OBJECTIVE: To investigate the effects and underlying mechanisms of VX765 on osteoarthritis (OA) and chondrocytes inflammation in rats. METHODS: Chondrocytes were isolated from the knee joints of 4-week-old Sprague Dawley (SD) rats. The third-generation cells were subjected to cell counting kit 8 (CCK-8) analysis to assess the impact of various concentrations (0, 1, 5, 10, 20, 50, 100 μmol/L) of VX765 on rat chondrocyte activity. An in vitro lipopolysaccharide (LPS) induced cell inflammation model was employed, dividing cells into control group, LPS group, VX765 concentration 1 group and VX765 concentration 2 group without obvious cytotoxicity. Western blot, real-time fluorescence quantitative PCR, and ELISA were conducted to measure the expression levels of inflammatory factors-transforming growth factor β ₁ (TGF-β ₁), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α). Additionally, Western blot and immunofluorescence staining were employed to assess the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Thirty-two SD rats were randomly assigned to sham surgery group (group A), OA group (group B), OA+VX765 (50 mg/kg) group (group C), and OA+VX765 (100 mg/kg) group (group D), with 8 rats in each group. Group A underwent a sham operation with a medial incision, while groups B to D underwent additional transverse incisions to the medial collateral ligament and anterior cruciate ligament, with removal of the medial meniscus. One week post-surgery, groups C and D were orally administered 50 mg/kg and 100 mg/kg VX765, respectively, while groups A and B received an equivalent volume of saline. Histopathological examination using HE and safranin-fast green staining was performed, and Mankin scoring was utilized for evaluation. Immunohistochemical staining technique was employed to analyze the expressions of matrix metalloproteinase 13 (MMP-13) and collagen type Ⅱ. RESULTS: The CCK-8 assay indicated a significant decrease in cell viability at VX765 concentrations exceeding 10 μmol/L ( P<0.05), so 4 μmol/L and 8 μmol/L VX765 without obvious cytotoxicity were selected for subsequent experiments. Following LPS induction, the expressions of TGF-β ₁, IL-6, and TNF-α in cells significantly increased when compared with the control group ( P<0.05). However, intervention with 4 μmol/L and 8 μmol/L VX765 led to a significant decrease in expression compared to the LPS group ( P<0.05). Western blot and immunofluorescence staining demonstrated a significant upregulation of Nrf2 pathway-related molecules Nrf2 and HO-1 protein expressions by VX765 ( P<0.05), indicating Nrf2 pathway activation. Histopathological examination of rat knee joint tissues and immunohistochemical staining revealed that, compared to group B, treatment with VX765 in groups C and D improved joint structural damage in rat OA, alleviated inflammatory reactions, downregulated MMP-13 expression, and increased collagen type Ⅱ expression. CONCLUSION VX765 can improve rat OA and reduce chondrocyte inflammation, possibly through the activation of the Nrf2 pathway.
Rats ; Animals ; Chondrocytes/metabolism* ; Matrix Metalloproteinase 13/metabolism* ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism* ; Collagen Type II/metabolism* ; Interleukin-6 ; Lipopolysaccharides/pharmacology* ; NF-E2-Related Factor 2/pharmacology* ; Inflammation/drug therapy* ; Osteoarthritis/metabolism* ; Transforming Growth Factor beta1/metabolism* ; Dipeptides ; para-Aminobenzoates

OBJECTIVE: To explore the effectiveness and feasibility of dexamethasone combined with oxybuprocaine hydrochloride gel on the prevention of postoperative sore throat after nasal endoscopy. METHODS: In the study, 60 patients with American Society of Anesthesiologist (ASA) physical statuses Ⅰ to Ⅱ, aged 18 to 72 years, scheduled for elective nasal endoscope surgery under general anesthesia requiring endotracheal intubation were randomly divided into dexamethasone combined with oxybuprocaine hydrochloride gel group (G group, n=30) and control group (C group, n=30). The patients in the G group received dexamethasone 0.1 mg/kg before induction and the oxybuprocaine gel was applied to the endotracheal catheter cuff and the front end within 15 cm. The patients in the C group received the same dose of saline and the saline was applied to the endotracheal catheter cuff and the front end within 15 cm. Then, all the patients in the two groups received the same induction and anesthesia maintainance. The operation time, anesthesia time, emergence time, extubation time and departure time were recorded. The intraoperative infusion volume, blood loss volume, propofol, remifentanil, rocuronium dosage were also recorded. The adverse reactions such as intraoperative hypotension, bradycardia and postoperative agitation were recorded. The postoperative sore throat score was recorded at the end of operation and 4 h, 8 h, 12 h, and 24 h after operation. RESULTS: Compared with the C group, the emergence time [(8.4±3.9) min vs. (10.8±4.7) min], extubation time [(8.8±3.7) min vs. (11.9±4.8) min], and departure time [(20.0±5.3) min vs. (23.0±5.8) min] were significantly shorter, and the propofol dosage [(11.8±1.8) mg/kg vs. (15.9±4.6) mg/kg], remifentanil dosage [(10.9±4.7) μg/kg vs. (14.1±3.6) μg/kg] were significantly less in the G group, and there was no difference of rocuronium dosage in the two groups. Compared with the C group the incidence of intraoperative hypotension [10%(3/30) vs. 30%(9/30)], bradycardia [16.7%(5/30) vs. 20%(6/30)] and postoperative agitation [6.7%(2/30) vs. 23.3%(7/30)] were significantly lower in the C group. The postoperative sore throat score at the end of operation, 4 h, 8 h, 12 h and 24 h after operation in the G group were significantly lower than in the C group respectively [0 (0, 1) vs. 1 (1, 2), 0 (0, 0) vs. 1 (1, 2), 0 (0, 0) vs. 1 (1, 2), 0 (0, 0) vs. 1 (0.75, 1), 0 (0, 0) vs. 1 (0, 1)]. CONCLUSION Dexamethasone combined with oxybuprocaine hydrochloride gel was effective and feasible on the prevention of postoperative sore throat after nasal endoscopy.
Adolescent ; Adult ; Aged ; Bradycardia/drug therapy* ; Dexamethasone/therapeutic use* ; Endoscopy/adverse effects* ; Humans ; Hypotension/drug therapy* ; Intubation, Intratracheal/adverse effects* ; Middle Aged ; Pain/drug therapy* ; Pharyngitis/prevention & control* ; Postoperative Complications/prevention & control* ; Procaine/analogs & derivatives* ; Propofol ; Remifentanil ; Rocuronium ; Young Adult

Objective To study the changes of metabolites in serum and tissues （kidney, liver and heart） of mice died of acute tetracaine poisoning by metabolomics, to search for potential biomarkers and related metabolic pathways, and to provide new ideas for the identification of cause of death and research on toxicological mechanism of acute tetracaine poisoning. Methods Forty ICR mice were randomly divided into control group and acute tetracaine poisoning death group. The model of death from acute poisoning was established by intraperitoneal injection of tetracaine, and the metabolic profile of serum and tissues of mice was obtained by ultra-high performance liquid chromatography-electrostatic field orbitrap high resolution mass spectrometry （UPLC-Orbitrap HRMS）. Multivariate statistical principal component analysis （PCA） and orthogonal partial least square-discriminant analysis （OPLS-DA） were used, combined with t-test and fold change to identify the differential metabolites associated with death from acute tetracaine poisoning. Results Compared with the control group, the metabolic profiles of serum and tissues in the mice from acute tetracaine poisoning death group were significantly different. Eleven differential metabolites were identified in serum, including xanthine, spermine, 3-hydroxybutylamine, etc.; twenty-five differential metabolites were identified in liver, including adenylate, adenosine, citric acid, etc.; twelve differential metabolites were identified in heart, including hypoxanthine, guanine, guanosine, etc; four differential metabolites were identified in kidney, including taurochenodeoxycholic acid, 11, 12-epoxyeicosatrienoic acid, dimethylethanolamine and indole. Acute tetracaine poisoning mainly affected purine metabolism, tricarboxylic acid cycle, as well as metabolism of alanine, aspartic acid and glutamic acid. Conclusion The differential metabolites in serum and tissues of mice died of acute tetracaine poisoning are expected to be candidate biomarkers for this cause of death. The results can provide research basis for the mechanism and identification of acute tetracaine poisoning.
Animals ; Biomarkers/metabolism* ; Chromatography, High Pressure Liquid ; Mass Spectrometry ; Metabolome ; Metabolomics ; Mice ; Mice, Inbred ICR ; Tetracaine

Para-aminobenzoate (PABA) is an important chemical for organic synthesis and extensively used in pharmaceutical and dye industry. In recent years, PABA has received increasing attention as a potential component of high-strength polymer. In Escherichia coli, three genes of pabA, pabB and pabC are responsible for PABA production from chorismate in folate synthetic pathway. However, E. coli does not accumulate or accumulates very few amounts of PABA under normal growth condition. In this study, the tyrosine-producing E. coli TYR002 constructed previously was used as the starting strain for developing PABA-producing strain. First, the activity of bifunctional chorismate mutase/prephenate dehydrogenase TyrA in E. coli TYR002 was weakened to reduce the production of tyrosine. Then, three different constitutive promoters were used to regulate the expression of pabA, pabB and pabC in recombinant plasmid which was transformed into E. coli for improving PABA production. The shake-flask fermentation showed that the different combination of constitutive promoters significantly affected the production of PABA, and the highest shake-flask fermentation titer was 0.67 g/L. After further condition optimization, the engineered E. coli produced 6.4 g/L PABA under 5 L fed-batch fermentation. This study could be a good reference for improving microbial production of PABA.
4-Aminobenzoic Acid ; Escherichia coli ; Plasmids

PURPOSE: Discontinuation of offending drugs can prevent drug-induced parkinsonism (DIP) before it occurs and reverse or cure it afterwards. The aim of this study was to investigate the prevalence of DIP and the utilization of offending drugs through an analysis of representative nationwide claims data. MATERIALS AND METHODS: We selected DIP patients of ages ranging from 40 to 100 years old with the G21.1 code from the Korean National Service Health Insurance Claims database from 2009 to 2015. The annual standardized prevalence of DIP was explored from 2009 to 2015. Trends were estimated using the compound annual growth rate (CAGR) and the Cochran-Armitage test for DIP over the course of 6 years. Additionally, the utilization of offending drugs was analyzed. RESULTS: The annual prevalence of DIP was 4.09 per 100000 people in 2009 and 7.02 in 2015 (CAGR: 9.42%, p<0.001). Levosulpiride use before and after DIP diagnosis showed a clear trend for decreasing utilization (CAGR: −5.4%, −4.3% respectively), whereas the CAGR for itopride and metoclopramide increased by 12.7% and 6.4%, respectively. In 2015, approximately 46.6% (858/1840 persons) of DIP patients were prescribed offending drugs after DIP diagnosis. The most commonly prescribed causative drug after DIP diagnosis was levosulpiride. CONCLUSION: The prevalence of DIP has increased. To prevent or decrease DIP, we suggest that physicians reduce prescriptions of benzamide derivatives that have been most commonly used, and that attempts be made to find other alternative drugs. Additionally, the need for continuing education about offending drugs should be emphasized.
Diagnosis ; Education, Continuing ; Humans ; Insurance, Health ; Korea ; Metoclopramide ; Parkinson Disease ; Parkinsonian Disorders ; Prescriptions ; Prevalence

No abstract available.
Hemorrhage ; Metoclopramide

BACKGROUND: People with the Ehlers-Danlos Syndromes (EDS), a group of heritable disorders of connective tissue, often report experiencing dental procedure pain despite local anesthetic (LA) use. Clinicians have been uncertain how to interpret this apparent LA resistance, as comparison of EDS and non-EDS patient experience is limited to anecdotal evidence and small case series. The primary goal of this hypothesis-generating study was to investigate the recalled adequacy of pain prevention with LA administered during dental procedures in a large cohort of people with and without EDS. A secondary exploratory aim asked people with EDS to recall comparative LA experiences. METHODS: We administered an online survey through various social media platforms to people with EDS and their friends without EDS, asking about past dental procedures, LA exposures, and the adequacy of procedure pain prevention. Among EDS respondents who both received LA and recalled the specific LA used, we compared agent-specific pain prevention for lidocaine, procaine, bupivacaine, mepivacaine, and articaine. RESULTS: Among the 980 EDS respondents who had undergone a dental procedure LA, 88% (n = 860) recalled inadequate pain prevention. Among 249 non EDS respondents only 33% (n = 83) recalled inadequate pain prevention (P < 0.001 compared to EDS respondents). The agent with the highest EDS-respondent reported success rate was articaine (30%), followed by bupivacaine (25%), and mepivacaine (22%). CONCLUSIONS: EDS survey respondents reported nearly three times the rate of LA non-response compared to non-EDS respondents, suggesting that LAs were less effective in preventing their pain associated with routine office dental procedures.
Anesthesia, Local ; Anesthetics, Local ; Bupivacaine ; Carticaine ; Cohort Studies ; Connective Tissue ; Dental Care ; Ehlers-Danlos Syndrome ; Friends ; Humans ; Lidocaine ; Mepivacaine ; Procaine ; Social Media ; Surveys and Questionnaires

No abstract available.
Disorders of Excessive Somnolence ; Humans ; Metoclopramide ; Parkinsonian Disorders

Hiccup is an intermittent, involuntary and erratic contraction of the diaphragm, immediately followed by a laryngeal closure. Persistent and intractable hiccups are rare but severe, keeping a person from doing daily activities; these can result in depression, fatigue, impaired sleep, dehydration, weight loss, malnutrition, and aspiration. Therefore, proper treatments are necessary. We present a case with intractable hiccup treated with an unusual treatment. A 61-year-old man presented with intractable hiccups, which started 6 years ago after subarachnoid and intraventricular hemorrhage. Conventional pharmacologic treatments including metoclopramide, gabapentin, and baclofen were unsuccessful. Cooperating with cardiothoracic surgeons, phrenic nerve clipping operation was done under intraoperative electrophysiologic monitoring. This method was successful that the symptoms were relieved. Reversible clipping done under intraoperative electrophysiologic monitoring can be a promising therapeutic method for persistent and intractable hiccups in patients with stroke.
Baclofen ; Dehydration ; Depression ; Diaphragm ; Electromyography ; Fatigue ; Hemorrhage ; Hiccup* ; Humans ; Malnutrition ; Methods ; Metoclopramide ; Middle Aged ; Phrenic Nerve* ; Stroke* ; Surgeons ; Weight Loss

Orofacial dyskinesia is a condition caused by various diseases in which the tongue, lips, or jaws move involuntarily. Up to now, the exact mechanism for these degenerative changes in the brain remains unknown. Among various hypotheses, the most widely accepted hypothesis is that orofacial dyskinesia is caused by supersensitivity of the dopamine receptors. As a result, metoclopramide, a dopaminergic receptor blocking agent has been chosen as a treatment agent for our study. We used metoclopramide in seven stroke patients who displayed symptoms of orofacial dyskinesia following brain damage and observed an improvement in the symptoms from all patients. This case report represented new therapeutic methods and will aid in the treatment of orofacial dyskinesia.
Brain ; Dopamine ; Dyskinesias ; Humans ; Jaw ; Lip ; Metoclopramide* ; Movement Disorders* ; Receptors, Dopamine ; Stroke* ; Tongue