Objective:To summarize the clinical phenotypes, genotypes, and treatment outcomes of NPRL2-related epilepsy. Methods:This was a case summary.Clinical data of patients with NRPL2 variants admitted to the Department of Pediatrics, Peking University People′s Hospital between October 1, 2013 and October 31, 2023 were retrospectively analyzed.Previous reports of patients with the same disease were reviewed. Results:Six cases of NPRL2-related epilepsy were collected, and 37 cases were reported in the previous literatures.The age of onset ranged from 3 days to 18 years with the median age of 24 months.There were 15 patients with onset in infancy.Among the 41 patients diagnosed with epilepsy, 73.1% (30/41) had focal seizures, 34.1% (14/41) had frontal lobe epilepsy, and 17.1% (7/41) had epileptic spasms.Among the patients with known cranial imaging, 58.6% (17/29) had cortical malformations. NPRL2 variants involved 11 nonsense mutations, 10 splice site mutations, 7 frameshift mutations, 1 large fragment deletion, and 14 missense mutations; among them, 39 mutations were pathogenic or likely pathogenic, while the rest 4 mutations had unclear pathogenicity.Among the 27 patients with known outcomes, 11 (40.7%) had no seizures after administration of 1 or 2 types of drugs, and 16 (59.2%) had drug-resistant epilepsy.Among the 16 patients, 1 had no seizures after treatment with 3 types of anti seizure medications, and 7 had no seizures after surgery.Most patients had varying degrees of delay in intellectual and motor development. Conclusions:Patients with NPRL2 variants usually present with frequent focal seizures and epileptic spasms, and the age of onset varies greatly.About half of the patients have drug-resistant epilepsy, half of whom have cortical malformations.For those with drug-resistant epilepsy and abnormal cranial imaging, surgery may be considered.

Objective:To summarize the phenotype and genotype of leukoencephalopathy with calcifications and cysts(LCC).Methods:A case summary.Clinical, imaging, and genetic data of 2 patients with early-onset LCC admitted to the Department of Pediatrics, Peking University People′s Hospital between December 2023 and August 2024 were retrospectively summarized.A review of the literature was also conducted.Results:Case 1: a 19-month-old female infant presented with febrile seizures in infancy and mild developmental delay.Trio whole-exome sequencing (trio-WES) identified compound heterozygous pathogenic variants in the SNORD118 gene: n.92C>T (paternally inherited) and n. 72A>G (maternally inherited). Case 2: an 11-year-and-4-month-old girl had non-specific encephalopathy in the neonatal period, developmental delay with regression, and seizures since early childhood.Trio-WES revealed compound heterozygous pathogenic variants in SNORD118: n.3C>T (paternally inherited) and n. 57G>C (maternally inherited). Both cases showed typical imaging findings of leukoencephalopathy, intracranial calcifications, and cysts.Case 2 has been treated with Bevacizumab for 3 months and remains under follow-up.Combining this 2 cases with previously reported genetically confirmed cases, a total of 97 LCC patients with identified SNORD118 variants were analyzed.The median age of onset was 5 years.Seventy-one cases had childhood onset, including 31 cases with onset at ≤1 year.The inaugural symptoms were: seizures in 40 patients (41.2%), motor disorders in 25 patients (25.8%), developmental delay or cognitive impairment in 19 patients (19.6%) and headaches or increased intracranial pressure in 13 patients (13.4%). Neurological dysfunctions progress during the course.All patients had typical leukoencephalopathy, intracranial calcifications and cysts, with varied imaging progress.A total of 61 variants of SNORD118 were reported and most were compound heterozygous variants.Treatment is primarily symptomatic.Three out of the 4 patients treated with Bevacizumab showed improvement. Conclusions:LCC is a rare autosomal recessive inherited cerebral microangiopathy, characterized by progressive neurological dysfunction and radiological triad of diffuse and asymmetric leukoencephalopathy, intracranial calcifications and cysts.Patients with pathogenic SNORD118 variants should definitely be diagnosed.Symptomatic treatment is the mainstay therapy and Bevacizumab may slow down the progression.

Objective:To summarize the phenotype and genotype of leukoencephalopathy with calcifications and cysts(LCC).Methods:A case summary.Clinical, imaging, and genetic data of 2 patients with early-onset LCC admitted to the Department of Pediatrics, Peking University People′s Hospital between December 2023 and August 2024 were retrospectively summarized.A review of the literature was also conducted.Results:Case 1: a 19-month-old female infant presented with febrile seizures in infancy and mild developmental delay.Trio whole-exome sequencing (trio-WES) identified compound heterozygous pathogenic variants in the SNORD118 gene: n.92C>T (paternally inherited) and n. 72A>G (maternally inherited). Case 2: an 11-year-and-4-month-old girl had non-specific encephalopathy in the neonatal period, developmental delay with regression, and seizures since early childhood.Trio-WES revealed compound heterozygous pathogenic variants in SNORD118: n.3C>T (paternally inherited) and n. 57G>C (maternally inherited). Both cases showed typical imaging findings of leukoencephalopathy, intracranial calcifications, and cysts.Case 2 has been treated with Bevacizumab for 3 months and remains under follow-up.Combining this 2 cases with previously reported genetically confirmed cases, a total of 97 LCC patients with identified SNORD118 variants were analyzed.The median age of onset was 5 years.Seventy-one cases had childhood onset, including 31 cases with onset at ≤1 year.The inaugural symptoms were: seizures in 40 patients (41.2%), motor disorders in 25 patients (25.8%), developmental delay or cognitive impairment in 19 patients (19.6%) and headaches or increased intracranial pressure in 13 patients (13.4%). Neurological dysfunctions progress during the course.All patients had typical leukoencephalopathy, intracranial calcifications and cysts, with varied imaging progress.A total of 61 variants of SNORD118 were reported and most were compound heterozygous variants.Treatment is primarily symptomatic.Three out of the 4 patients treated with Bevacizumab showed improvement. Conclusions:LCC is a rare autosomal recessive inherited cerebral microangiopathy, characterized by progressive neurological dysfunction and radiological triad of diffuse and asymmetric leukoencephalopathy, intracranial calcifications and cysts.Patients with pathogenic SNORD118 variants should definitely be diagnosed.Symptomatic treatment is the mainstay therapy and Bevacizumab may slow down the progression.

Objective To observe the value of deep learning image reconstruction(DLIR)algorithm in brain CT perfusion(CTP)using a protocol of 70 kVp and 40 ml contrast agent dose.Methods Totally 105 patients with suspected acute ischemic stroke(AIS)were prospectively enrolled and randomly divided into 3 groups,who underwent standard dose CTP scanning with 80 kVp and 150 mA combined with reconstruction as adaptive statistic iterative reconstruction V(ASIR-V)at 50％level(CN group,n=35),low dose(LD)scanning with 70 kVp and 100 mA combined with DLIR reconstruction at the highest level(DLIR-H)(LD group,n=35),or ultra-low dose(ULD)scanning with 70 kVp and 70 mA combined with DLIR-H reconstruction(ULD group,n=35).Radiation doses were compared among 3 groups.CT values and standard deviations(SDCT)of ROI of gray matter and white matter in the frontal,parietal and temporal lobes were measured.Signal-to-noise ratio(SNR)and contrast-to-noise ratio(CNR)between gray and white matter were calculated and compared among groups.Then pseudo-color images of cerebral blood volume(CBV),cerebral blood flow(CBF),mean transit time(MTT)and time to maximum of the tissue residual function(Tmax)were generated.The imaging quality of CTP pseudo-color images was evaluated,and the compatibility of the subjective scores within every kind of CTP pseudo-color images were assessed using Kappa test.Quantitative perfusion parameters were measured and compared among groups.Results Compared with CN group,both LD and ULD groups demonstrated significantly reduced volume CT dose index(CTDIvol),dose-length product(DLP)and effective dose(ED)(all adjusted P＜0.05).In ULD group,SDCT of white matter in frontal,parietal and temporal lobes were higher than those in CN group,and SDCT of white matter in parietal lobe was also higher than that in LD group(all adjusted P＜0.05).No significant difference of SDCT of gray matter was observed among groups(all P＞0.05).SNR of white matter in parietal and temporal lobes in both LD and ULD groups were lower than those in CN group(all P＜0.05),while no significant difference of SNR of white matter in frontal lobe,nor of gray matter in frontal,parietal and temporal lobes was found among groups(all P＞0.05).CNR of gray and white matter in the frontal,parietal and temporal lobes were not significantly different among groups(all P＞0.05).High consistency of inter-observer subjective scores of CBV maps,CBF maps and Tmax maps(Kappa of 0.623,0.644 and 0.638,respectively)were noticed,which of MTT maps had moderate consistency(Kappa=0.560).No significant difference of intra-obsever subjective scores of CTP pseudo-color images was found among groups(all P＞0.05).CBV,CBF,MTT and Tmax values of gray and white matter in frontal,parietal and temporal lobes were not significantly different among groups(all P＞0.05).Conclusion DLIR algorithm applicated in low radiation dose and reduced contrast agent dosage might ensure imaging quality.

Objective To observe the value of deep learning image reconstruction(DLIR)algorithm in brain CT perfusion(CTP)using a protocol of 70 kVp and 40 ml contrast agent dose.Methods Totally 105 patients with suspected acute ischemic stroke(AIS)were prospectively enrolled and randomly divided into 3 groups,who underwent standard dose CTP scanning with 80 kVp and 150 mA combined with reconstruction as adaptive statistic iterative reconstruction V(ASIR-V)at 50％level(CN group,n=35),low dose(LD)scanning with 70 kVp and 100 mA combined with DLIR reconstruction at the highest level(DLIR-H)(LD group,n=35),or ultra-low dose(ULD)scanning with 70 kVp and 70 mA combined with DLIR-H reconstruction(ULD group,n=35).Radiation doses were compared among 3 groups.CT values and standard deviations(SDCT)of ROI of gray matter and white matter in the frontal,parietal and temporal lobes were measured.Signal-to-noise ratio(SNR)and contrast-to-noise ratio(CNR)between gray and white matter were calculated and compared among groups.Then pseudo-color images of cerebral blood volume(CBV),cerebral blood flow(CBF),mean transit time(MTT)and time to maximum of the tissue residual function(Tmax)were generated.The imaging quality of CTP pseudo-color images was evaluated,and the compatibility of the subjective scores within every kind of CTP pseudo-color images were assessed using Kappa test.Quantitative perfusion parameters were measured and compared among groups.Results Compared with CN group,both LD and ULD groups demonstrated significantly reduced volume CT dose index(CTDIvol),dose-length product(DLP)and effective dose(ED)(all adjusted P＜0.05).In ULD group,SDCT of white matter in frontal,parietal and temporal lobes were higher than those in CN group,and SDCT of white matter in parietal lobe was also higher than that in LD group(all adjusted P＜0.05).No significant difference of SDCT of gray matter was observed among groups(all P＞0.05).SNR of white matter in parietal and temporal lobes in both LD and ULD groups were lower than those in CN group(all P＜0.05),while no significant difference of SNR of white matter in frontal lobe,nor of gray matter in frontal,parietal and temporal lobes was found among groups(all P＞0.05).CNR of gray and white matter in the frontal,parietal and temporal lobes were not significantly different among groups(all P＞0.05).High consistency of inter-observer subjective scores of CBV maps,CBF maps and Tmax maps(Kappa of 0.623,0.644 and 0.638,respectively)were noticed,which of MTT maps had moderate consistency(Kappa=0.560).No significant difference of intra-obsever subjective scores of CTP pseudo-color images was found among groups(all P＞0.05).CBV,CBF,MTT and Tmax values of gray and white matter in frontal,parietal and temporal lobes were not significantly different among groups(all P＞0.05).Conclusion DLIR algorithm applicated in low radiation dose and reduced contrast agent dosage might ensure imaging quality.

Acetaminophen (APAP) is the primary cause of drug-induced acute liver failure. Ovarian tumor deubiquitinase 6A (OTUD6A), a recently discovered deubiquitinase of the OTU family, has been primarily studied in tumor contexts. However, its role in APAP-induced liver injury (AILI) remains unclear. Therefore, this study aimed to investigate the involvement of OTUD6A in the pathogenesis of AILI. Our findings demonstrated a substantial upregulation of OTUD6A in both the liver tissue and isolated hepatocytes of mice following APAP stimulation. OTUD6A knockout exacerbated APAP-induced inflammation, hepatocyte necrosis, and liver injury, whereas OTUD6A overexpression alleviated these pathologies. Mechanistically, OTUD6A directly interacted with the enhancer of zeste homolog 2 (EZH2) and selectively removed K48-linked polyubiquitin chains from EZH2, enhancing its stability. This resulted in increased protein levels of EZH2 and H3K27me3, as well as reduced endoplasmic reticulum (ER) stress and cell death in hepatocytes. Collectively, our research uncovers a novel role for OTUD6A in mitigating APAP-induced liver injury by promoting EZH2 stabilization.

Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Objective:To summarize the clinical phenotypes, genotypes, and treatment outcomes of NPRL2-related epilepsy. Methods:This was a case summary.Clinical data of patients with NRPL2 variants admitted to the Department of Pediatrics, Peking University People′s Hospital between October 1, 2013 and October 31, 2023 were retrospectively analyzed.Previous reports of patients with the same disease were reviewed. Results:Six cases of NPRL2-related epilepsy were collected, and 37 cases were reported in the previous literatures.The age of onset ranged from 3 days to 18 years with the median age of 24 months.There were 15 patients with onset in infancy.Among the 41 patients diagnosed with epilepsy, 73.1% (30/41) had focal seizures, 34.1% (14/41) had frontal lobe epilepsy, and 17.1% (7/41) had epileptic spasms.Among the patients with known cranial imaging, 58.6% (17/29) had cortical malformations. NPRL2 variants involved 11 nonsense mutations, 10 splice site mutations, 7 frameshift mutations, 1 large fragment deletion, and 14 missense mutations; among them, 39 mutations were pathogenic or likely pathogenic, while the rest 4 mutations had unclear pathogenicity.Among the 27 patients with known outcomes, 11 (40.7%) had no seizures after administration of 1 or 2 types of drugs, and 16 (59.2%) had drug-resistant epilepsy.Among the 16 patients, 1 had no seizures after treatment with 3 types of anti seizure medications, and 7 had no seizures after surgery.Most patients had varying degrees of delay in intellectual and motor development. Conclusions:Patients with NPRL2 variants usually present with frequent focal seizures and epileptic spasms, and the age of onset varies greatly.About half of the patients have drug-resistant epilepsy, half of whom have cortical malformations.For those with drug-resistant epilepsy and abnormal cranial imaging, surgery may be considered.

PURPOSE: Lateral patellar compression syndrome (LPCS) is characterized by a persistent abnormally high stress exerted on the lateral articular surface of the patella due to lateral patellar tilt without dislocation and lateral retinaculum contracture, leading to anterior knee pain. The purpose of this study is to evaluate the efficacy and prognosis of lateral retinaculum release (LRR) combined with chondroplasty in the treatment of LPCS. METHODS: This retrospective study evaluated 40 patients who underwent LRR combined with chondroplasty for LPCS between 2020 and 2021. The assessment included improvement in postoperative tenderness and knee joint function. Patients were evaluated using the Lysholm, Tegner, and International Knee Documentation Committee 2000 scoring systems, as well as the visual analog scale, both preoperatively and postoperatively, with the paired comparisons analyzed using a t-test. Additionally, intraoperative observations were made regarding knee joint lesions, including cartilage damage and osteophyte formation, with analysis by the Chi-square test. RESULTS: The visual analog scale score for tenderness showed a significant decrease after surgery (p < 0.001). Evaluation of knee joint function also indicated significant improvements, as demonstrated by increased Lysholm, Tegner, and International Knee Documentation Committee 2000 scores postoperatively (p < 0.001, p = 0.011, p < 0.001, respectively). Furthermore, all LPCS patients included in the study presented with cartilage injuries and osteophyte formation. Significant differences were noted in the incidence of cartilage damage and osteophyte formation at different locations within the knee among patients with LPCS. CONCLUSION LRR combined with chondroplasty is an effective surgical approach for treating patients with LPCS, with satisfactory recovery observed at the 1-year follow-up. Additionally, the incidence of cartilage damage and osteophyte formation in LPCS patients varies significantly depending on the specific location within the knee joint.
Humans ; Male ; Female ; Retrospective Studies ; Adult ; Middle Aged ; Patella/surgery* ; Knee Joint/physiopathology* ; Recovery of Function ; Young Adult ; Treatment Outcome ; Cartilage, Articular/surgery* ; Adolescent

Objective To analyze the risk factors and survival status of Epstein-Barr virus(EBV)infection in pa-tients with aplastic anemia(AA)after haploid allogeneic hematopoietic stem cell transplantation(Haplo-HSCT).Methods Clinical data of 78 AA patients who underwent Haplo-HSCT in the hematology department of a hospital from January 1,2019 to October 31,2022 were analyzed retrospectively.The occurrence and onset time of EBV viremia,EBV-related diseases(EBV diseases),and post-transplant lymphoproliferative disorders(PTLD)were ob-served,risk factors and survival status were analyzed.Results Among the 78 patients,38 were males and 40 were females,with a median age of 33(9-56)years old;53 patients experienced EBV reactivation,with a total inci-dence of 67.9％,and the median time for EBV reactivation was 33(13,416)days after transplantation.Among pa-tients with EBV reactivation,49 cases(62.8％)were simple EBV viremia,2 cases(2.6％)were possible EBV di-seases,and 2 cases(2.6％)were already confirmed EBV diseases(PTLD).Univariate analysis showed that age 1＜40 years old at the time of transplantation,umbilical cord blood infusion,occurrence of acute graft-versus-host disease(aGVHD)after transplantation,and concurrent cytomegalovirus(CMV)infection were independent risk fac-tors for EBV reactivation in AA patients after Haplo-HSCT.Multivariate analysis showed that concurrent CMV in-fection was an independent risk factor for EBV reactivation in A A patients after Haplo-HSCT(P=0.048).Ritu-ximab intervention before stem cell reinfusion was a factor affecting the duration of EBV reactivation(P＜0.05).The mortality of EBV viremia,EBV diseases,and PTLD alone were 8.2％,50.0％,and 100％,respectively.The 2-year overall survival rate of patients with and without EBV reactivation were 85.3％,and 90.7％,respectively,difference was not statistically significant(P=0.897).However,patients treated with rituximab had 2-year lower survival rate than those who did not use it,with a statistically significant difference(P=0.046).Conclusion EBV reactivation is one of the serious complications in AA patients after Haplo-HSCT,which affects the prognosis and survival of patients.