The significance of ophthalmological features in diagnosis of thyroid-associated ophthalmopathy.

BACKGROUND: Thyroid-associated ophthalmopathy (TAO) is an autoimmune disorder. It has discriminable appearance. This study was conducted to dig the clinical significance of demographic characteristics and ophthalmologic diagram features in TAO diagnosis and stage/severity evaluation. RESULTS: We included 320 males and 633 females, with an average age of 41.75 ± 13.75. A majority of TAO patients had hyperthyroidism, and most of them were in the inactive stage and at the moderate level. The thyroid function type, stage and severity were closely associated with hypopsia, eyelid congestion, conjunctival congestion, corneal ulcer, ocular motility disorder, best corrected visual acuity, and extraocular muscle thickening. Using these features, we established different logistic regression models to predict thyroid function subtypes, abnormal thyroid function, stage, and severity, in which the AUC of the ROC curve and accuracies were satisfactory. CONCLUSION: Together, TAO subtype, stage and severity can be diagnosed by auxiliary references including demographic factors, symptoms from complains, and image features. These non-invasive indices can be applied in a timely manner in clinical estimating TAO status.

Research progress and application of artificial intelligence in thyroid associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is a complicated orbitopathy related to dysthyroid, which severely destroys the facial appearance and life quality without medical interference. The diagnosis and management of thyroid-associated ophthalmopathy are extremely intricate, as the number of professional ophthalmologists is limited and inadequate compared with the number of patients. Nowadays, medical applications based on artificial intelligence (AI) algorithms have been developed, which have proved effective in screening many chronic eye diseases. The advanced characteristics of automated artificial intelligence devices, such as rapidity, portability, and multi-platform compatibility, have led to significant progress in the early diagnosis and elaborate evaluation of these diseases in clinic. This study aimed to provide an overview of recent artificial intelligence applications in clinical diagnosis, activity and severity grading, and prediction of therapeutic outcomes in thyroid-associated ophthalmopathy. It also discussed the current challenges and future prospects of the development of artificial intelligence applications in treating thyroid-associated ophthalmopathy.

Chiral Naphthalenediimides with High-Efficiency Fluorescence and Circularly Polarized Luminescence in the Solid State for the Application in Organic Optoelectronics.

Naphthalenediimides (NDIs) have been extensively studied due to their tunable luminescent properties. However, generally, the monomers or aggregates of non-core substituted NDIs exhibit low fluorescence quantum yields (ΦFL <10 %) in the solid state, which limit their applications as light-emitting materials and render their chiral species unsuitable for circularly polarized luminescence (CPL). Herein, a series of non-core substituted chiral NDIs that exhibit high luminous efficiencies (ΦFL up to 56.8 % for racemate and 36.5 % for enantiomer) and a strong CPL behavior in the solid state is reported. These significant improvements are attributed to the unique molecular conformation of the chiral NDIs and the formation of distinctive discrete dimers. The structures of the NDIs were significantly simpler and more accessible than those of other NDIs. The findings evidence that non-core substituted NDIs can exhibit strong fluorescence in the solid state and provide a new pathway to improve photophysical properties of NDIs.

Synthesis, characterization and photocatalytic properties of In2.77S4/Ti3C2 composites.

Recently, the problem of water pollution, caused by antibiotics, is becoming more and more serious. Photocatalysis is one of the promising technologies for removing antibiotics from water. Herein, the In2.77S4/Ti3C2 composites were prepared by an in-situ hydrothermal growth method for photocatalytic degradation of tetracycline (TC). The as-developed composites were characterized by various methods. The UV-Vis DRS spectra reveals that the introduction of Ti3C2 makes the bandgap of the as-prepared composites smaller and the visible light absorption ability improved. The photocatalytic degradation efficiency of the as-prepared composite is enhanced under visible light illumination. It is shown as first increasing and then decreasing with increasing the content of Ti3C2 in the composite and reaches to the maximum of 89.3% in 90 min, which is higher than 75.1% of In2.77S4 and 6.7% of Ti3C2. The reason of improvement is the interface between In2.77S4 and Ti3C2 is tightly combined to form a heterojunction. Moreover, the photocurrent intensity of the as-obtained composite is improved, while its Nyquist arc radius is decreased. In addition, holes are the main active species and ·OH and ·O2 - play an auxiliary role during the degradation of TC.

Potential Therapeutic Activity of Berberine in Thyroid-Associated Ophthalmopathy: Inhibitory Effects on Tissue Remodeling in Orbital Fibroblasts.

Purpose: Berberine (BBR), an alkaloid produced by a traditional Chinese plant, was recently attributed multiple effects on lipometabolism, inflammation, and fibrosis. Thyroid-associated ophthalmopathy (TAO) is highly associated with these pathologic changes. Thus, we aimed to examine the potential therapeutic effect of BBR in an in vitro model of TAO. Methods: Orbital fibroblasts (OFs) obtained from control donors (n = 6) or patients with TAO (n = 6) were cultured. The CCK-8 assay was conducted for assessing the optimal concentration range. Oil Red O staining, Western blotting, and quantitative RT-PCR (qRT-PCR) were conducted to assess adipogenesis in OFs. RNA sequencing (RNA-seq) was used to screen the key pathways of the antiadipogenic effect mediated by BBR. Along with incremental concentrations of BBR, IL-1ß-induced expression of proinflammatory molecules was determined by ELISA and qRT-PCR. In addition, TGF-ß-induced hyaluronan (HA) production and fibrosis were evaluated by ELISA, qRT-PCR, and Western blotting. Results: TAO-OFs, but not control fibroblasts (CON-OFs), were readily differentiated into adipocytes with the commercial medium. Intracellular lipid accumulation was dose-dependently decreased by BBR, and adipogenic markers were also downregulated. Moreover, the PPARγ and AMPK pathways were screened out by RNA-seq and their downstream effectors were suppressed by BBR. Besides, BBR attenuated IL-1ß-induced expression of proinflammatory molecules in both TAO-OFs and CON-OFs by blocking nuclear factor-κB signaling. BBR's inhibitory effect on TGF-ß-mediated tissue remodeling was also confirmed in OFs. Conclusions: These findings demonstrate BBR has outstanding capabilities of controlling adipogenesis, inflammation, HA production, and fibrosis in OFs, highlighting its potential therapeutic role in TAO management.

Effect of early integrated robot-assisted gait training on motor and balance in patients with acute ischemic stroke: a single-blinded randomized controlled trial.

Background: Gait disruption is a common poststroke problem. Robot-assisted gait training (RAGT) might improve motor function, balance, and activities of daily living. Objective: We compared the clinical effectiveness of early integrated RAGT using the Walkbot robotic gym with an intensity-matched enhanced lower limb therapy (ELLT) program and with conventional rehabilitation therapy (CRT) in patients with acute ischemic stroke. Methods: A total of 192 patients with acute ischemic stroke were randomly assigned (1:1:1) to receive RAGT, ELLT, or CRT. All three groups received 45 min of training daily, 3 days a week, for 4 weeks consecutively. Before and after the 4-week treatment, the patients were assessed based on a 6-minute walking test (6MWT), functional ambulation classification (FAC), timed up and go (TUG) test, dual-task walking (DTW) test, Tinetti's test, Barthel's index (BI), stroke-specific quality of life (SS-QOL) scale, and gait analysis parameters. Results: After the 4-week intervention, the results of the 6MWT, FAC, TUG, DTW, Tinetti's test, BI, SS-QOL, and gait in the three groups significantly improved. Compared with ELLT and CRT groups, participants in the RAGT group had a better performance in 6MWT (199.11 ± 60.72 versus 182.47 ± 59.72 versus 173.69 ± 40.58, p = 0.035), FAC (4.10 ± 0.91 versus 3.69 ± 0.88 versus 3.58 ± 0.81, p = 0.044), DTW (10.29 ± 2.38 versus 12.92 ± 2.64 versus 13.89 ± 2.62, p = 0.031), SS-QOL (184.46 ± 20.53 versus 165.39 ± 20.49 versus 150.72 ± 20.59, p = 0.012), velocity (0.66 ± 0.22 versus 0.55 ± 0.23 versus 0.51 ± 0.20, p = 0.008), cycle duration (1.38 ± 0.40 versus 1.50 ± 0.38 versus 1.61 ± 0.30, p = 0.040), and swing phase symmetry ratio (SPSR, 1.10 ± 0.33 versus 1.21 ± 0.22 versus 1.48 ± 0.25, p = 0.021). The TUG, Tinetti's test, BI, and RMT results were similar, however. Conclusion: In the acute stroke phase, early integrated RAGT showed greater performance in gait rehabilitation than CRT and ELLT. Registration: ChiCTR1900026225.

The effects of polyphenols on fresh quality and the mechanism of partial freezing of tilapia fillets.

BACKGROUND: Fish is one of the most popular foods for consumers because of its abundant nutrition, tenderness and delicious taste. With increasing demand for tilapia fillets, practical preservation is widely used to maintain quality and safety during long-distance transportation and storage. Thus the effects of polyphenols (2 g L-1 ) on color, flavor quality and mechanism of tilapia fillets were studied during 49 days of partial freezing (-4 °C). RESULTS: Treatment with carnosic acid (CA), procyanidin (PA), quercetin (QE) and resveratrol (RSV) inhibited water migration, myoglobin oxidation and psychrophilic bacteria stability during partial freezing storage. Aeromonas and Acinetobacter were the dominant bacteria of tilapia fillets during -4 °C storage. The relative abundance of aromatic substances (T70/2) in the polyphenol groups (>20%) was richer than in the control (CON) group (17%). Partial least squares discriminant analysis results showed that the different odors of the control and polyphenol groups were completely separated. Moreover, 35 fatty acids were identified by gas chromatographic analysis. On 49 days, the ratios of unsaturated fatty acids in the PA group (58.64%), QE group (57.70%) and RSV group (57.25%) were higher than in the control group (57.19%), and the PA group was the highest. CONCLUSION: Polyphenol treatment effectively maintained freshness and improved the quality of tilapia fillets during partial freezing. The polyphenol treatment comprehensively sustained the color and flavor quality of tilapia fillets found in the proposed mechanism. In particular, PA treatment was considered a potential method for preserving the freshness of fillets. © 2022 Society of Chemical Industry.

Clustering and prediction of disease progression trajectories in Huntington's disease: An analysis of Enroll-HD data using a machine learning approach.

Introduction: Huntington's disease (HD) is a rare neurodegenerative disease characterized by cognitive, behavioral and motor symptoms that progressively worsen with time. Cognitive and behavioral signs of HD are generally present in the years prior to a diagnosis; however, manifest HD is typically assessed by genetic confirmation and/or the presence of unequivocal motor symptoms. Nevertheless, there is a large variation in symptom severity and rate of progression among individuals with HD. Methods: In this retrospective study, longitudinal natural history of disease progression was modeled in individuals with manifest HD from the global, observational Enroll-HD study (NCT01574053). Unsupervised machine learning (k-means; km3d) was used to jointly model clinical and functional disease measures simultaneously over time, based on one-dimensional clustering concordance such that individuals with manifest HD (N = 4,961) were grouped into three clusters: rapid (Cluster A; 25.3%), moderate (Cluster B; 45.5%) and slow (Cluster C; 29.2%) progressors. Features that were considered predictive of disease trajectory were then identified using a supervised machine learning method (XGBoost). Results: The cytosine adenine guanine-age product score (a product of age and polyglutamine repeat length) at enrollment was the top predicting feature for cluster assignment, followed by years since symptom onset, medical history of apathy, body mass index at enrollment and age at enrollment. Conclusions: These results are useful for understanding factors that affect the global rate of decline in HD. Further work is needed to develop prognostic models of HD progression as these could help clinicians with individualized clinical care planning and disease management.

Ocrelizumab treatment for relapsing-remitting multiple sclerosis after a suboptimal response to previous disease-modifying therapy: A nonrandomized controlled trial.

BACKGROUND: Many patients with multiple sclerosis (MS) experience suboptimal disease control despite the use of disease-modifying therapy (DMT). OBJECTIVE: To assess the efficacy and safety of ocrelizumab (OCR) in patients with relapsing-remitting MS (RRMS) and suboptimal response to prior DMTs. METHODS: Patients with RRMS and suboptimal responses (one clinically reported relapse and/or lesion activity) after ⩾ 6 months on another DMT were enrolled. OCR 600 mg was given intravenously every 24 weeks. The primary outcome was no evidence of disease activity (NEDA), defined as the absence of protocol-defined relapse, confirmed disability progression (CDP), T1 Gd-enhancing lesions, and new/enlarging T2 lesions. RESULTS: The intention-to-treat (ITT) population included 608 patients; NEDA was analyzed in a modified ITT (mITT) population (n = 576 (94.7%)). Over 96 weeks, 48.1% of mITT patients achieved NEDA, and most were free from protocol-defined relapse (89.6%), CDP (89.6%), and T1 Gd-enhancing lesions (95.5%); 59.5% had no new/enlarging T2 lesions. Safety observations were consistent with findings in the pivotal trials. CONCLUSION: Consistent efficacy of OCR on clinical and magnetic resonance imaging (MRI) disease activity measures and progression was shown in patients with RRMS and a suboptimal response to prior DMTs; no new safety signals were observed.

A naphthyridine-indole ligand for selective stabilization of G-quadruplexes and conformational conversion of hybrid topology.

The development of ligands to stabilize G-quadruplexes (G4s) or induce G4s to transition from metastable topology to stable topology is a potential strategy for inhibiting cancer cell proliferation. In this study, a novel G-quadruplex (G4) ligand based on a naphthyridine scaffold with two indole pendants, L5-DA, is reported to convert hybrid to the parallel topology. Circular dichroism (CD) and fluorescence spectroscopies were used to investigate the interactions between L5-DA and G4s. The CD spectra revealed that the L5-DA induced the conformational conversion from hybrid topologies to parallel topologies with a melting temperature increase of more than 30 °C. According to Förster resonance energy transfer assays, the presence of excess duplex competitor had no effect on the ligand-induced stabilization of the hybrid topology, confirming the L5-DA's selectivity for G4s over ds26. With IC50 values of 4.3 µM, the ligand showed significant cytotoxicity against HeLa cells and effectively induced growth inhibition and apoptosis in HeLa cells. Immunofluorescence microscopy revealed an increase in BG4 foci in the presence of the L5-DA, confirming ligand-induced G4s stabilization in HeLa cells. According to these results, the combination of naphthyridine and indole scaffold was an effective design strategy for G4s stabilization and conformational conversion of metastable G4 topology for inhibiting cancer cell growth.

The Association of Left Atrial Appendage Morphology to Atrial Fibrillation Recurrence After Radiofrequency Ablation.

Objective: The probability of late recurrent atrial fibrillation (AF) after radiofrequency ablation (RFA) has not yet been fully clarified. This study aims to study the association of left atrial appendage (LAA) morphology with AF recurrence after RFA. Methods: We retrospectively enrolled 84 patients (24 patients had persistent AF, 60 patients had paroxysmal AF) who underwent RFA in Shanghai East Hospital from June 2014 to May 2018. The mean follow-up of these patients was 618.6 days. According to preoperative transesophageal echocardiography (TEE), the morphology feature of LAA was classified and evaluated by two classification methods. The first method was divided into chicken-wing, windsock, cactus, and cauliflower, and the second method was divided into one lobe, two lobes, and multiple lobes. The correlation between morphological feature of LAA and the recurrence rate of AF after RFA was analyzed. Results: During follow-up, 12 patients (50%) and 10 patients (16.7%) had AF recurrence in persistent and paroxysmal AF, respectively. The LAA morphology was associated with the recurrence of AF after RFA with the chicken-wing highest recurrence risk (68.2%). The structure type of LAA was also related to the AF recurrence rate (p < 0.01). Compared with one lobe and multiple lobes, two lobes (recurrence, 47.6%) were more likely associated with the recurrence of AF (p < 0.02). Logistic regression analysis showed that the chicken-wing group had a higher risk of recurrence after RFA (OR = 8.13, p = 0.004), and the windsock group had a lower risk of recurrence (OR = 0.17, p = 0.002). Conclusion: The morphological feature of LAA is related to the recurrence risk of AF after RFA. LAA morphology assessment can predict the risk of AF recurrence.

MiR-132 down-regulates high glucose-induced ß-dystroglycan degradation through Matrix Metalloproteinases-9 up-regulation in primary neurons.

Cognitive dysfunction is one of the complications of diabetes. Unfortunately, there is no effective methods to block its progression currently. One of the pathophysiological mechanisms is synaptic protein damage and neuronal signal disruption because of glucose metabolism disorder. Dystroglycan protein, located in the post-synaptic membrane of neurons, links the intracellular cytoskeleton with extracellular matrix. Abnormal expression of dystroglycan protein affects neuronal biological functions and leads to cognitive impairment. However, there are no relevant studies to observe the changes of ß-dystroglycan protein in diabetes rat brain and in primary neurons under high glucose exposure. Our data demonstrated the alterations of cognitive abilities in the diabetic rats; ß-dystroglycan protein degradation occurred in hippocampal and cortical tissues in diabetic rat brain. We further explored the mechanisms underlying of this phenomenon. When neurons are exposed to high glucose environment in long-term period, microRNA-132 (miR-132) would be down-regulated in neurons. Matrix Metalloproteinases-9 (MMP-9) mRNA, as a target of miR-132, could be up-regulated; higher expression and overlay activity of MMP-9 protein could increase ß-DG protein degradation. In this way, ß-DG degradation may affect structure and functions among the synapses, which related to cognition decline. It may provide some theoretical basis for elucidating the molecular mechanism of diabetes-induced cognitive dysfunction.

Exploring Potential Biomarkers Underlying the Pathogenesis of Alzheimer's Disease by Bioinformatics Gene Analysis.

Alzheimer's disease (AD) is a neurodegenerative disease caused by both genetic and environmental factors. This study aimed to explore the underlying molecular mechanism of AD by bioinformatic gene analysis. The gene expression profiles of GSE16759 and GSE28146 were downloaded, and co-differentially expressed genes (co-DEGs) were identified by R software. Subsequently, the data were analyzed using a combined bioinformatics approach and predicted the microRNAs (miRNAs) targeting the key gene using miRNA databases. Based on the results of these analyses, ADAMTS1, CITED2, and GABRA2 were identified as co-DEGs. They were all associated with learning disorders (inference Score: 103.22, 140.41, and 96.26, respectively) and memory disorders (inference Score: 102.77, 132.68, and 81.80, respectively). The hub-genes of ADAMTS1, CITED2, and GABRA2 may be associated with AD. Additionally, miR-548c- 3p is probably a common target for ADAMTS1, CITED2, and GABRA2.

Hydrogen-bond-driven dimers of naphthyridine derivatives for selective identification of DNA G-quadruplexes.

G-quadruplex (GQ) ligands as potential anti-cancer drugs have received extensive attention. Large aromatic systems are usually considered in the design of the ligands to improve the binding with GQs, which are typically constructed by the combination of small modules with covalent bonds. In this study, we presented a non-covalent bond approach to construct GQ ligands with an extended planar structure. The ligands were stable dimers assembled through quadruplex intermolecular hydrogen bonds between two molecules of naphthyridine derivatives. Spectroscopic analyses showed that dimeric ligands could stabilize GQs with an increase of the melting temperature up to 12 °C and induced conformational conversion of hybrid GQs. Confocal fluorescence microscopy confirmed the enrichment of naphthyridine ligands in the nucleus. The ligands showed moderate cytotoxicity against HeLa cells with an IC50 value of 7.5 µg mL-1 and effectively induced growth inhibition and apoptosis in HeLa cells. These results confirmed the feasibility of the quick building of GQ ligands through intermolecular interactions of simple molecules that are easily obtained during synthesis, which is helpful for GQ ligand design and quick establishment of a ligand library through the self-assembly of easily available molecular components.

DDAH-1, via regulation of ADMA levels, protects against ischemia-induced blood-brain barrier leakage.

Dimethylarginine dimethylamino hydrolase-1 (DDAH-1) is an important regulator of nitric oxide (NO) metabolism that has been implicated in the pathogenesis of cardiovascular diseases. Nevertheless, its role in cerebral ischemia still needs to be elucidated. Herein, we examined the expression of DDAH-1 in the brain of rat by double-label immunofluorescence staining. DDAH-1 knock-out (DDAH-1-/-) and wild-type rats underwent middle cerebral artery occlusion/reperfusion (MCAO/R). After 24 h, neurological scores, TTC staining and TUNEL assay were used to evaluate neurological damages. 3 and 7-days infarct outcomes were also shown. Blood-brain-barrier (BBB) permeability was examined via Evans blue extravasation and tight junction (TJ) proteins expression and mRNA levels by western blot and RT-qPCR. The levels of plasma asymmetric dimethylarginine (ADMA), NO and ADMA in brain tissue were also assessed. In addition, supplementation of L-arginine to DDAH-1-/- rats was used to explore its role in regulating NO. DDAH-1 was abundantly distributed in cerebral cortex and basal nuclei, and mainly expressed in neurons and endothelial cells. DDAH-1-/- rats showed aggravated neurological damage and BBB disruption, including decrease of TJ proteins expression but indistinguishable mRNA levels after MCAO/R. DDAH-1 depletion and neurological damages were accompanied with increased ADMA levels and decreased NO concentrations. The supplementation with L-arginine partly restored the neurological damages and BBB disruption. To sum up, DDAH-1 revealed to have a protective role in ischemia stroke (IS) and IS-induced leakage of BBB via decreasing ADMA level and possibly via preventing TJ proteins degradation.

Long-Term Safety and Efficacy of Antiplatelet Therapy in Patients With Cerebral Infarction With Thrombocytopenia.

This study aimed to investigate the long-term safety and benefits of antiplatelet therapy in patients with cerebral infarction with thrombocytopenia, as evidence regarding this was limited. This cohort trial assessed patients with acute cerebral infarction with thrombocytopenia treated in the Neurology Department of Shanghai Tenth People's Hospital from January 2016 to December 2018, and enrolled patients were followed up for 9 months. The patients were divided into non-antiplatelet and antiplatelet groups based on the actual intake of antiplatelet drugs. Primary endpoints included hemorrhagic events, recurrence of cerebral infarction, and activity of daily living (ADL) score changes. To balance baseline clinical data, propensity score matching was applied, and there were finally 65 matched patients, including 30 and 35 in the antiplatelet and non-antiplatelet groups, respectively. There were no differences in hemorrhagic and cerebral infarction recurrence rates between the 2 groups. ADL score change was higher in the antiplatelet group than in the non-antiplatelet group (10 vs 5, p = 0.039). In multivariate regression analysis, antiplatelet therapy significantly predicted a positive change in ADL scores [B = 8.381, 95% confidence interval (0.56-16.19)]. In patients with acute cerebral infarction with thrombocytopenia, antiplatelet therapy could the improve the quality of life in the chronic stage.

Impact of homocysteine levels on clinical outcome in patients with acute ischemic stroke receiving intravenous thrombolysis therapy.

BACKGROUND: The purpose of this study was to retrospectively assess the potential correlation between clinical outcomes and homocysteine (Hcy) levels in acute ischemic stroke (AIS) patients after recombinant tissue plasminogen activator (rtPA) treatment. METHODS: AIS patients treated by rtPA were enrolled between September 2018 and March 2019 in the Stroke Center (Department of Neurology and Neurosurgery), Shanghai Tenth People's Hospital, Tongji University School of Medicine. Demographics, baseline and clinical characteristics, and modified Rankin Scale (mRS) score after three months from the onset were retrospectively analyzed. Then we compared data about demographics, baseline and clinical characteristics between patients with favorable (mRS score 0-2) and unfavorable (mRS score 3-6) outcomes. RESULTS: Among 141 patients, 36 patients had poor outcome, for an incidence of 25.53%. Univariate analysis showed that higher Hcy levels (OR = 1.07, 95% CI [1.02-1.12]), older age (OR = 1.06, 95% CI [1.02-1.10]), longer door to needle time (DNT) (OR = 1.03, 95% CI [1.01-1.05]), higher D-Dimer levels (OR = 1.33, 95% CI [1.03-1.71]), and higher National Institutes of Health Stroke Scale (NIHSS) score before treatment (OR = 1.21, 95% CI [1.08-1.35]) were each associated with poor outcome. Also, without internal carotid artery plaque (OR = 0.30, 95% CI [0.10-0.92]) showed a protective effect on patients' clinical outcome. Patients with higher levels of Hcy decline also showed an increased risk of poor outcome for AIS patients obtaining rtPA treatment (Non-adjusted: OR = 1.07, 95% CI [1.02-1.12]; Adjust model I adjusts for demographics (age, male): OR = 1.06, 95% CI [1.02-1.11]; Adjust model II adjusts for hospital care factors (onset to treatment, DNT): OR = 1.08, 95% CI [1.03-1.13]; Adjust model III adjusts for health and stroke factors (INR, D-Dimer, HGB, NIHSS score before treatment, smoking, drinking, hypertension, diabetes, coronary disease, hyperlipidemia, previous stroke, atrial fibrillation, hemorrhagic transformation, internal carotid artery plaque): OR = 1.06, 95% CI [1.02-1.11]). The results are very stable in all three models constructed. CONCLUSION: The results of this study indicate that increased Hcy level independently predicts unfavorable outcome in AIS patients accepting thrombolytic therapy. However, the contribution of Hcy to the outcome, although significant, is relatively small and perhaps not clinically significant when all the other confounders are considered.

Pharmacokinetic/pharmacodynamic data extrapolation models for improved pediatric efficacy and toxicity estimation, with application to secondary hyperparathyroidism.

In most drug development settings, the regulatory approval process is accompanied by extensive studies performed to understand the drug's pharmacokinetic (PK) and pharmacodynamic (PD) properties. In this article, we attempt to utilize the rich PK/PD data to inform the borrowing of information from adults during pediatric drug development. In pediatric settings, it is especially crucial that we are parsimonious with the patients recruited for experimentation. We illustrate our approaches in the context of clinical trials of cinacalcet for treating secondary hyperparathyroidism in pediatric and adult patients with chronic kidney disease, where we model both parathyroid hormone (efficacy endpoint) and corrected calcium levels (safety endpoint). We use population PK/PD modeling of the cinacalcet data to quantitatively assess the similarity between adults and children, and use this information in various hierarchical Bayesian adult borrowing rules whose statistical properties can then be evaluated. In particular, we simulate the bias and mean square error performance of our approaches in settings where borrowing is and is not warranted to inform guidelines for the future use of our methods.

Long noncoding RNA KCNQ1OT1 promotes apoptosis in neuroblastoma cells by regulating miR-296-5p/Bax axis.

Long noncoding RNAs (lncRNAs) are emerging as important regulators of multiple cellular processes such as cell invasion, growth, apoptosis and differentiation. LncRNAs can function as competing endogenous RNAs (ceRNAs) which sponge and sequester microRNA (miRNA) to regulate specific targets. Previously, we found that the target genes of several miRNAs, including FADD, Fas, Casp and Bax, are related to neuronal apoptosis and form a regulatory network. Among several factors, microRNA-296-5p expression was found to be negatively correlated with caspase activity and apoptosis. Here, we aimed to investigate the role of miR-296-5p in neuroblastoma (NB) cells. By performing quantitative real-time PCR (qRT-PCR), western blot and flow cytometry assays we analysed the expression of apoptotic markers in NB cells transfected with miR-296-5p mimics or inhibitor. Pathway-specific PCR array allowed us to identify the target genes of miR-296-5p. Using LncBase online tool, we predicted lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) as an upstream regulator of miR-296-5p. The binding of KCNQ1OT1 and miR-296-5p was validated via RNA immunoprecipitation and Biotin pull-down assays. We also demonstrate that miR-296-5p suppresses apoptosis of NB cells in vitro and in vivo. Mechanistically, miR-296-5p directly bound the 3'UTR of Bax mRNA, thus repressing Bax at the mRNA and protein level. Moreover, through bioinformatic analysis and molecular experiments, we showed that KCNQ1OT1 sponged miR-296-5p and impaired its effect on NB cell apoptosis. In summary, KCNQ1OT1 is a potent promoting factor of cell apoptosis, which acts by sponging miR-296-5p and upregulating Bax. Our findings identify a regulatory axis of cell fate in NB cells.