A multifunctional true caffeoyl coenzyme A O-methyltransferase enzyme participates in the biosynthesis of polymethoxylated flavones in citrus.

Polymethoxylated flavones (PMFs) have received extensive attention due to their abundant bioactivities. Citrus peels specifically accumulate abundant PMFs, and methylation modification is a key step in PMF biosynthesis; however, the function of reported O-methyltransferase (OMT) in citrus is insufficient to elucidate the complete methylation process of PMFs. In this study, we analyzed the accumulation pattern of PMFs in the flavedo of the sweet orange (Citrus sinensis) cultivar "Bingtangcheng" at different developmental stages. We found that accumulation of PMFs was completed at the early stage of fruit development (60-d after flowering). Furthermore, we characterized a true caffeoyl-CoA O-methyltransferase (named CsCCoAOMT1) from C. sinensis. Functional analysis in vitro showed that CsCCoAOMT1 preferred flavonoids to caffeoyl-CoA and esculetin. This enzyme efficiently methylated the 6-, 7- 8-, and 3'-OH of a wide array of flavonoids with vicinal hydroxyl groups with a strong preference for quercetin (flavonol) and flavones. The transient overexpression and virus-induced gene silencing experiments verified that CsCCoAOMT1 could promote the accumulation of PMFs in citrus. These results reveal the function of true CCoAOMTs and indicate that CsCCoAOMT1 is a highly efficient multifunctional O-methyltransferase involved in the biosynthesis of PMFs in citrus.

Uncommon optic nerve arteriovenous malformation: A case report and literature review.

BACKGROUND: The rapid progress in imaging techniques has led to an upsurge in the incidence of optic nerve arteriovenous malformations (AVMs) diagnoses. Nevertheless, a comprehensive integration addressing their diagnostic and therapeutic attributes remains elusive. CASE DESCRIPTION AND THE LITERATURE REVIEW: In this report, we present a case of optic nerve AVM in a patient who initially presented with progressive visual deterioration in the right eye. An orbital magnetic resonance imaging (MRI) scan revealed an abnormal signal intensity within the optic nerve region of the affected eye, and Computed Tomography Angiography (CTA) demonstrated the presence of a vascular malformation involving the optic nerve in the right eye. The diagnosis of optic nerve AVMs relies on Digital Subtraction Angiography (DSA). Given the challenging nature of surgical intervention, the patient opted for conservative management. Upon subsequent evaluation, no significant changes were observed in the patient's right visual acuity and visual field. Furthermore, a comprehensive literature review was conducted. CONCLUSIONS: In summary, the principal clinical presentations associated with optic nerve AVMs include a deterioration in both visual acuity and visual field. Angiography serves as the preferred diagnostic modality to confirm optic nerve AVMs. Microsurgical intervention or interventional embolization techniques may offer effective management approaches to address this complex condition.

Transcriptional insights of citrus defense response against Diaporthe citri.

Citrus melanose, caused by Diaporthe citri, is one of the most important and widespread fungal diseases of citrus. Previous studies demonstrated that the citrus host was able to trigger the defense response to restrict the spread of D. citri. However, the molecular mechanism underlying this defense response has yet to be elucidated. Here, we used RNA-Seq to explore the gene expression pattern at the early (3 days post infection, dpi) and late (14 dpi) infection stages of citrus leaves in response to D. citri infection, and outlined the differences in transcriptional regulation associated with defense responses. The functional enrichment analysis indicated that the plant cell wall biogenesis was significantly induced at the early infection stage, while the callose deposition response was more active at the late infection stage. CYP83B1 genes of the cytochrome P450 family were extensively induced in the callus deposition-mediated defense response. Remarkably, the gene encoding pectin methylesterase showed the highest upregulation and was only found to be differentially expressed at the late infection stage. Genes involved in the synthesis and regulation of phytoalexin coumarin were effectively activated. F6'H1 and S8H, encoding key enzymes in the biosynthesis of coumarins and their derivatives, were more strongly expressed at the late infection stage than at the early infection stage. Collectively, our study profiled the response pattern of citrus leaves against D. citri infection and provided the transcriptional evidence to support the defense mechanism.

Nobiletin as a chemopreventive natural product against cancer, a comprehensive review.

As a leading cause of death, second only to heart disease, cancer has always been one of the burning topics in medical research. When targeting multiple signal pathways in tumorigenesis chemoprevention, using natural or synthetic anti-cancer drugs is a vital strategy to reduce cancer damage. However, toxic effects, multidrug resistance (MDR) as well as cancer stem cells (CSCs) all prominently limited the clinical application of conventional anticancer drugs. With low side effects, strong biological activity, unique mechanism, and wide range of targets, natural products derived from plants are considered significant sources for new drug development. Nobiletin is one of the most attractive compounds, a unique flavonoid primarily isolated from the peel of citrus fruits. Numerous studies in vitro and in vivo have suggested that nobiletin and its derivatives possess the eminent potential to become effective cancer chemoprevention agents through various cellular and molecular levels. This article aims to comprehensively review the anticancer efficacy and specific mechanisms of nobiletin, enhancing our understanding of its chemoprevention properties and providing the latest research findings. At the end of this review, we also give some discussion and future perspectives regarding the challenges and opportunities in nobiletin efficient exploitation.

Treatment with a flow diverter-assisted coil embolization for ruptured blood blister-like aneurysms of the internal carotid artery: a technical note and analysis of single-center experience with pooled data.

Treatment of blood blister-like aneurysms (BBAs) of the supraclinoid internal carotid artery (ICA) with flow diverters (FDs) has become widespread in recent years. However, ruptured blood blister-like aneurysm (BBA) of ICA treatment with flow diverter-assisted coil embolization (FDAC) remains controversial. Moreover, limited direct comparative studies have been conducted between the two treatment modalities, FDs and FDAC, for BBAs. The purpose of this study was to document our experience and evaluate the effectiveness and safety of FDAC. We conducted a retrospective analysis of clinical and radiological information from ten patients who experienced ruptured BBAs of the supraclinoid ICA at our center from January 2021 to February 2023. The technical details of FDAC for ruptured BBAs were described, and the technical steps were named "pipeline embolization device (PED)-Individualized shaping(microcatheter)-Semi deploying-Rivet(coils)-Massage(microwire)" as the PEISSERM technique. Clinical outcomes were assessed using the modified Rankin Scale (mRS), whereas radiological results were determined through angiography. A pooled analysis was implemented, incorporating data from literature sources that reported perioperative and long-term clinical and angiographic outcomes of ruptured BBAs treated with FD and FDAC strategies, along with our data. Data in our analysis pool were categorized into FD and FDAC strategy groups to explore the preferred treatment modalities for BBAs. The PEISSERM technique was utilized to treat ten patients, seven males, and three females, with an average age of 41.7 years. A single PED was deployed in conjunction with coils in all ten patients. All PEDs were documented to have good wall apposition. The immediate postoperative angiograms demonstrated Raymond grade I in ten aneurysms. Angiographic follow-up of nine patients at 4-25 months showed total occlusion of the aneurysms. At the most recent follow-up, the mRS scores of nine patients hinted at a good prognosis. Pooled analysis of 233 ICA-BBA cases of FD revealed a technical success rate of 91% [95% confidence interval (CI), 0.88 to 0.95], a rate of complete occlusion of 79% (95% CI, 0.73 to 0.84), a recurrence rate of 2% (95% CI, 0.00 to 0.04), a rebleed rate of 2% (95% CI, 0.00 to 0.04), and the perioperative stroke rate was 8% (95% CI, 0.04 to 0.11). The perioperative mortality was 4% (95% CI, 0.01 to 0.07). The long-term good clinical outcome rate was 85% (95% CI, 0.80 to 0.90). The mortality rate was 6% (95% CI, 0.03 to 0.09). Results from the subgroup analysis illustrated that the FDAC strategy for BBAs had a significantly higher immediate postoperative complete occlusion rate (P < 0.001), total occlusion rate (P = 0.016), and a good outcome rate (P = 0.041) compared with the FD strategy. The FDAC strategy can yield a higher rate of good outcomes than the FD strategy. The PEISSERM technique employed by the FDAC is a reliable and effective treatment approach as it can minimize the hemodynamic burden of BBA's fragile dome, thereby achieving an excellent occlusion rate. The PEISSERM technique in the FDAC strategy contributes to understanding the BBA's treatment and offers a potentially optimal treatment for BBA.

Serum Ngb (Neuroglobin) Is Associated With Brain Metabolism and Functional Outcome of Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- Hypoxic-ischemic brain damage is a well-recognized physiopathologic mechanism after aneurysmal subarachnoid hemorrhage (aSAH). The Ngb (neuroglobin) is a hemoprotein predominantly expressed in the brain with a high affinity for oxygen. Relationship between serum Ngb level and brain metabolism in aSAH patients has not been investigated previously. Methods- Thirty-six consecutive severe aSAH patients (Glasgow Coma Scale score ≤8 on admission) with multimodal neuromonitoring and 36 matched healthy subjects were included. Serum Ngb level was analyzed in combination with other time-matched cerebral microdialysis parameters, brain tissue oxygen tension, and 12-month neurological outcomes. Results- Serum Ngb level was correlated positively with cerebral microdialysis parameters and brain tissue oxygen tension ( P<0.001). Poor functional outcome (modified Rankin Scale score >3) 12 months after aSAH was associated with higher Ngb level but independent of age, sex, and disease severity ( P<0.001). A similar association was found between high Ngb level and neuropsychological test results indicative of impairments in cognition, visual conceptualization, and frontal executive functions ( P<0.001). Conclusions- Ngb may be a potential biomarker for reflecting brain tissue oxygen tension, brain metabolism, and functional outcome in severe aSAH patients and merits further study in the context of aSAH.

Evolution of Nucleic Acid Aptamers Capable of Specifically Targeting Glioma Stem Cells via Cell-SELEX.

Glioma stem cells (GSCs), a particular group of cells from gliomas, are capable of infinite proliferation and differentiation. Recent studies have shown that GSCs may be the root of tumor recurrence, metastasis, and resistance. Early detection and targeted therapy of GSCs may significantly improve the survival rate of glioma patients. Therefore, molecular ligands capable of selectively recognizing GCSs are of great importance. The objective of this study is to generate DNA aptamers for selective identification of the molecular signature of GSCs using cell-based Systematic Evolution of Ligands by EXponential enrichment (cell-SELEX). GSCs were used as the positive selection target, while U87 cells were used in negative cycles for removal of DNA molecules binding to common glioma cell lines. Finally, we successfully identified one aptamer named W5-7 with a Kd value of 4.9 ± 1.4 nM. The sequence of the aptamer was further optimized, and its binding target was identified as a membrane protein. The aptamer W5-7 was stable in cerebral spinal fluid over 36 h and could also effectively detect glioma stem cells in cerebral spinal fluid samples. With its superb targeting properties and functional versatility, W5-7 holds great potential for use as a molecular probe for detecting and isolating GSCs.

Sex-dependent association of preoperative hematologic markers with glioma grade and progression.

Neutrophil-to-lymphocyte ratio (NLR), platelet-lymphocyte ratio, the systemic immune-inflammation index (SII), and red blood cell distribution width (RDW), have been recognized as promising predictors for histological grade and prognosis in multiple cancer types. However, few investigations illustrated the impacts of sex on the clinical utility of hematologic markers. Patients with primary gliomas were retrospectively reviewed. The association between grade and inflammatory markers by sex were investigated by univariate and multivariate analysis. The discrimination ability of logistic regression model was evaluated by the area under the receiver-operating characteristic curve (AUC) for high-grade glioma (HGG). Kaplan-Meier progressionfree survival (PFS) curves were plotted to assess the prognostic value of RDW. In subgroup analysis, distinctively elevated NLR and SII levels were exclusively present in male HGGs group (p = 0.001); whereas RDW notably increased in female HGGs group (p = 0.001). On multivariate analysis, increased odds ratio of HGGs was exclusively observed for female patients with elevated RDW (odds ratio = 1.589). Moreover, regression model developed by RDW exhibited an excellent discriminative ability for the prediction of HGGs in female patients (AUC = 0.817). Median progression time with RDW < 13.2 versus RDW ≥ 13.2 was 62.5 versus 33.0 months (log rank p = 0.017). Older females (≥ 45 years) with increased RDW levels portended worse survival (HR 3.693, 95% CI 1.747-8.325, p = 0.001). Meanwhile, the significant association of RDW levels with PFS in male subgroup was not observed (p > 0.05). In conclusion, superior to NLR and SII, RDW would be sex-specific predictor for tumor grade and progression for HGG female patients.

Ex vivo liver resection and autotransplantation with cardiopulmonary bypass for hepatoblastoma in children: A case report.

Some primary and secondary liver carcinomas cannot be resected using a conventional approach due to their size, location, or major vascular invasion. The aim of this study was to explore the application of ex vivo liver resection and autotransplantation for complicated HB in children. A 1.5-year-old girl with HB after repeated chemotherapy was analyzed. In this patient, tumor invasion includes the IV, V, and VIII liver segments, and thrombosis formed in the inferior vena cava and right atrium. It is difficult to obtain complete tumor resection using conventional hepatectomy. The patient was treated via ex vivo liver resection and autotransplantation, and tumor thrombus in the inferior vena cava and right atrium was removed via cardiopulmonary bypass. Operative methods and precautions were analyzed during and after the operation. The operation was completed successfully within 8 hours, and the liver's cold ischemia time was 190 minutes. The patient recuperated successfully, and the liver's function and AFP levels gradually tended to normalize 2 weeks after the operation. Ultrasonic examination revealed that the blood flow velocity of the hepatic vein, portal vein, and hepatic artery was good. The patient recovered and was discharged 3 weeks after the operation. Ex vivo liver resection and autotransplantation have great application value for complicated HB in children that is not suitable for conventional hepatic lobectomy.

Annular pancreas in China: 9 years' experience from a single center.

To summarize the clinical characteristics, diagnosis, treatment and prognosis among 152 children with annular pancreas (AP). A retrospective review of 152 patients with AP who were treated with surgical repair between January 2009 and August 2017 was performed at our pediatric surgical units. Presenting symptoms, birth weight, radiological findings, associated anomalies, the type of surgery performed were analyzed. (1) 152 patients were identified, out of which 82 were males, and 70 were females; (2) the average birth weight of children with AP was less than that of healthy newborns. The birth weights of 5.4% premature infants were less than 1500 g; the birth weight of 17% full-term infants, 69% premature infants and 50% post-term infants were less than 2500 g. (3) 100 (66%) patients presented symptoms during neonatal period and 43 (28%) patients had duodenal obstruction diagnosed by prenatal ultrasound scan. (4) All cases were managed surgically by open laparotomy, and all patients were duly discharged. AP most commonly presents symptoms in early neonatal period. Infants with AP are associated with a higher rate of low birth weight, and it was because swallowed amniotic fluid could not be absorbed and impaired insulin secretion caused by abnormal pancreas. Ultrasonography, abdominal plain film and upper gastrointestinal series (UGI) are helpful, but cannot make the diagnosis, and surgery is the only effective way to diagnose and treat AP.

Antioxidant Capacity, Anticancer Ability and Flavonoids Composition of 35 Citrus (Citrus reticulata Blanco) Varieties.

Citrus (Citrus reticulate Blanco) is one of the most commonly consumed and widely distributed fruit in the world, which is possessing extensive bioactivities. Present study aimed to fully understand the flavonoids compositions, antioxidant capacities and in vitro anticancer abilities of different citrus resources. Citrus fruits of 35 varieties belonging to 5 types (pummelos, oranges, tangerines, mandarins and hybrids) were collected. Combining li quid chromatography combined with electrospray ionization mass spectrometry (LC-ESI-MS/MS) and ultra-performance liquid chromatography combined with diode array detector (UPLC-DAD), a total of 39 flavonoid compounds were identified, including 4 flavones, 9 flavanones and 26 polymethoxylated flavonoids (PMFs). Each citrus fruit was examined and compared by 4 parts, flavedo, albedo, segment membrane and juice sacs. The juice sacs had the lowest total phenolics, following by the segment membrane. Four antioxidant traits including 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC) and cupric reducing antioxidant capacity (CUPRAC) were applied for the antioxidant capacities evaluation. Three gastric cancer cell lines, SGC-7901, BGC-823 and AGS were applied for the cytotoxicity evaluation. According to the results of correlation analysis, phenolics compounds might be the main contributor to the antioxidant activity of citrus extracts, while PMFs existing only in the flavedo might be closely related to the gastric cancer cell line cytotoxicity of citrus extracts. The results of present study might provide a theoretical guidance for the utilization of citrus resources.

Comparative Transcriptomic Analysis of Grape Berry in Response to Root Restriction during Developmental Stages.

Root restriction improved berry quality by being involved in diverse aspects of grapevine life. However, the molecular mechanism driving this process is not understood very well. In this study, the 'Summer Black' grape berry (Vitis vinifera × V. labrusca) under root restriction was investigated, which showed an increase of total soluble solids (TSS), color index of red grapes (CIRG) value, anthocyanins accumulation, total phenolics and total procyanidins contents during berry development compared with those in control berries. The transcriptomic changes induced by root restriction in 'Summer Black' grape over the course of berry development were analyzed by RNA-Seq method. A total of 29,971 genes were generated in 'Summer Black' grape berry during development, among which, 1606 genes were significantly responded to root restriction. Furthermore, 1264, 313, 141, 246 and 19 sequences were significantly changed at S1, S2, S3, S4 and S5 sample points, respectively. The gene (VIT_04s0023g02290) predicted as a salicylate O-methyltransferase was differentially expressed in all developmental stages. Gene Ontology (GO) enrichment showed that response to organic nitrogen, response to endogenous stimulus, flavonoid metabolic process, phenylpropanoid biosynthetic process and cell wall macromolecule metabolic process were the main significant differential categories. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment revealed plant-pathogen interaction, plant hormone signal transduction, flavone and flavonol biosynthesis, flavonoid biosynthesis and glucosinolate biosynthesis were the main significant differential pathways. The results of the present study provided a genetic base for the understanding of grape berry fruit quality improvement under root restriction.

Selection of DNA aptamers against epidermal growth factor receptor with high affinity and specificity.

Epidermal growth factor receptor (EGFR/HER1/c-ErbB1), is overexpressed in many solid cancers, such as epidermoid carcinomas, malignant gliomas, etc. EGFR plays roles in proliferation, invasion, angiogenesis and metastasis of malignant cancer cells and is the ideal antigen for clinical applications in cancer detection, imaging and therapy. Aptamers, the output of the systematic evolution of ligands by exponential enrichment (SELEX), are DNA/RNA oligonucleotides which can bind protein and other substances with specificity. RNA aptamers are undesirable due to their instability and high cost of production. Conversely, DNA aptamers have aroused researcher's attention because they are easily synthesized, stable, selective, have high binding affinity and are cost-effective to produce. In this study, we have successfully identified DNA aptamers with high binding affinity and selectivity to EGFR. The aptamer named TuTu22 with Kd 56±7.3nM was chosen from the identified DNA aptamers for further study. Flow cytometry analysis results indicated that the TuTu22 aptamer was able to specifically recognize a variety of cancer cells expressing EGFR but did not bind to the EGFR-negative cells. With all of the aforementioned advantages, the DNA aptamers reported here against cancer biomarker EGFR will facilitate the development of novel targeted cancer detection, imaging and therapy.

Enhanced Treatment Options for Dural Arteriovenous Fistulas at the Craniocervical Junction: Endovascular Embolization Versus Microsurgery? A Single-Center 23-Year Experience.

OBJECTIVE: The occurrence of dural arteriovenous fistulas (DAVFs) at the craniocervical junction (CCJ) is an uncommon vascular malformation. The diagnosis and treatment of CCJ DAVFs present a formidable challenge. This study aims to investigate the effect of endovascular embolization and microsurgery on improving patient prognosis. METHODS: This retrospective study included patients diagnosed with CCJ DAVFs who received treatment at the First Affiliated Hospital of Fujian Medical University between January 2000 and January 2023. The clinical records, imaging data, and treatment methods were obtained from the hospital's medical record system. The patients were classified into microsurgery and embolization groups based on the surgical technique employed for treatment. The primary outcome measures were surgical-associated neurological dysfunction (SAND) and long-term neurological outcomes. The Cox proportional hazard regression was utilized to determine hazard ratios and 95% confidence intervals (CI) to assess the relationship between treatment methods and prognosis. Kaplan-Meier survival analysis was employed to evaluate the incidence of SAND in both cohorts. RESULTS: This study recruited 46 patients with an average age of 53.72 ± 13.83 years. In the microsurgery group, there were 12 cases (26.1%) observed. While in the embolization group, there were 34 cases (73.9%). Of these patients, 16 (34.8%) experienced SAND after treatment. In the microsurgery group, there were 8 cases (75.0%), while in the embolization group, only 8 cases (23.5%) were reported. Specifically, the embolization group exhibited a significantly lower risk of SAND [adjusted hazard ratio = 0.259, 95% CI = 0.096-0.700; P = 0.008)] compared to the microsurgery group. Additionally, the combined Borden grade 2-3 was found to be significantly associated with SAND (adjusted hazard ratio = 3.150, 95% CI = 1.132-8.766; P = 0.028). The results of the Kaplan-Meier survival analysis indicated a statistically significant difference in the occurrence of favorable functional outcomes between the 2 groups (log-rank P = 0.0081). CONCLUSIONS: CCJ DAVFs are uncommon disorders characterized by a diverse range of clinical manifestations. The functional prognosis of endovascular treatment may be superior to microsurgery.

Metabolome and Transcriptome Analysis Revealed the Basis of the Difference in Antioxidant Capacity in Different Tissues of Citrus reticulata 'Ponkan'.

Citrus is an important type of fruit, with antioxidant bioactivity. However, the variations in the antioxidant ability of different tissues in citrus and its metabolic and molecular basis remain unclear. Here, we assessed the antioxidant capacities of 12 tissues from Citrus reticulata 'Ponkan', finding that young leaves and root exhibited the strongest antioxidant capacity. Secondary metabolites accumulated differentially in parts of the citrus plant, of which flavonoids were enriched in stem, leaf, and flavedo; phenolic acids were enriched in the albedo, while coumarins were enriched in the root, potentially explaining the higher antioxidant capacities of these tissues. The spatially specific accumulation of metabolites was related to the expression levels of biosynthesis-related genes such as chalcone synthase (CHS), chalcone isomerase (CHI), flavone synthase (FNS), O-methyltransferase (OMT), flavonoid-3'-hydroxylase (F3'H), flavonoid-6/8-hydroxylase (F6/8H), p-coumaroyl CoA 2'-hydroxylase (C2'H), and prenyltransferase (PT), among others, in the phenylpropane pathway. Weighted gene co-expression network analysis (WGCNA) identified modules associated with flavonoids and coumarin content, among which we identified an OMT involved in coumarin O-methylation, and related transcription factors were predicted. Our study identifies key genes and metabolites influencing the antioxidant capacity of citrus, which could contribute to the enhanced understanding and utilization of bioactive citrus components.

Plasma biomarkers in patients with familial cavernous malformation and their first-degree relatives.

Background: We aimed to explore the differences in plasma biomarker levels between patients with familial cerebral cavernous malformations (FCCM) and their healthy first-degree relatives (FDRs) and between FCCM patients with and without severe chronic disease aggressiveness (CDA). Methods: Magnetic resonance imaging (MRI) scanning and genetic testing was performed in patients with multiple CCMs and their FDRs. Sixty-seven plasma biomarkers were tested using a customised multiplex bead immunoassay kit. Univariate and multivariate unconditional logistic regression analyses were conducted to determine the associations between plasma factors and the risk of developing FCCM and severe CDA. Receiver operating characteristic (ROC) curves were generated for each independent risk factor. Results: Plasma factors of 37 patients with FCCM and 37 FDRs were examined. Low CD31 (P < 0.001) and BDNF levels (P = 0.013) were independent risk factors for FCCM. The best model was achieved by combining the results of CD31 and BDNF (AUC = 0.845, sensitivity 0.838, specificity 0.784, cutoff score - 4.295) to distinguish patients with FCCM from healthy FDRs. Low serpin E1/PAI-1 (P = 0.011) and high ROBO4 levels (P = 0.013) were independent risk factors for severe CDA in patients with FCCM. The best model was achieved by combining the results of E1/PAI-1 and ROBO4 levels (AUC = 0.913, sensitivity 1.000, specificity 0.760, cutoff score - 0.525) to identify patients with FCCM and severe CDA. Conclusions: The plasma concentrations of CD31 and BDNF seem to be lower in patients with FCCM than in their healthy FDRs. Low serpin E1/PAI-1 and high ROBO4 concentrations may be correlated with high lesion burden and risk of recurrent bleeding.

Naoxueshu Oral Liquid Accelerates Post-Craniotomy Hematoma Absorption in Patients: An Open-Label, Multicenter, and Randomized Controlled Trial.

OBJECTIVE: To investigate whether Naoxueshu Oral Liquid (NXS) could promote hematoma absorption in post-craniotomy hematoma (PCH) patients. METHODS: This is an open-label, multicenter, and randomized controlled trial conducted at 9 hospitals in China. Patients aged 18-80 years with post-craniotomy supratentorial hematoma volume ranging from 10 to 30 mL or post-craniotomy infratentorial hematoma volume less than 10 mL, or intraventricular hemorrhage following cranial surgery were enrolled. They were randomly assigned at a 1:1 ratio to the NXS (10 mL thrice daily for 15 days) or control groups using a randomization code table. Standard medical care was administered in both groups. The primary outcome was the percentage reduction in hematoma volume from day 1 to day 15. The secondary outcomes included the percentage reduction in hematoma volume from day 1 to day 7, the absolute reduction in hematoma volume from day 1 to day 7 and 15, and the change in neurological function from day 1 to day 7 and 15. The safety was closely monitored throughout the study. Moreover, subgroup analysis was performed based on age, gender, history of diabetes, and etiology of intracerebral hemorrhage (ICH). RESULTS: A total of 120 patients were enrolled and randomly assigned between March 30, 2018 and April 15, 2020. One patient was lost to follow-up in the control group. Finally, there were 119 patients (60 in the NXS group and 59 in the control group) included in the analysis. In the full analysis set (FAS) analysis, the NXS group had a greater percentage reduction in hematoma volume from day 1 to day 15 than the control group [median (Q1, Q3): 85% (71%, 97%) vs. 76% (53%, 93%), P<0.05]. The secondary outcomes showed no statistical significance between two groups, either in FAS or per-protocol set (P>0.05). Furthermore, no adverse events were reported during the study. In the FAS analysis, the NXS group exhibited a higher percentage reduction in hematoma volume on day 15 in the following subgroups: male patients, patients younger than 65 years, patients without diabetes, or those with initial cranial surgery due to ICH (all P<0.05). CONCLUSIONS: The administration of NXS demonstrated the potential to promote the percentage reduction in hematoma volume from day 1 to day 15. This intervention was found to be safe and feasible. The response to NXS may be influenced by patient characteristics. (Registration No. ChiCTR1800017981).

Prevalence, genetic and clinical characteristics in first-degree relatives of patients with familial cerebral cavernous malformations in China.

OBJECTIVE: This study aims to investigate the prevalence of familial cerebral cavernous malformations (FCCMs) in first-degree relatives (FDRs) using familial screening, to describe the distribution of initial symptoms, lesion count on cranial MRI and pathogenic gene in patients. METHODS: Patients with multiple CCMs who enrolled from the Treatments and Outcomes of Untreated Cerebral Cavernous Malformations in China database were considered as probands and FDRs were recruited. Cranial MRI was performed to screen the CCMs lesions, and whole-exome sequencing was performed to identify CCM mutations. MRI and genetic screening were combined to diagnose FCCM in FDRs, and the results were presented as prevalence and 95% CIs. The Kaplan-Meier (KM) method was used to calculate the cumulative incidence of FCCM. RESULTS: 33 (76.74%) of the 43 families (110 FDRs) were identified as FCCM (85 FDRs). Receiver operating characteristic analysis revealed three lesions on T2-weighted imaging (T2WI) were the strong indicator for distinguishing probands with FCCM (sensitivity, 87.10%; specificity, 87.50%). Of the 85 FDRs, 31 were diagnosed with FCCM, resulting in a prevalence of 36.5% (26.2%-46.7%). In families with FCCMs, the mutation rates for CCM1, CCM2 and CCM3 were 45.45%, 21.21% and 9.09%, respectively. Furthermore, 53.13% of patients were asymptomatic, 17.19% were intracranial haemorrhage and 9.38% were epilepsy. The mean age of symptom onset analysed by KM was 46.67 (40.56-52.78) years. CONCLUSION: Based on MRI and genetic analysis, the prevalence of CCMs in the FDRs of families with FCCMs in China was 36.5%. Genetic counselling and MRI screening are recommended for FDRs in patients with more than three CCM lesions on T2WI.