Publications by authors named "Xiaoxia Zhu"

157 Publications

Digestive promoting effect and mechanism of Jiao Sanxian in rats.

J Ethnopharmacol 2021 Jun 11:114334. Epub 2021 Jun 11.

Department of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, 210009, People's Republic of China. Electronic address:

Ethnopharmacological Relevance: Jiao Sanxian, a customary term for the three Traditional Chinese Medicines of charred hawthorn (Crataegi Fructus), charred malt (Hordei Fructus Germinatus) and Liu Shenqu (Massa Medicata Fermentata), is a classic prescription for the treatment of functional dyspepsia (FD). This prescription is called "Jiao Sanxian" in China because people believe that it is a miracle medicine for enhancing digestion and improving stagnation of digestive system. Even though Jiao Sanxian is widely used in clinical treatment, the underlying mechanism has not been clarified to date.

Aim Of The Study: The present study is aimed to explore the efficacy and mechanism of Jiao Sanxian in improving the symptoms of FD in rats by using multiple pharmacological methods.

Materials And Methods: The Sprague Dawley (SD) rats were divided into control, model, Jiao Sanxian decoction low-dosage (JSXD LD), Jiao Sanxian decoction medium-dosage (JSXD MD), and Jiao Sanxian decoction high-dosage (JSXD HD) group at random. A FD model was established with reserpine, and animals were given intragastric administration. During this period, weight and food intake of animals were recorded. Samples of rat gastric antrum, spleen, and duodenum were collected for pathological staining and immunohistochemical determination of ghrelin protein expression after 19 days of treatment. Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentration of related brain gut peptides in serum. Moreover, 16S rRNA sequencing was used to valuate the influence of intestinal flora structure of the cecal contents of experimental rats. And plasma metabolomics by Ultra Performance Liquid Chromatography coupled with Quadrupole-Time-of-flight mass spectrometry (UPLC-Q/TOF-MS) were performed to further reveal the mechanism of action.

Results: Jiao Sanxian decoction (JSXD) group with different dosage could increase body weight and food intake, improve histopathological changes, and alter disordered brain gut peptides in FD rats. 16S rRNA sequencing results described that JSXD improved the disorder of structural composition, biodiversity and function of gut microbiota in FD rats. Metabolomics illustrated 26 metabolites with JSXD treatment underwent continuous changes, which revealed JSXD might exert digestive effect by ameliorating abnormal metabolic pathways. The most relevant metabolic pathways were arachidonic acid metabolism, pyruvate metabolism, glycerophospholipid metabolism, alanine, aspartate and glutamate metabolism.

Conclusions: JSXD can improve functional dyspepsia in rats and the mechanism is related to regulate secretion of brain gut peptides, significantly improve the disorder of intestinal flora, and ameliorated multi-metabolic pathways.
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http://dx.doi.org/10.1016/j.jep.2021.114334DOI Listing
June 2021

Neuroprotective Activities of Constituents from Phyllosticta capitalensis, an Endophyte Fungus of Loropetalum chinense var. rubrum.

Chem Biodivers 2021 Jun 8. Epub 2021 Jun 8.

China Pharmaceutical University, Department of Natural Medicinal Chemistry, China Pharmaceutical University Xuanwumen Campus, No.24, Tongjiaxiang, Gulou Dis, China Pharmaceutical University Jiangning Campus, No.639,Longmiandadao, Jiangnin, 210009, Nanjing, CHINA.

One new dioxolanone derivative, guignardianone G ( 1 ) and twelve known compounds ( 2 - 13 ) were isolated from the 95% ethanol extract of the plant endophytic fungus Phyllosticta capitalensis cultured in rice medium. Among the known compounds isoaltenuene ( 3 ), brassicasterol ( 7 ), 5,6-epoxyergosterol ( 8 ), citreoanthrasteroid A ( 9 ), demethylincisterol A ( 10 ), chaxine C ( 11 ) were reported from Phyllosticta sp. for the first time. The structures of 1 was elucidated by 1D- and 2D-NMR experiments and HR-ESI-MS data analysis, and its absolute configuration was established through the comprehensive use of the methods of modified Mosher methods, calculations of ECD spectra and optical rotation values. The neuroprotective activity of compounds 1 - 9 , 11 - 13 were evaluated on PC12 cells damage induced by glutamate, and compounds 9 and 12 showed potential neuroprotective activities and compounds 9 and 12 with half effective concentration (EC 50 ) of 24.2 and 33.9 μ M, respectively.
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http://dx.doi.org/10.1002/cbdv.202100314DOI Listing
June 2021

IL-17 drives salivary gland dysfunction via inhibiting TRPC1-mediated calcium movement in Sjögren's syndrome.

Clin Transl Immunology 2021 29;10(4):e1277. Epub 2021 Apr 29.

Department of Pathology Shenzhen Institute of Research and Innovation The University of Hong Kong Hong Kong.

Objectives: This study aims to determine a role of interleukin-17A (IL-17) in salivary gland (SG) dysfunction and therapeutic effects of targeting IL-17 in SG for treating autoimmune sialadenitis in primary Sjögren's syndrome (pSS).

Methods: Salivary IL-17 levels and IL-17-secreting cells in labial glands of pSS patients were examined. Kinetic changes of IL-17-producing cells in SG from mice with experimental Sjögren's syndrome (ESS) were analysed. To determine a role of IL-17 in salivary secretion, IL-17-deficient mice and constructed chimeric mice with IL-17 receptor C (IL-17RC) deficiency in non-hematopoietic and hematopoietic cells were examined for saliva flow rates during ESS development. Both human and murine primary SG epithelial cells were treated with IL-17 for measuring cholinergic activation-induced calcium movement. Moreover, SG functions were assessed in ESS mice with salivary retrograde cannulation of IL-17 neutralisation antibodies.

Results: Increased salivary IL-17 levels were negatively correlated with saliva flow rates in pSS patients. Both IL-17-deficient mice and chimeric mice with non-hematopoietic cell-restricted IL-17RC deficiency exhibited no obvious salivary reduction while chimeric mice with hematopoietic cell-restricted IL-17RC deficiency showed significantly decreased saliva secretion during ESS development. In SG epithelial cells, IL-17 inhibited acetylcholine-induced calcium movement and downregulated the expression of transient receptor potential canonical 1 via promoting mRNA stabilisation. Moreover, local IL-17 neutralisation in SG markedly attenuated hyposalivation and ameliorated tissue inflammation in ESS mice.

Conclusion: These findings identify a novel function of IL-17 in driving salivary dysfunction during pSS development and may provide a new therapeutic strategy for targeting SG dysfunction in pSS patients.
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http://dx.doi.org/10.1002/cti2.1277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082715PMC
April 2021

Dasatinib inhibits proliferation of liver cancer cells, but activation of Akt/mTOR compromises dasatinib as a cancer drug.

Acta Biochim Biophys Sin (Shanghai) 2021 May 7. Epub 2021 May 7.

Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China.

Dasatinib is a multi-target protein tyrosine kinase inhibitor. Due to its potent inhibition of Src, Abl, the platelet-derived growth factor receptor (PDGFR) family kinases, and other oncogenic kinases, it has been investigated as a targeted therapy for a broad spectrum of cancer types. However, its efficacy has not been significantly extended beyond leukemia. The mechanism of resistance to dasatinib in a wide array of cancers is not clear. In the present study, we investigated the effect of dasatinib on hepatocellular carcinoma cell growth and explored the underlying mechanisms. Our results showed that dasatinib potently inhibited the proliferation of SNU-449 cells, but not that of other cell lines, such as SK-Hep-1, even though it inhibited the phosphorylation of Src on both negative and positive regulation sites in all these cells. Dasatinib activated the phosphoinositide-dependent protein kinase1 (PDK1)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway in SK-Hep-1 cells, but not in SNU-449 cells. Blocking the Akt/mTOR signaling pathway strongly promoted the efficacy of dasatinib in SK-Hep-1 cells. In SNU-449 cells, dasatinib promoted apoptosis and the cleavage of caspase-3 and caspase-7, induced cell cycle arrest in the G1 phase, and inhibited the expression of Cyclin-dependent kinase (CDK4)/6/CyclinD1 complex. These findings demonstrate that dasatinib exerts its anti-proliferative effect on hepatocellular cell proliferation by blocking the Src family kinases; however, it causes Akt activation, which compromises dasatinib as an anti-cancer drug.
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http://dx.doi.org/10.1093/abbs/gmab061DOI Listing
May 2021

Lycium barbarum mitigates radiation injury via regulation of the immune function, gut microbiota, and related metabolites.

Biomed Pharmacother 2021 Jul 3;139:111654. Epub 2021 May 3.

Tianjin University of Traditional Chinese Medicine, Tianjin, China; Beijing Institute of Radiation Medicine, Beijing, China. Electronic address:

Previous studies have suggested that Lycium barbarum (L. barbarum) has a radioprotective function, although more in-depth investigation is still required. We investigated the radioprotective efficacy of extract of the fruits of L. barbarum (LBE) and its radioprotective mechanisms. Mice were exposed to 8.5 Gy, 5.5 Gy, or 6.0 Gy total body irradiation (TBI), and the survival rate, lymphocyte percentage, amount of cytokines, and viability of the irradiated cells, as well as the gut microbiome and fecal metabolomics were studied. LBE enhanced the survival of the mice exposed to 8.5 Gy γ-ray TBI or 5.5 Gy X-ray TBI. After 6.0 Gy γ-ray TBI, LBE exhibited good immunomodulatory properties, mainly characterized by the accelerated recovery of lymphocyte percentages, and the enhanced expression of immune-related cytokines. LBE reconstituted the gut microbiota of irradiated mice, increased the relative abundance of potentially beneficial genera (e.g., Turicibacter, Akkermansia), and decreased the relative abundance of potentially harmful bacterial genera (e.g., Rikenellaceae_RC9_gut_group). Beneficial regulatory effects of LBE on the host metabolites were also noted, and the major upregulated metabolites induced by LBE, such as Tetrahydrofolic acid and N-ornithyl-L-taurine, were positively correlated with the immune factor interleukin (IL)-6. In vitro, LBE also increased the vitality of rat small intestinal epithelial cells (IEC-6) after 4.0 Gy γ-ray irradiation and promoted the growth of Akkermansia muciniphila. These results confirmed a radioprotective function of LBE and indicated that the radioprotective mechanism may be due to immunomodulation and the synergistically modulating effect on the gut microbiota and related metabolites.
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http://dx.doi.org/10.1016/j.biopha.2021.111654DOI Listing
July 2021

Ultrasensitive DNA methyltransferase activity sensing and inhibitor evaluation with highly photostable upconversion nanoparticle transducer.

Mikrochim Acta 2021 Apr 23;188(5):169. Epub 2021 Apr 23.

School of Public Health, Nantong University, Nantong, 226019, China.

Sensitive and accurate detection of DNA methyltransferase (MTase) is conducive to the understanding of the fundamental biological processes related to DNA methylation, clinical disease diagnosis, and drug discovery. Herein, a new fluorescence transducer based on Förster resonance energy transfer (FRET) between the donor upconversion nanoparticles (UCNPs) and the efficient acceptor gold nanorods (AuNRs) for MTase activity analysis and its inhibitor screening is presented. A double-strand DNA linker between UCNPs and AuNRs could be digested by restriction endonuclease HhaI, preventing the FRET process and recovering the upconversion luminescence (UCL) intensity. With the treatment of MTase, the cutting site was disturbed by the methylation of cytosine, blocking the enzyme digestion. The transducer presented here showed an excellent analytical performance toward MTase M.HhaI in the concentration range 0.08~24 U mL with a detection limit of 0.057 U mL calculated according to the UCL intensity changes at 656 nm excited by 980 nm CW laser, which is superior to most of the reported methods. Furthermore, the as-fabricated transducer also demonstrated high testing and screening capability toward enzyme inhibitors' evaluation. The method takes the advantage of low background fluorescence of UCNPs to improve the accuracy of the measurement, which can be developed as a general strategy for the analysis of various disease-related methyltransferase activity and their corresponding inhibitors, offering a promising strategy for high-performance diagnosis, high-efficient drug exploitation, and treatment effectiveness evaluation.
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http://dx.doi.org/10.1007/s00604-021-04831-zDOI Listing
April 2021

Performance of Ultrasound in the Clinical Evaluation of Gout and Hyperuricemia.

J Immunol Res 2021 5;2021:5550626. Epub 2021 Apr 5.

Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China 200040.

Objective: To evaluate monosodium urate (MSU) crystal deposition and related lesions in the joints of patients with gout and hyperuricemia (HUA) using ultrasound. To explore the association between ultrasound findings and clinical features in gout and HUA.

Methods: A total of 202 patients with gout and 43 asymptomatic patients with HUA were included. The clinical data and ultrasonic assessment results were collected and statistically analyzed.

Results: Deposition of MSU crystals was found in 25.58% (11/43) of patients with asymptomatic HUA and 76.24% (154/202) of patients with gout. Of the 1,082 joints from patients with gout examined, 33.09% (358/1082) displayed MSU crystal deposition. In the joints with MSU crystal deposition, 77.37% (277/358) had a history of attacks. Among the joints of gouty arthritis, double contour sign (DCS), hyperechoic aggregate (HAG), and tophi were found in 32.65% (159/487), 7.80% (38/487), and 24.64% (120/487) of the joints, respectively. DCS and tophi, but not HAG, increasingly appeared with the extension of gout duration. In patients with more than 15 years of gout history, DCS, Tophi, and HAG were found in 48.18%, 40.00%, and 6.36% of US assessed joints, respectively. In patients with gout, synovial lesion and bone erosion were found in 17.74% (192/1082) and 7.58% (82/1082) of joints, respectively. The synovial lesion was related to HAG, while bone erosion was related to tophi and DCS. Nephrolithiasis was detected in 20.30% (41/202) of patients with gout and 4.65% (2/43) of HUA patients, indicating that nephrolithiasis occurred in more patients with gout than in patients with HUA.

Conclusion: HAG is an early performance of MSU crystal deposition in joints of gout and HUA. Both DCS and tophi are risk factors for bone erosion. Early urate-lowering therapy (ULT) should be considered in patients with gout, DCS, or tophi.
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http://dx.doi.org/10.1155/2021/5550626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041551PMC
April 2021

Higher postoperative plasma EV PD-L1 predicts poor survival in patients with gastric cancer.

J Immunother Cancer 2021 Mar;9(3)

Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shanxi Key Laboratory of Birth Defects and Cell Regeneration, Key Laboratory of Cellular Physiology (Shanxi Medical University) of Ministry of Education, Shanxi Medical University, Taiyuan, China

Background: The satisfactory prognostic indicator of gastric cancer (GC) patients after surgery is still lacking. Perioperative plasma extracellular vesicular programmed cell death ligand-1 (ePD-L1) has been demonstrated as a potential prognosis biomarker in many types of cancers. The prognostic value of postoperative plasma ePD-L1 has not been characterized.

Methods: We evaluated the prognostic value of preoperative, postoperative and change in plasma ePD-L1, as well as plasma soluble PD-L1, in short-term survival of GC patients after surgery. The Kaplan-Meier survival model and Cox proportional hazards models for both univariate and multivariate analyzes were used. And the comparison between postoperative ePD-L1 and conventional serum biomarkers (carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9) and CA72-4) in prognostic of GC patients was made.

Results: The prognostic value of postoperative ePD-L1 is superior to that of preoperative ePD-L1 on GC patients after resection, and also superior to that of conventional serum biomarkers (CEA, CA19-9 and CA72-4). The levels of postoperative ePD-L1 and ePD-L1 change are independent prognostic factors for overall survival and recurrence free survival of GC patients. High plasma level of postoperative ePD-L1 correlates significantly with poor survival, while high change in ePD-L1 level brings the significant survival benefit.

Conclusions: The level of plasma postoperative ePD-L1 could be considered as a candidate prognostic biomarker of GC patients after resection.
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http://dx.doi.org/10.1136/jitc-2020-002218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986771PMC
March 2021

Highly specific and label-free histological identification of microcrystals in fresh human gout tissues with stimulated Raman scattering.

Theranostics 2021 1;11(7):3074-3088. Epub 2021 Jan 1.

State Key Laboratory of Surface Physics and Department of Physics, Human Phenome Institute, Multiscale Research Institute of Complex Systems, Academy for Engineering and Technology, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Fudan University, Shanghai 200433, China.

Gout is a common metabolic disease with growing burden, caused by monosodium urate (MSU) microcrystal deposition. In situ and chemical-specific histological identification of MSU is crucial in the diagnosis and management of gout, yet it remains inaccessible for current histological methods. Stimulated Raman scattering (SRS) microscopy was utilized to image MSU based on its fingerprint Raman spectra. We first tested SRS for the diagnosis capability of gout and the differentiation power from pseudogout with rat models of acute gout arthritis, calcium pyrophosphate deposition disease (CPDD) and comorbidity. Then, human synovial fluid and surgical specimens (n=120) were were imaged with SRS to obtain the histopathology of MSU and collagen fibers. Finally, quantitative SRS analysis was performed in gout tissue of different physiological phases (n=120) to correlate with traditional histopathology including H&E and immunohistochemistry staining. We demonstrated that SRS is capable of early diagnosis of gout, rapid detection of MSU in synovial fluid and fresh unprocessed surgical tissues, and accurate differentiation of gout from pseudogout in various pathophysiological conditions. Furthermore, quantitative SRS analysis revealed the optical characteristics of MSU deposition at different pathophysiological stages, which were found to matched well with corresponding immunofluorescence histochemistry features. Our work demonstrated the potential of SRS microscopy for rapid intraoperative diagnosis of gout and may facilitate future fundamental researches of MSU-based diseases.
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http://dx.doi.org/10.7150/thno.53755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847673PMC
January 2021

Adeno-associated virus-mediated delivery of anti-miR-199a tough decoys attenuates cardiac hypertrophy by targeting .

Mol Ther Nucleic Acids 2021 Mar 17;23:406-417. Epub 2020 Nov 17.

Department of Medical Ultrasound, Laboratory of Ultrasound Imaging Drug, West China Hospital, Sichuan University, Chengdu 610041, China.

MicroRNAs (miRNAs) are important regulators in the process of cardiac hypertrophy and heart failure. Previous studies have shown that miR-199a is upregulated in pressure-overload cardiac hypertrophy and that inhibition of miR-199a attenuates cardiac hypertrophy . However, the therapeutic role of anti-miR-199a treatment in the cardiac hypertrophy model is less known. Here, we show an efficient and useful method to treat mouse cardiac hypertrophy and restore cardiac function through injection of adeno-associated virus (AAV)-mediated anti-miR-199a tough decoys (TuDs). RNA-seq transcriptome analysis indicated that genes related to cytoplasmic translation and mitochondrial respiratory chain complex assembly were upregulated in anti-miR-199a-treated recovered hearts. We further validated that PGC-1α is the direct target of miR-199a involved in the therapeutic effect and the regulation of the PGC-1α/ERRα axis and that the downstream pathway of mitochondrial fatty acid oxidation and oxidative phosphorylation constitute the underlying mechanism of the restored mitochondrial structure and function in our anti-miR-199a-treated mice. Our study highlights the important regulatory role of miR-199a in cardiac hypertrophy and the value of the AAV-mediated miRNA delivery system.
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http://dx.doi.org/10.1016/j.omtn.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787996PMC
March 2021

The immune dysregulations in COVID-19: Implications for the management of rheumatic diseases.

Mod Rheumatol 2021 Jan 26:1-13. Epub 2021 Jan 26.

Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong and Chongqing International Institute for Immunology, Hong Kong, China.

The pandemic of COVID-19 has caused global social impact and high health risk. Clinical observations have suggested that elevated levels of inflammatory mediators are associated with disease severities in COVID-19 patients, in which the immunological profiles indicate the hyperactivation of innate immune cells and dysregulated adaptive immune responses. The increasing prevalence and disease progression of COVID-19 has emerged as a pressing challenge for the management of rheumatic patients with immune dysregulations. Here we review the immune dysregulations in COVID-19 and discuss the management of COVID-19 patients with rheumatic diseases.
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http://dx.doi.org/10.1080/14397595.2020.1868673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852258PMC
January 2021

Construction of Radiation Surviving/Resistant Lung Cancer Cell Lines with Equidifferent Gradient Dose Irradiation.

Dose Response 2020 Oct-Dec;18(4):1559325820982421. Epub 2020 Dec 22.

Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.

Radiotherapy plays an increasingly crucial role in the treatment of non-small cell lung cancer (NSCLC). Local tumor recurrence and tumor progression caused by intratumoral heterogeneity induced radiotherapy resistance remain the primary causes of radiotherapy failure. However, the lack of a suitable cell line model has hampered the exploration of the dynamic mechanisms of radiation resistance. We established 3 groups of equidifferent gradient dose irradiation surviving/resistant human lung cancer cell lines based on A549, H520, and H460 cells with clinical conventional fractionated radiotherapy (CFRT) (2 Gy × 20 F, 2 Gy × 30 F, and 2 Gy × 40 F). The radiosensitivity of the cells was detected by clone formation assay, EDU cell proliferation assay, neutral comet assay, and γ-H2AX immunofluorescence staining. The radiosensitivity and proliferation viability were increased in a received dose-dependent manner. Compared with parental cells, DNA double-strand breaks (DSBs) in cell lines that received higher-dose irradiation were significantly reduced. We successfully constructed equidifferent gradient dose irradiation surviving/resistant NSCLC cell lines whose radiation surviving and resistant abilities were increased in a received dose-dependent manner. This preclinical cell model could be used to dynamically observe and detect the radiation surviving/resistant biomarkers during radiotherapy stress, elucidate the mechanism of radiation resistance.
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http://dx.doi.org/10.1177/1559325820982421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758662PMC
December 2020

Prevalence and risk factors of self-reported wrist and hand symptoms and clinically confirmed carpal tunnel syndrome among office workers in China: a cross-sectional study.

BMC Public Health 2021 01 6;21(1):57. Epub 2021 Jan 6.

Department of Rehabilitation Medicine, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China.

Background: Carpal tunnel syndrome (CTS) is a common cause of pain, numbness and tingling in the wrist and hand region and is associated with repetitive wrist and hand use in office workers. However, scarce knowledge exists about the epidemiology of clinically confirmed CTS among Chinese office workers. This study aimed to investigate the prevalence of wrist/hand symptoms and CTS in office workers in China and to identify associated risk factors.

Methods: A cross-sectional survey was carried out in a metropolitan city in China involving 969 respondents (aged 17-49 years) from 30 workplaces. A questionnaire was distributed to each participant to collect their demographic, work-related physical and psychosocial factors, and wrist and hand symptoms. The wrist and hand pain/numbness symptoms were marked on a body chart and the nature and intensity of symptoms, nocturnal symptoms, as well as aggravating activities were also recorded. Clinically confirmed CTS cases were screened based on the history, Phalen's test, Tinel Sign and skin sensation testing among symptomatic respondents. Logistic regression was employed to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for the occurrence of self-reported wrist and hand symptoms and clinically confirmed CTS.

Results: The clinically confirmed CTS prevalence was 9.6%. The prevalence of wrist and hand symptoms were 22 and 15%, respectively. Frequently working in pain was associated with higher odds of CTS. Multivariate modelling adjusted for age and gender showed that prolonged computer use time and working without breaks were associated with presence of wrist/hand symptoms (adjusted ORs: 1.11 (95% CI 1.02-1.22) and 1.88 (95% CI 1.12-3.14)). Educational level was inversely associated with CTS and smoking was associated with wrist/hand complaints (adjusted OR: 2.20 (95% CI 1.19-4.07)).

Conclusions: The prevalence of work-related clinically confirmed CTS symptoms among young office workers in China is high. Frequently working in pain is closely associated with clinically confirmed CTS. Intense computer use and no breaks at work are associated with wrist and hand symptoms.
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http://dx.doi.org/10.1186/s12889-020-10137-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789363PMC
January 2021

Fungal endocarditis with heart valve replacement and atrial fibrillation posing a treatment challenge: A case report.

Medicine (Baltimore) 2020 Nov;99(48):e22487

Department of Neurology, The Affiliated Hefei Hospital of Anhui Medical University, Hefei, Anhui, P.R. China.

Rationale: Fungal endocarditis (FE) is a rare disease, in which antifungal treatment is necessary. When FE is complicated with prosthetic heart valve and/or atrial fibrillation, the coadministration of antifungal agents and warfarin is inevitable. We report a case of rheumatic heart disease with atrial fibrillation who developed FE following prosthetic heart valve replacement. The international normalized ratio (INR) increased significantly during the antifungal treatment with fluconazole. A discussion of the antifungal strategy in FE patients with prosthetic heart valves and/or atrial fibrillation and the interaction between antifungal agents and warfarin was performed.

Patient Concerns: A 54-year-old Chinese woman experienced intermittent fevers, aphemia, and weakness in her right extremities. Her temperature was 38.7°C, and there was atrial fibrillation with heart rate 110 times/min. Neurological examination revealed that she had drowsiness, Broca aphasia, right central facial paralysis, and hemiplegia (Medical Research Council scale, upper limb grade 0, lower limb grade II).

Diagnoses: Multiple infarction on magnetic resonance imaging and the occlusion of left middle cerebral artery suggested the occurrence of cerebral embolism. The presence of Candida parapsilosis in the results of 4 blood cultures and the existence of valve vegetation in the reexamination of echocardiogram supported the diagnosis of FE.

Interventions: The patient was given antifungal therapy with fluconazol. The INR increased dramatically on the 9th day of antifungal treatment, and subcutaneous bruising occurred at the intravenous infusion site. The antagonist of vitamin K1 was used and warfarin was reduced to a smaller dosage. The antifungal agent was replaced with caspofungin.

Outcomes: Her speech improved significantly, and the muscle strength of her paralyzed side reached the Medical Research Council scale of grade IV. She continued to receive caspofungin for antifungal treatment with relatively stable INR and waited for heart valve surgery.

Lessons: The choice of antifungal agents is often a big challenge for FE patients, especially when they need warfarin for anticoagulation. It is better to administer a low dose of warfarin while carefully monitoring the INR or choose the antifungal drugs with little or no effect on warfarin.
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http://dx.doi.org/10.1097/MD.0000000000022487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710166PMC
November 2020

Anton's syndrome as a presentation of Trousseau syndrome involving the bilateral optic radiation.

J Int Med Res 2020 Nov;48(11):300060520972907

Department of Neurology, The Affiliated Hefei Hospital of 12485Anhui Medical University, Hefei, Anhui, P.R. China.

Anton's syndrome is a rare neuropsychiatric syndrome that is characterized by cortical blindness and anosognosia with visual confabulation, but without global cognitive impairment. We herein report a rare case of Anton's syndrome as a presentation of Trousseau syndrome involving the bilateral optic radiation. The patient had been diagnosed with gallbladder cancer 2 months previously, and he was admitted to the hospital with confusion and quadriplegia. He was found to be blind, but denied any visual impairment and demonstrated visual confabulation despite evidence of his blindness. These signs were consistent with a diagnosis of Anton's syndrome. Brain computed tomography (CT) and magnetic resonance imaging revealed infarcts in the bilateral temporo-parieto-occipital junction with hemorrhagic transformation, mainly involving the bilateral optic radiation. The presence of gallbladder cancer with peripheral metastasis on abdominal CT, as well as markedly increased tumor markers and D-dimer levels, supported the presence of cancer-related hypercoagulability and the diagnosis of Trousseau syndrome.
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http://dx.doi.org/10.1177/0300060520972907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705385PMC
November 2020

Aldosterone up-regulates voltage-gated potassium currents and NKCC1 protein membrane fractions.

Sci Rep 2020 09 24;10(1):15604. Epub 2020 Sep 24.

Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33620, USA.

Na-K-2Cl Cotransporter (NKCC1) is a protein that aids in the active transport of sodium, potassium, and chloride ions across cell membranes. It has been shown that long-term systemic treatment with aldosterone (ALD) can enhance NKCC1 protein expression and activity in the aging cochlea resulting in improved hearing. In the present work, we used a cell line with confirmed NKCC1 expression to demonstrate that in vitro application of ALD increased outward voltage-gated potassium currents significantly, and simultaneously upregulated whole lysate and membrane portion NKCC1 protein expression. These ALD-induced changes were blocked by applying the mineralocorticoid receptor antagonist eplerenone. However, application of the NKCC1 inhibitor bumetanide or the potassium channel antagonist Tetraethyl ammonium had no effect. In addition, NKKC1 mRNA levels remained stable, indicating that ALD modulates NKCC1 protein expression via the activation of mineralocorticoid receptors and post-transcriptional modifications. Further, in vitro electrophysiology experiments, with ALD in the presence of NKCC1, K channel and mineralocorticoid receptor inhibitors, revealed interactions between NKCC1 and outward K channels, mediated by a mineralocorticoid receptor-ALD complex. These results provide evidence of the therapeutic potential of ALD for the prevention/treatment of inner ear disorders such as age-related hearing loss.
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http://dx.doi.org/10.1038/s41598-020-72450-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515911PMC
September 2020

Ultrasound assessment of skin thickness and stiffness: the correlation with histology and clinical score in systemic sclerosis.

Arthritis Res Ther 2020 08 26;22(1):197. Epub 2020 Aug 26.

Division of Rheumatology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China.

Background: Ultrasound is a useful tool to evaluate and quantify skin lesions. Few studies have assessed the criterion validity of skin ultrasound in systemic sclerosis (SSc). The aims of the study were to investigate skin thickness and stiffness using ultrasound and shear wave elastography (SWE) in SSc and to validate skin ultrasound measurements against histological skin thickness.

Methods: A total of 22 patients with diffuse cutaneous SSc (dcSSc), 22 with limited cutaneous SSc (lcSSc), and 22 age- and gender-matched healthy controls were enrolled. Skin thickness and stiffness were measured by B-mode ultrasound with SWE imaging on the bilateral fingers and hands. Additional ultrasound evaluation was carried out in 13 patients (9 dcSSc and 4 lcSSc) on their dorsal forearms, followed by skin biopsy conducted in the same skin areas. Correlations between ultrasound measurements and histological skin thickness and modified Rodnan skin score (mRSS) were investigated using Spearman's correlation.

Results: Compared with controls, ultrasound-measured skin thickness and skin stiffness were significantly higher in patients with SSc (p < 0.001) and even higher in those with dcSSc. No clear correlation could be established between ultrasound-determined skin thickness and stiffness at the same site. Ultrasound-measured skin thickness correlated well with histological skin thickness (r = 0.6926, p = 0.009). A weaker association was also observed between histological skin thickness and local mRSS (r = 0.5867, p = 0.050).

Conclusions: Ultrasound is a reliable tool for quantifying skin involvement in SSc. Ultrasound-measured skin thickness showed good agreement with histological skin thickness.
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http://dx.doi.org/10.1186/s13075-020-02285-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448329PMC
August 2020

Predicting the metabolic characteristics of neorudin, a novel anticoagulant fusion protein, in patients with deep vein thrombosis.

Thromb Res 2020 10 1;194:121-134. Epub 2020 Jun 1.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China. Electronic address:

Introduction: Recombinant neorudin (EPR-hirudin, EH) is an inactive prodrug that is converted to its active metabolite, hirudin variant 2-Lys47 (HV2), at the thrombus site. We aimed to investigate the mechanism underlying site-selective bioconversion of EH to HV2 at the thrombus target site and metabolic transformation of EH in patients with deep vein thrombosis (DVT).

Materials And Methods: Metabolites in healthy volunteer plasma and urine after intravenous administration of EH were determined to elucidate how EH was metabolised after releasing HV2 at the target site in patients with DVT. After intravenous administration of EH in rats with venous thrombosis, the concentrations of EH in the blood and thrombus and the antithrombotic activity of EH were measured to predict whether EH could release HV2 at the thrombus site to exert anticoagulant effect in patients with DVT.

Results: In healthy volunteers, EH and HV2 were predominantly excreted in the urine. Nine EH metabolites and ten HV2 metabolites truncated at the C-terminal were identified as N-terminal fragments, and these had the same cleavage sites. In rats with venous thrombosis, the area under the curve ratio of HV2 between the thrombus and blood was 29.5. The weight of wet thrombus was decreased with the production of HV2 by the cleavage of EH. The prothrombin time (PT) and prothrombin time (TT) changed proportionally to the concentration of EH and HV2 in the blood.

Conclusion: EH selectively accumulates and releases HV2 in the thrombus to exert antithrombotic effects, thus lowering the bleeding risk. Moreover, after conversion, EH may follow the same metabolic profile as that of HV2 in patients with DVT.
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http://dx.doi.org/10.1016/j.thromres.2020.05.048DOI Listing
October 2020

Clinical efficacy of ceramic versus resin-based composite endocrowns in Chinese adults: study protocol for a randomized controlled trial.

Trials 2020 Jun 22;21(1):559. Epub 2020 Jun 22.

Department of Conservative and Endodontic Dentistry, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Road, Guangzhou, 510515, China.

Background: Endocrown restoration is widely used to restore endodontically treated teeth. However, the clinical effects of different computer-aided design/computer-aided manufacturing (CAD/CAM) materials for endocrown restoration are not clear. The primary objective of this trial is to compare the clinical efficacy of resin-based bloc and ceramic endocrowns for restoring endodontically treated teeth.

Methods: The proposed resin-based bloc and ceramic endocrown assessment trial is a parallel group-designed randomized controlled trial. We will recruit 156 adults between 18 and 75 years old with a minimum of one such molar. The inclusion criteria were good oral hygiene habits, root apex of molar without evident damage, receipt of standard endodontic treatment, need for endocrown restoration, and only one endocrown restoration performed per patient. Patients participating in another study or those with systemic diseases, disabilities, or known allergies to used materials will be excluded. All patients will be randomized and restored with resin-based bloc and ceramic endocrown according to a random number table. Clinical evaluations will be performed at baseline and after treatment at 6, 12, and 24 months, in accordance with the modified Federation Dentaire Internationale (FDI) criteria, by two independent evaluators. The primary outcome is marginal adaptation; secondary outcomes include wear, tooth integrity, fracture of material and retention, marginal staining, and patient view. All data will be analyzed by an independent statistician. Signed rank-sum tests will be used for intragroup comparisons. Wilcoxon rank-sum tests will be used for intergroup comparisons. Hierarchical logistic regression will be used to adjust the baseline and other important indicators.

Discussion: This study will investigate endocrowns of two CAD/CAM materials for endodontically treated molars. The results may help clinicians choose the better CAD/CAM material option and explain to patients the advantages and disadvantages of these two materials with evidence-based support. For patients, the results may lead to improvement in long-term restoration.

Trial Registration: ClinicalTrials.gov NCT04033380. Registered on 24 July 2019.
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http://dx.doi.org/10.1186/s13063-020-04506-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310236PMC
June 2020

[Combination of Radiation Therapy and Immunotherapy for Non-small Cell Lung Cancer: Peer Exchange on Frontier Academic Topics].

Zhongguo Fei Ai Za Zhi 2020 Jun;23(6):532-540

Department of Radiotherapy, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

Lung cancer is the leading cause of cancer death worldwide as well as in China. For many years, conventional oncologic treatments such as surgery, chemotherapy, and radiotherapy (RT) have dominated the field of non-small cell lung cancer (NSCLC). The recent introduction of immunotherapy in clinical practice, led to a paradigm shift in lung cancer as in many other solid tumors. Recent pre-clinical and clinical data have shown RT may also modify antitumor immune responses through induction of immunogenic cell death and reprogramming of the tumor microenvironment. This has led many to reexamine RT as a partner therapy to immuno-oncology treatments and investigate their potential synergy in an exponentially growing number of clinical trials. Clinical trials combining radiotherapy and immunotherapy are attracting major attention, experts were invited to discuss frontier and controversial academic topics: (1) Recent developments of clinical synergy between radiation and immune checkpoint inhibitors (ICIs) in the treatment of NSCLC; (2) Will immunotherapy and radiotherapy increase the toxicity risk for cancer patients; (3) How to cope the mixed responses/disassociated responses phenomenon in checkpoint inhibition therapy to NSCLC with local ablative therapy; (4) Combining radiotherapy and immunotherapy in the treatment of NSCLC brain metastases.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2020.102.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309548PMC
June 2020

Letter by Cao et al Regarding Article, "Stroke Risk as a Function of Atrial Fibrillation Duration and CHADS-VASc Score".

Circulation 2020 03 9;141(10):e597-e598. Epub 2020 Mar 9.

Department of Neurology, Hefei Affiliated Hospital of Anhui Medical University (S.C., M.X.), Hefei, Anhui P.R. China.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044621DOI Listing
March 2020

Expressionof langerhans cell and plasmacytoid dendritic cell markers, and toll-like receptor 7/9 signaling pathway proteins in verruca vulgaris lesions.

Medicine (Baltimore) 2020 Feb;99(8):e19214

Department of Dermatology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Langerhans cells (LCs) and plasmacytoid dendritic cells (pDCs) play an important role in the cutaneous immune response to viral infection. Verruca vulgaris (VV) is a chronic benign disease caused by human papillomavirus (HPV) infection.To investigate the possible roles of LCs, pDCs and toll-like receptor (TLR)7/9 signaling pathways in the pathogenesis of VV, we detected the expression of CD1a, CD2AP, CD123, TLR7/9, IFN regulatory factor 7 (IRF7), and interleukin-1 receptor-associated kinase 1 (IRAK1) in VV lesions.The expression of CD1a, CD2AP, CD123, TLR7/9, IRF7, and IRAK1 in 20 VV lesions was tested by immunohistochemistry. The density and number of stained cells were compared between VV lesions and the perilesional normal skin.The density and number of CD1a-, CD2AP-, CD123-, TLR9-, and IRAK1-positive cells in the papillary layer of VV lesions were significantly higher than those in the perilesional normal skin (P < .05). There were no significant differences in the density and positive rate of CD1a+ cells in the epidermis and of TLR7 and IRF7 cells in the dermis between VV lesions and the perilesional normal skin at the edge (P > .05).In VV, the number of LCs increases only in the dermis, indicating that LC's antigen-presenting function might not be inhibited. The increased number of pDCs in VV lesions suggests that HPV infection may recruit the pDCs to the virus-infected epithelium. We speculate that the TLR7/9 downstream signaling pathway is not fully activated in VV, leading to difficulty of HPV removal and the relapse of HPV-infected lesions.
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http://dx.doi.org/10.1097/MD.0000000000019214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034720PMC
February 2020

Preclinical pharmacokinetics of M10 after intragastrical administration of M10-H and M10-Na in Wistar rats.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Mar 30;1140:121905. Epub 2019 Nov 30.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Haidian District, Beijing 100850, China. Electronic address:

As a myricetin derivative, M10 is a potent agent of anti-chronic colonic inflammation. It has better activity than myricetin in preventing azoxymethane/dextran sulfate sodium - induced ulcerative colitis. Here, we introduce a sensitive quantification method based on ultra performance liquid chromatography-tandem mass spectrometry for the determination of M10-H and M10-Na in Wistar rat plasma. Samples were treated with L - ascorbic acid and phosphate buffer solution to maintain stability and with acetonitrile to remove the proteins in the plasma. The supernatant was separated with BEH C18 column and eluted with ultrapure water and acetonitrile both containing 0.1% formic acid. The detection was performed by a triple quadrupole mass spectrometer with positive electrospray ionization mode in multiple reactive monitoring. This method was validated for the carryover effect, selectivity, accuracy, precision, matrix effect, stability, and recovery. A linear correlation was established between concentration and response by the calibration curves over 10-2000 ng·mL (r > 0.99). This method was applied to a pharmacokinetic study of intragastrical administration of M10-H and M10-Na in Wistar rats. In addition, the relative bioavailability of M10-H to M10-Na in Wistar rats was 60 ± 19%, calculated by the ratio of area under concentration (AUC) of M10-H to M10-Na after intragastrical administration of a single dose (100 mg·kg for M10-H and M10-Na, respectively) in Wistar rats.
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http://dx.doi.org/10.1016/j.jchromb.2019.121905DOI Listing
March 2020

Understanding hormone and hormone therapies' impact on the auditory system.

J Neurosci Res 2020 09 5;98(9):1721-1730. Epub 2020 Feb 5.

Department of Medical Engineering, Global Center for Hearing & Speech Research, University of South Florida, Tampa, FL, USA.

Hormones such as estrogen, progesterone, and aldosterone all demonstrate vital roles in sustaining auditory function through either the maintenance of cochlear neurons, up/down regulation of critical molecules (i.e., IGF-1, BDNF, etc.), or generation of the endocochlear potential. With disease and/or age, hormone expression begins to decline drastically, which ultimately affects cochlear structures and the integrity of cochlear cells. The following review explores the latest findings as well as realistic outcomes for hormone therapy treatment in the auditory system. This information could serve as a potential guide for patients considering hormone therapy as a medicinal choice to alleviate the signs of onset of presbycusis-age-related hearing loss. Additional scientific investigations could also be carried out to further enhance recent findings.
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http://dx.doi.org/10.1002/jnr.24588DOI Listing
September 2020

Promotion of Myofibroblast Differentiation and Tissue Fibrosis by the Leukotriene B -Leukotriene B Receptor Axis in Systemic Sclerosis.

Arthritis Rheumatol 2020 06 30;72(6):1013-1025. Epub 2020 Apr 30.

Huashan Hospital and Fudan University, Shanghai, China.

Objective: To investigate the role of the inflammatory lipid mediator leukotriene B (LTB ) and its receptor, BLT1, in the development and progression of systemic sclerosis (SSc).

Methods: Serum levels of LTB were compared in 64 patients with SSc and 80 healthy controls. Skin and lung tissue sections from patients with SSc and healthy donors were immunostained for leukotriene A hydrolase (LTA H), the critical enzyme for LTB synthesis, and BLT1, in combination with different cell markers. In mouse models of SSc using bleomycin or angiotensin II challenge or immunization with the DNA topoisomerase I, genetic or pharmacologic interruption of the LTB -BLT1 axis in mice was carried out to assess its effects on systemic disease features and myofibroblast markers. Immunoblotting was performed to examine the signaling pathway in fibroblasts and endothelial cells following stimulation with LTB or with serum from SSc patients.

Results: Serum LTB levels were 44.93% higher in patients with SSc than in matched healthy controls (mean ± SD 220.3 ± 74.75 pg/ml versus 152.0 ± 68.05 pg/ml; P < 0.0001), and this was associated with the patient subsets of SSc-associated interstitial lung disease and diffuse cutaneous SSc. Levels of LTA H and BLT1 were increased in lesional areas of the skin and lungs of SSc patients, and both were abundant in myofibroblasts and endothelial cells. Interruption of the LTB -BLT1 axis in mouse models of SSc significantly mitigated dermal and pulmonary fibrosis, with 54.00% and 52.65% fewer α-smooth muscle actin-positive myofibroblasts accumulating in the skin and lungs of mice, respectively, after bleomycin challenge. Immunoblotting of cultures with recombinant LTB -stimulated fibroblasts and endothelial cells or with serum from SSc patients showed that fibroblast-myofibroblast and endothelial-mesenchymal transitions were promoted via BLT1, and that this was dependent on activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway but independent of the release of transforming growth factor β (TGFβ) by fibroblasts or endothelial cells.

Conclusion: The LTB -BLT1 axis may contribute to fibrosis in SSc by directly promoting myofibroblast differentiation via the PI3K/Akt/mTOR pathway, and this appears to operate independently of autocrine secretion of TGFβ.
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http://dx.doi.org/10.1002/art.41192DOI Listing
June 2020

Letter by Zhu and Ding Regarding Article, "Carotid Plaque Neovascularization Detected With Superb Microvascular Imaging Ultrasound Without Using Contrast Media".

Stroke 2020 01 9;51(1):e11. Epub 2019 Dec 9.

Department of Cardiology, The Second Affiliated Hospital of Anhui Medical University, P.R. China.

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http://dx.doi.org/10.1161/STROKEAHA.119.027872DOI Listing
January 2020

Characterization and Hemostatic Potential of Two Kaolins from Southern China.

Molecules 2019 Aug 30;24(17). Epub 2019 Aug 30.

Academy of Military Medical Sciences, Beijing 100850, China.

The physicochemical properties and potential hemostatic application of Wenchang kaolin and Maoming kaolin were inspected and evaluated. Chemical composition analysis, Fourier transform infrared (FTIR) spectroscopy, surface area determination, X-ray diffraction, particle size, scanning electron microscopy (SEM) observations, and zeta potential analysis were performed to quantify the physical and chemical properties of the two kaolins. The results showed that both kaolins have typical FTIR bands of kaolinite with a weight fraction for kaolinite over 90 wt%. Larger conglobate aggregates of Maoming kaolin demonstrated wider particle size distributions with two peaks at 3.17 and 35.57 μm, while the book-like Wenchang kaolin had narrow particle size distribution, with a frequent size of 5.64 μm. Furthermore, thrombelastography, the whole blood clotting tests (WBCT), plasma recalcification time (PRT) measurement, and MTT assay were performed to measure the clotting activities and biocompatibility of the two kaolins. The results showed that both kaolins could promote blood coagulation with good cytocompatibility, while Wenchang kaolin had a better procoagulant activity than Maoming kaolin. These findings demonstrated Wenchang kaolin to be a more suitable local source material for application as a hemostatic agent.
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http://dx.doi.org/10.3390/molecules24173160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749497PMC
August 2019

Letter by Zhu et al Regarding Article, "Atrial Fibrillation Known Before or Detected After Stroke Share Similar Risk of Ischemic Stroke Recurrence and Death".

Stroke 2019 09 25;50(9):e263. Epub 2019 Jul 25.

Department of Cardiology, The Second Affiliated Hospital of Anhui Medical University, Hefei, P.R. China.

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http://dx.doi.org/10.1161/STROKEAHA.119.026368DOI Listing
September 2019

Design of immunogens: The effect of bifunctional chelator on immunological response to chelated copper.

J Pharm Biomed Anal 2019 Sep 3;174:263-269. Epub 2019 Jun 3.

Department of Infectious Disease, Division 2nd, the Third People's Hospital of Nantong, Jiangsu, 226006, China. Electronic address:

To produce specific antibodies for the detection and quantification of copper ions, bifunctional chelators (BFCs) are commonly applied in the preparation of copper conjugates. However, some copper-chelator complexes exhibit limited stability under in vivo conditions. In this study, Cu was coupled with carrier proteins via three different macrocyclic BFCs: p-SCN-Bn-DOTA, p-SCN-Bn-NOTA, and p-SCN-Bn-TETA. The stability in plasma and the immunogenicity of three copper immunoconjugates were compared. The chelators other than p-SCN-Bn-DOTA were very stable in plasma, with <9% dissociation of Cu over 96 h. The immune response varied depending on the choice of chelator; notably, antisera from the Cu-NOTA-KLH conjugate demonstrated the best reactivity toward chelated Cu. p-SCN-Bn-NOTA, which showed significant advantages over the other chelators, was used for antibody production. The efficiency of immune-positive hybridoma production was satisfactory, and the resultant monoclonal antibodies (McAbs) 4B7 showed sensitivity (half-maximal inhibitory concentration (IC) of 8.9 ng/mL) to chelated Cu, with a working range from 1.21 to 48.9 ng/mL. The recovery of Cu from water samples was 85.7-108%, and the intra- and inter-assay coefficients of variation were 4.0-10.1% and 7.1-11.4%, respectively. Compared with previously reported McAb specific to Cu, DF4, the sensitivity of the newly developed assay was improved 100-fold. The results of this study indicate the utility of NOTA for the efficient generation of highly sensitive McAbs against Cu.
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http://dx.doi.org/10.1016/j.jpba.2019.06.001DOI Listing
September 2019

Cochlear pharmacokinetics - Micro-computed tomography and learning-prediction modeling for transport parameter determination.

Hear Res 2019 09 1;380:46-59. Epub 2019 Jun 1.

Department of Electrical and Microelectronic Engineering, Rochester Institute of Technology, Rochester, NY, USA; Microsystems Engineering, Rochester Institute of Technology, Rochester, NY, USA. Electronic address:

Inner ear disorders such as sensorineural deafness and genetic diseases may one day be treated with local drug delivery to the inner ear. Current pharmacokinetic models have been based on invasive methods to measure drug concentrations, limiting them in spatial resolution, and restricting the research to larger rodents. We developed an intracochlear pharmacokinetic model based on an imaging, learning-prediction (LP) paradigm for learning transport parameters in the murine cochlea. This was achieved using noninvasive micro-computed tomography imaging of the cochlea during in vivo infusion of a contrast agent at the basal end of scala tympani through a cochleostomy. Each scan was registered in 3-D to a cochlear atlas to segment the cochlear regions with high accuracy, enabling concentrations to be extracted along the length of each scala. These spatio-temporal concentration profiles were used to learn a concentration dependent diffusion coefficient, and transport parameters between the major scalae and to clearance. The LP model results are comparable to the current state of the art model, and can simulate concentrations for cases involving different infusion molecules and different drug delivery protocols. Forward simulation results with pulsatile delivery suggest the pharmacokinetic model can be used to optimize drug delivery protocols to reduce total drug delivered and the potential for toxic side effects. While developed in the challenging murine cochlea, the processes are scalable to larger animals and different drug infusion paradigms.
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http://dx.doi.org/10.1016/j.heares.2019.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669082PMC
September 2019