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1.
BMC Med Inform Decis Mak ; 21(1): 301, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34724938

RESUMO

BACKGROUND: Early identification of the occurrence of arrhythmia in patients with acute myocardial infarction plays an essential role in clinical decision-making. The present study attempted to use machine learning (ML) methods to build predictive models of arrhythmia after acute myocardial infarction (AMI). METHODS: A total of 2084 patients with acute myocardial infarction were enrolled in this study. (All data is available on Github: https://github.com/wangsuhuai/AMI-database1.git) . The primary outcome is whether tachyarrhythmia occurred during admission containing atrial arrhythmia, ventricular arrhythmia, and supraventricular tachycardia. All data is randomly divided into a training set (80%) and an internal testing set (20%). Apply three machine learning algorithms: decision tree, random forest (RF), and artificial neural network (ANN) to learn the training set to build a model, then use the testing set to evaluate the prediction performance, and compare it with the model built by the Global Registry of Acute Coronary Events (GRACE) risk variable set. RESULTS: Three ML models predict the occurrence of tachyarrhythmias after AMI. After variable selection, the artificial neural network (ANN) model has reached the highest accuracy rate, which is better than the model constructed using the Grace variable set. After applying SHapley Additive exPlanations (SHAP) to make the model interpretable, the most important features are abnormal wall motion, lesion location, bundle branch block, age, and heart rate. Among them, RBBB (odds ratio [OR]: 4.21; 95% confidence interval [CI]: 2.42-7.02), ≥ 2 ventricular walls motion abnormal (OR: 3.26; 95% CI: 2.01-4.36) and right coronary artery occlusion (OR: 3.00; 95% CI: 1.98-4.56) are significant factors related to arrhythmia after AMI. CONCLUSIONS: We used advanced machine learning methods to build prediction models for tachyarrhythmia after AMI for the first time (especially the ANN model that has the best performance). The current study can supplement the current AMI risk score, provide a reliable evaluation method for the clinic, and broaden the new horizons of ML and clinical research. Trial registration Clinical Trial Registry No.: ChiCTR2100041960.


Assuntos
Infarto do Miocárdio , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiologia , Humanos , Aprendizado de Máquina , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
2.
J Immunother Cancer ; 9(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34599025

RESUMO

The use of immune checkpoint inhibitors (ICIs) is rising exponentially in numerous cancers, but immune-related adverse events can occur. We report a rare case of high-grade drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome developed stepwise in a patient with gastric cancer after nivolumab treatment. Subclinical myocarditis was sensitively detected by cardiovascular magnetic resonance 3 weeks after initiating nivolumab. Eruption, eosinophilia, and interstitial pneumonitis occurred 1 week later. Corticosteroids were started and his condition improved. Four months later, when he was still on steroids tapering off, acute kidney injury and sequential herpes zoster virus activation developed. Severe acute tubulointerstitial nephritis (ATN) with an intense infiltration of lymphocytes was observed on renal biopsy. In blood, a substantial shift to Th2 response, an increase of Th17 cells, and strikingly enriched granzyme B+ and perforin+ CD8+ T cells were detected at ATN onset. Serum interleukin (IL)-5, IL-17, interferon gamma, and IL-6 levels were consistently elevated. Further molecular profiling identified a DRESS risk allele human leukocyte antigen (HLA)-A*31:01 in this patient. His ATN responded favorably to a high dose of corticosteroids. In parallel, complete antitumor response was observed during the clinical course of DRESS. This is the first ever case report of nivolumab-associated DRESS syndrome with exploration of the mechanisms from the histopathological, cellular and molecular aspects. Nivolumab-induced DRESS may result from type IV hypersensitivity-related 'off-target effect' and PD-1 block-mediated 'on-target effect'. HLA risk alleles may constitute the genetic susceptible basis. HLA typing assay has the potential to screen susceptible individuals to avoid ICI-induced DRESS.

3.
Nanoscale ; 13(39): 16448-16456, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34522946

RESUMO

Two-dimensional (2D) materials have been demonstrated to be promising candidates to design high performance photodetectors owing to their strong light-matter interaction. However, the performance of 2D material photodetectors is still unsatisfactory, such as slow response speed due to defects and vulnerable contact interface, which impede their rapid development in the field of optoelectronics. In this paper, we obtained the ideal and large photosensitive van der Waals Schottky interface by the laminating-flipping method. Hence, a fast response speed (<1 ms) and high detectivity (>1012 Jones) are observed on the van der Waals Schottky junction photodiode. More importantly, benefiting from the flat Schottky interface (the roughness ∼0.6 nm), a sub-bandgap light response modulated by the Schottky barrier height (cut-off edge at 1050 nm) has been detected based on the large Au/MoSe2 sensitive Schottky interface internal photoemission. As a result, a universal strategy for the sub-bandgap near-infrared van der Waals Schottky junction detector of 2D materials was obtained.

4.
J Clin Pharm Ther ; 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34592785

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Oral anticoagulants (OACs), including warfarin and newer direct-acting OACs (DOACs), have been used for decades to prevent thromboembolic diseases. A drug utilization study was performed to determine the prescribing patterns of OACs. METHODS: Data were extracted from the Cooperation Project of Hospital Prescription Analysis in China. A total of 455,490 prescription records from 43 tertiary hospitals in five cities of China (Beijing, Shanghai, Guangzhou, Hangzhou and Chengdu) were selected for inclusion. Quarterly trends of defined daily doses (DDDs) and defined daily dose cost (DDDC) from 1 January 2015 to 31 December 2019 were calculated. RESULTS AND DISCUSSION: Warfarin was the most widely used OAC with DDDs between 189,982 and 176,323 from the first quarter (Q1) of 2015 to the fourth quarter (Q4) of 2019, whereas the use of DOACs increased rapidly during this period. DDDs of rivaroxaban increased from 5409 in Q1 of 2015 to 125,800 in Q4 of 2019, whereas the DDDC declined from 160.5 to 45.7. From Q1 of 2018, rivaroxaban became the most prescribed OAC, surpassing warfarin, in patients diagnosed with deep vein thrombosis. In addition, the DDDs of rivaroxaban exceeded those of warfarin in patients diagnosed with non-valvular atrial fibrillation since the second quarter (Q2) of 2019. DDDs in outpatients and inpatients increased by 80.6% and 71.4%, respectively, and the DDDC for outpatients in Q4 of 2019 was 6.7-fold higher than that in Q1 of 2015. Among patients of all ages, the DDDs in elderly patients increased from 36.8% in Q1 of 2015 to 59.4% in Q4 of 2019. Moreover, the departments of cardiology and cardiothoracic surgery prescribed the majority of the OACs. WHAT IS NEW AND CONCLUSION: In this study, we describe OAC prescription patterns in China. DOACs, especially rivaroxaban, contribute to the continuous increase in the use of OACs. In the investigated population of China, outpatients and elderly patients were observed to be administered the highest proportion of DOACs.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34532938

RESUMO

There are few reports about purely organic phosphorescence scintillators, and the relationship between molecular structures and radioluminescence in organic scintillators is still unclear. Here, we presented isomerism strategy to study the effect of molecular structures on radioluminescence. The isomers can achieve phosphorescence efficiency of up to 22.8 % by ultraviolet irradiation. Under X-ray irradiation, both m-BA and p-BA show excellent radioluminescence, while o-BA has almost no radioluminescence. Through experimental and theoretical investigation, we found that radioluminescence was not only affected by non-radiation in emissive process, but also highly depended on the material conductivity caused by the different molecular packing. This study not only allows us to clearly understand the relationship between the molecular structures and radioluminescence, but also provides a guidance to rationally design new organic scintillators.

6.
Nat Mater ; 20(11): 1539-1544, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34426660

RESUMO

High-efficiency blue phosphorescence emission is essential for organic optoelectronic applications. However, synthesizing heavy-atom-free organic systems having high triplet energy levels and suppressed non-radiative transitions-key requirements for efficient blue phosphorescence-has proved difficult. Here we demonstrate a simple chemical strategy for achieving high-performance blue phosphors, based on confining isolated chromophores in ionic crystals. Formation of high-density ionic bonds between the cations of ionic crystals and the carboxylic acid groups of the chromophores leads to a segregated molecular arrangement with negligible inter-chromophore interactions. We show that tunable phosphorescence from blue to deep blue with a maximum phosphorescence efficiency of 96.5% can be achieved by varying the charged chromophores and their counterions. Moreover, these phosphorescent materials enable rapid, high-throughput data encryption, fingerprint identification and afterglow display. This work will facilitate the design of high-efficiency blue organic phosphors and extend the domain of organic phosphorescence to new applications.

7.
Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi ; 35(6): 501-504;510, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34304507

RESUMO

Objective:To investigate the relevant influencing factors for perioperative airway events of infantile subglottic hemangioma, and to further discuss the strategies of perioperative airway management. Methods:A total of 36 infants with subglottic hemangioma that had no response to the drug therapy and underwent surgical treatment from July 2007 to April 2017 were enrolled. The relevant influencing factors, including gender, age, birth weight, age of onset, degree of tracheal stenosis and histories of underlying diseases(congenital heart disease and respiratory disease), were also recorded simultaneously. Intraoperative SpO2 decline, intraoperative emergency tracheal intubation, intraoperative emergency tracheotomy, whether preserving tracheal intubation after operation or not, and postoperative emergency tracheal intubation were included in the perioperative airway events of infantile subglottic hemangioma. The relevant influencing factors of perioperative airway events were analyzed so that meaningful statistical indicators were selected for grouped logistic regression analysis, and the correlation was evaluated based on OR value and 95% confidence interval(CI). Based on the correlation between influencing factors and airway events, perioperative airway management was discussed. Results:①The degree of tracheal stenosis was a risk factor for SpO2 decline(95%CI[2.121-33.818]); ②The degree of airway stenosis, history of comorbid cardiovascular disease and respiratory disease were the influencing factors for intraoperative emergency tracheal intubation(95%CI[0.863-21.692], [0-+∞] and [1.741-232.403], respectively); ③The degree of airway stenosis was the influencing factor for postoperative emergency tracheal intubation(95%CI[1.277-20.421]); ④The degree of airway stenosis was a risk factor for whether preserving postoperative tracheal intubation or not(95%CI[1.523-13.296]). Conclusion:①Infants with a history of preoperative underlying diseases are more likely to present with intraoperative airway instability and SpO2 decline, which deserves more preoperative and postoperative attention. Tracheal intubation should be performed timely in case of intraoperative SpO2 decline. ②Preoperative tracheotomy should be performed in infants with preoperative grade Ⅲ airway stenosis, especially those with comorbid heart diseases or respiratory diseases. ③The degree of airway stenosis is an extremely important influencing factor for perioperative airway management of infantile subglottic hemangioma. For infants whose airway stenosis were greater than 60% of airway diameter, the airway maintenance should be closely monitored. Once SpO2 decreases, tracheal intubation should be performed immediately. It's recommended to preserve tracheal intubation so as to ensure the airway stability. The tracheal intubation could be prolonged to 48-72 hours postoperatively. ④The surgical approach has no significant effect on perioperative airway management.


Assuntos
Hemangioma , Estenose Traqueal , Manuseio das Vias Aéreas , Hemangioma/cirurgia , Humanos , Lactente , Intubação Intratraqueal , Estudos Retrospectivos
8.
Front Immunol ; 12: 683577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248967

RESUMO

Dyskinesia is a serious complication of Parkinson's disease during levodopa (L-DOPA) treatment. The pathophysiology of L-DOPA-induced dyskinesia (LID) is complex and not fully illuminated. At present, treatment of dyskinesia is quite limited. Recent studies demonstrated neuroinflammation plays an important role in development of LID. Thus, inhibition of neuroinflammation might open a new avenue for LID treatment. Resveratrol (RES) is the most well-known polyphenolic stilbenoid and verified to possess a large variety of biological activities. DA neurotoxicity was assessed via behavior test and DA neuronal quantification. The movement disorders of dyskinesia were detected by the abnormal involuntary movements scores analysis. Effects of RES on glial cells-elicited neuroinflammation were also explored. Data showed that RES attenuated dyskinesia induced by L-DOPA without affecting L-DOPA's anti-parkinsonian effects. Furthermore, RES generated neuroprotection against long term treatment of L-DOPA-induced DA neuronal damage. Meanwhile, RES reduced protein expression of dyskinesia molecular markers, ΔFOS B and ERK, in the striatum. Also, there was a strong negative correlation between DA system damage and ΔFOS B level in the striatum. In addition, RES inhibited microglia and astroglia activation in substantia nigra and subsequent inflammatory responses in the striatum during L-DOPA treatment. RES alleviates dyskinesia induced by L-DOPA and these beneficial effects are closely associated with protection against DA neuronal damage and inhibition of glial cells-mediated neuroinflammatory reactions.


Assuntos
Discinesias/etiologia , Discinesias/fisiopatologia , Levodopa/efeitos adversos , Resveratrol/farmacologia , Animais , Biomarcadores , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Discinesias/tratamento farmacológico , Discinesias/metabolismo , Masculino , Oxidopamina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Ratos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/fisiopatologia
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(6): 581-584, 2021 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-34096031

RESUMO

OBJECTIVE: To delineate the nature and origin of a chromosomal aberration detected in a boy with mental retardation. METHODS: The proband and his parents were subjected to routine G-banded chromosomal karyotyping and single nucleotide polymorphism array (SNP-array) analysis. RESULTS: The karyotype of the proband was determined as 46, XX, add(8)(p23). No karyotypic abnormality was detected in either of his parents. SNP-array has identified a 34.9 Mb duplication at 8p23.1q11.1 and a 6.78 Mb microdeletion at 8p23.1pter in the proband. No copy number variation was detected in either parent. CONCLUSION: The child was diagnosed with 8p inverted duplication deletion syndrome, which might be induced by non-allelic homologous recombination between olfactory genes in the 8p23.1 region.


Assuntos
Testes Genéticos , Criança , Bandeamento Cromossômico , Análise Citogenética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino
10.
Onco Targets Ther ; 14: 2953-2965, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33976553

RESUMO

Introduction: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies. Methods: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics. Results: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes. Conclusion: Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.

11.
Front Oncol ; 11: 682017, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968789

RESUMO

Background: Tumor mutation burden has been proven to be a good predictor for the efficacy of immunotherapy, especially in patients with hypermutation. However, most research focused on the analysis of hypermutation in individual tumors, and there is a lack of integrated research on the hypermutation across different cancers. This study aimed to characterize hypermutated patients to distinguish between these patients and non-hypermutated patients. Methods: A total of 5,980 tumor samples involving 23 types of solid tumors from the in-house database were included in the study. Based on the cutoff value of tumor mutation burden (TMB), all samples were divided into hypermutated or non-hypermutated groups. Microsatellite instability status, PD-L1 expression and other mutation-related indicators were analyzed. Results: Among the 5,980 tumor samples, 1,164 were selected as samples with hypermutation. Compared with the non-hypermutated group, a significant increase in the mutation rates of DNA mismatch repair genes and polymerase genes was detected in the hypermutated group, and there was an overlap between high TMB and high microsatellite instability or high PD-L1. In addition, we found that EGFR, KRAS and PIK3CA had a high frequency of both single nucleotide variation and copy number variation mutations. These identified mutant genes were enriched in the oncogenic signaling pathway and the DNA damage repair pathway. At the same time, the somatic cell characteristics and distribution of the two groups were significantly different. Conclusions: This study identified genetic and phenotypic characteristics of hypermutated tumors and demonstrated that DNA damage repair is critically involved in hypermutation.

12.
Cell Biol Toxicol ; 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33928466

RESUMO

Clinical surgical practices have found that children who undergo multiple anesthesia may have an increased risk of deficiencies in cognition and fine motor control. Here, we report that YT521-B homology domain family 1 (YTHDF1), a critical reader protein for N6-methyladenosine-modified mRNA, was significantly downregulated in the prefrontal cortex of young mice after multiple sevoflurane anesthesia exposures. Importantly, sevoflurane led to a decrease in protein synthesis in mouse cortical neurons that was fully rescued by YTHDF1, suggesting that anesthesia may affect early brain development by affecting m6A-dependent mRNA translation. Transcriptome-wide experiments showed that numerous mRNA targets related to synaptic functions in the prefrontal mouse cortex were associated with m6A methylation and YTHDF1. In particular, we found that synaptophysin, a critical presynaptic protein, was specifically modified by m6A methylation and associated with YTHDF1, and m6A methylation of synaptophysin decreased with multiple sevoflurane exposures. Importantly, we showed that fine motor control skills and cognitive functions were impaired in mice with multiple anesthesia exposures, and these effects were fully reversed by reintroducing YTHDF1 through a blood-brain barrier (BBB)-crossing viral delivery system. Finally, we found that the fine motor skills in children who underwent prolonged anesthesia were compromised 6 months after surgery. Our findings indicated that impairment in the translational regulation of mRNA via N6-methyladenosine methylation is a potential mechanism underlying the effects of anesthesia on neural development in the young brain. 1. N6-methyladenosine (m6A) modifications were involved in anesthesia-induced neurotoxicity. 2. Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor deficits in young mice. 3. YTHDF1, a m6A reader protein, rescued sevoflurane-induced protein synthesis inhibition and fine motor deficits in young mice.

14.
Sleep Breath ; 25(4): 1897-1903, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33550561

RESUMO

PURPOSE: Difficult mask ventilation (DMV) is a potentially life-threatening situation that can arise during anesthesia. However, most clinical predictors of DMV are based on European and US populations. On the other hand, most predictive models consist of multiple factors and complicated assessments. Since obstructive sleep apnea (OSA) is among the most important risk factors associated with DMV, the apnea-hypopnea index (AHI) may play an important role in determining patient risk.The purpose of this study was to investigate the relationship between DMV and AHI, and to determine preoperative risk factors for DMV in Chinese patients. METHODS: A prospective cohort trial enrolled patients scheduled for elective surgery. After obtaining informed consent, patient demographic information was collected, and patients were tested with pre-operative polysomnography. The anesthesiologist who managed the airway graded the mask ventilation. The difficult mask ventilation was defined as the mask ventilation provided by an unassisted anesthesiologist without oral airway or other adjuvant. A logistic regression model was used to analyze the association between AHI and DMV. RESULTS: A total of 159 patients were analyzed. For both primary and secondary outcomes, the unadjusted and adjusted odds ratio for DMV showed significant increases by 5 AHI units. AHI, age, and the Mallampati classification were found to be independent predictive factors for DMV. CONCLUSIONS: AHI is associated with DMV as a novel independent risk factor in Chinese patients. Along with age and Mallampati classification, AHI should be included in establishing a superior predictive strategy for DMV screening. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-DDD-17013076.

15.
J Clin Pharm Ther ; 46(3): 744-753, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33386628

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Pregnancy after transplantation is a challenge owing to the high risk of adverse maternal and foetal outcomes, and immunosuppressants may further impact these outcomes. There are no head-to-head randomized controlled trials comparing influences of cyclosporin and tacrolimus on pregnancy outcomes. Thus, we systematically reviewed and meta-analysed observational studies assessing the comparative influences of these two drugs on pregnancy outcomes in liver/kidney transplant recipients. METHODS: Relevant studies comparing pregnancy outcomes with tacrolimus and cyclosporin head-to-head were searched in PubMed, EMBASE and Web of Science (from 1 January 2000 to 20 March 2020). The weighted mean difference and odds ratio (OR) were calculated to compare continuous and dichotomous variables, respectively, with 95% confidence intervals (CIs). Publication bias was estimated using funnel plots. The study quality was assessed according to the modified Newcastle-Ottawa scale. RESULTS AND DISCUSSION: Overall, 10 observational studies of low quality, including a total of 1080 post-liver or kidney transplant pregnancies, were identified. Tacrolimus-treated recipients experienced a lower risk of gestational hypertension (28.0%; OR: 1.74; 95% CI: 1.27-2.39; p < 0.01). Cyclosporin-treated recipients showed a lower incidence of caesarean section (40.3%; OR: 0.62; 95% CI: 0.46-0.82; p < 0.01). Additionally, cyclosporin performed better in terms of the live birth rate (78.0%; OR: 1.38; 95% CI: 1.02-1.88; p = 0.04). No significant differences in the incidences of pre-eclampsia, gestational diabetes, preterm delivery and birth weight were observed. WHAT IS NEW AND CONCLUSION: Tacrolimus performed better in patients with gestational hypertension, while cyclosporin was associated with a lower incidence of caesarean section and a higher incidence of live birth. The findings are based on relatively low-quality evidence, but may provide a reference for clinicians in their clinical monitoring and obstetric care for post-transplant pregnancies.

16.
Biomed Chromatogr ; 35(2): e4989, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32959916

RESUMO

A simple and sensitive LC-MS/MS method was established to quantify total and free mycophenolic acid (MPA) plasma concentrations during immunosuppressive medication for pediatric renal transplantation. The chromatographic separation was performed with the Hypersil GOLD C18 column, using a mobile phase consisting of 0.1% formic acid in water and acetonitrile (60:40, v/v) at an isocratic flow rate of 0.4 ml/min. An Agilent 6420 triple quadrupole mass spectrometer was operated via a positive electrospray ionization interface using the transitions m/z 321.14 → 206.9 for MPA and m/z 324.15 → 209.9 for MPA-d3 (internal standard). The linearity was 0.1-50 µg/ml for total MPA and 0.0025-0.5 µg/ml for free MPA. The within-run and between-run precisions were all <5% and accuracy was within 96.23-107.63%. The validated method was successfully aspplied to a pharmacokinetic study in 28 pediatric renal recipients. The mean free fraction of MPA in our patients was 0.89% (ranging from 0.62 to 1.25%) and albumin level played a major role in the variability of free fraction of MPA, thus, in pediatric patients with hypoproteinemia, close free drug monitoring and dose adjustments should be considered to prevent toxicity.


Assuntos
Cromatografia Líquida/métodos , Imunossupressores/sangue , Ácido Micofenólico/sangue , Espectrometria de Massas em Tandem/métodos , Adolescente , Criança , Pré-Escolar , Monitoramento de Medicamentos , Feminino , Humanos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Transplante de Rim , Modelos Lineares , Masculino , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
J Clin Lab Anal ; 35(2): e23606, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33146929

RESUMO

BACKGROUND: Viral encephalitis is common in childhood. It is an acute brain parenchymal inflammation caused by a variety of viral infection, and enterovirus accounts for the majority. Due to atypical clinical manifestations, pathogenic testing is important for assisting clinical diagnosis. The purpose of this study was to evaluate the performance of the multiplex PCR assay compared with quantitative real-time PCR for enterovirus detection. METHODS: A prospective case-control study was performed involving 103 pediatric patients suspected for viral encephalitis and cerebrospinal fluid (CSF) samples were collected and tested for 9 pathogens using multiplex PCR assay during April to November in 2018. In parallel, an aliquot of samples was tested for enterovirus infection by real-time PCR assay. RESULTS: There were 85.4% children were confirmed as viral encephalitis on discharge, the remaining ones were diagnosed as other CNS diseases, such as epilepsy. The specificity of the two methods was the same as that of the clinical diagnosis, but the sensitivity and consistency with clinical diagnosis of multiplex PCR were both higher than the real-time PCR. Besides of enterovirus, multiplex PCR could also detect coinfection of enterovirus with Epstein-Barr virus and mumps virus. CONCLUSION: Results of multiplex PCR method are more consistent with the clinical diagnosis and are superior to real-time PCR for detecting enterovirus in CSF.

18.
Cell Mol Neurobiol ; 41(1): 163-171, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32318898

RESUMO

Traditionally, hydrogen peroxide (H2O2) was formed from cellular oxidative metabolism and often viewed as toxic waste. In fact, H2O2 was a benefit messenger for neuron-glia signaling and synaptic transmission. Thus, H2O2 was a double-edged sword and neuroprotection vs. neurotoxicity produced by H2O2 was difficult to define. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been implicated as an intracellular regulator of neuronal growth. Inactivation of Nrf2 participated in the development of Parkinson's disease (PD). Thus, suitable activation of Nrf2 was essential for the prevention and treatment of PD. This study aimed to explore whether H2O2-conferred neuroprotective effects to support neuronal survival. H2O2 were added into primary neuron-glia, neuron-astroglia and neuron-microglia co-cultures in concentration- and time-dependent manners. H2O2 increased dopamine (DA) neuronal survival in concentration- and time-dependent manners. In addition, glial cells Nrf2 activation involved in H2O2-supported DA neuronal survival with the following phenomenons. First, H2O2 activated Nrf2 signaling pathway. Second, H2O2 generated beneficial neuroprotection in neuron-glia, neuron-astroglia and neuron-microglia co-cultures but not in neuron-enriched cultures. Third, silence of Nrf2 in glial cells abolished H2O2-conferred DA neuronal survival. This study demonstrated that physiological concentration of H2O2-supported DA neuronal survival via activation of Nrf2 signaling in glial cells. Our data permit to re-evaluate the role of H2O2 in the pathogenesis and therapeutic strategies for PD.


Assuntos
Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/metabolismo , Peróxido de Hidrogênio/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Neuroglia/metabolismo , Transdução de Sinais , Animais , Sobrevivência Celular/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Ratos Endogâmicos F344 , Fatores de Tempo
19.
Eur J Clin Pharmacol ; 77(1): 45-53, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32803290

RESUMO

AIM: Mizoribine (MZR) is an immunosuppressant for the prevention of allograft rejection in Asian countries, but the great variability in pharmacokinetics (PK) limits its clinical use. This study was to explore genetic and clinical factors that affect the MZR PK process. METHODS: Blood samples and clinical data were collected from 60 Chinese renal transplant recipients. MZR plasma concentration was measured at pre-dose (0 h) and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 h post-dose by high performance liquid chromatography with an ultraviolet detector. PK parameters were calculated by non-compartmental analysis. High-throughput sequenced single nucleotide polymorphism was applied screening possible genetic factors. RESULTS: Extensive inter-individual MZR PK differences were reflected in the process of elimination (ke, CL/F, MRT and t1/2) and intestinal absorption (Cmax and Tmax), as well as in the dose-normalized exposure (AUC0-12h/D). From 146 SNPs within 39 genes screened, AUC0-12h/D was found higher in recipients with CREB1 rs11904814 TT than with G allele carriers (3.135 ± 0.928 versus 2.084 ± 0.379 µg h ml-1 mg-1, p = 0.007). Recipients with SLC28A3 rs10868138 TT had lower t1/2 as compared to C allele carriers (0.728 ± 0.189 versus 0.951 ± 0.196 h, p = 0.001). Serum creatinine (SCr) explained 35.5% of C0/D variability (p < 0.001). Pure effects of genotypes CREB1 and SLC28A3 were 13.7% (p = 0.004) and 17.5% (p = 0.001) for AUC0-12h/D and t1/2, respectively. When additionally taking SCr into models, CREB1 and SLC28A3 genotypes explained 20.0% (p = 0.038) and 46.5% (p < 0.001) of AUC0-12h/D and t1/2 variability, respectively. CONCLUSION: CREB1 and SLC28A3 genotypes, as well as SCr, are identified as determinants in predicting inter-individual MZR PK differences in renal transplant recipients.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Imunossupressores/farmacocinética , Transplante de Rim , Proteínas de Membrana Transportadoras/genética , Ribonucleosídeos/farmacocinética , Adulto , Idoso , Ciclosporina/uso terapêutico , Feminino , Genótipo , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Ribonucleosídeos/sangue , Tacrolimo/uso terapêutico , Transplantados , Adulto Jovem
20.
Oxid Med Cell Longev ; 2020: 2963540, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33294118

RESUMO

Neuroinflammation plays a crucial role in the pathological process of Parkinson's disease (PD). Nod-like receptor protein 3 (NLRP3) inflammasome was highly located in microglia and involved in the process of neuroinflammation. Activation of the NLRP3 inflammasome has been confirmed to contribute to the progression of PD. Thus, inhibition of NLRP3 inflammasome activation could be an important breakthrough point on PD therapy. Ellagic acid (EA) is a natural polyphenol that has been widely found in soft fruits, nuts, and other plant tissues with anti-inflammatory, antioxidant, and neuroprotective properties. However, the mechanisms underlying EA-mediated anti-inflammation and neuroprotection have not been fully elucidated. In this study, a lipopolysaccharide- (LPS-) induced rat dopamine (DA) neuronal damage model was performed to determine the effects of EA on the protection of DA neurons. In addition, the DA neuronal MN9D cell line and microglial BV-2 cell line were employed to explore whether EA-mediated neuroprotection was through an NLRP3-dependent mechanism. Results indicated that EA ameliorated LPS-induced DA neuronal loss in the rat substantia nigra. Further, inhibition of microglial NLRP3 inflammasome signaling activation was involved in EA-generated neuroprotection, as evidenced by the following observations. First, EA reduced NLRP3 inflammasome signaling activation in microglia and subsequent proinflammatory cytokines' excretion. Second, EA-mediated antineuroinflammation and further DA neuroprotection from LPS-induced neurotoxicity were not shown upon microglial NLRP3 siRNA treatment. In conclusion, this study demonstrated that EA has a profound effect on protecting DA neurons against LPS-induced neurotoxicity via the suppression of microglial NLRP3 inflammasome activation.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Ácido Elágico/farmacologia , Inflamassomos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Inflamassomos/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
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