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Glioblastoma multiforme (GBM) is a highly malignant central nervous system tumor with a poor prognosis. Developing new therapeutic drugs is crucial. This study evaluates deoxyelephantopin (DET), a major component of *Elephantopus scaber* L., for its potential anti-GBM effects. The effects of DET on GBM cell lines were investigated using the MTT assay and Annexin-V kit to assess cell death and apoptosis. Western blot analysis examined apoptosis and cell cycle-related proteins. ELISA kits measured VEGF and TGF-β levels. In vivo, NOD SCID mice were injected with GL-261 cells and treated with DET to evaluate tumor growth and survival. DET inhibited GBM cell growth in a time- and dose-dependent manner. MTT and Annexin-V assays confirmed cell death and apoptosis. Western blot analysis showed DET downregulated Bcl-2 and increased caspase-3, Bax, and cytochrome c levels. ELISA results indicated that DET suppressed VEGF and TGF-β expression. DET treatment also decreased phosphorylation of AKT and STAT-3, CDK4, cyclin D2, MMP2, and MMP9 levels. In vivo, DET significantly inhibited tumor growth and improved survival rates in mice. DET exhibits significant in vitro and in vivo anticancer effects, making it a promising candidate for further research and potential clinical application against GBM., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: Hypercatecholaminergic conditions are known to cause heart failure and cardiac fibrosis when severe. Although previous investigations have studied the effects of beta-blockade in experimental models of catecholaminergic states, the detailed benefits of beta-blockade in more realistic models of hyper-adrenergic states were less clear. In this study, we examined acute cardiac changes in rats with hyperacute catecholamine-induced heart failure with and without propranolol treatment. Male Sprague-Dawley rats (n = 12) underwent a 6-hour infusion of epinephrine and norepinephrine alone, with an additional propranolol bolus (1 mg/kg) at hour 1 (n = 6). Cardiac tissues were examined after 6 hours. Cardiac immunohistochemistry revealed significantly decreased expression of phosphorylated p-38 (left ventricle, P = 0.021; right ventricle, P = 0.021), with upregulation of reactive oxidative species and other profibrosis proteins, after catecholamine infusion alone. After 1 propranolol 1 mg/kg bolus, the levels of phosphorylated-p38 returned to levels comparable with sham (left ventricle, P = 0.021; right ventricle, P = 0.043), with additional findings including downregulation of the apoptotic pathway and profibrotic proteins. We conclude that catecholamine-induced heart failure exerts damage through the p-38 mitogen-activated protein kinase pathway and demonstrates profibrotic changes mediated by matrix metalloproteinase 9, alpha-smooth muscle actin, and fibroblast growth factor 23. Changes in these pathways attenuated acute catecholamine-induced heart failure after propranolol bolus 1 mg/kg. We conclude that propranolol bolus at 1 mg/kg is able to mediate the effects of catecholamine excess through the p-38 mitogen-activated protein kinase pathway, profibrosis, and extrinsic apoptosis pathway., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation., (© 2024. The Author(s).)

Pneumonia stands as the leading infectious cause of childhood mortality annually, underscoring its significant impact on pediatric health. Although dexamethasone (DXMS) is effective for treating pulmonary inflammation, its therapeutic potential is compromised by systemic side effects and suboptimal carrier systems. To address this issue, the current study introduces solid lipid nanoparticles encapsulating hydrophobic dexamethasone palmitate (DXMS-Pal-SLNs) as an anti-inflammatory nanoplatform to treat pneumonia. The specialized nanoparticle formulation is characterized by high drug loading efficiency, low drug leakage and excellent colloidal stability in particular during nebulization and is proficiently designed to target alveolar macrophages in deep lung regions via local delivery with the nebulization administration. In vitro analyses revealed substantial reductions in the secretions of tumor necrosis factor-α and interleukin-6 from alveolar macrophages, highlighting the potential efficacy of DXMS-Pal-SLNs in alleviating pneumonia-related inflammation. Similarly, in vivo experiments showed a significant reduction in the levels of these cytokines in the lungs of mice experiencing lipopolysaccharide-induced pulmonary inflammation after the administration of DXMS-Pal-SLNs via nebulization. Furthermore, the study demonstrated that DXMS-Pal-SLNs effectively control acute infections without causing pulmonary infiltration or excessive recruitment of immunocytes in lung tissues. These findings highlight the potential of nebulized DXMS-Pal-SLNs as a promising therapeutic strategy for mitigating pneumonia-related inflammations.

Background and Objectives: When seizure onset affects a whole hemisphere, hemispheric disconnections are efficient and safe procedures. However, both lateral peri-insular hemispherotomy and vertical paramedian hemispherotomy approaches report a failure rate around 20%, which can be explained by residual connections giving rise to persistent seizures. In this study, we present the interhemispheric vertical hemispherotomy (IVH), a technical variation of the vertical paramedian hemispherotomy approach, that aims to increase seizure control avoiding residual connections while exposing the corpus callosum., Methods: This is a retrospective study of IVH in two centers, with analysis of clinical and MRI data and outcomes. A detailed description of the technique is provided with a video., Results: IVH was performed in 39 children. The mean age at surgery was 7.2 years, and etiologies were as follows: malformations of cortical development (n = 14), Rasmussen's encephalitis (n = 10), stroke (n = 10), post-traumatic (3), and Sturge-Weber Syndrome (2). Hemispheric disconnection was complete on postoperative MRI in 34 cases. There was no mortality, hydrocephalus occurred in one case, and subdural collection occurred in four cases. A second surgery was performed in four cases because of seizure relapse (n = 3) and/or incomplete disconnection on MRI (n = 4). With a mean follow-up of 3.2 years, International League Against Epilepsy class I epilepsy outcome was obtained for 37/39 patients., Conclusion: IVH is a safe and effective variation of the vertical approaches for hemispheric disconnection. It allows a good exposure and anatomic control of the corpus callosum, which is a frequent site of incomplete disconnection. IVH may be limited by the thalamic volume and the ventricular size, notably in hemimegalencephaly cases., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Augmentation cystoplasty (AC) is an effective surgical procedure for patients with neurogenic bladder whenever conservative treatments have failed. The present study aimed to determine the risks of metabolic complications, malignancy, long-term outcomes and histopathologic changes of native bladder and the augmented intestine after AC in children with neurogenic bladder. Pediatric patients < 18 years who underwent AC between 2000 and 2020 were enrolled. Early postoperative complications, long-term outcomes and histopathologic changes in mucosal biopsies of native bladder and the augmented intestine after AC were reviewed. Twenty-two patients with a mean age of 7.6 ± 4.4 years were included. The ileum was used in 19 patients and the sigmoid colon in 3 patients. The length of hospital stay was 14.8 ± 6.8 days. Post-operatively, the urinary continence rate improved from 22.7 to 81.8% (p < 0.001). Hydronephrosis resolved in 17 of 19 patients. Vesicoureteral reflux resolved in 16 (64.0%) of the refluxing ureter units and was downgraded in 7 (28.0%). Grades of hydronephrosis and reflux significantly improved following AC (p < 0.001). The estimated glomerular filtration rate also significantly increased (p = 0.012). Formation of urinary tract stones was the most frequent late complication (in 8 patients, 36.4%). Life-threatening spontaneous bladder perforation occurred in 1 patient. After a mean follow-up of 13.4 ± 5.9 years, there were no cases of mortality, new-onset symptomatic metabolic acidosis, or changes in serum electrolytes. Of the 17 patients who were followed for > 10 years, no cases of malignancy or metaplastic changes were identified in the native bladder or augmented bowel epithelium. AC is a safe and effective procedure with low surgical and metabolic complication rates. In addition, AC provides a satisfactory continence rate and long-term protection of renal function, increases functional capacity, and regresses reflux and hydronephrosis. Individualized surveillance is recommended for the early identification of urolithiasis and metabolic disturbances., (© 2024. The Author(s).)

Background: Stereoelectroencephalography (SEEG) is an effective presurgical invasive evaluation for drug-resistant epilepsies. The introduction of robotic devices provides a simplified, accurate, and safe alternative to the conventional SEEG technique. We report our institutional experience with robot-assisted SEEG and compare its in vivo accuracy, operation efficiency, and safety with the more traditional SEEG workflow., Methods: All patients with medically refractory focal epilepsy who underwent SEEG depth electrode implantation between 2014 and 2022 were included in this study. Technical advancements of the robot-assisted technique are described. Analyses of patient demographics, electrode implantation accuracy, operation time, and procedure-related complications were performed., Results: One hundred and sixty-six patients underwent 167 SEEG procedures. The first 141 procedures were performed using a conventional approach involving a Leksell stereotactic system, and the last 26 procedures were robot-assisted. Among the 1726 depth electrodes that were inserted, the median entry point localization error was as follows: conventional (1.0 mm; range, 0.1-33.5 mm) and robot-assisted (1.1 mm; range, 0-4.8 mm) (P = 0.17). The median target point localization error was as follows: conventional (2.8 mm; range, 0.1-49 mm) and robot-assisted (1.8 mm; range, 0-30.3 mm) (P < 0.001). The median operation time was significantly reduced with the robot-assisted workflow (90 min vs. 77.5 min; P < 0.01). Total complication rates were as follows: conventional (17.7%) and robot-assisted (11.5%) (P = 0.57). Major complication rates were 3.5% and 7.7% (P = 0.77), respectively., Conclusions: SEEG is a safe and highly accurate method that provides essential guidance for epilepsy surgery. Implementing SEEG in conjunction with multimodal planning systems and robotic devices can further increase safety margin, surgical efficiency, and accuracy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

We aimed to assess the efficacy of eplerenone, a steroidal mineralocorticoid receptor antagonist known to reduce blood pressure and mitigate cardiovascular disease (CVD) progression, in retarding the progression of chronic kidney disease (CKD) and CVD in a rat model of type 4 cardiorenal syndrome (CRS). We grouped rats into four experimental categories: sham surgery, sham treatment with eplerenone, nephrectomy without eplerenone (Nx), and nephrectomy with eplerenone (Nx + EP). For the Nx + EP group, rats received five-sixths nephrectomy, inducing CKD and CVD conditions such as renal hypertension and hyperglycemia, and were then treated with eplerenone (100 mg/kg/day, orally) over 4 weeks after an initial 4-week observation period. Heart rate, blood pressure, blood sugar levels, and sympathetic nerve excitation were monitored biweekly. In addition, assessments of renal and cardiac tissues, including evaluation of renal tubulointerstitial injury, glomerular injury, and cardiomyocyte hypertrophy, were conducted at week 8. Eplerenone administration mitigated CKD and CVD progression in the Nx + EP group, evident by improved blood pressure (217.3 ± 5.4 versus 175.3 ± 5.6), blood sugar (121.8 ± 1.3 versus 145.6 ± 6.0) level, reduced sympathetic nerve excitation, and cardiomyocyte hypertrophy compared to the Nx group. However, renal tubulointerstitial injury, glomerular injury, and cardiovascular dysfunction, which were increased in rats with type 4 CRS, did not show significant changes with eplerenone treatment. Our study demonstrated that eplerenone treatment did not exacerbate type 4 CRS but improved blood pressure, blood sugar levels, sympathetic nerve excitation, and cardiomyocyte hypertrophy in this model., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: The authors report no conflicts of interest.

Background/aim: Lung adenocarcinoma (LUAD) is the deadliest cancer, and approximately 20% of stage I LUAD cases recur after surgical resection due to its high intratumor heterogeneity. Reactive oxygen species (ROS) have been detected in LUAD and are involved in carcinogenesis and tumor progression. Here, a comprehensive analysis was performed to evaluate the effects of antioxidants on the prognosis of LUAD., Materials and Methods: The Cancer Genome Atlas (TCGA) database was used to study the relationship of gene expression of different ROS-scavenging enzymes with the progression and prognosis of LUAD., Results: Using TCGA LUAD datasets, we found that catalase (CAT) expression was significantly down-regulated in LUAD tissues compared to normal tissues, CAT down-regulation differed significantly between different grades of LUAD, low CAT expression was independently correlated with a worse prognosis in LUAD, and the expression of the CAT gene was associated with an inhibition of the "cell cycle". A panel of LUAD cells (CL1-0, CL1-1, CL1-3, and CL1-5), which harbored mutated p53 (R248W), with gradually increasing invasiveness showed a gradual decrease in CAT expression. Silencing of CAT upregulated cell growth in A549 cells, which harbor wild-type p53 and show high CAT expression and was associated with an increase in the expression of BUB1B, PLK1, and PKMYT1. Finally, over 38% (186/490) of LUAD cases with a p53 mutation exhibited significantly lower CAT expression than those with wild-type p53., Conclusion: CAT expression is a potent favorable prognostic marker for LUAD and may represent a drug target., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Atypical teratoid rhabdoid tumors (ATRT) is a rare but aggressive malignancy in the central nervous system, predominantly occurring in early childhood. Despite aggressive treatment, the prognosis of ATRT patients remains poor. RRM2, a subunit of ribonucleotide reductase, has been reported as a biomarker for aggressiveness and poor prognostic conditions in several cancers. However, little is known about the role of RRM2 in ATRT. Uncovering the role of RRM2 in ATRT will further promote the development of feasible strategies and effective drugs to treat ATRT., Methods: Expression of RRM2 was evaluated by molecular profiling analysis and was confirmed by IHC in both ATRT patients and PDX tissues. Follow-up in vitro studies used shRNA knockdown RRM2 in three different ATRT cells to elucidate the oncogenic role of RRM2. The efficacy of COH29, an RRM2 inhibitor, was assessed in vitro and in vivo. Western blot and RNA-sequencing were used to determine the mechanisms of RRM2 transcriptional activation in ATRT., Results: RRM2 was found to be significantly overexpressed in multiple independent ATRT clinical cohorts through comprehensive bioinformatics and clinical data analysis in this study. The expression level of RRM2 was strongly correlated with poor survival rates in patients. In addition, we employed shRNAs to silence RRM2, which led to significantly decrease in ATRT colony formation, cell proliferation, and migration. In vitro experiments showed that treatment with COH29 resulted in similar but more pronounced inhibitory effect. Therefore, ATRT orthotopic mouse model was utilized to validate this finding, and COH29 treatment showed significant tumor growth suppression and prolong overall survival. Moreover, we provide evidence that COH29 treatment led to genomic instability, suppressed homologous recombinant DNA damage repair, and subsequently induced ATRT cell death through apoptosis in ATRT cells., Conclusions: Collectively, our study uncovers the oncogenic functions of RRM2 in ATRT cell lines, and highlights the therapeutic potential of targeting RRM2 in ATRT. The promising effect of COH29 on ATRT suggests its potential suitability for clinical trials as a novel therapeutic approach for ATRT., (© 2023. The Author(s).)

Background: Motor recovery following a stroke is related to the initial stroke severity and corticospinal tract integrity. One of the outcomes representing corticospinal tract integrity is the motor evoked potential (MEP). This study aimed to investigate the predictive value of MEP for motor recovery in patients with acute ischemic stroke., Patients and Methods: Patients with hemiparesis secondary to initial acute ischemic stroke were enrolled. MEPs of the upper limb were assessed as preserved (MEP+) or absent (MEP-) response ≤10 days post-stroke. Fugl-Meyer assessment (FMA) was performed at baseline and post-stroke at 30 and 90 days. A modified Rankin scale (mRS) was conducted at 90 days post-stroke. Patients were divided into two groups according to the highest FMA score of MEP- patients. Generalized estimating equations and logistic regression were used for our study analysis., Results: Sixty-one participants were included in this study. The highest FMA score of MEP- patients ≤10 days after stroke was 38. Among patients with an initial FMA score ≤38, FMA scores at 30 and 90 days post-stroke were significantly higher in MEP + patients than in MEP- patients. Proportional recovery at 30 and 90 days post-stroke was significantly higher in MEP + patients than in MEP- patients. MEP + patients had a higher percentage of good functional outcomes than MEP- patients, without statistical difference. Among patients with initial FMA score >38, FMA scores were 60.4 ± 4.8 and 63.9 ± 2.9 and proportional recovery was 65.2 ± 27.0% and 83.7 ± 24.6% at 30 and 90 days post-stroke, respectively., Conclusions: Among patients with moderate-to-severe ischemic stroke, MEP + patients had better motor recoveries (approximately 70%) than MEP- patients at 90 days post-stroke. MEP + patients had better functional outcomes than MEP- patients.

Introduction: Incidence, health consequences, and social burden associated with child maltreatment appeared to be borne disproportionately by very young children. We conducted a population-based data linkage study to explore child- and family-level factors that affect receiving different diagnoses of maltreatment injuries and investigate excessive mortality throughout toddlerhood., Methods: We conducted a retrospective cohort study comprising 2.2 million infants born in 2004-2014 in Taiwan. Incident cases of child maltreatment were defined by hospitalization or emergency department visits for three heterogeneous diagnostic groups of maltreatment-related injuries (i.e., maltreatment syndrome, assaults, and undetermined causes) within 12 months after birth. The generalized linear model and landmark survival analyses were used to evaluate risk factors., Results: An estimated 2.9‰ of infants experienced at least one maltreatment-related injury, with a three-year mortality rate of 1.3%. Low birthweight was associated with increased risk of receiving the diagnosis of three maltreatment injuries, particularly maltreatment syndrome (adjusted Incidence Rate Ratio [aIRR] = 4.08, 95% confidence interval [CI]: 2.93-5.68). Socially advantaged family condition was inversely linked with receiving the diagnosis of maltreatment syndrome and assaults (e.g., high income: aIRR = 0.55 and 0.47), yet positively linked with undetermined cause (aIRR = 2.05, 95% CI: 1.89-2.23). For infants exposed to maltreatment, low birth weight and non-attendance of postnatal care were highly predictive of fatality; low birthweight served as a vital predictor for premature death during toddlerhood (aIRR = 6.17, 95% CI: 2.36-15.4)., Conclusions: Raising awareness of maltreatment-related injuries in infancy and predictors should be a priority for appropriate follow-up assessment and timely intervention., (© 2023. The Author(s).)

Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article.

Background: Migraine is one of four major chronic diseases that cause disability. Decreases in regional cerebral blood flow (rCBF) occur during migraine attacks. Laser therapy is extensively employed in treating other vascular diseases; nevertheless, its effectiveness in migraine management remains largely unknown. Therefore, we evaluated the effect of low-level intravascular laser irradiation of blood (ILIB) therapy in patients with migraine., Methods: We performed an observational case-control study in 24 patients suffering from migraine. Patients were divided into an ILIB treatment group and a traditional rehabilitation group. This study performed clinical assessments and single-photon emission computed tomography (SPECT) prior to and after the treatment and 1 month later. Changes in rCBF-SPECT between groups and between timepoints were compared to clinical outcomes., Results: Nine patients undergoing rehabilitation and fifteen patients undergoing ILIB were studied from baseline to 1 month follow-up. The ILIB group, visual analog scale for pain (P = 0.001), Montreal Cognitive Assessment (P = 0.003), and Athens Insomnia Scale (P < 0.001) symptom scores significantly improved after treatment. SPECT imaging showed a 1.27 ± 0.27 fold increase in rCBF after ILIB treatment, and no significant differences in the rehabilitation group., Conclusions: Low-level ILIB therapy is associated with better clinical and vascular outcomes, and may be a feasible treatment option for migraine. Although our sample size was small, our data provide a starting point for migraine laser therapy research., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Acute cardiomyopathy is a significant global health concern and one of the leading causes of death in developed countries. Prior studies have shown an association between acute cardiomyopathy and low vitamin D levels. Although paricalcitol, a vitamin D receptor (VDR) activator, has demonstrated clinical benefits in patients with advanced kidney disease, its effect on cardiac remodeling in cardiomyopathy is unknown. This study aimed to investigate the relative effects of paricalcitol on cardiomyopathy in rats. Wistar-Kyoto rats were administered vehicle (sham control group) or isoproterenol to induce cardiomyopathy. Rats administered isoproterenol were subsequently treated with paricalcitol (experimental group) or vehicle (isoproterenol group). Picrosirius red and immunofluorescence staining were used to analyze cardiac fibrosis and hypertrophy. Immunohistochemistry staining was used to confirm the molecular mechanisms involved in isoproterenol-induced cardiomyopathy in rats. Injection of paricalcitol could reduce collagen and transforming growth factor-beta 1 (TGF-β1) levels while activating fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor-23 (FGF23) without the help of Klotho, thereby reducing myocardial hypertrophy and fibrosis. As a VDR activator, paricalcitol reduces isoproterenol-induced cardiac fibrosis and hypertrophy by reducing the expression of TGF-β1 and enhancing the expression of VDR, FGFR1, and FGF23., Competing Interests: None

Serum and glucocorticoid-regulated kinase 1 (SGK1) is expressed in neuronal cells and involved in the pathogenesis of hypertension and metabolic syndrome, regulation of neuronal function, and depression in the brain. This study aims to identify the cellular mechanisms and signaling pathways of SGK1 in neuronal cells. In this study, the SGK1 inhibitor GSK650394 is used to suppress SGK1 expression in PC12 cells using an in vitro neuroscience research platform. Comparative transcriptomic analysis was performed to investigate the effects of SGK1 inhibition in nervous cells using mRNA sequencing (RNA-seq), differentially expressed genes (DEGs), and gene enrichment analysis. In total, 12,627 genes were identified, including 675 and 2152 DEGs at 48 and 72 h after treatment with GSK650394 in PC12 cells, respectively. Gene enrichment analysis data indicated that SGK1 inhibition-induced DEGs were enriched in 94 and 173 genes associated with vascular development and functional regulation and were validated using real-time PCR, Western blotting, and GEPIA2. Therefore, this study uses RNA-seq, DEG analysis, and GEPIA2 correlation analysis to identify positive candidate genes and signaling pathways regulated by SGK1 in rat nervous cells, which will enable further exploration of the underlying molecular signaling mechanisms of SGK1 and provide new insights into neuromodulation in cardiovascular diseases.

Introduction: Malignant germ cell tumors (MGCTs) can develop either extracranially or intracranially. Growing teratoma syndrome (GTS) may develop in these patients following chemotherapy. Reports on the clinical characteristics and outcomes of GTS in children with MGCTs are limited., Methods: We retrospectively collected the data, including the clinical characteristics and outcomes of five patients in our series and 93 pediatric patients selected through a literature review of MGCTs. This study aimed to analyze survival outcomes and risk factors for subsequent events in pediatric patients with MGCTs developing GTS., Results: The sex ratio was 1.09 (male/female). In total, 52 patients (53.1%) had intracranial MGCTs. Compared with patients with extracranial GCTs, those with intracranial GCTs were younger, predominantly boys, had shorter intervals between MGCT and GTS, and had GTS mostly occurring over the initial site (all p < 0.001). Ninety-five patients (96.9%) were alive. However, GTS recurrence (n = 14), GTS progression (n = 9), and MGCT recurrence (n = 19) caused a substantial decrease in event-free survival (EFS). Multivariate analyses showed that the only significant risk factors for these events were incomplete GTS resection and different locations of GCT and GTS. Patients without any risk had a 5-year EFS of 78.8% ± 7.8%, whereas those with either risk had 41.7% ± 10.2% (p < 0.001)., Conclusion: For patients with high-risk features, every effort should be made to closely monitor, completely remove, and pathologically prove any newly developed mass to guide relevant treatment. Further studies incorporating the risk factors into treatment strategies may be required to optimize adjuvant therapy., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Atypical teratoid rhabdoid tumor (AT/RT) occurs at a younger age and is associated with a worse prognosis than medulloblastoma; however, these two tumor entities are mostly indistinguishable on neuroimaging. The aim of our study was to differentiate AT/RT and medulloblastoma based on their clinical and MRI features to enhance treatment planning and outcome prediction., Methods: From 2005-2021, we retrospectively enrolled 16 patients with histopathologically diagnosed AT/RT and 57 patients with medulloblastoma at our institute. We evaluated their clinical data and MRI findings, including lesion signals, intratumoral morphologies, and peritumoral/distal involvement., Results: The age of children with AT/RT was younger than that of children with medulloblastoma (2.8 ± 4.9 [0-17] vs. 6.5 ± 4.0 [0-18], p < 0.001), and the overall survival rate was lower (21.4% vs. 66.0%, p = 0.005). Regarding lesion signals on MRI, AT/RT had a lower ADC min (cutoff value ≤544.7 × 10 -6  mm 2 /s, p < 0.001), a lower ADC ratio (cutoff value ≤0.705, p < 0.001), and a higher DWI ratio (cutoff value ≥1.595, p < 0.001) than medulloblastoma. Regarding intratumoral morphology, the "tumor central vein sign" was mostly exclusive to medulloblastoma (24/57, 42.1%; AT/RT 1/16, 6.3%; p = 0.007). Regarding peritumoral invasion on T2WI, AT/RT was more prone to invasion of the brainstem (p < 0.001) and middle cerebellar peduncle (p < 0.001) than medulloblastoma., Conclusions: MRI findings of a lower ADC value, more peritumoral invasion, and absence of the "tumor central vein sign" may be helpful to differentiate AT/RT from medulloblastoma. These distinct MRI findings together with the younger age of AT/RT patients may explain the worse outcomes in AT/RT patients., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Schizencephaly is a congenital cerebral malformation characterized by clefts in the hemispheres of the brain, where variations in semiology often make it difficult to localize epileptogenic focus. Here, we report on a series of patients who underwent stereo-encephalography (SEEG) for epileptogenic focus localization and subsequent SEEG-guided surgical intervention., Methods: Four patients (ages 27, 33, 27, 25 years) with a mean seizure history of 16 years (range 8-22 years) were analyzed. Data pertaining to semiology, video encephalography (EEG), magnetic resonance imaging, positron emission tomography, and invasive EEG studies, surgical intervention and post-surgery outcome were collected and analyzed., Results: All seizure onset zones were within the extent of schizencephaly; however, the limbic system (including the hippocampus, amygdala, cingulate gyrus, or insula) was involved in early spreading. Two patients underwent SEEG-guided radiofrequency thermo-ablation (RFTA) in the seizure onset zone, 1 patient underwent lesionectomy via craniotomy, and 1 underwent neither RFTA nor lesionectomy. At 2 years post-surgery, the outcomes were as follows: Engel grade Ia (n = 2), Ib (n = 1), and III (n = 1)., Conclusions: This article reports on a precise approach to treating patients with schizencephaly dependent of seizure onset zone and functional cortex mapping. Subsequent SEEG-guided surgical interventions (radiofrequency thermo-ablation and lesionectomy) were shown to reduce seizure frequency, while preserving the neurologic functions in drug-resistant epilepsy patients with schizencephaly., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to evaluate the impact of variant factors on finger replantation and revascularisation after traumatic amputation, which also included duty shift and the level of main operator. Methods: To determine the prognostic factors for the survival rate of finger replantation and revascularisation after traumatic finger amputation, we retrospectively reviewed the cases of finger replantation conducted from January 2001 to December 2017. Data collected consisted of the basic information of the patients, trauma-related factors, details of the operation and treatment outcomes. Descriptive statistics and data analysis was performed to assess outcomes. Results: In total, 150 patients with 198 replanted digits were enrolled in this study. The median age of the participants was 42.5 years, and 132 (88%) patients were men. The overall successful replantation rate was 86.4%. Seventy-three (36.9%) digits had Yamano type 1 injury; 110 (55.6%), Yamano type 2 injury and 15 (7.6%), Yamano type 3 injury. In total, 73 (36.9%) digits were completely amputated and 125 (63.1%) were not. Half of the replantation procedures (101, 51.0%) were performed during night shift (16:00-00:00), 69 (34.8%) during day shift (08:00-16:00) and 28 (14.1%) during graveyard shift (00:00-08:00). Multivariate logistic regression demonstrated that the trauma mechanism and type of amputation (complete vs. incomplete) significantly affect the survival rate of replantation. Conclusions: The trauma mechanism and type of amputation (complete vs. incomplete) significantly affect the survival rate of replantation. Other factors including duty shift and the level of operator did not reach statistically significance. Further studies must be conducted to validate the results of the current study. Level of Evidence: Level III (Prognostic).

Exposure to hypoxia during the early postnatal period can have adverse effects on vital organs. Neonatal Sprague-Dawley rats housed in a hypoxic chamber were compared to those in a normoxic chamber from postnatal days 0 to 7. Arterial blood was collected to evaluate renal function and hypoxia. Kidney morphology and fibrosis were evaluated using staining methods and immunoblotting. In the kidneys of the hypoxic group, protein expressions of hypoxia-inducible factor-1 were higher than those in the normoxic group. Hypoxic rats had higher levels of hematocrit, serum creatinine, and lactate than normoxic rats. Body weight was reduced, and protein loss of kidney tissue was observed in hypoxic rats compared to normoxic rats. Histologically, hypoxic rats showed glomerular atrophy and tubular injury. Renal fibrosis with collagen fiber deposition was observed in the hypoxic group. The expression of nicotinamide adenine dinucleotide phosphate oxidases was enhanced in the kidneys of hypoxic rats. Proteins involved in apoptosis were upregulated in the kidneys of hypoxic rats. An increase in the expression of pro-inflammatory cytokines was also observed in the kidneys of hypoxic rats. Hypoxic kidney injury in neonatal rats was associated with oxidative stress, inflammation, apoptosis, and fibrosis.

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Primary liver cancer is one of the leading causes of death globally. Liver cancer has a unique geographical distribution, as its etiologies include chronic viral infections and aging. We hypothesize that the human development index (HDI), current health expenditure (CHE) per capita, and CHE-to-gross domestic product ratio (CHE/GDP) influence the incidence, mortality, and mortality-to-incidence ratios (MIRs) of liver cancer worldwide. Data were obtained from the Global Cancer Observatory (GLOBOCAN) database and the World Health Organization. MIRs and the changes in MIR over time (δMIR) were used to evaluate the correlation of expenditures on healthcare and the HDI disparities via Spearman's rank correlation coefficient. The crude incidence and mortality were significantly associated with HDI, CHE per capita, and CHE/GDP. Specifically, there were significant associations between δMIR and HDI, as well as between δMIR and CHE per capita. However, there were no significant associations between δMIR and CHE/GDP. Evidently, a favorable liver cancer δMIR was not associated with CHE/GDP, although it had a significant association with HDI and CHE per capita. These results are worthy of the attention of public health systems in correlation to improved outcomes in liver cancer.

Medulloblastoma (MB) was classified into four molecular subgroups: WNT, SHH, group 3, and group 4. In 2017, 12 subtypes within 4 subgroups and 8 subtypes within non-WNT/non-SHH subgroups according to the differences of clinical features and biology were announced. In this study, we aimed to identify the heterogeneity of molecular features for discovering subtype specific factors linked to diagnosis and prognosis. We retrieved 70 MBs in children to perform RNA sequencing and a DNA methylation array in Taiwan. Integrated with clinical annotations, we achieved classification of 12 subtypes of pediatric MBs in our cohort series with reference to the other reported series. We analyzed the correlation of cell type enrichment in SHH MBs and found that M2 macrophages were enriched in SHH β, which related to good outcomes of SHH MBs. The high infiltration of M2 macrophages may be an indicator of a favorable prognosis and therapeutic target for SHH MBs. Furthermore, C11orf95-RELA fusion was observed to be associated with recurrence and a poor prognosis. These results will contribute to the establishment of a molecular diagnosis linked to prognostic indicators of relevance and help to promote molecular-based risk stratified treatment for MBs in children.

The obesity genetic effect may play a major role in obesogenic environment. A combined case-control and an 18-month follow-up were carried out, including a total of 311 controls and 118 obese cases. All participants were aged in the range of 20-55 y/o. The body mass index (BMI) of obese cases and normal controls was in the range of 27.0-34.9 and 18.5-23.9 kg/m 2 , respectively. The rs712221 on Estrogen receptor1 (ESR1) and rs2016520 on Peroxisome proliferator-activated receptor delta (PPARD) showed significant associations with obesity. The TT (odds ratio (OR): 2.42; 95% confidence interval (CI): 1.46-4.01) and TT/TC (OR: 2.80; 95% CI: 1.14-6.85) genotypes on rs712221 and rs2016520 had significantly higher obesity risks, respectively. Moreover, the synergic effect of these two risk SNPs (2-RGH) exhibited an almost geometrical increase in obesity risk (OR: 7.00; 95% CI: 2.23-21.99). Obese individuals with 2-RGH had apparently higher changes in BMI increase, body weight gain and dietary fiber intake but a lower total energy intake within the 18-month follow-up.

Multifunctional sequential targeted delivery system is developed as an efficient therapeutic strategy against malignant tumors with selective accumulation and minimal systemic drug absorption. The therapeutic system is comprised of microfluidized dextran microgels encapsulating cisplatin/superparamagnetic iron oxide nanoparticles (SPIONs)-loaded trilaurin-based lipid nanoparticles (LNPs). The microgel system is imparted hierarchically dual targeting via dextran and folic acid (FA) residues, leading to increases both in retention of the microgels in colon and in cellular uptake of the therapeutic LNPs by colon cancer cells while being used for oral therapeutic delivery. Encapsulation of the therapeutic LNPs into dextran microgels attained by microfluidized crosslinking reaction reduces gastrointestinal adhesion and prevents the FA-modified LNPs from cellular transport by proton-coupled FA transporters in small intestine during their oral delivery to colon. Upon enzymatic degradation of the dextran microgels by dextranase present exclusively in colon, LNPs thus released become more recognizable and readily internalized by FA receptor-overexpressing colon cancer cells. The combined chemo/magnetothermal therapeutic effect of dual targeted lipid nanoparticle-loaded microgels from entrapped lipidized cisplatin and alternating magnetic field-treated SPIONs significantly inhibits tumor growth and suppresses metastatic peritoneal carcinomatosis in orthotopic colon cancer-bearing mice., (© 2022 Wiley-VCH GmbH.)

Background: Laparoscopic sleeve gastrectomy (LSG) is a relative safe procedure in bariatric surgery. However, relatively few studies had been assessed its comprehensive efficacies. In the current study, the efficacies of LSG were comprehensively explored on glycemic control and cardiovascular disease (CVD) risk reduction., Methods: A total of 95 obese patients, who owned body mass index (BMI) of more than 35, were recruited. All of them primarily underwent LSG from 2014 to 2016. Type 2 diabetes mellitus (T2DM) remission was defined as levels of glycated hemoglobin (A1C) and fasting blood glucose (FBG) of less than 6.4% and 125 mg/dL, respectively. The further efficacies of LSG on CVD and coronary heart disease (CHD) risks were explored by using original- and recalibrated Framingham 10-year CHD risk scores and the other 3 well-established CVD risk prediction models., Results: Systolic blood pressure (SBP), serum FBG, A1C, triglyceride (TG), BMI, and body weight showed significantly declined and high-density lipoprotein-cholesterol (HDL) displayed twice higher than beginning level after LSG. The 71 of 95 patients with obesity were T2DM; 62 of them exhibited persistent DM remission until 1 year after LSG. Cardiovascular age, general cardiovascular risk (GCVR), and atherosclerotic cardiovascular disease risk (ASCVD) also showed significant decrements after LSG. We also observed significant reductions in estimated CVD and CHD risks., Conclusion: LSG resulted in a persistent T2DM remission and corrected metabolic abnormalities. Subsequently, LSG also benefits declined risks of CVD and 10-year CHD developments. LSG may be helpful for primary CVD care in obese patients with BMI of more than 35., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Atrial fibrillation (AF) is a significant independent risk factor for 1-year mortality in patients with first acute ischemic stroke (AIS). The CHA2DS2-VASc score was initially developed to assess the risk of stroke in patients with AF. Recently, this scoring system has been demonstrated to have clinical value for predicting long-term clinical outcomes in AIS but the evidence is insufficient. This large-scale prospective cohort study investigated the independent predictive value of the score in such patients., Methods: We included patients with AIS from the Taiwan Stroke Registry (TSR) during 2006-2016 as the present study population. Patients were divided into those with high (≥2) and low (<2) CHA2DS2-VASc scores. We further analyzed and classified patients according to the presence of AF. The clinical endpoint was major adverse cardiac and cerebrovascular events (MACCEs) at 1 year after the index AIS., Results: A total of 62,227 patients with AIS were enrolled. The median age was 70.3 years, and 59% of the patients were women. After confounding factors were controlled, patients with high CHA2DS2-VASc scores had significantly higher incidence of 1-year MACCEs (adjusted hazard ratio [HR] = 1.63; 95% confidence interval [CI] = 1.52, 1.76), re-stroke (adjusted HR = 1.28; 95% CI = 1.16, 1.42), and all-cause mortality (adjusted HR = 2.03; 95% CI = 1.83, 2.24) than those with low CHA2DS2-VASc scores did. In the comparison between AF and non-AF groups, the AF group had increased MACCEs (adjusted HR = 1.74; 95% CI = 1.60, 1.89), myocardial infarction (adjusted HR = 4.86; 95% CI = 2.07, 11.4), re-stroke (adjusted HR = 1.47; 95% CI = 1.26, 1.71), and all-cause mortality (adjusted HR = 1.90; 95% CI = 1.72, 2.10). The Kaplan-Meier curve revealed that both CHA2DS2-VASc scores and AF were independent risk predictors for 1-year MACCEs and mortality., Conclusions: The CHA2DS2-VASc score and AF appeared to consistently predict 1-year MACCEs of AIS patients and provide more accurate risk stratification. Therefore, increased use of the CHA2DS2-VASc score may help improve the holistic clinical assessment of AIS patients with or without AF., Competing Interests: The authors have declared that no competing interests exist.

Bilateral nucleus tractus solitarii (NTS) lesions, possibly caused by enterovirus 71 infection, cause severe neurogenic hypertension, leading to acute heart failure (HF), pulmonary edema, and death within hours. Alpha-adrenergic blockers attenuate blood pressure and ameliorate HF and pulmonary edema, thereby prolonging survival time. However, the molecular mechanisms of these blockers are not clear. In this study, we investigated these mechanisms in a rat model of 6-hydroxydopamine (6-OHDA)-induced HF. Sprague-Dawley rats were treated with prazosin 10 min after the microinjection of 6-OHDA into the NTS. Immunohistochemistry and dihydroethidium (DHE) staining were used for analysis. In the cardiac tissue of 6-OHDA-induced HF, in situ expression of tumor necrosis factor-alpha (TNF-α), fibroblast growth factor-23 (FGF23), and FGF receptor 1 (FGFR1) increased, but in situ expression of Vitamin D receptor (VDR) decreased. DHE staining revealed several heart cells with high reactive oxygen species production. Prazosin treatment decreased TNF-α, FGF23, and FGFR1 expression in the heart of rats with 6-OHDA-induced HF. It also prevented cardiomyopathy caused by 6-OHDA-induced bilateral NTS lesions by inhibiting the FGF23-FGFR1 pathway and downregulating TNF-α expression. In situ, FGF23, FGFR1, VDR, superoxide, and TNF-α in the heart were found to be involved in acute HF in our rat model of 6-OHDA-induced bilateral NTS lesions. These findings are potentially useful for treating fatal enterovirus 71 infection-induced NTS lesions and HF., Competing Interests: None

Objectives: Patients with end-stage renal disease (ESRD) are at a high risk of cardiovascular events (CVEs), and kidney transplantation (KT) has been reported to improve risk of CVEs and survival. As the association of KT timing on long-term survival and clinical outcomes remains unclear, we investigated the association of different KT waiting times with clinical outcomes., Design: Retrospective observational cohort study., Setting: We conducted an observational cohort study using data from the National Health Insurance Research Database in Taiwan. Adult patients who initiated KT therapy from 1997 to 2013 were included., Participants: A total of 3562 adult patients who initiated uncomplicated KT therapy were included and categorised into four groups according to KT waiting times after ESRD: group 1 (<1 year), group 2 (1-3 years), group 3 (3-6 years) and group 4 (>6 years)., Primary Outcome Measures: The main outcomes were composite of all-cause death, non-fatal myocardial infarction or non-fatal stroke, based on the primary diagnosis in medical records during hospitalisation., Results: Compared with group 1, the adjusted risk of primary outcome events (all-cause death, non-fatal myocardial infarction or non-fatal stroke) increased by 1.67 times in group 2 (95% CI: 1.40 to 2.00; p<0.001), 2.17 times in group 3 (95% CI: 1.73 to 2.71; p<0.001) and 3.10 times in group 4 (95% CI: 2.21 to 4.35; p<0.001). The rates of primary outcome events were 6.7%, 13.4% and 14.0% within 5 years, increasing to 19.5%, 26.3% and 30.8% within 10 years in groups 1, 2 and 3, respectively., Conclusions: Our results demonstrate that early KT is associated with superior long-term cardiovascular outcomes compared with late KT in selected patients with ESRD receiving uncomplicated KT, suggesting that an early KT could be a better treatment option for patients with ESRD who are eligible for transplantation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Severe hyper-catecholaminergic states likely cause heart failure and cardiac fibrosis. While previous studies demonstrated the effects of beta-blockade in experimental models of single-catecholamine excess states, the detailed benefits of beta-blockade in more realistic models of hyper-adrenergic states are less clearly understood. In this study, we examined different therapeutic dosages and the effects of propranolol in rats with hyper-acute catecholamine-induced heart failure, and subsequent cardiopulmonary changes. Rats (n = 41) underwent a 6 h infusion of epinephrine and norepinephrine alone, with additional low-dose (1 mg/kg) or high-dose propranolol (10 mg/kg) at hour 1. Cardiac and pulmonary tissues were examined after 6 h. Catecholamine-only groups had the lowest survival rate. Higher doses of propranolol (15 mg/kg) caused similarly low survival rates and were not further analyzed. All low-dose propranolol rats survived, with a modest survival improvement in the high-dose propranolol groups. Left ventricular (LV) systolic pressure and LV end-diastolic pressure improved maximally with low-dose propranolol. Cardiac immunohistochemistry revealed an LV upregulation of FGF-23 in the catecholamine groups, and this improved in low-dose propranolol groups. These results suggest catecholamine-induced heart failure initiates early pre-fibrotic pathways through FGF-23 upregulation. Low-dose propranolol exerted cardio-preventative effects through FGF-23 downregulation and hemodynamic-parameter improvement in our model of hyper-acute catecholamine-induced heart failure.

Objectives: To investigate structural connectivity after total callosotomy., Methods: Deterministic fiber tracking (tractography) of whole brain white matter was performed on 13 epilepsy patients pre- and post-callosotomy. The analysis of structural connectivity was based on graph theory and network-based analysis with a focus on the inter- and intrahemispheric networks. Clinical demographic data including seizure patterns and outcomes were scored for the identification of correlations., Results: After total callosotomy, structural interhemispheric networks were significantly interrupted. Specific changes were observed in the structural intrahemispheric networks in both hemispheres: 3 edges presented with significant decreases in the left hemisphere, whereas 2 edges presented with significant decreases in the right hemisphere. No global changes were observed in the network density, average weighted strength, average characteristic path length, or global efficiency of intrahemispheric networks. The intrahemispheric hubs and nodal efficiency were minimal changed after callosotomy., Conclusion: While there was a significant decrease in structural interhemispheric connectivity post-callosotomy, we observed synchronously decremented changes of intrahemispheric edges in each hemisphere. This study suggests that white matter maintains the structural connectivity intrahemispherically although functional connectivity recovered after total callosotomy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: We assessed the effect of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on ischemic stroke prevention in the Asian population with type 2 diabetes (T2D) without established cardiovascular disease., Research Design and Methods: This retrospective cohort study examined data obtained from the Taiwan National Health Insurance Research Database for the period from 1998 to 2018. The follow-up ended upon the occurrence of hospitalization for ischemic stroke. The median follow-up period was 3 years. The effect of GLP-1RA exposure time on the development of hospitalization for ischemic stroke was assessed., Results: The GLP-1RA and non-GLP-1RA user groups both included 6,534 patients. Approximately 53% of the patients were women, and the mean age was 49 ± 12 years. The overall risk of ischemic stroke hospitalization for GLP-1RA users was not significantly lower than that for GLP-1RA nonusers (adjusted hazard ratio [HR] 0.69 [95% CI 0.47-1.00]; P = 0.0506), but GLP-1RA users with a >251-day supply during the study period had a significantly lower risk of ischemic stroke hospitalization than GLP-1RA nonusers (adjusted HR 0.28 [95% CI 0.11-0.71]). Higher cumulative dose of GLP-1 RAs (>1,784 mg) was associated with significantly lower risk of ischemic stroke hospitalization. The subgroup analyses defined by various baseline features did not reveal significant differences in the observed effect of GLP-1RAs., Conclusions: Longer use and higher dose of GLP-1 RAs were associated with a decreased risk of hospitalization for ischemic stroke among Asian patients with T2D who did not have established atherosclerotic cardiovascular diseases, but who did have dyslipidemia or hypertension., (© 2022 by the American Diabetes Association.)

In this study, a plasmon-semiconductor nanotheranostic system comprising Au nanostars/graphene quantum dots (AuS/QD) hybrid nanoparticles loaded with BNN6 and surface modified with PEG-pyrene was developed for the photo-triggered hyperthermia effect and NO production as the dual modality treatment against orthotopic triple-negative breast cancer. The structure and morphology of the hybrid nanodevice was characterized and the NIR-II induced thermal response and NO production was determined. The hybrid nanodevice has shown enhanced plasmonic energy transfer from localized surface plasmonic resonance of Au nanostars to QD semiconductor that activates the BNN6 species loaded on QD surfaces, leading to the effective NO production and the gas therapy in addition to the photothermal response. The increased accumulation of the NIR-II-responsive hybrid nanotheranostic in tumor via the enhanced permeation and retention effects was confirmed by both in vivo fluorescence and photoacoustic imaging. The prominent therapeutic efficacy of the photothermal/NO combination therapy from the BNN6-loaded AuS@QD nanodevice with the NIR-II laser irradiation at 1064 nm against 4T1 breast cancer was observed both in vitro and in vivo. The NO therapy for the cancer treatment was evidenced with the increased cellular nitrosative and oxidative stress, nitration of tyrosine residues of mitochondrial proteins, vessel eradication and cell apoptosis. The efficacy of the photothermal treatment was corroborated directly by severe tissue thermal ablation and tumor growth inhibition. The NIR-II triggered thermal/NO combination therapy along with the photoacoustic imaging-guided therapeutic accumulation in tumor shows prominent effect to fully inhibit tumor growth and validates the promising strategy developed in this study., (Copyright © 2022. Published by Elsevier B.V.)

Low testosterone levels are associated with increased risk of cardiovascular disease; however, most previous studies assessed the relationship of testosterone levels with a history of cardiovascular (CV) events rather than with CV risk prediction scores consequently neglecting the effect of testosterone on CV risk in healthy young individuals. The aim of this study was to investigate the relationship between testosterone levels and predict the 10-year risk of cardiovascular disease. This retrospective cohort study was conducted through a large medical health examination system in four metropolises in Taiwan. Two risk scores were used to predict the 10-year cardiovascular risk of participants: the Framingham Risk Score (FRS) (2008) and the Atherosclerotic Cardiovascular Disease (ASCVD) Risk Estimator (2013). Multivariate-adjusted logistic regression was used to calculate odds ratios (ORs) for the correlation of testosterone level reduction with the increase in predicted CV risk. We used the MJ Health Research Foundation database to collect reports of 125,414 individuals who underwent medical checkups between 2007 and 2016. The final sample size included 1,253 male participants. A reduction in testosterone level between two subsequent medical checkups was associated with higher CV risk estimated by the FRS and ASCVD Risk Estimator in young participants aged 30-49 years (OR = 0.804, 95% CI: 0.711-0.909, p < 0.01 and OR = 0.841, 95% CI: 0.742-0.953, p < 0.01, respectively). Reduction in total testosterone levels increases CV risk in men aged 30 to 49 years, while the CV risk is not influenced by low testosterone levels at baseline., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Tu, Chen, Hung, Kuo, Tsan, Chu, Lee and Liao.)

Background: Aging-related hypogonadism in men is related to the deterioration of overall health. Those with this disease rarely receive treatment. The hypertriglyceridemic waist (HTGW) phenotype is a tool for predicting abnormalities of cardiovascular metabolism. However, the relationship between the HTGW phenotype and hypogonadism remains undetermined. This study aimed to determine the association between HTGW phenotype and hypogonadism in different age groups., Methods: Data of this cross-sectional study were obtained from MJ Health Screening Center in Taiwan from 2007 to 2016. The HTGW phenotype was divided into four categories based on whether the waist circumference (WC) and triglyceride levels were normal. WC of <90 cm and triglyceride level of <150 mg/dL were defined as normal. Hypogonadism was defined as a testosterone level of <300 ng/dL., Results: Overall, 6442 male participants were divided into three age groups: <50, 50-64, and ≥65 years (n = 4135, 1958, and 349; age groups 1, 2, and 3, respectively). The overall prevalence of hypogonadism was 10.6%. In group 1, participants with HTGW (odds ratio, 1.98; 95% confidence interval (CI), 1.354-2.896) had a higher risk of hypogonadism than those with normal WC and normal triglyceride levels after adjustment for body mass index and fasting blood glucose level. In group 2, participants with HTGW (odds ratio, 1.873; 95% CI, 1.099-3.193) had an increased risk of hypogonadism after adjustment for body mass index, fasting blood glucose level, Cholesterol levels, high-density lipoprotein (HDL) levels, low-density lipoprptein (LDL) levels and smoking status. However, no relationship was observed between HTGW phenotype and hypogonadism in group 3., Conclusion: HTGW phenotype was highly associated with hypogonadism in Taiwanese adult men. More attention should be paid to men aged <50 years with HTGW., Competing Interests: The authors have declared that no competing interests exist.

Abstract: Cerebrovascular disease is the second commonest cause of mortality globally and among the commonest causes of disability. However, research executed to probe the heavy metal exposure-stroke incidence relationship is scarce. Accordingly, we executed our study to probe the relationship of heavy metal concentrations (ie, concentrations of lead [Pb], mercury [Hg], cadmium [Cd], and arsenic) in the serum and urine of acute ischemic stroke (AIS) patients with several patient variables.For enrollment, we chose patients who had a first AIS within 7 days after the onset of a stroke. Thus, 33 newly diagnosed patients with AIS were recruited. We determined the aforementioned metals' concentrations by executing inductively coupled plasma mass spectrometry. We also gauged the association between such metal concentrations and patient variables by employing Spearman correlation coefficient. To examine the differences in metal concentrations between the different variables, we implemented an independent Mann-Whitney U test.In our cohort analysis, we noted serum Pb and Cd concentrations to be positively correlated with serum creatinine and hemoglobin. Serum and urine Cd concentrations had a negative correlation with impaired HbA1c in AIS patients. Urine Hg had a positive correlation with C-reactive protein in the participants. Participants who smoked or consumed alcohol had significantly higher Pb and Cd levels in serum than did those who neither smoked nor drank. Patients with AIS who smoked or consumed alcohol had high levels of serum Pb and serum Cd than did those who did not. Patients with AIS who consumed alcohol had significantly higher Pb and Hg urine concentrations than did those who did not.Our study indicated that serum Cd and Pb elevation increased the AIS risk in southern Taiwan patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Intracranial germinoma (IG) rarely occurs in adults. Its optimal treatment strategy is unclear. We evaluated the outcomes of radiotherapy in adults with intracranial germinoma. Data of 29 adult patients (age, 18-52 years; median age, 24.3 years) with IG treated with radiotherapy at Taipei Veterans General Hospital were retrospectively reviewed. They were followed up for a median time of 5.9 years (range, 1.0-12.8 years). We used the Kaplan-Meier method to estimate the progression-free survival (PFS) and overall survival (OS), and univariate and multivariate Cox proportional hazards regression models to identify the factors affecting PFS. PFS and OS were compared between adult and pediatric patients with IG. The 1-, 3-, and 5-year PFS rates were 96.6%, 85.8%, and 77.8%, respectively, in the adult patients, and the OS rate were all 100%. Seven patients (24.1%) experienced recurrence, and in six of them, salvage therapy successfully controlled the disease. Two patients (6.9%) died after 5 years of follow-up due to disease progression and central pontine myelinolysis. In the univariate and multivariate Cox analysis, bifocal lesions had a significantly lower PFS than those with single lesions (p = 0.008). Kaplan-Meier survival analysis showed that adult patients had a poorer PFS (p = 0.06) and OS (p = 0.025) than pediatric patients. Our study showed bifocal lesions were associated with lower PFS than a single lesion among adult IG patients, and adult IG patients tended to have poorer PFS and OS compared to pediatric IG patients. For adult patients with bifocal IG, we recommend treatment with craniospinal irradiation, whole ventricle irradiation (WVI) with chemotherapy, or frequent spine images follow-up for patients who received only WVI., Competing Interests: The authors have declared that no competing interests exist.

Background: Several studies have suggested mechanisms whereby excessive fructose intake increases blood pressure (BP). Glucose transporter 5 (GLUT5) is a fructose transporter expressed on enterocytes, and its involvement in the nucleus tractus solitarius (NTS)-modulated increase in BP following fructose intake remains unclear., Objectives: Herein, we investigated whether NTS Glut5 knockdown (KD) can alleviate fructose-induced hypertension in rat models., Methods: Male Wistar-Kyoto rats (6-8 weeks old; average weight: 230 g) were randomly assigned into 4 groups [control (Con), fructose (Fru), fructose + scrambled (Fru + S), and Fru +  KD]. The Con group rats had ad libitum access to regular water, and the other 3 groups were provided 10% fructose water ad libitum for 4 weeks (2 weeks before lentiviral transfection in the Fru + S and Fru + KD groups). Glut5 short hairpin RNA was delivered into the NTS of rats using a lentivirus system. Fructose-induced hypertension was assessed via the tail-cuff technique, a noninvasive blood pressure measurement approach. GLUT5-associated and other insulin signaling pathways in the NTS of rats were assessed using immunofluorescence and immunoblotting analyses. We evaluated between-group differences using the Mann-Whitney U test or Kruskal-Wallis 1-way ANOVA., Results: Compared with the Fru + S group, the Fru + KD group had reduced sympathetic nerve hyperactivity (48.8 ± 3.2 bursts/min; P < 0.05), improved central insulin signaling, upregulated protein kinase B (AKT; 3.0-fold) and neuronal NO synthase (nNOS; 2.78-fold) expression, and lowered BP (17 ± 1 mmHg, P < 0.05). Moreover, Glut5 KD restored signaling dependent on adenosine 5'-monophosphate-activated protein kinase and reduced fructose-induced oxidative stress 2.0-fold, and thus decreased NAD(P)H oxidase in p67-phox 1.9-fold within the NTS., Conclusions: Fructose-induced reactive oxygen species generates in the NTS of rats through GLUT5 and receptor for advanced glycation end products signaling, thus impairing the AKT-nNOS-NO signaling pathway and ultimately causing hypertension., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Gastric bypass (GB) is an effective treatment for those who are morbidly obese with coexisting type 2 diabetes mellitus (T2DM) or non-alcoholic fatty liver disease (NAFLD). Fibroblast growth factors (FGFs) are involved in the regulation of energy metabolism., Methods: We investigated the roles of FGF 19, FGF 21, and total bile acid among those with morbidly obese and T2DM undergoing GB. A total of 35 patients were enrolled. Plasma FGF 19, FGF 21, and total bile acid levels were measured before surgery (M0), 3 months (M3), and 12 months (M12) after surgery, while the hepatic steatosis index (HSI) was calculated before and after surgery., Results: Obese patients with T2DM after GB presented with increased serum FGF 19 levels ( p = 0.024) and decreased total bile acid ( p = 0.01) and FGF 21 levels ( p = 0.005). DM complete remitters had a higher FGF 19 level at M3 ( p = 0.004) compared with DM non-complete remitters. Fatty liver improvers tended to have lower FGF 21 ( p = 0.05) compared with non-improvers at M12., Conclusion: Changes in FGF 19 and FGF 21 play differential roles in DM remission and NAFLD improvement for patients after GB. Early increases in serum FGF 19 levels may predict complete remission of T2DM, while a decline in serum FGF 21 levels may reflect the improvement of NAFLD after GB.

Spinal metastasis from malignant primary brain tumors (MPBTs) in pediatric patients is rare and often appears as enhancing lesions on MRI. However, some indolent enhancing spinal lesions (IESLs) resulting from previous treatment mimic metastasis on MRI, leading to unnecessary investigation and treatment. In 2005-2020, we retrospectively enrolled 12 pediatric/young patients with clinical impression of spinal metastasis and pathological diagnosis of their spinal lesions. Three patients had MPBT with IESL, and 9 patients had malignant tumors with metastases. The histopathologic diagnosis of IESL was unremarkable marrow change. We evaluated their MRI, CT, and bone scan findings. The following imaging findings of IESL vs. spinal metastasis were noted: (1) IESLs appeared round/ovoid (3/3, 100%), whereas spinal metastasis appeared irregular (9/9, 100%) (P = 0.005); (2) target-shaped enhancement was noted in (3/3, 100%) vs. (0/9, 0%) of cases, respectively (P = 0.005); (3) pathologic fracture of the vertebral body was noted in (1/3, 33.3%) vs. (9/9, 100%) of cases, respectively (P = 0.045); (4) expansile vertebral shape was noted in (0/3, 0%) vs. (9/9, 100%) of cases, respectively (P = 0.005); (5) obliteration of the basivertebral vein was noted in (0/3, 0%) vs. (9/9, 100%) of cases, respectively (P = 0.005); and (6) osteoblastic change on CT was noted in (3/3, 100%) vs. (2/9, 22.2%) of cases, respectively (P = 0.034). IESL in pediatric patients with MPBT can be differentiated from metastasis based on their imaging characteristics. We suggest close follow-up rather than aggressive investigation and treatment for IESL., (© 2022. The Author(s).)

Background: Carpal tunnel syndrome (CTS), 1 of the most common peripheral neuropathies of the upper extremity, has been studied for decades regarding its epidemiology and associated medical conditions. We conducted a large-scale, age- and gender-matched study from an Asian population database to investigate the relationship between the incidence and the demographic characteristics., Methods: A retrospective cohort study using data of National Health Insurance Research Database was conducted. One million enrollees in Taiwan was used to identify 9442 patients with CTS and 37,768 randomly selected controls, in a control-case ratio of 4:1. Diagnoses of CTS were ascertained from January 1, 2003, to December 31, 2012. Sociodemographic and medical characteristics were evaluated to assess the correlation with CTS., Results: Annual incidence of CTS was approximately 0.4% during the 10-year-period in Taiwan, with higher incidence rate in female sex and middle age of group (50-59 years). Among the medical conditions, previous wrist injuries, obesity, gout, and rheumatoid arthritis were associated with CTS most significantly., Conclusions: Carpal tunnel syndrome has presented a relatively constant incidence in Taiwan. Female gender with middle age seemed to have the highest incident rate during a 10-year period from 2003 to 2012. Among the risk factors of CTS, previous wrist injuries, obesity, gout, and rheumatoid arthritis were demonstrated to be the most significantly correlated comorbidities., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: To evaluate whether waist circumference (WC) or hyperglycemia is more closely associated with hypogonadism in middle-aged men. Research Design and Methods . This cross-sectional study analyzed male participants under 65 years old from the MJ Health Screening Center in Taiwan from 2007 to 2016. Basic patient characteristics with relevant parameters were obtained. We used the chi-square test to perform a correlation analysis for HbA1c and WC between participants with and without hypogonadism. A one-way ANOVA with post hoc Scheffe's method was applied to compare the mean testosterone (T) among the HbAlc and WC groups (normal blood sugar with normal WC (NBSNW), abnormal blood sugar with normal WC (ABSNW), normal blood sugar with abnormal WC (NBSAW), and abnormal blood sugar with abnormal waist circumference (ABSAW))., Results: The 5,680 participants were divided into two groups based on the presence ( n = 599) or absence of hypogonadism ( n = 5,081), which was defined as total testosterone (TT) < 300 ng/dL. The mean TT of group NBSAW (443.71 ± 220.59 ng/dl) was significantly lower than that of group ABSNW (506.64 ± 191.08 ng/dl, p < 0.001). Moreover, the mean TT of group ABSAW (398.89 ± 146.24 ng/dl) was significantly lower than that of group ABSNW (506.64 ± 191.08 ng/dl, p < 0.001). The ORs after adjusting for BMI, TG, HDL, SBP, and DBP were statistically significant when comparing NBSAW vs. NBSNW (OR = 2.846; 95%CI = 2.266-3.575; p < 0.001), ABSNW vs. NDNW (OR = 1.693; 95%CI = 1.309-2.189; p < 0.001), and ABSAW vs. NBSNW (OR = 4.613; 95%CI = 3.634-5.856; p < 0.001)., Conclusion: The current study showed that WC should be the risk factor that is more closely associated with hypogonadism than hyperglycemia in middle-aged men., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2021 Po-Sheng Hsu et al.)

Medulloblastoma is the most common embryonic brain tumor in children. We investigated a cohort of 52 Asian medulloblastoma patients aged between 0 and 19 years old, who received surgical resections and post-resection treatments in the Taipei Medical University Hospital and the Taipei Veterans General Hospital. Genome-wide RNA sequencing was performed on fresh-frozen surgical tissues. These data were analyzed using the CIBERSORTx immune deconvolution software. Two external clinical and molecular datasets from United States (n = 62) and Canada (n = 763) were used to evaluate the transferability of the gene-signature scores across ethnic populations. The abundance of 13 genes, including DLL1, are significantly associated with overall survival (All Cox regression P < 0.001). A gene-signature score was derived from the deep transcriptome, capable of indicating patients' subsequent tumor recurrence (Hazard Ratio [HR] 1.645, confidence interval [CI] 1.337-2.025, P < 0.001) and mortality (HR 2.720, CI 1.798-4.112, P < 0.001). After the adjustment of baseline clinical factors, the score remains indicative of recurrence-free survival (HR 1.604, CI 1.292-1.992, P < 0.001) and overall survival (HR 2.781, CI 1.762-4.390, P < 0.001). Patients stratified by this score manifest not only distinct prognosis but also different molecular characteristics: Notch signaling ligands and receptors are comparatively overexpressed in patients with poorer prognosis, while tumor infiltrating natural killer cells are more abundant in patients with better prognosis. Additionally, immunohistochemical staining showed the DLL1 protein, a major ligand in the Notch signaling pathway, and the NCAM1 protein, a representative biomarker of natural killer cells, are present in the surgical tissues of patients of four molecular subgroups, WNT, SHH, Group 3 and Group 4. NCAM1 RNA level is also positively associated with the mutation burden in tumor (P = 0.023). The gene-signature score is validated successfully in the Canadian cohort (P = 0.009) as well as its three molecular subgroups (SHH, Group 3 and Group 4; P = 0.047, 0.018 and 0.040 respectively). In conclusion, pediatric medullablastoma patients can be stratified by gene-signature scores with distinct prognosis and molecular characteristics. Ligands and receptors of the Notch signaling pathway are overexpressed in the patient stratum with poorer prognosis. Tumor infiltrating natural killer cells are more abundant in the patient stratum with better prognosis., (© 2021. The Author(s).)

Fluoranthene, a high-molecular-weight polycyclic aromatic hydrocarbon (PAH), is widely present in air pollutants, including fine inhalable particulate matter. 3-Bromofluoranthene (3-BrFlu), which is a brominated fluoranthene and halogenated PAH, is generated from waste combustion, metallurgical processes, cement production, e-waste dismantling, and photoreaction. Vascular endothelial cells have key functions in the homeostasis and the development of the cardiovascular system. The zebrafish model has been widely employed to study cardiotoxicity and embryotoxicity. However, no evidence has indicated that 3-BrFlu induces cytotoxicity in vascular endothelial cells, or cardiotoxicity and embryotoxicity in zebrafish. In this study, 3-BrFlu induced concentration-dependent changes in embryo- and cardiotoxicity. Cytotoxicity was also induced by 3-BrFlu in a concentration-dependent manner through apoptosis and necrosis in vascular endothelial cells, SVEC4-10 cells. The activities of caspase-3, -8, and -9 were induced by 3-BrFlu via an intrinsic pathway constituting Bcl-2 downregulation, Bad upregulation, and mitochondrial dysfunction; the extrinsic pathway included the expression of death receptors, including tumour necrosis factor α and Fas receptors. These results indicated that 3-BrFlu caused cardio- and embryotoxicity in zebrafish through vascular endothelial cells cytotoxicity resulting from caspase-dependent apoptosis through intrinsic and extrinsic pathways., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Recent studies have proposed associations between systemic sclerosis (SSc) and atherosclerosis and between SSc and cardiovascular disease. However, in Asia, no large-scale studies have focused on the association between peripheral arterial disease (PAD) and SSc., Setting: A nationwide observation retrospective cohort study., Participants: The National Health Insurance Research Database was used for selecting patients diagnosed with SSc from 2000 to 2011. Patients diagnosed with PAD before the index date were excluded., Primary and Secondary Outcome Measures: The SSc cohort comprised 1106 patients with SSc, and the non-SSc cohort comprised 4424 matched controls. The Cox proportional hazards regression model was used for analysing the adjusted risk of PAD between the case and control patients., Results: The SSc cohort exhibited a significantly higher risk (HR=2.15, 95% CI=1.47 to 3.14) of PAD than did the non-SSc cohort. Patients with heart failure exhibited the highest risk of PAD (adjusted HR=2.10, 95% CI=1.20 to 3.70). Moreover, even without any comorbidities, the SSc cohort exhibited a significantly higher risk (adjusted HR=4.17 fold, 95% CI=1.98 to 8.77) of PAD than did the non-SSc cohort., Conclusion: SSc is associated with a significantly high risk of PAD. Further studies are required to reduce the PAD risk among patients with SSc., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)