Disruption of CerS6-mediated sphingolipid metabolism by FTO deficiency aggravates ulcerative colitis.

BACKGROUND AND AIMS: Deregulation of RNA N6-methyladenosine (m6A) modification in intestinal epithelial cells (IECs) influences intestinal immune cells and leads to intestinal inflammation. We studied the function of fat mass-and obesity-associated protein (FTO), one of the m6A demethylases, in patients with ulcerative colitis (UC). METHODS: We analysed colon tissues of Ftoflox/flox; Villin-cre mice and their Ftoflox/flox littermates with dextran sulfate sodium (DSS) using real-time PCR and 16s rRNA sequencing. RNA and methylated RNA immunoprecipitation sequencing were used to analyse immunocytes and IECs. Macrophages were treated with conditioned medium of FTO-knockdown MODE-K cells or sphingosine-1-phosphate (S1P) and analysed for gene expression. Liquid chromatograph mass spectrometry identified C16-ceramide. RESULTS: FTO downregulation was identified in our in-house cohort and external cohorts of UC patients. Dysbiosis of gut microbiota, increased infiltration of proinflammatory macrophages, and enhanced differentiation of Th17 cells were observed in Ftoflox/flox;Villin-cre mice under DSS treatment. FTO deficiency resulted in an increase in m6A modification and a decrease in mRNA stability of CerS6, the gene encoding ceramide synthetase, leading to the downregulation of CerS6 and the accumulation of S1P in IECs. Subsequentially, the secretion of S1P by IECs triggered proinflammatory macrophages to secrete serum amyloid A protein 1/3, ultimately inducing Th17 cell differentiation. In addition, through bioinformatic analysis and experimental validation, we identified UC patients with lower FTO expression might respond better to vedolizumab treatment. CONCLUSIONS: FTO downregulation promoted UC by decreasing CerS6 expression, leading to increased S1P accumulation in IECs and aggravating colitis via m6A-dependent mechanisms. Lower FTO expression in UC patients may enhance their response to vedolizumab treatment.

An Unexpected Decrease in Vibrational Entropy of Multicomponent Rutile Oxides.

High-entropy oxides (HEOs), featuring infinite chemical composition and exceptional physicochemical properties, are attracting much attention. The configurational entropy caused by a component disorder of HEOs is popularly believed to be the main driving force for thermal stability, while the role of vibrational entropy in the thermodynamic landscape has been neglected. In this study, we systematically investigated the vibrational entropy of multicomponent rutile oxides (including Fe0.5Ta0.5O2, Fe0.333Ti0.333Ta0.333O2, Fe0.25Ti0.25Ta0.25Sn0.25O2, and Fe0.21Ti0.21Ta0.21Sn0.21Ge0.16O2) by precise heat capacity measurements. It is found that vibrational entropy gradually decreases with increasing component disorder, beyond what one could expect from an equilibrium thermodynamics perspective. Moreover, all multicomponent rutile oxides exhibit a positive excess vibrational entropy at 298.15 K. Upon examinations of configuration disorder, size mismatch, phase transition, and polyhedral distortions, we demonstrate that the excess vibrational entropy plays a pivotal role in lowering the crystallization temperature of multicomponent rutile oxides. These findings represent the first experimental confirmation of the role of lattice vibrations in the thermodynamic landscape of rutile HEOs. In particular, vibrational entropy could serve as a novel descriptor to guide the predictive design of multicomponent oxide materials.

A Hypochlorite-Activated Theranostic Prodrug for Selective Imaging of High Myeloperoxidase Expression Acute Myeloid Leukemia Cells and Drug Release.

Acute myeloid leukemia (AML) is a fatal hematologic disease. Diagnosis and proper treatment are important for prognosis. High myeloperoxidase (MPO) expression AML cells are characterized with high levels of hypochlorite (ClO-). In this study, we report a ClO--activated theranostic agent, FNC, for AML therapy. FNC responds to ClO- specifically in high MPO expression AML cells, resulting in bright fluorescence and chlorambucil release. FNC can be used to quickly distinguish high MPO expression AML cells from other cells, including low MPO expression leukemia and activated inflammatory cells. FNC exhibits selective toxicity to highly MPO expression AML cells and can efficiently inhibit tumor growth. Meanwhile, FNC can be used to indicate differentiation through the detection of ClO-.

Relationship between magnetic resonance imaging findings and prognosis of intracranial tuberculosis.

BACKGROUND: Intracranial tuberculosis (TB) is an intracranial infection caused by Mycobacterium tuberculosis. Magnetic resonance imaging (MRI), in particular enhanced MRI scan, has the ability to detect characteristic lesions of tuberculous meningitis or cerebral parenchymal TB. PURPOSE: To analyze the relationship between MRI findings and prognosis of patients with intracranial TB. MATERIAL AND METHODS: In this retrospective study, a total of 60 patients were confirmed with intracranial TB in the hospital from May 2019 to December 2020. All enrolled patients underwent TB-related laboratory examinations, cranial MRI, and contrast-enhanced MRI. Laboratory tests were analyzed and the relationship between clinical prognosis and cranial MRI features was evaluated. RESULTS: Of the 60 patients, 28 (46.67%) had disseminated TB complications, 20 (36.67%) had secondary TB complications, and the remaining 10 (16.66%) had lymphatic TB or spinal TB complications. Of the patients, 25 had good short-term prognosis and 35 had poor short-term prognosis; 44 patients had good long-term prognosis and 16 had poor long-term prognosis. The incidence of cerebral parenchymal tuberculomas on enhanced MRI was significantly higher in the group with good prognosis compared to that in the group with poor prognosis (P < 0.05). Logistic analysis suggested that hydrocephalus (odds ratio [OR] = 0.057, 95% confidence interval [CI] = 0.003-0.444; P = 0.018) and cistern involvement (OR = 0.100, 95% CI = 0.011-0.581; P = 0.017) were independent risk factors for poor short-term prognosis. CONCLUSION: MRI can display the pathological changes of intracranial TB in detail; hydrocephalus and cistern involvement were independent risk factors for poor short-term prognosis.

Hypoxia Increases ATX Expression by Histone Crotonylation in a HIF-2α-Dependent Manner.

Autotaxin (ATX), the key enzyme that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC), is involved in tumorigenesis through the ATX-LPA axis and is regarded as a valuable target in tumor therapy. Hypoxia is a major feature of solid tumors and contributes to tumor development with striking alterations in the gene expression profile. Here, we show that hypoxia induces ATX expression in a hypoxia-inducible factor (HIF) 2α-dependent fashion in human colon cancer SW480 cells. HIF-2α is directly bound to specific hypoxia response elements (HREs) in the ATX promoter. Under hypoxic conditions, knockout or inhibition of ATX suppressed the migration of SW480 cells, which could be rescued by the addition of LPA, suggesting that the induction of ATX during hypoxia promotes cancer cell migration through the ATX-LPA axis. Further studies showed that ATX expression was induced by HIF-2α through recruiting p300/CBP, which led to crotonylation but not acetylation of histone H3 in the ATX promoter region during hypoxia. Moreover, elevation of cellular histone crotonylation levels could induce ATX expression under normoxic conditions. In conclusion, our findings reveal that ATX is induced in SW480 cells during hypoxia by histone crotonylation in a HIF-2α-dependent manner, while as a novel mechanism of ATX expression regulation, the upregulation of ATX expression by histone crotonylation is not confined to hypoxia.

Magnetic Property, Heat Capacity and Crystal Structure of Mononuclear Compounds Based on Substitute Tetrazole Ligand.

Three mononuclear compounds formulated as {M[(2-1H-tetrazol-5-yl)pyridine]2(H2O)2} (M = FeII (1), CoII (2), CuII (3)) were reported and synthesized. Their space group is monoclinic, P21/c, revealed by single-crystal X-ray diffraction. Antiferromagnetic interactions exist in Compounds 1, 2 and 3, as evidenced by magnetic and low-temperature heat capacity measurements. In addition, their thermodynamic functions were determined by a relaxation calorimeter, indicating that Compound 1 exhibits a Schottky anomaly in low-temperature heat capacity. This work can provide an important fundamental basis for the research of the thermophysical properties of molecular-based magnetic materials.

Target-Binding Accelerated Response for Sensitive Detection of Basal H2O2 in Tumor Cells and Tissues via a Dual-Functional Fluorescence Probe.

Aberrant production of H2O2 is involved in cancer. The levels of H2O2 are significantly higher in tumor cells than in normal cells. It is important to develop fluorescent probes to image basal H2O2 selectively in tumor cells. So far, a cancer cell-targeting probe to image basal H2O2 has not been reported. Thus, we developed a fluorescent probe, BBHP, which contains benzil as a H2O2-recognition site and biotin as a target binding motif for the selective and sufficient detection of H2O2 in tumor cells. BBHP enables a selective fluorescence turn-on response to H2O2. The binding of the probe with biotin receptors can greatly accelerate the fluorescence response to H2O2. As a result, BBHP can sufficiently image basal H2O2 in biotin receptor-positive cancer cells and tumor tissues. Finally, BBHP was successfully applied to discriminate between cancerous and normal tissues.

A simple method for the preparation of CeO2with high antioxidant activity and wide application range.

Cerium oxide (CeO2) is a well-known antioxidant with the ability to scavenge reactive oxygen species due to its unique electronic structure and chemical properties. Although many methods to enhance the antioxidant activity of CeO2have been reported, its antioxidant activity is still not high enough, and some enhancement effects are limited by the material concentration. There are also some CeO2obtained with high antioxidant activity at high concentrations, which is not conducive to the application of biomedicine. Therefore, it is urgent to obtain CeO2material with low cell cytotoxicity, high antioxidant activity and wide application range. In this work, rod-like metal organic framework derived CeO2(CeO2-MOF) was prepared by a simple method. Compared with the CeO2nanorods prepared by hydrothermal method, it shows better antioxidant activity compared with the CeO2nanorods prepared by hydrothermal method. Moreover, the advantage of CeO2-MOF's antioxidant activity is not affected by the hydroxyl radical and material concentrations The reason why CeO2-MOF has higher antioxidant activity should be attributed to its higher Ce3+content and larger specific surface area. In addition, CeO2-MOF also exhibits low cytotoxicity to HeLa cells and PC12 cellsin vitro. The strategy of using MOF as a structural and compositional material to create CeO2provides a new method to explore highly efficient and biocompatible CeO2for practical applications.

Association between ABCB1 C3435T polymorphism and antiepileptic drug resistance in epilepsy: An updated meta-analysis based on 62 studies.

OBJECTIVE: Previous clinical studies and meta-analyses have shown controversial results on the association between C3435T polymorphism of the ABCB1 gene and anti-epileptic drug (AED) resistance. Based on the fact that sample size and confounding factors could contribute to the inconsistency, we performed an updated meta-analysis by including the most recent studies, and subgroup analysis was conducted to evaluate the effect of confounding factors on the association. MATERIALS AND METHODS: We searched articles in 6 electronic databases including PubMed, Medline, Embase, Web of science, Cochrane Library, CNKI (China National Knowledge Infrastructure) for relevant articles up to June 2020. RESULTS: The current analysis showed that the C allele of C3435T variant was a risk factor for drug resistance in the overall populations (C allele vs. T allele, OR: 1.13; 95% CI: 1.02 - 1.25; p = 0.02) and in the Caucasians (C allele vs. T allele, OR: 1.09; 95% CI: 1.09 - 1.43; p = 0.002), while no association was observed in Asians and Indians. Particularly, our study reported for the first time that the 3435T allele was more common in epilepsy patients with drug resistance in the Tunisian population (C allele vs. T allele, OR: 0.31; 95% CI: 0.15 - 0.65; p = 0.002). In addition, our present analysis suggested an association between C3435T and AED resistance in cryptogenic, symptomatic, but not in idiopathic patients. Subgroup studies based on age and gender showed no association. CONCLUSION: AED resistance in Caucasian and Tunisian populations may benefit from ABCB1 C3435T genotyping. We recommend that more details, such as gender and etiology of epilepsy, should be taken into account to draw a reliable conclusion in future studies.

Alternatones A and B, two polyketides possessing novel skeletons from entophyte Alternaria alternate L-10.

On our ongoing searching for bioactive natural products derived from entophytes, two polyketides possessing novel skeletons, alternatones A-B (1-2), were identified from the culture of Alternaria alternate L-10. Their structures were established by a combination of spectroscopic and single-crystal X-ray diffraction with Cu Ka radiation. Alternatone A (1) exhibited cytotoxic activity against human hepatoma carcinoma HepG-2 cell line. The putative biosynthetic pathways for compounds 1-2 were also proposed.

Generic Structure Extraction with Bi-Level Optimization for Graph Structure Learning.

Currently, most Graph Structure Learning (GSL) methods, as a means of learning graph structure, improve the robustness of GNN merely from a local view by considering the local information related to each edge and indiscriminately applying the mechanism across edges, which may suffer from the local structure heterogeneity of the graph (i.e., the uneven distribution of inter-class connections over nodes). To overcome the drawbacks, we extract the graph structure as a learnable parameter and jointly learn the structure and common parameters of GNN from the global view. Excitingly, the common parameters contain the global information for nodes features mapping, which is also crucial for structure optimization (i.e., optimizing the structure relies on global mapping information). Mathematically, we apply a generic structure extractor to abstract the graph structure and transform GNNs in the form of learning structure and common parameters. Then, we model the learning process as a novel bi-level optimization, i.e., Generic Structure Extraction with Bi-level Optimization for Graph Structure Learning (GSEBO), which optimizes GNN parameters in the upper level to obtain the global mapping information and graph structure is optimized in the lower level with the global information learned from the upper level. We instantiate the proposed GSEBO on classical GNNs and compare it with the state-of-the-art GSL methods. Extensive experiments validate the effectiveness of the proposed GSEBO on four real-world datasets.

General characteristics and reasons for the discontinuation of drug clinical trials in mainland China.

BACKGROUND: Although discontinuation is common in clinical trials, no study has been conducted to analyse the current situation and reasons for the suspension or discontinuation of drug clinical trials in China. This study aims to analyse the general characteristics and reasons for the discontinuation of registered clinical trials in mainland China and to identify the associated factors. METHODS: We conducted a cross-sectional observational study of discontinued trials registered in the Drug Trial Registration and Information Publication Platform before March 31, 2020. All trials with a status of terminated or stopped recorded in the platform were classified as discontinued trials and included in the analysis. The basic characteristics of the discontinued trials were recorded, reasons for trial discontinuation were recorded and divided into 4 categories as drug development strategy, trial planning, trial conduct and studied drug. Pearson's chi-square test and fisher's exact test were used to compare the differences in reasons for discontinuation between neoplasm trials and non-neoplasm trials, and to examine the associations of trial characteristics with different reasons related to trials discontinuation. RESULTS: Three hundred twelve discontinued trials were included in this study. The studied drugs were mainly chemical drugs [229 (73.4%)], and indications of the studied drugs were mainly neoplasms [77 (24.7%)]. Geographical location of the discontinued trials were mostly in northern [114 (36.5%)] and eastern [96 (30.8%)] China. Study type of the included trials was mainly bioequivalence studies [97 (31.1%)]. The most common reason for trial discontinuation was commercial or strategic decision [84 (26.9%)], followed by futility/lack of efficacy [70 (22.4%)]. The number of trial centers, sample size and whether participants had been enrolled were significantly associated with trial discontinuation (P <  0.05). Multiple center trials showed a higher rate of trial discontinuation due to trial conduct related reasons than single center trials (P <  0.05), trials with sample size > 500 showed a higher rate of trial discontinuation due to studied drug related reasons (P < 0.05), and trials enrolled participants showed a lower rate of trial discontinuation due to commercial or strategic decision and a higher rate of trial discontinuation due to studied drug related reasons than trials without enrolled participants (P < 0.05). Besides, neoplasm trials showed a higher rate of trial discontinuation due to poor recruitment and safety comparing with non-neoplasm trials (P < 0.05). CONCLUSIONS: Trial discontinuation in China mainly occurred because of commercial or strategic decision and futility/lack of efficacy of the studied drug. Clinical trials with multiple centers and a large sample size may more likely be discontinued due to trial conduct related reasons such as good clinical practice. Discontinuation due to drug safety and lack of efficacy in multiple center trials with a large sample size deserves more attention to avoid resources wastes. Full communication with regulatory authorities such as Center for Drug Evaluation and research institutes to develop a feasible protocol is important for sponsors to avoid trial discontinuation due to protocol issues.

Physical and antibacterial properties of bacterial cellulose films supplemented with cell-free supernatant enterocin-producing Enterococcus faecium TJUQ1.

In this study, a composite film was prepared with bacterial cellulose (BC) of Gluconacetobacter xylinus and cell-free supernatant (CFS) of Enterococcus faecium TJUQ1, which was named BC-E. The optimum conditions for the preparation of the composite film with a minimal antibacterial activity were the soak of BC in 80 AU/mL CFS for 6 h. By scanning electron microscope observation, the surface network structure of BC-E was denser than that of BC. The tensile strength of BC and BC-E was 4.65 ± 0.88 MPa and 16.30 ± 0.92 MPa, the elongation at break of BC and BC-E was 3.33 ± 0.89% and 31.60 ± 1.15%, respectively, indicating the mechanical properties of BC-E were significantly higher than that of BC (P < 0.05). The swelling ratio of BC-E (456.67 ± 7.20%) was lower than that of BC (1377.78 ± 9.07%), demonstrating BC-E films presented better water resistance. BC-E films were soaked with 320 AU/mL CFS, and then used to pack the ground meat with 6.55 log10 CFU/g of Listeria monocytogenes. After 8 days of storage, the number of bacteria decreased by 3.16 log10 CFU/g. Similarly, total mesophilic bacterial levels in the ground meat decreased by 2.41 log10 CFU/g compared to control groups.

Biocontrol Efficacy of Bacillus cereus Strain Bc-cm103 Against Meloidogyne incognita.

Root-knot nematodes (Meloidogyne spp.) are soilborne pathogens that infect vegetable crops and cause major economic losses worldwide annually. Therefore, there is an urgent need for novel nematicides or biological control agents to reduce the damage caused by root-knot nematodes. In this study, we tested efficacy of the Bacillus cereus strain Bc-cm103, isolated from the rhizoplane of Cucumis metuliferus, against Meloidogyne incognita. Strain Bc-cm103 fermentation broth caused 100% mortality of the nematode second-stage juveniles within 12 h and decreased the egg hatching rate by 40.06% within 72 h compared with sterile water. Confocal laser-scanning microscopy revealed that strain Bc-cm103 formed a biofilm on cucumber (C. sativus) roots, which protected the roots from the infection of M. incognita. Additionally, strain Bc-cm103 activated the defense-responsive genes PR1, PR2, LOX1, and CTR1 in cucumber. Furthermore, strain Bc-cm103 significantly reduced the appearance of root galls in pot, split-root, and field tests. These results indicated that B. cereus strain Bc-cm103 had a strong suppressive effect on M. incognita and therefore could be used as a potential biocontrol agent against this pathogen.

Volatile Organic Compounds of Bacillus cereus Strain Bc-cm103 Exhibit Fumigation Activity against Meloidogyne incognita.

Bacillus cereus strain Bc-cm103 shows nematicidal activity and, therefore, has been used as a biological control agent to control the root-knot nematode Meloidogyne incognita. However, it remains unknown whether volatile organic compounds (VOCs) produced by B. cereus strain Bc-cm103 are effective in biocontrol against M. incognita. Therefore, in this study, we investigated the activity of Bc-cm103 VOCs against M. incognita. The B. cereus strain Bc-cm103 significantly repelled the second-stage juveniles (J2s) of M. incognita. In vitro evaluation of VOCs produced by the fermentation of Bc-cm103 in a three-compartment Petri dish revealed the mortality rates of M. incognita J2s as 90.8% at 24 h and 97.2% at 48 h. Additionally, evaluation of the ability of Bc-cm103 VOCs to suppress M. incognita infection in a double-layered pot test showed that root galls on cucumber roots decreased by 46.1%. Furthermore, 21 VOCs were identified from strain Bc-cm103 by solid-phase microextraction gas chromatography-mass spectrometry, including alkanes, alkenes, esters, and sulfides. Among them, dimethyl disulfide (30.63%) and S-methyl ester butanethioic acid (30.29%) were reported to have strong nematicidal activity. Together, these results suggest that B. cereus strain Bc-cm103 exhibits fumigation activity against M. incognita.

Intratumoral heterogeneity and genetic characteristics of prostate cancer.

Prostate cancer is a heterogeneous disease and optimum gene targeting treatment is often impermissible. We aim to determine the intratumoral genomic heterogeneity of prostate cancer and explore candidate genes for targeted therapy. Exome sequencing was performed on 37 samples from 16 patients with prostate cancer. Somatic variant analysis, copy number variant (CNV) analysis, clonal evolution analysis and variant spectrum analysis were used to study the intratumoral genomic heterogeneity and genetic characteristics of metastatic prostate cancer. Our study confirmed the high intratumoral genetic heterogeneity of prostate cancer in many aspects, including number of shared variants, tumor mutation burden (TMB), variant genes, CNV burden, weighted genome instability index (wGII), CNV profiles, clonal evolutionary process, variant spectrum and mutational signatures. Moreover, we identified several common genetic characteristics of prostate cancer. Alterations of DNA damage repair genes, RTK/RAS pathway associated gene RASGRF1 and autophagy gene EPG5 may be involved in tumorigenesis in prostate cancer. CNV burden and DNA damage repair (DDR) genes may be associated with metastasis of prostate cancer.

Estrogen Exerts Neuroprotective Effects in Vascular Dementia Rats by Suppressing Autophagy and Activating the Wnt/ß-Catenin Signaling Pathway.

Vascular dementia (VD) is a clinical syndrome of acquired cognitive dysfunction caused by various cerebrovascular factors. Estrogen is a steroid hormone involved in promoting neuronal survival and in regulating many signaling pathways. However, the mechanism by which it confers neuroprotective effects in VD remains unclear. Here, we aimed to investigate the effect of estrogen on neuronal injury and cognitive impairment in VD rats. Adult female rats were randomly divided into four groups (sham, model, estrogen early and estrogen later treatment) and received sham surgery or bilateral ovariectomy and permanent occlusion of bilateral common carotid arteries (BCCAO). The early treatment group received daily intraperitoneal injections of 17ß-estradiol (100 µg/kg/day) for 8 weeks starting the day after BCCAO. The later treatment group was administered the same starting 1 week after BCCAO. Learning and memory functions were assessed using the Morris water maze. Morphological changes within the hippocampal CA1 region were observed by hematoxylin/eosin staining and electron microscopy. Expression of proteins associated with autophagy and signaling were detected by immunohistochemical staining and Western blot. We found that estrogen significantly alleviated cognitive damage and neuronal injury and reduced the expression of Beclin1 and LC3B, indicating a suppression of autophagy. Moreover, estrogen enhanced expression of ß-catenin and Cyclin D1, while reducing glycogen synthase kinase 3ß, suggesting activation of Wnt/ß-catenin signaling. These results indicate that estrogen ameliorates learning and memory deficiencies in VD rats, and that this neuroprotective effect may be explained by the suppression of autophagy and activation of Wnt/ß-catenin signaling.

Estimation of the LDL subclasses in ischemic stroke as a risk factor in a Chinese population.

BACKGROUND: Acute ischemic stroke (AIS) is one of the leading causes of mortality and long-term disability worldwide. Our study aims to clarify the role of low-density lipoproteins (LDL) subclasses in the occurrence of AIS and develop a risk xprediction model based on these characteristics to identify high-risk people. METHODS: Five hundred and sixty-six patients with AIS and 197 non-AIS controls were included in this study. Serum lipids and other baseline characteristics including fasting blood glucose (GLU), serum creatinine (Scr), and blood pressure were investigated in relation to occurrence of AIS. The LDL subfractions were classified and measured with the Lipoprint System by a polyacrylamide gel electrophoresis technique. RESULTS: Levels of LDL-3, LDL-4 and LDL-5 subclasses were significantly higher in the AIS group compared to the non-AIS group and lower level of LDL-1 was prevalent in the AIS patients. Consistently, Spearman correlation coefficient demonstrated that sd-demonevels, especially LDL-3 and LDL-4 levels, were significantly positively correlated with AIS. Furthermore, there is a significant positive correlation between small dense LDL (sd-LDL, that is LDL-3 to 7) levels and serum lipids including total cholesterol (TC), Low density lipoprotein cholesterol (LDL-C), and Triglyceride (TG). Increased LDL-3 and LDL-4 as well as decreased LDL-1 and LDL-2 were correlated to the occurrence of AIS, even in the people with normal LDL-C levels. A new prediction model including 12 variables can accurately predict the AIS risk in Chinese patients (AUC = 0.82 ± 0.04). CONCLUSIONS: Levels of LDL subclasses should be considered in addition to serum LDL-C in assessment and management of AIS. A new prediction model based on clinical variables including LDL subtractions can help clinicians identify high of AIS, even in the people with norm.

DL-3-n-butylphthalide alleviates vascular cognitive impairment by regulating endoplasmic reticulum stress and the Shh/Ptch1 signaling-pathway in rats.

BACKGROUND: DL-3-n-butylphthalide (NBP) has been approved to be effective in improving cognitive deficits. The aim of the current study was to determine whether NBP protects against cognitive deficits in a rat model of vascular dementia (VD) induced by chronic cerebral hypoperfusion (CCH) by regulating the sonic hedgehog (Shh)/patched1 (Ptch1) pathway and endoplasmic reticulum stress (ERS)-related markers. METHODS: Adult male Sprague-Dawley rats were subjected to permanent bilateral occlusion of the common carotid arteries (2VO) to established the model of VD. These rats were randomly divided into five groups: sham, model, NBP30 (30 mg/kg), NBP 60 (60 mg/kg), and NBP 120 (120 mg/kg) groups. The Morris water maze test was used to assess for cognitive function at 4 weeks after operation. RESULTS: NBP significantly alleviated spatial learning and memory impairment, and inhibited the loss of neurons in the CA1 region of the hippocampus. Western blot analysis and real-time quantitative polymerase chain reaction analysis revealed that plasticity-related synaptic markers and the Shh/Ptch1 pathway significantly increased in the NBP treated groups, while ERS-related markers decreased. CONCLUSION: The results of the current study prove that the Shh/Ptch1 pathway plays an essential role in the model of VD. NBP had protective effects on cognitive impairment induced by CCH. This mechanism was associated with ERS and the Shh/Ptch1 pathway. Meanwhile, the Shh/Ptch1 pathway and ERS may interact with each other.

Small airway dysfunction may be an indicator of early asthma: findings from high-resolution CT.

BACKGROUND: Increasing attention is now focused on the role of the small airways in asthma. Patients with small airway asthma typically have a preserved forced expiratory volume in 1 second, with disproportionate small airway dysfunction. OBJECTIVE: The aim of this study was to determine whether there are structural changes in the large airways in patients with small airway asthma. METHODS: Nine patients with small airway asthma and 20 healthy controls underwent high-resolution computed tomography (HRCT) scan. The apicoposterior segmental bronchus in the left upper lobe (LB1+2) and the posterior basal segmental bronchus in the left lower lobe (LB10) were identified on HRCT images. The luminal area (LA), wall area (WA), and wall area percentage (WA%) of each bronchus were measured from the 2nd (lobar) to the 6th generation and compared between the patients with small airway asthma and the healthy controls. RESULTS: The WA% of the 6th generation in the patients with small airway asthma was higher than that in the healthy controls; the difference was statistically significant (LB1 + 2, P = .040; LB10, P = .033). CONCLUSION: Structural changes in the large airways of patients with small airway asthma may represent an early stage of asthma.