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BackgroundThe relationship between serum calcium levels and the prognosis of cerebral infarction remains controversial.PurposeThis study aims to investigate the correlation between serum calcium levels and in-hospital mortality in critically ill patients with ischemic stroke admitted to the intensive care unit (ICU).MethodsA retrospective cohort study was conducted using data from the MIMIC-IV database. Demographic and clinical data of all participants were collected including gender, age, hypertension, diabetes, myocardial infarction, heart failure, chronic obstructive pulmonary disease, hemoglobin, potassium, sodium, anion gap, platelets, white blood cells, glucose, creatinine, Glasgow coma score (GCS), IV-tPA administration (rt-PA), and mechanical thrombectomy (MT). The outcome measure was in-hospital death. Multivariable-adjusted logistic regression analysis, curve fitting, interaction analysis, and threshold effect analysis were employed to evaluate the relationship between serum calcium levels and in-hospital mortality among ICU patients with cerebral infarction.ResultsA total of 2,680 critically ill patients with cerebral infarction were enrolled, with a mean serum calcium level of 8.6 ± 0.8 mg/dL. The overall in-hospital mortality rate was 19.5%, where Group 1 (serum calcium < 8.0 mg/dL) had a mortality rate of 27.7%, Group 2 (serum calcium 8–9 mg/dL) had a rate of 19.8%, and Group 3 (serum calcium ≥ 9 mg/dL) had a rate of 13.9%. There was a non-linear, S-shaped relationship between serum calcium levels and in-hospital mortality. Serum calcium levels within the range of 7.70–9.50 mg/dL were found to be independently associated with increased in-hospital mortality in ICU patients with cerebral infarction. No significant interactions were detected in subgroup analyses, and the results of sensitivity analyses remained stable.ConclusionSerum calcium levels are independently associated with in-hospital mortality in critically ill patients with cerebral infarction in the ICU setting. Within the range of 7.70–9.50 mg/dL, lower serum calcium levels increase the risk of in-hospital death among these patients, emphasizing the importance of close monitoring by ICU physicians.

Abstract This study aimed to investigate the relationship between hypertension and Alzheimer’s disease (AD) and demonstrate the key role of stroke in this relationship using mediating Mendelian randomization. AD, a neurodegenerative disease characterized by memory loss, cognitive impairment, and behavioral abnormalities, severely affects the quality of life of patients. Hypertension is an important risk factor for AD. However, the precise mechanism underlying this relationship is unclear. To investigate the relationship between hypertension and AD, we used a mediated Mendelian randomization method and screened for mediating variables between hypertension and AD by setting instrumental variables. The results of the mediated analysis showed that stroke, as a mediating variable, plays an important role in the causal relationship between hypertension and AD. Specifically, the mediated indirect effect value for stroke obtained using multivariate mediated MR analysis was 54.9%. This implies that approximately 55% of the risk of AD owing to hypertension can be attributed to stroke. The results suggest that the increased risk of AD owing to hypertension is mediated through stroke. The finding not only sheds light on the relationship between hypertension and AD but also indicates novel methods for the prevention and treatment of AD. By identifying the critical role of stroke in the link between hypertension and AD, this study provides insights into potential interventions that could mitigate the impact of hypertension on AD. This could help develop personalized treatments and help improve the quality of life of patients with AD who suffer from hypertension.

BackgroundMultiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system. Currently, the pathological mechanisms of MS are not fully understood, but research has suggested that iron metabolism disorder may be associated with the onset and clinical manifestations of MS.Methods and materialsThe study utilized publicly available databases and bioinformatics techniques for gene expression data analysis, including differential expression analysis, weighted correlation network analysis, gene enrichment analysis, and construction of logistic regression models. Subsequently, Mendelian randomization was used to assess the causal relationship between different iron metabolism markers and MS.ResultsThis study identified IREB2, LAMP2, ISCU, ATP6V1G1, ATP13A2, and SKP1 as genes associated with multiple sclerosis (MS) and iron metabolism, establishing their multi-gene diagnostic value for MS with an AUC of 0.83. Additionally, Mendelian randomization analysis revealed a potential causal relationship between transferrin saturation and MS (p=2.22E-02; OR 95%CI=0.86 (0.75, 0.98)), as well as serum transferrin and MS (p=2.18E-04; OR 95%CI=1.22 (1.10, 1.36)).ConclusionThis study comprehensively explored the relationship between iron metabolism and MS through integrated bioinformatics analysis and Mendelian randomization methods. The findings provide important insights for further research into the role of iron metabolism disorder in the pathogenesis of MS and offer crucial theoretical support for the treatment of MS.

BackgroundThere is increasing evidence that the types of immune cells are associated with various neurodegenerative diseases. However, it is currently unclear whether these associations reflect causal relationships.ObjectiveTo elucidate the causal relationship between immune cells and neurodegenerative diseases, we conducted a two-sample Mendelian randomization (MR) analysis.Materials and methodsThe exposure and outcome GWAS data used in this study were obtained from an open-access database (https://gwas.mrcieu.ac.uk/), the study employed two-sample MR analysis to assess the causal relationship between 731 immune cell features and four neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). All immune cell data was obtained from Multiple MR methods were used to minimize bias and obtain reliable estimates of the causal relationship between the variables of interest and the outcomes. Instrumental variable selection criteria were restricted to ensure the accuracy and effectiveness of the causal relationship between species of immune cells and the risk of these neurodegenerative diseases.ResultsThe study identified potential causal relationships between various immune cells and different neurodegenerative diseases. Specifically, we found that 8 different types of immune cells have potential causal relationships with AD, 1 type of immune cells has potential causal relationships with PD, 6 different types of immune cells have potential causal relationships with ALS, and 6 different types of immune cells have potential causal relationships with MS.ConclusionOur study, through genetic means, demonstrates close causal associations between the specific types of immune cells and AD, PD, ALS and MS, providing useful guidance for future clinical researches.

Creutzfeldt⁃Jakob disease (CJD) is a group of clinically rare neurodegenerative diseases caused by misfolding of prion proteins, and is the most common type of human prion diseases. Since the prion characteristics were recognized in the 1970s, the diagnostic detection technology has made great progress, especially the real⁃time quaking⁃induced conversion (RT⁃QuIC). This paper describes the pathogenesis of CJD, the mechanism of action of RT⁃QuIC and its application in the diagnosis of CJD in order to promote the application and development of RT⁃QuIC technology in the field of CJD.

Objective To report clinical phenotype and gene mutation characteristics of one case of early⁃onset Alzheimer's disease (EOAD) associated with PSEN2 V214L mutation and conduct a pedigree analysis. Methods and Results A 63⁃year⁃old male proband with no family history of dementia, onset at 58 years old, had memory loss as the first manifestation and progressive aggravation of symptoms. Neuropsychological tests showed a score of 1 on Mini⁃Mental State Examination (MMSE), 0 on Montreal Cognitive Assessment (MoCA), 71 on Activities of Daily Living Scale (ADL), and 3 on Hachinski Ischemic Score (HIS). Head MRI revealed extensive cortical atrophy, with prominent atrophy of bilateral hippocampal, multiple hyperintensity in deep white matter (Fazekas grade 2). Exons of high⁃throughput sequencing of dementia⁃related genes showed that both the proband and his sister had heterozygous missense mutations in exon 8 of PSEN2 gene c.640G>T (p.V214L) and heterozygous splicing mutations in exon 28 of SORL1 gene c.3815⁃4A>C. The proband was finally diagnosed with EOAD associated with PSEN2 V214L mutation, and the proband's sister was considered as an absolute risk group for Alzheimer's disease (AD). Conclusions The PSEN2 V214L mutation probably causes EOAD. Further investigations should be conducted to evaluate the effects on the production of amyloid β⁃protein 40 and 42 (Aβ40 and Aβ42), then verify its pathogenicity.

The hydraulic system drives the cutter head mechanism to realize the excavation of large tunnel boring equipment, which puts forward the technical requirements of high pressure and large flow to the pump source. The traditional small displacement axial piston pump uses a planar valve plate. However, under high flow and heavy load conditions, the planar valve plate configuration is prone to uneven wear due to the high-pressure and -velocity (PV) value and pressure shock, which ultimately affects the reliability of the system. A simulation analysis of the load-bearing characteristics of the spherical valve plate mechanism is conducted. The Computational Fluid Dynamics (CFD) method was used to construct flow field models for different valve plate oil film structures to calculate differences in their load-bearing capacities. Additionally, the reasons for variations in load-bearing characteristics based on the curvature radius of the spherical valve plate were analyzed. The simulation results demonstrate that the spherical valve plate exhibits superior leak and load-bearing performance compared to the traditional flat valve plate. Furthermore, the curvature radius of the spherical valve plate directly affects the pulsation characteristics of the piston pump. Smaller curvature radii increase the contact area of the oil film, resulting in greater fluctuation in oil film load-bearing, whereas larger curvature radii lead to increased oil film leakage. Using simulation calculations on heavy-load, high-displacement axial piston pumps, it is determined that the optimal curvature radius for stable load-bearing is 350 mm.

Background and purposeAs one of the most aggressive malignant tumor in the central nervous system, the main cause of poor outcome of glioblastoma (GBM) is recurrence, a non-invasive method which can predict the area of recurrence pre-operation is necessary.To investigate whether there is radiological heterogeneity within peritumoral edema and identify the reproducible radiomic features predictive of the sites of recurrence of glioblastoma(GBM), which may be of value to optimize patients’ management.Materials and methodsThe clinical information and MR images (contrast-enhanced T1 weighted and FLAIR sequences) of 22 patients who have been histologically proven glioblastoma, were retrospectively evaluated. Kaplan-Meier methods was used for survival analysis. Oedematous regions were manually segmented by an expert into recurrence region, non-recurrence region. A set of 94 radiomic features were obtained from each region using the function of analyzing MR image of 3D slicer. Paired t test was performed to identify the features existing significant difference. Subsequently, the data of two patients from TCGA database was used to evaluate whether these features have clinical value.ResultsTen features with significant differences between the recurrence and non-recurrence subregions were identified and verified on two individual patients from the TCGA database with pathologically confirmed diagnosis of GBM.ConclusionsOur results suggested that heterogeneity does exist in peritumoral edema, indicating that the radiomic features of peritumoral edema from routine MR images can be utilized to predict the sites of GBM recurrence. Our findings may further guide the surgical treatment strategy for GBM.

BackgroundCustomized fetal growth charts assume birthweight at term to be normally distributed across the population with a constant coefficient of variation at earlier gestational ages. Thus, standard deviation used for computing percentiles (e.g., 10th, 90th) is assumed to be proportional to the customized mean, although this assumption has never been formally tested.MethodsIn a secondary analysis of NICHD Fetal Growth Studies-Singletons (12 U.S. sites, 2009-2013) using longitudinal sonographic biometric data (n = 2288 pregnancies), we investigated the assumptions of normality and constant coefficient of variation by examining behavior of the mean and standard deviation, computed following the Gardosi method. We then created a more flexible model that customizes both mean and standard deviation using heteroscedastic regression and calculated customized percentiles directly using quantile regression, with an application in a separate study of 102, 012 deliveries, 37-41 weeks.ResultsAnalysis of term optimal birthweight challenged assumptions of proportionality and that values were normally distributed: at different mean birthweight values, standard deviation did not change linearly with mean birthweight and the percentile computed with the normality assumption deviated from empirical percentiles. Composite neonatal morbidity and mortality rates in relation to birthweight < 10th were higher for heteroscedastic and quantile models (10.3% and 10.0%, respectively) than the Gardosi model (7.2%), although prediction performance was similar among all three (c-statistic 0.52-0.53).ConclusionsOur findings question normality and constant coefficient of variation assumptions of the Gardosi customization method. A heteroscedastic model captures unstable variance in customization characteristics which may improve detection of abnormal growth percentiles.Trial registrationClinicalTrials.gov identifier: NCT00912132.

Nanocarriers have been recognized as an effective strategy for developing novel boron-containing delivery agents for boron neutron capture therapy (BNCT) of refractory tumors. Herein, a chitosan-lactobionic acid-thioctic acid-modified hollow mesoporous silica composite loaded with carborane was prepared to achieve effective treatment of hepatocellular carcinoma by BNCT. Notably, the composite remained stable under physiological conditions and exhibited high selective uptake in liver cancer cells. In the tumor microenvironment, the composite could effectively release carborane into the tumor tissue under the dual stimulation of pH and redox. The composite showed excellent efficacy in BNCT treatment of liver cancer cells. Meanwhile, the composite could exert antioxidant and anti-inflammatory effects to reduce the toxic side effects during BNCT. In tumor-bearing mice, the composite could accumulate in tumor tissue with high selectivity. In addition, the composite could be effectively cleared from the normal tissues and could overcome the inflammatory response generated in vivo by the materials in biological applications. Overall, the composite is a promising boron-containing delivery agent in the treatment of hepatocellular carcinoma by BNCT, and can facilitate the biological applications of the silica-like materials in BNCT.

Abstract Aims/Introduction Pregnant women with gestational diabetes mellitus (GDM) have been reported to have higher serum triglyceride (TG) levels during the entire gestational period. However, whether TGs contribute to the incidence of GDM remains unclear. This study aimed to evaluate whether higher serum TG level during early first trimester is associated with GDM. Materials and Methods A prospective single‐center cohort study was carried out among pregnant women (n = 2,949) who received regular antenatal care in Fu Xing Hospital, Capital Medical University, Beijing, China. GDM was diagnosed between 24 and 28 gestational weeks. Serum TG levels were measured during gestational weeks 6–8 (TG0) and 16–18 (TG1). TG elevation was the difference between TG1 and TG0. Results In total, 581 pregnant women developed GDM. A 13.1, 18.5 and 28.8% incidence of GDM was observed in women with low, referent and high TG0 levels, respectively. Among women with prepregnancy body mass index

Objective To report the clinical phenotype and gene mutation characteristics of a case with leucine⁃rich repeat kinase 2 (LRRK2) gene mutation⁃associated semantic variant primary progressive aphasia. Methods and Results The clinical data of a patient with language comprehension impairment as the first symptom were analyzed, including clinical manifestations, neuropsychological and linguistic assessments, cerebrospinal fluid biomar kertests, brain images and genetic testings. We made a systematic discussion in combination with relevant literatures. The results showed that the main clinical manifestations of the patient were difficulty in understanding words and difficulty in finding words. Aphasia Battery of Chinese test showed that the temporal lobe damage was prominent. Head MRI showed asymmetric atrophy of the bilateral frontal and temporal lobes, which was significant on the left side. 18F⁃FDG PET further suggested that the glucose metabolism in the bilateral anterior temporal lobes and bilateral frontal lobes was reduced. Cognitive impairment and dyskinesia gene detection revealed thatthe patient had a heterozygous mutation in exon 25 3468G>C of LRRK2 gene, which was the first report at home and abroad. The clinical diagnosis was semantic variant primary progressive aphasia. Conclusions This patient carries mutations in the LRRK2 gene. It is likely that due to changes in the structure and function of the encoded LRRK2 protein, which causes tau pathologic changes, and in turn leads to the degeneration and atrophy of the frontotemporallobe and semantic variant primary progressive aphasia. The discovery ofthis gene mutation expands the gene mutation spectrum of frontotemporal lobe dege⁃neration. DOI：10.3969/j.issn.1672⁃6731.2020.06.012

BackgroundThe clinical spectrum of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is expanding over time. However, the long-term management and prognosis of this disorder are still controversial. Therefore, this study aimed to report the clinical profiles and treatment outcomes of MOGAD in our center.MethodsThis was a single-center case-series study. Clinical and para-clinical data, along with treatment outcomes of patients with MOGAD were analyzed.ResultsA total of 27 patients were identified, of which 19 (70%) patients were women, and the median age at disease onset was 40 years (range 20–67). A total of 47 episodes were observed, with optic neuritis (53%) being the most frequent presentation and 60% of them were unilateral. Other presentations included rhombencephalitis (RE) (17%), limbic encephalitis (9%), simultaneous optic neuritis and myelitis (9%), acute disseminated encephalomyelitis (ADEM)-like presentation (6%), myelitis (4%), and ADEM (2%). One patient presenting with RE also met the diagnostic criteria of area postrema syndrome (APS). Another patient with RE presented with imaging characteristics of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). A total of 29 lumbar punctures were recorded, among which an elevated protein level was found in 34% of the samples, pleocytosis was found in 14% of the samples, and positive intrathecal oligoclonal bands were found in 19% of the patients. One patient was found to have anti-N-methyl-D-aspartate receptor antibodies both in his serum and cerebrospinal fluid. Intravenous methylprednisolone (IVMP) was administrated for 85% of the attacks while both IVMP and intravenous immunoglobulin were for 6% of the attacks. Moreover, nine patients received maintenance therapy. Among them, six patients were treated with mycophenolate mofetil, three patients were treated with prednisone, rituximab, and teriflunomide, respectively. The median follow-up period was 20 months (range 6–127). At follow-up, twelve (44%) patients experienced a relapsing course, and the median time to the first relapse was 9.5 months (range 2–120). The median Expanded Disability Status Scale score at nadir was 3.5 (range 2–8) and was 0 (range 0–3) at the last follow-up.ConclusionThe clinical spectrum of MOGAD is heterogenous, wherein APS and CLIPPERS-form can occur. The long-term outcome of MOGAD seems benign. Further studies are warranted to determine the risk factors of relapse and identify the optimal steroid-sparing agents.

Background and ObjectivesFew studies have evaluated the impact of red blood cell distribution width (RDW) on prognosis for critically ill patients with acute stroke according to recent studies. The aim of this study was to investigate the association between RDW and mortality in these patients.MethodsClinical data were extracted from the eICU Collaborative Research Database (eICU-CRD) and analyzed. The exposure of interest was RDW measured at admission. The primary outcome was in-hospital mortality. Binary logistic regression models and interaction testing were performed to examine the RDW-mortality relationship and effect modification by acute myocardial infarction and hypertension (HP).ResultsData from 10,022 patients were analyzed. In binary logistic regression analysis, after adjusting for potential confounders, RDW was found to be independently associated with in-hospital mortality {odds ratio (OR) 1.07, [95% confidence interval (CI) 1.03 to 1.11]; p = 0.001}. Higher RDW linked to an increase in mortality (OR, 1.07; 95% CI, 1.03 to 1.11; P for trend < 0.0001). Subgroup analysis showed that, in patients combined with AMI and without HP (both P-interaction

Motion control of truck-mounted concrete pump booms is an important part of concrete construction work. The quality of the boom movement will affect the efficiency and safety of construction operations. To make the boom move quickly and steadily, its hydraulic control system needs to be improved. In this article, we firstly combine independent metering control (IMC) and active disturbance rejection control (ADRC). The hydraulic system that controls the boom is meliorated by replacing the traditional proportional directional spool valve with four cartridge flow control valves to realize IMC. Meanwhile, a fuzzy linear ADRC algorithm is proposed for a new IMC hydraulic system where ADRC is linearized and combined with fuzzy logic to achieve better motion control performance of boom sections. According to the results of experiments conducted using all six boom sections, compared with the PID control algorithm, the fuzzy linear active disturbance rejection control (FLADRC) proposed in this article can improve the stability and rapidity of valves controlled by hydraulic cylinders by 10.0% to 66.7% in different working conditions.

It is widely believed that amyloid β⁃protein (Aβ) plays a core role in the pathogenesis of Alzheimer's disease (AD). Thus A β is one of main targets in the therapeutic explorations for AD. Currently, clearance of A β by passive immunotherapy is an important strategy for the treatment of AD. However, no consistent conclusions have been obtained from various clinical trails. We summarize the current situations of A β⁃directed passive immunotherapy for AD, and speculate that the failure of A β⁃directed passive immunotherapy for AD may be related to the intrinsic characteristics of A β⁃IgG glycosylation. Therefore, modifications of N ⁃ glycosylation on the Fc domain of A β⁃IgG and using a sequential administration mode of proinflammation⁃antiinflammation may be an effective strategy for passive immunotherapy for AD. DOI：10.3969/j.issn.1672⁃6731.2019.12.014

Abstract Background The prevalence of diabetes and prediabetes were estimated to be 10.9% and 35.7% in the Chinese adult population, respectively, and the middle-aged and elderly Chinese are at even higher risk of diabetes and prediabetes than younger population. With the increasing trend of aging in China, the burden of diabetes and related complications will be aggravated. Objectives Through comparing the indices of insulin resistance and β-cell function between subjects with different glucose metabolic status, to analyze the differential role of insulin resistance and β-cell function in the development of prediabetes and type 2 diabetes (T2DM) in the middle-aged and elderly Chinese population. Methods In this cross-sectional study, we enrolled 512 participants aged 50 and over. The indices of insulin resistance (homoeostasis model assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance (Adipo-IR), and indices of β-cell function [HOMA-β), fasting C-peptide to glucose ratio (FCPRI) and postprandial C-peptide to glucose ratio (PCPRI)] were calculated. Association of insulin resistance and β-cell function with prediabetes or T2DM were evaluated by multivariate logistic regression analysis, in which potential confounding factors were adjusted. Results Of the 509 participants with complete information, 263 (51.7%) had normal glucose tolerance (NGT), 161 (31.6%) were in prediabetic status and 85 (16.7%) were overt T2DM. With the advancing of unfavorable glucose metabolism, the insulin resistance (HOMA-IR and Adipo-IR) and β-cell function (FCPRI, PCPRI) deteriorated (P trend

Glycyrrhiza glabra L., known as licorice, is one of the most famous herbs in the world. In this study, we investigated the phytochemical and antitumor activities of G. glabra, especially its anti-colorectal cancer activities. G. glabra was extracted with 70% methanol, and the ethyl acetate layer was separated by silica gel, ODS, LH-20 column chromatography, and semi-preparative HPLC to obtain the compounds. The structures were determined by NMR and MS methods. Three new compounds named licopyranol A–C (1–3), and eighteen known compounds (4–21) were isolated. Compounds with an isoprenyl group or dimethylpyran ring showed better antitumor activities. Licopyranol A (1) and glycyrol (5) both inhibited the proliferation, reduced clone formation and promoted apoptosis of RKO cells. The Western blotting assays showed that glycyrol significantly reduced the expression of E-cadherin, β-catenin, c-Myc, and GSK-3β proteins in RKO cells, suggesting that glycyrol may inhibit the growth of colorectal cancer RKO cells via the Wnt/β-catenin signaling pathway.

Abstract Background Metabolites present in human urine can be influenced by individual physiological parameters (e.g., body mass index [BMI], age, and sex). Observation of altered metabolites concentrations could provide insight into underlying disease pathology, disease prognosis and diagnosis, and facilitate discovery of novel biomarkers. Methods Quantitative metabolomics analysis in the urine of 183 healthy individuals was performed based on high‐resolution liquid chromatography–mass spectrometry (LC–MS). Coefficients of variation were obtained for 109 urine metabolites of all the 183 human healthy subjects. Results Three urine metabolites (such as dehydroepiandrosterone sulfate, acetaminophen glucuronide, and p‐anisic acid) with CV183 > 0.3, for which metabolomics studies have been scarce, are considered highly variable here. We identified 30 age‐related metabolites, 18 BMI‐related metabolites, and 42 sex‐related metabolites. Among the identified metabolites, three metabolites were found to be associated with all three physiological parameters (age, BMI, and sex), which included dehydroepiandrosterone sulfate, 3‐methylcrotonylglycine and N‐acetyl‐aspartic acid. Pearson's coefficients demonstrated that some age‐, BMI‐, and sex‐related compounds are strongly correlated, suggesting that age, BMI, and sex could affect them concomitantly. Conclusion Metabolic differences between distinct physiological statuses were found to be related to several metabolic pathways (such as the caffeine metabolism, the amino acid metabolism, and the carbohydrate metabolism), and these findings may be key for the discovery of new diagnostics and treatments as well as new understandings on the mechanisms of some related diseases.

Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke with high disability and high mortality rates, and there is no effective treatment. The predilection site of ICH is in the area of the basal ganglia and internal capsule (IC), where exist abundant white matter (WM) fiber tracts, such as the corticospinal tract (CST) in the IC. Proximal or distal white matter injury (WMI) caused by intracerebral parenchymal hemorrhage is closely associated with poor prognosis after ICH, especially motor and sensory dysfunction. The pathophysiological mechanisms involved in WMI are quite complex and still far from clear. In recent years, the neuroprotection and repairment capacity of mesenchymal stem cells (MSCs) has been widely investigated after ICH. MSCs exert many unique biological effects, including self-recovery by producing growth factors and cytokines, regenerative repair, immunomodulation, and neuroprotection against oxidative stress, providing a promising cellular therapeutic approach for the treatment of WMI. Taken together, our goal is to discuss the characteristics of WMI following ICH, including the mechanism and potential promising therapeutic targets of MSCs, aiming at providing new clues for future therapeutic strategies.

Fascaplysin is a natural marine product originating from sponges, attracting widespread attention due to its potential inhibitory activities against CDK4. However, its clinical application has been largely limited because of serious adverse effects caused by planar skeleton. To reduce the serious adverse effects, 18 tetrahydro-β-carboline analogs (compounds 6a-i and 7a-i) were designed and synthesized via breaking the planarity of fascaplysin, and the biological activities of the synthesized compounds were evaluated by MTT assay and CDK4/CycD3 enzyme inhibition assay. The title compounds showed varying degrees of inhibitory activities, especially the cytotoxicity of compound 6c against HeLa cells (IC50 = 1.03 ± 0.19 μM) with quite weak cytotoxicity toward the normal cells WI-38 (IC50 = 311.51 ± 56.06 μM), and the kinase inhibition test indicated that compound 6c was a potential CDK4 inhibitor. In order to further compare the action mechanisms of planar and nonplanar molecules on CDK4, the studied complexes of CDK4 bound with fascaplysin and three representative compounds (compound 6a-c) with bioactivities gradient were constructed by molecular docking and further verified through molecular dynamic simulation, which identified the key residues contributing to the ligands’ binding. By comparing the binding modes of the constructed systems, it could be found that the residues contributing significantly to compound 6c′s binding were highly consistent with those contributing significantly to fascaplysin’s binding. Through the design, synthesis of the nonplanar fascaplysin derivatives, and binding mechanism analysis, some valuable hints for the discovery of antitumor drug candidates could be provided.

Understanding implications of passive smoke exposure during pregnancy is an important public health issue under the Developmental Origins of Health and Disease paradigm. In a prospective cohort of low-risk non-smoking pregnant women (NICHD Fetal Growth Studies—Singletons, 2009–2013, N = 2055), the association between first trimester passive smoke exposure and neonatal size was assessed by race/ethnicity. Plasma biomarker concentrations (cotinine, nicotine) assessed passive smoke exposure. Neonatal anthropometric measures included weight, 8 non-skeletal, and 2 skeletal measures. Linear regression evaluated associations between continuous biomarker concentrations and neonatal anthropometric measures by race/ethnicity. Cotinine concentrations were low and the percent above limit of quantification varied by maternal race/ethnicity (10% Whites; 14% Asians; 15% Hispanics; 49% Blacks). The association between cotinine concentration and infant weight differed by race/ethnicity (Pinteraction = 0.034); compared to women of the same race/ethnicity, per 1 log-unit increase in cotinine, weight increased 48g (95%CI -44, 139) in White and 51g (95%CI -81, 183) in Hispanic women, but decreased -90g (95%CI -490, 309) in Asian and -93g (95%CI -151, -35) in Black women. Consistent racial/ethnic differences and patterns were found for associations between biomarker concentrations and multiple non-skeletal measures for White and Black women (Pinteraction

Abstract Background Mixed cerebrovascular disease is a diagnostic entity that presents with hemorrhagic and ischemic stroke clinically and/or subclinically. Here, we report a patient with mixed vascular risk factors, who presented with multiple intracerebral hemorrhages and a simultaneously occurring cerebral infarction with hemorrhagic transformation. Case presentation A 63-year-old male with no history of trauma or prior neurological disease presented with a sudden onset of weakness in his right limbs, followed by an episode of focal seizure without impaired awareness. The patient had a 4-year history of deep vein thrombosis in the lower limbs, and a 2-year history of Raynaud’s phenomenon in the hands. He also had a family history of hypertension and thrombophilia. Head computed tomography plain scans showed two high densities in the bilateral parietal lobes and one mixed density in the left frontal lobe. The patient was diagnosed with mixed cerebrovascular disease. In this report, we make a systematic clinical reasoning regarding the etiological diagnosis, and discuss the possible pathogenic mechanisms leading to mixed cerebrovascular disease. We exclude coagulopathy, endocarditis, atrial fibrillation, patent foramen ovale, brain tumor, cerebral venous thrombosis, cerebral vascular malformation, cerebral amyloid angiopathy and vasculitis as causative factors. We identify hypertension, hereditary protein S deficiency, hypercholesteremia and hyperhomocysteinemia as contributing etiologies in this case. Conclusion This case presents complex underlying mechanisms of mixed cerebrovascular disease, in which hypertension and hyperhomocysteinemia are considered to play a central role.

Vorinostat (SAHA) with great therapeutic potential has been approved by the FDA for the treatment of cutaneous T-cell lymphoma as the first HDACs inhibitor, but the drawbacks associated with hydroxamic acid group (poor stability, easy metabolism, weak binding ability to class IIa isozymes, and poor selectivity) have been exposed during the continuous clinical application. Based on the pharmacophore of HDAC inhibitors, two series of compounds with novel zinc binding group (ZBG) were designed and synthesized, and the antitumor bioactivities were evaluated in four human cancer cell lines (A549, Hela, HepG2, and MCF-7). Among the synthesized compounds, compounds a6, a9, a10, b8, and b9 exhibited promising inhibitory activities against the selected tumor cell lines, especially compounds a9 and b8 on Hela's cytostatic activity (a9: IC50 = 11.15 ± 3.24 μM; b8: IC50 = 13.68 ± 1.31 μM). The enzyme inhibition assay against Hela extracts and HDAC1&6 subtypes showed that compound a9 had a certain broad-spectrum inhibitory activity, while compound b8 had selective inhibitory activity against HDAC6, which was consistent with Western blot results. In addition, the inhibitory mechanism of compounds a9 and b8 in HDAC1&6 were both compared through computational approaches, and the binding interactions between the compounds and the enzymes target were analyzed from the perspective of energy profile and conformation. In summary, the compounds with novel ZBG exhibited certain antitumor activities, providing valuable hints for the discovery of novel HDAC inhibitors.

Dairy mastitis is a disease of dairy cattle caused by a variety of pathogenic microorganisms which has biought huge economic losses aused huge economic losses to the world. In this paper, Harmine derivatives and tetrahydro-β-carboline derivatives synthesized by the splice method are shown to have a good inhibitory effect on the pathogenic bacteria of dairy mastitis. The results of a bacteriostatic test on pathogenic bacteria of dairy cow mastitis (S. dysgalactiae, S. pyogenes, B. subtilis and P. vulgaris) showed that compound 7l had the best bacteriostatic effect on Streptococcus dysgalactiae, with a mic value of 43.7 μ g/mL. When the concentration of 7l was 1 × MIC and 2 × MIC, it had a significant inhibitory effect on Streptococcus dysgalactiae, and there was almost no growth of Streptococcus dysgalactiae at 4 × MIC. The binding properties of target compound 7l to amine oxidase [flavin-containing] A protein were simulated by the molecular docking technique. The ligand 7l achieved strong binding with the receptor through three hydrogen bonds. The hydrogen bonds were amino acid residues thr-52, arg-51 and ser-24, which are the main force for the compound to bind to active sites.

Abstract Introduction Recent research had shown blood glucose was not the only cause of large for gestational age infant (LGA), the contributions of other fuels such as lipids also play an important role in fetal development. However the association between maternal triglyceride at early trimester and the risk of LGA has not yet been clearly elucidated. This research evaluated the association of maternal early trimester TG level with the risk of LGA infant in Chinese mothers. Methods 2839 pregnant women were recruited at the first visit of their perinatal health care and followed up prospectively till after delivery. The demographic, maternal characteristics were extracted from a questionnaire. Infant characteristics were collected at delivery. Maternal fasting serum total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (HDL-C)levels, were measured in 6~8th, 16th, 24th, and 36th gestational weeks. Fasting serum glucose levels were measured at 6~8th, 24th, and 36th gestational weeks. Logistic regression model was used to calculate the odds ratio (OR) and 95% confidence intervals. Results A consistently lower TG level was observed in mothers with non-LGA infant than mothers with LGA infant and TG level of mothers of LGA infants increased faster than that of control group. The incidence of LGA infants between two groups (TG 1.19 mmol/L) gave birth to infants with higher birth weight (BW) than the other two groups (TG

Objective: This study was to evaluate effects of high normal blood pressure (HNBP) in early pregnancy on total preeclampsia, early preeclampsia, and severe preeclampsia. Methods: We conducted a multicenter, national representative retrospective cohort study. HNBP was defined as systolic blood pressure between 130 and 140 mmHg or diastolic blood pressure between 85 and 90 mmHg. We used multivariable logistic regression to examine the associations of HNBP and the risks of above three types of preeclampsia. Results: We included 58 054 women who were normotensive and nulliparous in early pregnancy. 4 809 (8.3%) fulfilled the definition of having HNBP, 16 682 (28.7%) were in normal blood pressure group, and 36 563 (63.0%) were in optimal blood pressure group. The incidence rates of total preeclampsia, early preeclampsia, and severe preeclampsia were 2.1% (1 217), 0.8% (491), and 1.4% (814), respectively. Compared to having optimal blood pressure, women with HNBP had significantly higher odds of total preeclampsia (odds ratio (OR) = 4.028, 95% confidence interval (CI) 3.377, 4.804), severe preeclampsia (OR = 3.542, 95% CI 2.851, 4.400), and early preeclampsia (OR = 8.163, 95% CI 6.219, 10.715). Our restricted cubic spline results supported the dose–response relationship between continuous blood pressure and the odds ratio of three types of preeclampsia. The fraction of early preeclampsia associated with prehypertension was 58.6%, which was higher than those of total preeclampsia (42.2%) or severe preeclampsia (40.5%). Conclusion: Women in early pregnancy with HNBP more likely develop total preeclampsia, early preeclampsia and severe preeclampsia, compared to those with optimal blood pressure. HNBP contribute more to early preeclampsia than severe preeclampsia. Our study provided robust epidemiological evidences for monitoring HNBP in early pregnancy to reduce the risks of preeclampsia.

Chalcone derivatives, as a hot research field, exhibit a variety of physiological bioactivities and target multiple biological receptors. Based on the skeleton of (E)-1,3-diphenyl-2-propene-1-one, 14 chalcone derivatives were designed and synthesized, and evaluated as the antitumor candidates agents against four human cancer cell lines (A549, Hela, HepG2, and HL-60) as well as one normal cell line (WI-38). Among the title compounds, compound a14 showed better inhibitory activity against HepG2 cells (IC50 = 38.33 µM) and had relatively weak cytotoxicity towards normal cells WI-38 (IC50 = 121.29 µM). In this study, apoptosis, cycle arrest, assessment of reactive oxygen species (ROS) level, and measurement of mitochondrial membrane potential were adopted to explore the inhibitory mechanism of a14 towards HepG2. Compound a14 could effectively block the division of HepG2 cell lines in the G2/M phase and robustly induced generation of ROS, demonstrating that the generation of ROS induced by a14 was the main reason for resulting in the apoptosis of HepG2 cells. Moreover, the mitochondrial membrane potential (MMP) of HepG2 cells treated with a14 was significantly decreased, which was closely related to the enhanced ROS level. Furthermore, based on Western blot experiment, cell apoptosis induced by a14 also involved the expression of B-cell lymphoma-2 (Bcl-2) family and Caspase 3 protein. In summary, compound a14 could contribute to the apoptosis of HepG2 cells through regulating ROS-mitochondrial pathway, which provides valuable hints for the discovery of novel anti-tumor drug candidates.

A series of 16 new derivatives of harmine N9-Cinnamic acid were synthesized and fully characterized using NMR and MS. The in vitro antibacterial evaluation revealed that most of the synthesized harmine derivatives displayed better antibacterial activities against Gram-positive strains (S. aureus, S. albus and MRSA) than Gram-negative strains (E. coli and PA). In particular, compound 3c showed the strongest bactericidal activity with a minimum inhibitory concentration of 13.67 μg/mL. MTT assay showed that compound 3c displayed weaker cytotoxicity than harmine with IC50 of 340.30, 94.86 and 161.67 μmol/L against WI-38, MCF-7 and HepG2 cell lines, respectively. The pharmacokinetic study revealed that the distribution and elimination of 3c in vivo were rapid in rats with an oral bioavailability of 6.9%.

In order to develop agents with superior chemopreventive and chemotherapeutic properties against hepatocellular carcinomas, mitochondria-targeted hydroxycinnamic acids (MitoHCAs) were synthesized by conjugation with a triphenylphosphonium cation. These synthetic compounds were evaluated for their antioxidant activities in hepatic mitochondria, including against OH∙− and ROO∙− induced lipid peroxidation. H2O2 production was decreased significantly by increasing glutathione peroxidase and catalase activities. In addition, cell proliferation data from three cell lines (HepG2, L02 and WI38) indicated that the MitoHCAs were selective for cancer cells. Interestingly, the MitoHCAs both with or without Ca2+ triggered mitochondrial dysfunction by inducing mitochondrial swelling, collapsing the mitochondrial membrane potential and causing cytochrome c release. In particular, an inhibitor of the mitochondrial permeability transition pore (mPTP), cyclosporin A, attenuated mitochondrial damage and cell apoptosis, indicating that mPTP may be involved in the antiproliferative activity of MitoHCAs. Further studies focused on structural optimization of these compounds are onging.

A series of prodrugs based on BIIB021, designed for nitroreductase (NTR), were synthesized and tested in vitro for their cytotoxic effects as potential anticancer agents. The results revealed that compounds 1c and 2c exhibited promising antitumor activity, with IC50 values of 0.72 and 1.12 µM, respectively. Notably, both compounds demonstrated lower toxicity to normal WI-38 cells compared to the positive control BIIB021 (IC50 = 495.51 and 570.27 µM vs. 261 µM). Cell cycle analysis indicated that both compounds induced cell cycle arrest in the G2/M phase, accompanied by a concomitant decrease in the population of the G0/G1 phase in HeLa cells, ultimately leading to apoptosis. These preliminary findings suggested that compounds 1c and 2c held the potential to serve as promising lead compounds for further structural optimization and in vivo validation studies. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) is now classified as an autoimmune astrocytopathic disease targeting aquaporin 4 (AQP4). NMO can affect cerebral hemisphere beyond optic nerve and spinal cord, resulting in cognitive impairment. In recent years, cognitive impairment in NMO has been increasingly concerned. The characteristics of cognitive impairment in NMO and its neuropathological mechanism have been researched in many studies. This paper selected two high-quality studies by Chinese scholars regarding cognitive impairment in NMO which were published in foreign journals during the past 2 years, and focused on study methods and results. DOI: 10.3969/j.issn.1672-6731.2016.05.002

1 patient with SSPE at 4 y. He had had measles and measles encephalitis at 7.5 months. In China, the first and the second measles immunizations are recommended at 8 months and at 18–24 months, respectively. We recommend above immunizations should be given separately at 6 months and at 12–15 months.