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ObjectiveTo explore the material basis and molecular mechanism of Linggui Qihua prescription （LGQH） against myocardial fibrosis in heart failure with preserved ejection fraction （HFpEF）. MethodLiquid chromatography-mass spectrometry （LC-MS） was used to qualitatively analyze the active components of LGQH. AutoDock software was employed for molecular docking between the active components of LGQH and target proteins including α-smooth muscle actin （α-SMA）， type Ⅰ collagen （ColⅠ）， type Ⅲ collagen （ColⅢ）， matrix metalloproteinase-9 （MMP-9）， and tissue inhibitor of metalloproteinase-1 （TIMP-1）. In vivo experiments were conducted on 40 spontaneously hypertensive rats （SHRs） aged 4 weeks， which were divided into an HFpEF group， an Entresto group （0.018 g·kg-1）， and low- and high-dose LGQH groups （3.87， 7.74 g·kg-1）. A high-fat， high-salt， and high-sugar diet was administered for 16 weeks along with intraperitoneal injection of streptozotocin solution for 8 weeks to establish an HFpEF model in rats. The blank group consisted of 10 Wistar Kyoto （WKY） rats and 10 SHRs. After successful modeling， the WKY， SHR， and HFpEF groups were given equal volumes of normal saline， while the other three groups received predetermined interventions. Daily oral gavage was performed for 6 weeks. After intervention， echocardiography was conducted to measure left ventricular （LV） anterior wall thickness （LVAWd）， LV posterior wall thickness （LVPWd）， LV internal diameter at end-diastole （LVIDd）， LV ejection fraction （LVEF）， isovolumic relaxation time （IVRT）， early diastolic peak velocity of mitral valve inflow （E）， and early diastolic mitral annular velocity （e'）. The E/e' ratio was calculated. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum atrial natriuretic peptide （ANP）， B-type natriuretic peptide （BNP）， and galectin-3 （Gal-3）. Myocardial fibrosis was observed through Masson staining of pathological sections， and collagen volume fraction （CVF） and perivascular fibrosis ratio （PFR） were calculated. Real-time polymerase chain reaction （PCR） and Western blot were employed to detect LV myocardial mRNA and protein expression of α-SMA， ColⅠ， ColⅢ， MMP-9， and TIMP-1. ResultLC-MS identified 13 active components in LGQH. Molecular docking indicated stable binding of the 13 compounds with five target proteins. In vivo experiments showed that compared with the blank group， the HFpEF group had significantly increased LVAWd， LVPWd， LVIDd， IVRT， E/e'， ANP， BNP， Gal-3， CVF， and PFR. LV myocardial α-SMA， ColⅠ， and ColⅢ mRNA and protein expression was significantly upregulated， while MMP-9/TIMP-1 mRNA and protein ratios were significantly downregulated （P<0.05， P<0.01）. Compared with the HFpEF group， LGQH might dose-dependently reduce LVAWd， LVPWd， LVIDd， IVRT， E/e'， ANP， BNP， Gal-3， CVF， and PFR， downregulated myocardial α-SMA， ColⅠ， ColⅢ mRNA expression， α-SMA， and ColⅠ protein expression， and upregulated MMP-9/TIMP-1 mRNA and protein expression （P<0.05， P<0.01）. ConclusionLGQH contains multiple active components and may inhibit myocardial fibrosis in HFpEF rats. It may further alleviate LV hypertrophy， dilation， and diastolic dysfunction， making it an effective Chinese medicinal prescription for treating HFpEF.
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The neural stimulator is a core component of animal robots. While the control effect of animal robots is influenced by various factors, the performance of the neural stimulator plays a decisive role in regulating animal robots. In order to optimize animal robots, embedded neural stimulators had been developed using flexible printed circuit board technology. This innovation not only enabled the stimulator to generate parameter-adjustable biphasic current pulses through control signals, but also optimized its carrying mode, material, and size, overcoming the disadvantages of traditional backpack or head-inserted stimulators, which have poor concealment and are prone to infection. Static, in vitro, and in vivo performance tests of the stimulator demonstrated that it not only had precise pulse waveform output capability, but also was lightweight and small in size. It had excellent in vivo performance in both laboratory and outdoor environments. Our study has high practical significance for the application of animal robots.
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Animals , RoboticsABSTRACT
Objective:To investigate the mechanism of Mycobacterium tuberculosis ( Mtb) WhiB2 in the pathogenesis of tuberculosis. Methods:A recombinant vector of pET28a-WhiB2 for heterogeneous expression of WhiB2 was constructed. The target protein WhiB2 and the inclusion bodies were purified. The differences between denatured and non-denatured WhiB2 were analyzed by circular dichroism and nuclear magnetic resonance. Ferrous ion (Fe 2+ ) was used to restore the iron-sulfur cluster of WhiB2. The interaction between WhiB2 and the upstream promoter sequence of the WhiBMtb gene was analyzed by nuclear magnetic resonance. The tertiary structure of WhiB2 and interacting proteins were analyzed and protein structure alignment was performed based on bioinformatics. Results:The structure of the renatured WhiB2 was basically the same as that of the non-denatuous WhiB2. In addition, Fe 2+ could restore the iron-sulfur cluster of WhiB2. It was found that WhiB2 could bind to the upstream promoter sequence of the WhiBMtb/WhiB2Ms gene. Conclusions:Mtb WhiB2 played a key role in the pathogenesis of tuberculosis, which would contribute to future exploration of novel targets against Mtb.
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In recent years, molecular targeted therapy has effectively improved the prognosis of advanced non-small cell lung cancer (NSCLC) patients with driver gene-positive, of which the efficacy is particularly significant for NSCLC patients with human epidermal growth factor receptor gene mutation, echinoderm microtubule-associated protein-4-anaplastic lymphoma kinase fusion gene, ROS1 gene rearrangement, etc. The selection of targeted therapy drugs is particularly important for advanced NSCLC patients with positive driver genes.
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Rivaroxaban is one of the new oral anticoagulants (NOAC) for preventing stroke and systemic embolism in patients with non-valvular atrial fibrillation. It has clear pharmacokinetic parameters, stable plasma concentration, less drug-drug interaction and higher compliance of patients. However, the discrepancy of pharmacokinetics between individuals and drug-induced hemorrhage events frequently occur clinically, therefore the association of gene polymorphism with drug metabolism has become a research hotspot. This article reviews the research progress on pharmacokinetic characteristics of rivaroxaban and its relationship with gene polymorphism, to provide a reference for the individualized rational use of rivaroxaban.
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Objective:To verify the accuracy of the International Warfarin Pharmacogenetics Consortium(IWPC)model, identify the effects of genetic and clinical factors on steady-state doses of Warfarin, and establish a Warfarin dose prediction model for the Han-Chinese population aged 75 years and over under the guidance of pharmacogenetics.Methods:A total of 544 Han-Chinese patients receiving Warfarin therapy for atrial fibrillation were divided into two groups: those aged 75 years and over(n=164)and those aged below 75 years(n=380). Data for the whole population and the two age groups were each substituted into the IWPC prediction model for accuracy verification.Demographic and clinical characteristics of 164 patients aged 75 years and over were recorded, and the genotypes of CYP2 C9 and VKORC1- G1639 A were detected by polymerase chain reaction.A new pharmacogenetic-guided dosing algorithm for the elderly was obtained by stepwise multiple linear regression.The accuracy of the new model was compared with that of the IWPC model. Results:The predictive accuracy of IWPC for steady-state dosing of warfarin was 35.47% in all subjects, 33.75% in 164 subjects aged below 75 years, and only 28.70% in subjects aged 75 years and over, respectively.In 164 subjects aged 75 years and over, three genotypes of *1/*1, *1/*3 and *1/*2 were detected in CYP2 C9 polymorphism, and the CYP2 C9*1/*1 genotype was the most common one, with a frequency of 87.80%(144/164), followed by the CYP2 C9*1/*3 genotype, at 11.59%(19/164). GG, GA and AA genotypes were detected in VKORC1 polymorphism, among which the AA genotype accounted for 82.32%(135/164)and the GG genotype accounted for only 1.83%(3/164). The steady state dose for Warfarin in patients with the wild-type CYP2 C9*1/*1 was higher than in those with the heterozygote CYP2 C9*1/*3 and *1/*2(3.18±0.86 mg/d vs.2.27±0.51 mg/d, t=5.637, P<0.05). Patients with a mutant homozygotic AA genotype of VKORC1 required lower maintenance doses than those with the heterozygotic GA and GG genotypes(2.96±0.66 mg/d vs. 3.59±1.43 mg/d, t=-2.092, P<0.05). The steady-state dose for Warfarin in subjects carrying CYP2 C9 (*1/*2 or *3)and VKORC1 (GA and GG)was(2.00±0.63)mg/d, lower than in those carrying other genotype combinations( P<0.05). We established a new Warfarin dosing algorithm for elderly subjects aged 75 years and over containing height, creatinine, amiodarone usage, CYP2 C9 and VKORC1 mutants, and the accuracy of the new model was 56.0%, which could explain 56.0% of individual variability, and the accuracy was higher than that of the IWPC algorithm(56.0% vs. 45.8%, P<0.05). Conclusions:Polymorphisms of CYP2 C9 and VKORC1 clearly affect the steady-state dose for Warfarin in the elderly Han-Chinese population aged 75 years and over.A combination of pharmacogenomics with clinical factors can better guide warfarin medication in Han-Chinese people aged 75 years and over.
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Objective:To study the correlation between the Rivaroxaban concentration and bleeding events in patients with nonvalvular atrial fibrillation(NVAF).Methods:This was a retrospective study.According to the inclusion and exclusion criteria, 369 patients with NVAF taking Rivaroxaban admitted to Beijing Hospital or Tianjin Medical University General Hospital from January 2018 to June 2019 were enrolled.Clinical data including sex, height, weight, liver and kidney function, drug valley concentrations and peak concentrations, doses, CHADS2 scores and bleeding events after 6 months of medication were recorded.Results:The average drug valley concentration was (44.92±38.39) mg/L, the average drug peak concentration was (226.96±139.34) mg/L, and the average CHADS2 score was (2.8±1.2). Among the 369 patients, 22 had bleeding events.The peak drug concentration and valley drug concentration were similar between those with or without bleeding events( P=0.324 and 0.960, respectively). With the increase of age, the peak drug concentration and valley drug concentration were significantly elevated(all P<0.001). In addition, compared with those without bleeding events, patients with bleeding events had a significantly higher average valley concentration( P=0.009), valley/dose ratio( P=0.001), peak/dose ratio( P=0.028)and similar peak drug concentration( P=0.360). Conclusions:Age affects the peak and valley drug concentration of Rivaroxaban, especially for the elderly, who should be given appropriately reduced doses.Monitoring the peak and valley drug concentration is of great significance for patients at high-risk for bleeding.
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Objectives:To investigate the relationships between CYP2C9 and VKORC1 polymorphism and the steady-state dose of warfarin in Chinese Han patients with nonvalvular atrial fibrillation.Methods:A total 544 Chinese Han patients with atrial fibrillation who received warfarin anticoagulant therapy in Department of Cardiology of Beijing Hospital, Tongren Hospital, Xuanwu Hospital, Anzhen Hospital and Tiantan Hospital were enrolled from January 2016 to may 2019. The genotype and allele frequency in exon 1, 2, 3, 7 of CYP2C9 gene and 1639 site of VKORC1 gene were analyzed; and the general information, warfarin steady-state dose and concomitant medication of patients were recorded.Results:There were four genotypes CYP2C9:CYP2C9*1*1 (93.57%, 509/544), CYP2C9*1 *2 (0.18%, 1/544), CYP2C9*1 *3 (5.88%, 32/544) and CYP2C9*1 *60 (0.37%, 2/544); while VKORC1 had three genotypes: AA (82.72%, 450/544), GA (15.99%, 87/544) and GG (1.29%, 7/544). After reaching the anticoagulation index (INR 2.0-3.0), the steady-state dose of warfarin was the highest in patients with CYP2C9 *1/*1 and VKORC1 GA/GG genotypes, reaching (3.70±1.34) mg/d. The lowest steady-state dose of warfarin was (2.17±0.29)mg/d in patients with both new mutations ( F=22.09, P<0.001). Multiple linear regression analysis showed that body surface area, use of amiodarone, CYP2C9 and VKORC1 genotypes were the independent influencing factors of warfarin steady-state dose ( t=4.44, -2.90, -6.96, 2.14; P<0.05) and the steady-state dose prediction model of warfarin was established. Conclusion:Body weight, height, body surface area, gender, smoking, and combination of amiodarone may significantly affect the steady-state dose of warfarin in patients. CYP2C9 and VKORC1 mutant genotypes were significantly related to the steady-state dose of warfarin. The prediction model based on genetic factors and other influencing factors may effectively predict the steady-state dose of warfarin in Han patients with atrial fibrillation.
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Objective: To review the advances in diagnosis and treatment of acute scaphoid fractures. Methods: The characteristic, classification, diagnosis, and treatment of acute scaphoid fractures were reviewed and summarized. Results: As one of the common fracture in hand, scaphoid fractures are generally classified as either undisplaced and stable or displaced and unstable. CT and MRI has best diagnostic specificity and sensitivity respectively. Most undisplaced and stable fractures can be treated successfully by plaster immobilization, whereas the displaced and unstable fractures have great prognosis after open reduction and internal fixation. Conclusion: Acute scaphoid fractures should be diagnosed and treated at an early stage, and choose the appropriate treatment according to the location and stability of the fracture.
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Objective To analyze the clinical characteristics of hospital-acquired pneumonia in bedridden patients aged 90 years and over.Methods From January 1,2015 to August 1,2015,40 bedridden elderly patients(≥90 years)with hospital-acquired pneumonia admitted to Beijing Hospital were assigned into the observation group,with 40 non-bedridden elderly patients (≥ 90 years)with community acquired pneumonia serving as the control group.Basic clinical data,infection symptoms and inflammation markers,and changes in serological test results before and after pneumonia were compared between the groups.Results Compared with the control group,the observation group had much lower body mass index(20.7± 1.2)kg/m2 vs.(25.1 ± 3.1) kg/m2 (t=-8.43,P＜0.01),and was accompanied with more diseases and associated with more symptoms during infection (all P＜ 0.05).Meanwhile,patients with lung infections in the observation group were more likely to have atrial fibrillation,often with increased levels of brain natriuretic peptide(1 047.9 ± 193.5) pg/L vs.(3 387.8± 763.8) μg/L (t =-3.39,P＜0.01) and abnormalities in troponin,but without obvious elevations of inflammatory markers such as white blood cells,C reactive protein and procaleitonin.Conclusions Bedridden patients aged 90 years and over with hospital-acquired pneumonia may show atypical clinical presentations and increased accompanying symptoms.Comprehensive geriatric assessment is critical for good prognosis.
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Objective To investigate the clinical efficacy of warming and unblocking acupuncture in treating scapulocostal syndrome.Method Eighty patients with scapulocostal syndrome meeting the inclusion criteria were allocated by simple randomization to warming and unblocking acupuncture and conventional acupuncturegroups, 40 cases each.The warming and unblocking acupuncture group received warming and unblocking acupuncture at points Tianzong(SI11), Jianjing(GB21)and Dazhui(GV14)on the affected side and affected chest Huatuo jiaji(Ex-B2)points and uniform reinforcing-reducing acupuncture at points Quchi(LI11), Hegu(LI4)and Waiguan(TE5).The conventional acupuncture group received uniform reinforcing-reducing acupuncture at the same points as those in the warming and unblocking acupuncture group after arrival of qi.Both groupswere treated once every other day, 10 days as a course, for a total of one course.Pain severity was assessed using the Pain Visual Analogue Scale(VAS) in the two groups of patients before and after treatment.Theclinical therapeutic effects were evaluated by follow-up at one month after the completion of treatment.Result The total efficacy rate was 95.0% (38/40) in the warming andunblocking acupuncture group and 80.0% (32/40) in the conventional acupuncture group; there was a statistically significant difference (P<0.05).The PainVisual Analogue Scale(VAS) score was significantly lower in the two groups of patients after treatment than before treatment; there was a statistically significant difference (P<0.05).The VAS score was decreased more in the warming and unblocking acupuncture group after treatment and at the follow-up one month after the completion of treatment (P<0.05).Conclusion Warming and unblocking acupuncture has clinically a better therapeutic effect onscapulocostal syndrome.
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Objective:To observe the analgesic effect of acupuncture and to explore its central analgesic mechanism in rheumatoid arthritis rabbits.Methods:A total of 60 flap-eared white rabbits were randomly assigned into a normal control group (n=6),a model group (n=6),a body-acupuncture group (n=24),and a buccal acupuncture group (n=24).The later 2 groups were further randomly assigned into 0,0.5,1,and 2 h subgroups,with 6 cases in each group.The rheumatoid arthritis model was established by induction of eggalbumin.In the body acupuncture group,bilateral Xiyan and Zusanli were punctured for 15 s while in the buccal acupuncture group,acupuncture was applied to Xi for 15 s,with the needle retaining for 30 min.The pain threshold was detected with PL-200,taking struggle movements of rabbits as a measurement index,response latency from irradiation to struggling movements as the rabbit's pain threshold.The contents of β-endorplhin (β-EP) and cholecystokinin-8 (CCK-8) in cerebrospinal fluid were examined by radioimmunoassay.Results:Compared with the control group,pain threshold and CCK-8 levels decreased significantly (P＜0.01) and the concentration of β-EP significantly increased (P＜0.05) in the model group.The pain threshold in the body-acupuncture group and the buccal acupuncture group at 0 and 1 h (P＜0.05 or P＜0.01) increased significantly,while the β-EP and CCK-8 contents in the bodyacupuncture group and the buccal acupuncture group were significantly higher than those in the model group (P＜0.01 or P＜0.05).Both β-EP and CCK-8 contents in the buccal acupuncture group at 0 h were significantly higher than those in the body-acupuncture group (P＜0.05).Conclusion:The analgesic effect of buccal acupuncture is superior to that of body-acupuncture.Both buccal acupuncture and body-acupuncture can effectively raise the pain threshold in acute arthritis rabbits,which is closely associated with their effects in the up-regulation of β-EP and CCK-8 contents in cerebrospinal fluid.
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Four cases of pituitary acromegalic cardiomyopathy were reported and relative literature was reviewed in this article.Four patients were all males aged 45-63 y.The patients were diagnosed as pituitary adenoma,then NYHA grade Ⅲ-Ⅳ heart failure developed.One patient had both acromegaly and coronary heart disease,and all patients had arrhythmia attacks.The growth hormone levels were not under control in 3 patients,and for the remaining patient with normalized growth hormone the end-stage heart failure also developed.The onset of pituitary acromegalic cardiomyopathy is hidden; when the disease progresses to advanced heart failure,the prognosis would be poor in most cases.So early diagnosis and timely treatment is of great importance in acromegalic cardiomyopathy.