The brain CT data were imported into 3D Slicer software to rebuild the protective cap through 3D printing. The cap was worn on the head of the patient, thereby preventing secondary braindamage. The follow-up results were compared with 53 patients without protective capduring the same period. Results: There were no statistically significant differences in age, skull defect location and follow-up time between the two groups (all P>0.05).Among 45 patients, 47 brain protective caps (2 cases with bilateral skull defects) were successfully designed. The time for image post-processingand 3D printing was (21.2±6.0) min and (62.4±8.3) min, respectively. There were 6 cases of low compliance, 9 cases of moderate compliance, 32 cases of high compliance, respectively. Six cases with low conformity were redesigned and printed, 2 of 9 cases with moderate conformity were redesigned and printed, and the remaining 7 cases reached high compliance after grinding and packaging. In the current study, 45 patients with brain protective caps were followed up for 3 months, and no secondary brain injury occurred. However, among 53 patients without brain protective caps during the same period, 4 patients had secondary accidental brain compression. The incidence of injury was 7.5 %, and the difference was statistically significant (P<0.001). Conclusion: Brain protective cap designed based on cranial CT and 3D printing can be used in patients with skull defects to protect the brain tissue from secondary crush damage and has certain clinical value.
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Lesiones Encefálicas , Neoplasias Encefálicas , Craniectomía Descompresiva , Adulto , Encéfalo , Craniectomía Descompresiva/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Impresión Tridimensional , Cráneo/cirugíaRESUMEN
No abstract available.
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Unicompartmental knee arthroplasty (UKA) is an effective treatment for end-stage anteromedial osteoarthritis of the knee. Medial tibial plateau fracture or femoral condyle fracture may occur after UKA, and its treatment is very challenging. The causes leading to this complication include: surgical technique errors, such as the weakening of posterior cortical strength of the tibial platform during operation, the reduction of bone mass due to too much tibial osteotomy, and the stress concentration in the bone bed due to bad alignment of the prosthesis, etc. Prosthesis design factors, such as press-fit fixation design of cementless UKA prosthesis, and multiple nail holes fixation for tibial osteotomy guide, etc. And the morphology of tibial plateau, such as tibial platform in Asian people with narrow and small shap and medial overhanging condyles. Correct selection of patients, strict surgical principles and standardized surgical techniques are the keys to prevent periprosthetic fractures during and after medial UKA. After the diagnosis is confirmed, the treatment choice mainly depends on the fracture pattern and the stability of the prosthesis.
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Artroplastia de Reemplazo de Rodilla , Prótesis de la Rodilla , Osteoartritis de la Rodilla , Fracturas Periprotésicas , Artroplastia de Reemplazo de Rodilla/efectos adversos , Artroplastia de Reemplazo de Rodilla/métodos , Humanos , Articulación de la Rodilla/cirugía , Prótesis de la Rodilla/efectos adversos , Osteoartritis de la Rodilla/diagnóstico , Osteoartritis de la Rodilla/cirugía , Fracturas Periprotésicas/diagnóstico , Fracturas Periprotésicas/etiología , Fracturas Periprotésicas/cirugía , Tibia/cirugíaRESUMEN
Objective: To explore the feasibility of a method based on neuroimaging and surface markers for locating scalp projection of intracranial lesions. Methods: The clinical data of 46 patients who were used 'double-circle method' for locating scalp projection of intracranial lesions at Department of Neurosurgery,the First Affiliated Hospital of Xiamen University from January to June 2021 were retrospective analyzed. All patients with 2 electrodes(artificial fiducials) randomly attached to scalp had been examed thin-layer brain CT. The distances from the center of each fiducial to the root of the nose and tragus were measured through the images. A compass was used to draw two arcs with the root of nose and the tragus as the center and the pre-measured distance as the radius on patient's scalp. Then two arcs' intersection on the scalp was the fiducial. The method was named 'double-circle method'. Two neurosurgeons were arranged to perform fiducial identification with double-circle method, and record the error between the result and the actual fiducial point.Independent sample t test was used for data comparison, and Kappa test was used to analysis the inter-group consistency. Results: Ninety-two fiducial points of 46 patients were collected. Time consuming of doctor A was (8.1±2.3) minutes(range:5 to 15 minutes)and doctor B was (8.9±3.5) minutes(range:4 to 17 minutes).The positioning error from the doctor A was (4.4±2.4)mm(range:0 to 12 mm) and doctor B was(4.2±2.6) mm(range:0 to 14 mm)(t=-0.575,P=0.567),the difference was not statistically significant. The Kappa value of the consistency test of error between two doctors was 0.517(P=0.001).The consistency was moderate.Eight patients used 'double-circle method' and neuronavigation for locating scalp projection of intracranial lesions at the same time. The diameter of the lesions was (3.8±0.9)cm (range: 2.6 to 5.1 cm), and the positioning error of the 'double-circle method' and navigation was (4.0±1.9) mm(range: 1 to 6 mm), and all patients were confirmed to be accurately located during surgery. Conclusion: 'Double-circle method' is a simple,convenient and accurate way in locating intracranial lesions and has certain clinical significance.
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Neuronavegación , Cuero Cabelludo , Humanos , Neuroimagen , Neuronavegación/métodos , Estudios Retrospectivos , Cuero Cabelludo/diagnóstico por imagenRESUMEN
1. Eggshell quality is important for the poultry industry. Calcium is deposited during eggshell formation, and protein kinase C alpha (PRKCA) is involved in transmembrane transport of calcium ions in cells. However, the biological function of PRKCA in poultry is still not understood. Therefore, the aim of this study was to explore the association of mRNA expression and single nucleotide polymorphisms (SNPs) of the PRKCA gene with eggshell quality in laying ducks. 2. The mRNA expression and SNPs of the PRKCA gene were detected by real-time fluorescence quantitative PCR (qRT-PCR) and sequencing of PCR products in 45-week-old female Sansui ducks, which is a high production layer duck breed in China. The association of mRNA expression and SNPs in the PRKCA gene with layer duck eggshell traits was analysed using SPSS (v18.0) software. 3. The results demonstrated that PRKCA mRNA was widely expressed in all examined tissues, and expression was highest in kidney and lowest in the gizzard. Furthermore, the PRKCA mRNA level in uterus was significantly positively correlated with eggshell strength and eggshell weight (P < 0.05). Three novel SNPs, the synonymous mutations of g.9571770 T > C in exon 5, g.9583222 C > T and g.9583227 G > A in exon 7, were found in the PRKCA gene, giving four haplotypes and 10 diplotypes, which affected the mRNA secondary structure and free energy. The g.9583222 C > T and g.9583227 G > A mutations were significantly associated with eggshell strength (P < 0.05). Diplotype H1H1 was advantageous for increasing the strength and thickness of an eggshell. 4. In conclusion, the study showed that the mRNA transcription and genetic variation in the PRKCA gene could significantly affect the strength of duck eggshell and that the PRKCA gene is an important candidate gene for improving eggshell quality in poultry.