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Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. Abnormal energy metabolism in microvascular endothelium is involved in the progression of diabetic retinopathy. Bile Acid G-Protein-Coupled Membrane Receptor (TGR5) has emerged as a novel regulator of metabolic disorders. However, the role of TGR5 in diabetes mellitus-induced microvascular dysfunction in retinas is largely unknown. Herein, enzyme-linked immunosorbent assay was used for analyzing bile acid (BA) profiles in diabetic rat retinas and retinal microvascular endothelial cells (RMECs) cultured in high glucose medium. The effects of TGR5 agonist on streptozotocin (STZ)-induced diabetic retinopathy were evaluated by HE staining, TUNEL staining, retinal trypsin digestion, and vascular permeability assay. A pharmacological inhibitor of RhoA was used to study the role of TGR5 on the regulation of Rho/Rho-associated coiled-coil containing protein kinase (ROCK) and western blot, immunofluorescence and siRNA silencing were performed to study the related signaling pathways. Here we show that bile acids were downregulated during DR progression in the diabetic rat retinas and RMECs cultured in high glucose medium. The TGR5 agonist obviously ameliorated diabetes-induced retinal microvascular dysfunction in vivo, and inhibited the effect of TNF-α on endothelial cell proliferation, migration, and permeability in vitro. In contrast, knockdown of TGR5 by siRNA aggravated TNF-α-induced actin polymerization and endothelial permeability. Mechanistically, the effects of TGR5 on the improvement of endothelial function was due to its regulatory role on the ROCK signaling pathway. An inhibitor of RhoA significantly reversed the loss of tight junction protein under TNF-α stimulation. Taken together, our findings suggest that insufficient BA signaling plays an important pathogenic role in the development of DR. Upregulation or activation of TGR5 may inhibit RhoA/ROCK-dependent actin remodeling and represent an important therapeutic intervention for DR.
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Retinopatia Diabética/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Western Blotting , Linhagem Celular , Retinopatia Diabética/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Retina/efeitos dos fármacos , Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/farmacologia , Cicatrização/efeitos dos fármacos , Cicatrização/ética , Quinases Associadas a rho/genética , Proteína rhoA de Ligação ao GTP/genéticaRESUMO
BACKGROUND: The morbidity of rifampicin/multidrug-resistant tuberculous meningitis (RR/MDR-TBM) has shown an increasing trend globally. Its mortality rate is significantly higher than that of non-rifampicin/multidrug-resistant tuberculous meningitis (NRR/MDR-TBM). This article aimed to explore risk factors related to RR/MDR-TBM, and compare therapeutic effects of linezolid (LZD)- and non-linezolid-containing regimen for RR/MDR-TB patients in Shenzhen city. Furthermore, we aimed to find a better therapy for pathogen-negative TBM with RR/MDR-TBM related risk factors. METHODS: We conducted a retrospective study enrolling 137 hospitalized cases with confirmed TBM from June 2014 to March 2020. All patients were divided into RR/MDR-TBM group (12 cases) and NRR/MDR-TBM group (125 cases) based on GeneXpert MTB/RIF and (or) phenotypic drug susceptibility test results using cerebral spinal fluid (CSF). The risk factors related to RR/MDR-TBM were investigated through comparing clinical and examination features between the two groups. The mortality rate of RR/MDR-TBM patients treated with different regimens was analyzed to compare their respective therapeutic effects. A difference of P < 0.05 was considered statistically significant. RESULTS: Most patients (111/137, 81%) were from southern or southwestern China, and a large proportion (72/137, 52.55%) belonged to migrant workers. 12 cases were RR/MDR-TBM (12/137, 8.8%) while 125 cases were NRR/MDR-TBM (125/137, 91.2%). The proportion of patients having prior TB treatment history in the RR/MDR-TBM group was significantly higher than that of the NRR/MDR-TBM group (6/12 vs. 12/125, 50% vs. 10.5%, P < 0.01). No significant difference was observed on other clinical and examination features between the two groups. Mortality was significantly lower in RR/MDR-TBM patients on linezolid-containing treatment regimen than those who were not (0/7 versus 3/5, 0% versus 60%, P = 0.045). CONCLUSIONS: The main related risk factor of RR/MDR-TBM is the history of anti-tuberculosis treatment. Linezolid-containing regimen appears to lower mortality rate of RR/MDR-TBM significantly in our study. We think Linezolid should be evaluated prospectively in the treatment of RR/MDR-TBM.
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Mycobacterium tuberculosis , Tuberculose Meníngea , Tuberculose Resistente a Múltiplos Medicamentos , Antituberculosos/uso terapêutico , China/epidemiologia , Humanos , Linezolida/uso terapêutico , Estudos Retrospectivos , Rifampina/uso terapêutico , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
PURPOSE: This study was designed to develop a computer-aided diagnosis (CAD) system based on a convolutional neural network (CNN) to diagnose patients with pituitary tumors. METHODS: We included adult patients clinically diagnosed with pituitary adenoma (pituitary adenoma group), or adult individuals without pituitary adenoma (control group). After pre-processing, all the MRI data were randomly divided into training or testing datasets in a ratio of 8:2 to create or evaluate the CNN model. Multiple CNNs with the same structure were applied for different types of MR images respectively, and a comprehensive diagnosis was performed based on the classification results of different types of MR images using an equal-weighted majority voting strategy. Finally, we assessed the diagnostic performance of the CAD system by accuracy, sensitivity, specificity, positive predictive value, and F1 score. RESULTS: We enrolled 149 participants with 796 MR images and adopted the data augmentation technology to create 7960 new images. The proposed CAD method showed remarkable diagnostic performance with an overall accuracy of 91.02%, sensitivity of 92.27%, specificity of 75.70%, positive predictive value of 93.45%, and F1-score of 92.67% in separate MRI type. In the comprehensive diagnosis, the CAD achieved better performance with accuracy, sensitivity, and specificity of 96.97%, 94.44%, and 100%, respectively. CONCLUSION: The CAD system could accurately diagnose patients with pituitary tumors based on MR images. Further, we will improve this CAD system by augmenting the amount of dataset and evaluate its performance by external dataset.
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Imageamento por Ressonância Magnética/métodos , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/diagnóstico , Inteligência Artificial , Humanos , Redes Neurais de ComputaçãoRESUMO
Ligand engineering of aromatic heterocyclic cations in two-dimensional (2D) Dion-Jacobson (DJ) perovskites has been widely explored in recent years. In this study, how the positional isomers of aromatic heterocyclic cations tune the lattice of 2D perovskites, thereby influencing the transport and recombination dynamics of charge carriers, has been investigated through nonadiabatic molecular dynamics simulations. We demonstrate that the meta-substituted 3-(aminomethyl)pyridinium (3AMPY) cations greatly reduce the strength of electron-vibration coupling since the strong hydrogen-bonding network introduced by the changes in the arrangement of spacer cations significantly suppresses the structural thermal fluctuations. Compared to the para-substituted 4-(aminomethyl)pyridinium (4AMPY) cation, using the asymmetric 3AMPY as a spacer cation can achieve improved in-plane transport performance, enhanced thermal stability, and suppressed charge carrier recombination through weakening electron-vibration interactions. Our results explain the observed lifetime difference between the two types of DJ-phase perovskites in experiments and provide new guidance for optimizing the performance of perovskite devices.
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Due to the complicated clinical features of mitochondrial encephalomyopathy, simplified mitochondrial disease criteria (MDC) have recently been established in Europe. This study evaluated the sensitivity and specificity of this scoring system in Chinese patients. Seventy-eight patients with suspected mitochondrial encephalomyopathy were recruited to be scored by the simplified MDC and were further classified into "possible" (2-4), "probable" (5-7), or "definite" categories (≥8). Significant differences were observed between the total scores in the mitochondrial encephalomyopathy group and the other myopathy group. In the mitochondrial encephalomyopathy group, 73.5% of patients had a score above 8, whereas in the other myopathy group, the "definite" percentage was only 3.2%, suggesting the proposed MDC scoring system has a high sensitivity for diagnosis of mitochondrial encephalomyopathy in China. Moreover, there were significant differences in the clinical scores and imaging portions of the MDC, suggesting that the simplified MDC may distinguish mitochondrial disorder from other multisystem disorders to aid in early diagnosis prior to a muscle biopsy.
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Povo Asiático/etnologia , Encefalomiopatias Mitocondriais/diagnóstico , Encefalomiopatias Mitocondriais/etnologia , Índice de Gravidade de Doença , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/classificação , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/etnologia , Encefalomiopatias Mitocondriais/classificação , Adulto JovemRESUMO
In the recent decades, obesity rates among children and adolescents, especially males, have increased significantly. This worldwide phenomenon is thought to significantly affect the levels of sex hormones. However, the association between waist circumference (a marker of abdominal obesity) and sex hormone levels in children and adolescents is unknown. In this study, 4031 participants aged 6-19 years from the United States National Health and Nutrition Examination Survey (NHANES) in the USA were enrolled in this study. The common confounders of age, race, body mass index, educational level, family income, diabetes, and time of sample collection were also collected. The participants missing any of the above information were excluded from the study. We used multiple linear regression and other multiple statistics to assess the associations between waist circumference and serum testosterone, estradiol, sex hormone-binding globulin (SHBG), free androgen index (FAI), and testosterone/estradiol ratio (T/E2). Waist circumference remained associated with sex hormone levels in children and adolescents after controlling for covariates. As waist circumference increases, testosterone levels in children and adolescents show an overall decline after a brief increase, with the inflection point for waist circumference of 65-66 cm. In addition, waist circumference positively correlates with estradiol levels in male children (ß = 0.007, 95% confidence interval: 0.004-0.009). Moreover, circulating SHBG decreases in children and adolescents as waist circumference increases. In conclusion, this study highlighted waist circumference as a vital indicator affecting sex hormone levels in children and adolescents.
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Estradiol , Hormônios Esteroides Gonadais , Humanos , Masculino , Adolescente , Criança , Estados Unidos/epidemiologia , Inquéritos Nutricionais , Circunferência da Cintura , Testosterona , Obesidade , Globulina de Ligação a Hormônio SexualRESUMO
1. The present study investigated the relationship between antituberculosis (anti-TB) drug-induced hepatotoxicity and genetic polymorphisms of two important drug-metabolizing enzymes involved in the metabolism of isoniazid, namely N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1). 2. A polymerase chain reaction direct sequencing approach was used to detect genetic polymorphisms of the NAT2 and CYP2E1 genes in tuberculosis (TB) patients with (n = 101) or without (n = 107) anti-TB drug-induced hepatotoxicity. Associations between various genetic polymorphisms and anti-TB drug-induced hepatotoxicity were then determined. 3. Patients with NAT2 (282TT , 590AA and 857GA) alleles had an increased susceptibility to anti-TB drug-induced hepatotoxicity. The slow acetylator NAT2 genotypes (especially NAT2*6A/7B and NAT2*6A/6A) were risk factors for hepatotoxicity (odds ratio (OR) 9.57 (P < 0.001) for NAT2*6A/7B; OR 5.24 (P = 0.02) for NAT2*6A/6A). 4. The CYP2E1 genotype per se was not significantly associated with the development of anti-TB drug-induced hepatotoxicity. However, the combination of the CYP2E1 C1/C1 genotype with a slow acetylator NAT2 genotype increased the risk of anti-TB drug-induced hepatotoxicity (OR 5.33; P = 0.003) compared with the combination of a rapid acetylator NAT2 genotype with either a C1/C2 or C2/C2 genotype. 5. Thus, slow acetylators with the NAT2*6A/7B and NAT2*6A/6A genotypes combined with the C1/C1 CYP2E1 genotype may be involved in the pathogenesis of anti-TB drug-induced hepatotoxicity. 6. The present findings may be explained, in part, by changes in the metabolism of the anti-TB drug isoniazid induced via NAT2 and CYP2E1, a metabolic process known to produce hepatotoxic intermediates.
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Antituberculosos/efeitos adversos , Arilamina N-Acetiltransferase/genética , Povo Asiático/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Citocromo P-450 CYP2E1/genética , Polimorfismo Genético/genética , Adulto , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
An FI-KR non-separated method coupled with FAAS for the determination of Fe(II) and Fe(III) was developed. With 60 s of sampling at a flow rate of 6.0 mL x min(-1), EF of 41 for Fe(III) and 9 for Fe(II) were obtained. The precision (RSD, n = 11) for Fe(III) and Fe(II) was 2.3% and 3.1% at the 0.04 mg x L(-1) level respectively. When 0.1 per thousand phi TEA was used as masking reagent, the recovery rate for Fe(III) and Fe(II) was from 97% to 101% and from 96% to 100% respectively.
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Background: Tumor cells with a hybrid metabolic state, in which glycolysis and oxidative phosphorylation (OXPHOS) can be used, usually have a strong ability to adapt to different stress environments due to their metabolic plasticity. However, few studies on tumor cells with this phenotype have been conducted in the field of renal cell carcinoma (RCC). Methods: The metabolic pathway (glycolysis, OXPHOS) related gene sets were obtained from the Molecular Signatures Database (V7.5.1). The gene expression matrix, clinical information, and mutation data were obtained by Perl programming language (5.32.0) mining, the Cancer Genome Atlas and International Cancer Genome Consortium database. Gene Set Enrichment Analysis (GSEA) software (4.0.3) was utilised to analyse glycolysis-related gene sets. Analysis of survival, immune infiltration, mutation, etc. was performed using the R programming language (4.1.0). Results: Eight genes that are highly associated with glycolysis and OXHPOS were used to construct the cox proportional hazards model, and risk scores were calculated based on this to predict the prognosis of clear cell RCC patients and to classify patients into risk groups. Gene Ontology, the Kyoto Encyclopaedia of Genes and Genomes, and GSEA were analysed according to the differential genes to investigate the signal pathways related to the hybrid metabolic state. Immunoinfiltration analysis revealed that CD8+T cells, M2 macrophages, etc., had significant differences in infiltration. In addition, the analysis of mutation data showed significant differences in the number of mutations of PBRM1, SETD2, and BAP1 between groups. Cell experiments demonstrated that the DLD gene expression was abnormally high in various tumor cells and is associated with the strong migration ability of RCC. Conclusions: We successfully constructed a risk score system based on glycolysis and OXPHOS-related genes to predict the prognosis of RCC patients. Bioinformatics analysis and cell experiments also revealed the effect of the hybrid metabolic activity on the migration ability and immune activity of RCC and the possible therapeutic targets for patients.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Prognóstico , Biologia Computacional , Fenótipo , Neoplasias Renais/genéticaRESUMO
The preference for social novelty is crucial to the social life of humans and rodents. However, the neural mechanisms underlying social novelty preference are poorly understood. Here, we found that chronic social defeat stress (CSDS) reduced the preference for social novelty in mice by impairing the response of CaMKIIα+ neurons in the CA3 region of dorsal hippocampus (dCA3) during approach to an unfamiliar mouse. The deficits of social novelty preference in CSDS-treated mice were reversed by activating the output from dCA3 to the GABAergic neurons in the lateral septum (LS). The activation of GABAergic projection from LS recruited a circuit that inhibited the Foxb1+ neurons in the parvafox nucleus (PFN), which drove social avoidance by projecting to the lateral periaqueductal gray (lPAG). These results suggest that a previously unidentified circuit of dCA3CaMKIIα+âLSGABA+âPFNFoxb1+âlPAG mediates the deficits of social novelty preference induced by CSDS.
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Derrota Social , Estresse Psicológico , Animais , Fatores de Transcrição Forkhead , Neurônios GABAérgicos , Hipocampo , Camundongos , Camundongos Endogâmicos C57BL , Comportamento SocialRESUMO
BACKGROUND: The aim of the present study is to investigate the clinical value and characteristics of peripheral blood lymphocyte subsets in patients with pulmonary tuberculosis (PTB) using flow cytometry. METHODS: The absolute counts of T, CD4+ T, CD8+ T, natural killer (NK), NKT and B lymphocytes in 217 cases of PTB were detected, and the variations in lymphocyte subset counts between different ages and genders and between aetiological detection results and chest radiography results were analysed. RESULTS: In 75.3% of the patients with PTB, six subset counts were lower than the normal reference range, and 44% showed lower-than-normal CD4+ T lymphocyte levels. The counts of T, CD4+ T, CD8+ T and B lymphocytes were significantly lower in patients aged >60 years, and the NKT cell counts were significantly lower in female patients than in male patients. Among the patients with positive aetiological results, 40.8% had reduced CD8+ T counts; these were significantly lower than those in patients with negative aetiological results (P = 0.0295). The cell counts of T, CD4+ T, CD8+ T and B lymphocytes reduced as lesion lobe numbers increased. The counts of T, CD4+ T and CD8+ T lymphocytes were significantly higher in the group with lesions affecting one lobe than in the groups with two to three lobes or four to five lobes, and the counts of B lymphocytes were significantly higher in the group with one lobe and the group with two to three lobes than in the group with four to five lobes. The counts of CD4+ T and CD8+ T lymphocytes were highest in the no cavity group and showed a downward trend with the increase in cavities; the T lymphocyte count was significantly higher in the no cavity group than in the group with five or more cavities (P = 0.014), and the CD8+ T lymphocyte count was significantly higher in the no cavity group than in the group with one to two cavities and the group with five or more cavities (P = 0.001 and 0.01, respectively). CONCLUSIONS: In most patients with tuberculosis, immune function is impaired. The absolute counts of peripheral blood lymphocyte subsets are closely related to the aetiological results and lesion severity in patients with PTB; this could be used as evidence for immune intervention and monitoring curative effects.
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Subpopulações de Linfócitos , Tuberculose Pulmonar , Linfócitos B , Feminino , Humanos , Contagem de Linfócitos , Masculino , Subpopulações de Linfócitos T , Linfócitos TRESUMO
OBJECTIVE: To study the possible relationship between polymorphic N-acetyltransferase 2 (NAT2) acetylator status and antituberculosis drug-induced hepatotoxicity and to elucidate the molecular mechanism of antituberculosis drug-induced hepatotoxicity. METHODS: Blood samples from 101 tuberculosis cases with antituberculosis drug-induced hepatotoxicity and from 107 tuberculosis without antituberculosis drug-induced hepatotoxicity were collected for a case-control study. DNA of the subjects was extracted and amplified by polymerase chain reaction (PCR). The single nucleotide polymorphisms of NAT2 were determined by direct PCR sequencing. The genotype frequencies were compared between cases and controls by χ(2) test, using SPSS 12.0 software, and the association between the disease and genotypes was analyzed. RESULTS: Among the 101 patients with antituberculosis drug-induced liver injury, 36 patients (35.6%) were found with 282 T/T, 12 (11.9%) with 590 A/A, and 48 (47.5%) with 857 G/A or A/A. However, among the 107 controls, 9 patients (8.4%) were found with 282 T/T, 3 (2.8%) with 590 A/A, and 33 (33.8%) with 857 G/A or A/A. The patients with 282 T/T, 590 A/A, or 857 G/A or A/A genotype had a higher risk of antituberculosis drug-induced hepatotoxicity than those with 282 C/C or C/T, 590 G/G or G/A, or 857 G/G, and the OR values were 6.03 (95%CI: 2.88 - 12.62; χ(2) = 22.73, P < 0.05), 4.67 (95%CI: 1.42 - 15.44; χ(2) = 6.40, P < 0.05) and 2.03 (95%CI: 1.16 - 3.57; χ(2) = 6.08, P < 0.05) respectively. There were 40 patients with slow acetylator (39.6%) in cases with hepatotoxicity and 13 with slow acetylator (12.2%) in controls without hepatotoxicity. Patients with slow acetylator genotype (OR = 4.74, 95% CI = 2.42 - 9.28; χ(2) = 20.62, P < 0.05) had a significantly higher risk of antituberculosis drug-induced hepatotoxicity than those with rapid or intermediate acetylator genotypes. Among the cases, 19.8% (20/101) were found with NAT2(*)6A/7B, and 11.9% (12/101) with NAT2(*)6A/6A, whereas among the controls, 2.8% (3/107) were found with NAT2(*)6A/7B, and 2.8% (3/107) with NAT2(*)6A/6A respectively, the patients with NAT2(*)6A/7B and NAT2(*)6A/6A had a much higher risk of antituberculosis drug-induced hepatotoxicity, and the OR values were 8.40 (95%CI: 2.85 - 24.73; χ(2) = 14.90, P < 0.05) and 4.67 (95%CI: 1.42 - 15.44; χ(2) = 6.40, P < 0.05) respectively. CONCLUSION: Perhaps, the slow acetylation genotypes of NAT2 were the main risk factors of developing antituberculosis drug-induced hepatotoxicity.
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Antituberculosos/efeitos adversos , Arilamina N-Acetiltransferase/genética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Adulto , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Tuberculose/tratamento farmacológico , Tuberculose/genética , Adulto JovemRESUMO
A flow injection two steps elution method on-line sorption and preconcentration system coupled to flame atomic absorption spectrometry (FAAS) was developed for the determination of trace Zn in water samples. The conventional elution procedure was divided into two steps: elution procedure and detection procedure. During the elution procedure, the eluent was pumped into KR by the suction of the peristaltic pump and through PTFE tube instead of peristaltic pump tube. By the new method, the dispersion of the analyte was decreased notably, and high absorbance peak value was achieved. Because the eluent was not through the peristaltic pump tube, the peristaltic pump tube was protected from being eroded. Emptying procedure was added in order to insure the veracity and repeatability of the experiment of every time. With 60 s (sample throughput of 37 x h(-1)) of sampling at a flow rate of 6.0 mL x min(-1), an enhancement factor (EF) of 28 (higher than 9 achieved by conventional elution method) and a detection limit (3sigma) of 0.35 x L(-1) were obtained. The precision (RSD, n=11) was 2.1% at the 20 microg x L(-1) level. When 0.1% phi triethannolamine was used as masking reagent, the recovery rate was from 98.7% to 99.6%.
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BACKGROUND: Several clinical trials of dapagliflozin in patients with type 2 diabetes mellitus (T2DM) at elevated cardiovascular risk have observed reduced hospitalization for heart failure (HHF). Several studies have also suggested cardiovascular benefits for patients with HF regardless of whether or not they have T2DM. OBJECTIVE: This meta-analysis was conducted to evaluate the therapeutic effects of dapagliflozin in patients with HF. METHODS: The PubMed, Embase, Cochrane Library, and Web of Science databases were systematically searched from database inception to 15 February 2020. Clinical studies of dapagliflozin use in patients with HF were included. Data on HHF, all-cause mortality, cardiovascular death, major adverse cardiovascular events (MACE), systolic blood pressure, body weight, glycated hemoglobin (HbA1c), and adverse events were collected for analysis. RESULTS: Four randomized controlled trials involving 6738 patients with HF were included in this meta-analysis. Patients receiving dapagliflozin showed a significantly lower incidence of HHF [risk ratio (RR) 0.72; P < 0.00001], all-cause mortality (RR 0.83; P = 0.004), cardiovascular death (RR 0.86; P = 0.03), and MACE (RR 0.88; P = 0.03). Moreover, patients receiving dapagliflozin also showed significant improvements in systolic blood pressure and body weight. However, no statistical difference was observed in HbA1c. In addition, hypoglycemia, volume depletion, and renal impairment was not more frequent with dapagliflozin than with placebo. CONCLUSION: This meta-analysis suggests that dapagliflozin could be a therapeutic strategy for patients with HF regardless of the presence or absence of T2DM.
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Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/epidemiologia , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Hemoglobinas Glicadas , Insuficiência Cardíaca/epidemiologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversosRESUMO
With the widespread use of PD-1/PD-L1 monoclonal antibodies (mAbs) in the treatment of multiple malignant tumors, they were also gradually applied to advanced renal cell carcinoma (aRCC). Nowadays, multiple PD-1/PD-L1 mAbs, such as nivolumab, avelumab, and pembrolizumab, have achieved considerable efficacy in clinical trials. However, due to the primary, adaptive, and acquired resistance to these mAbs, the efficacy of this immunotherapy is not satisfactory. Theories also vary as to why the difference in efficacy occurs. The alterations of PD-L1 expression and the interference of cellular immunity may affect the efficacy. These mechanisms demand to be revealed to achieve a sustained and complete objective response in patients with aRCC. Tyrosine kinase inhibitors have been proven to have synergistic mechanisms with PD-1/PD-L1 mAb in the treatment of aRCC, and CTLA-4 mAb has been shown to have a non-redundant effect with PD-1/PD-L1 mAb to enhance efficacy. Although combinations with targeted agents or other checkpoint mAbs have yielded enhanced clinical outcomes in multiple clinical trials nowadays, the potential of PD-1/PD-L1 mAbs still has a large development space. More potential mechanisms that affect the efficacy demand to be developed and transformed into the clinical treatment of aRCC to search for possible combination regimens. We elucidate these mechanisms in RCC and present existing combination therapies applied in clinical trials. This may help physicians' select treatment options for patients with refractory kidney cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/mortalidade , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Ensaios de Seleção de Medicamentos Antitumorais , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Mutação , Receptor de Morte Celular Programada 1/metabolismo , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/farmacologiaRESUMO
OBJECTIVE: The purposes of this study were to describe the ultrasonographic findings in hepatic tuberculosis (TB) after administration of a second-generation sulfur hexafluoride-filled microbubble contrast agent and to correlate these findings with pathologic characteristics. METHODS: Twenty-four hepatic TB lesions in 15 patients were studied with conventional ultrasonography (CUS) and contrast-enhanced ultrasonography (CEUS). Pathologic characteristics of the lesions were evaluated and were then correlated with enhancement patterns. RESULTS: The appearance of hepatic TB on CUS was variable and nonspecific with respect to the shape, echogenicity, and boundary of the lesions. The diameters of the lesions obtained from CEUS were statistically larger than those from CUS, with largest diameters +/- SD of 4.2 +/- 1.8 and 3.1 +/- 1.9 cm, respectively. During the arterial phase, 13 of 24 lesions (54.2%) showed a rapidly and markedly enhanced rim with a hypoenhanced or nonenhanced center; 9 of 24 lesions (37.5%) showed transient enhancement of the whole lesion with inconsistent intensities. During the portal phase, most lesions showed distinct wash-out of the contrast agent and maintained a hypoechoic appearance. Pathologic studies confirmed that the different appearances of hepatic TB on CEUS were related to the different pathologic stages of the lesions. CONCLUSIONS: Findings of hepatic TB on CEUS may be helpful in differentiating the diagnosis from other hepatic focal lesions. Correlation with pathologic findings would enrich the understanding of CEUS findings in hepatic TB.
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Meios de Contraste , Fosfolipídeos , Hexafluoreto de Enxofre , Tuberculose Hepática/diagnóstico por imagem , Ultrassonografia Doppler em Cores , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose Hepática/patologiaRESUMO
As the second largest carbon flux in terrestrial ecosystems, the soil CO2 flux is closely related to the atmospheric CO2 concentration. The soil CO2 flux is the sum of biotic respiration and abiotic geochemical CO2 exchange; however, little is known about abiotic CO2 fluxes in arid areas. To investigate the relative contribution of abiotic and biotic soil CO2 fluxes over a diurnal course, the abiotic CO2 flux was distinguished by autoclaving sterilization in both saline and alkaline soils at an arid site in northwestern China. The results demonstrated that: (1) Over the diurnal course, the abiotic CO2 was a significant component of the soil CO2 flux in both saline and alkaline soil, which accounted for more than 56% of the diurnal soil CO2 flux. (2) There was a dramatic difference in the temperature response between biotic and abiotic CO2 fluxes: the response curves of biotic respiration were exponential in the saline soil and quadratic in the alkaline soil, while the abiotic CO2 flux was linearly correlated with soil temperature. They were of similar magnitude but with opposite signs: resulting in almost neutral carbon emissions on daily average. (3) Due to this covering up effect of the abiotic CO2 flux, biotic respiration was severely underestimated (directly measured soil CO2 flux was only one-seventh of the biotic CO2 flux in saline soil, and even an order of magnitude lower in alkaline soil). In addition, the soil CO2 flux masked the temperature-inhibition of biotic respiration in the alkaline soil, and veiled the differences in soil biological respiration between the saline and alkaline soils. Hence, the soil CO2 flux may not be an ideal representative of soil respiration in arid soil. Our study calls for a reappraisal of the definition of the soil CO2 flux and its temperature dependence in arid or saline/alkaline land. Further investigations of abiotic CO2 fluxes are needed to improve our understanding of arid land responses to global warming and to assist in identifying the underlying abiotic mechanisms.
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OBJECTIVE: To observe the relationship between the genetic polymorphism of P450-2E1 and the risk for antituberculosis drug-induced hepatotoxicity in a Chinese population. METHODS: Blood samples and clinical data were collected from 85 patients with antituberculosis drug-induced hepatotoxicity and 100 tuberculosis patients without hepatotoxicity as the control. DNA was extracted from the blood samples, and the frequencies of P450-2E1 RsaI genotypes were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The relationship between the polymorphisms of P450-2E1 RsaI and the antituberculosis drug-induced hepatotoxicity was analyzed. Predisposing factors for antituberculosis drug-induced hepatitis, such as gender, age, and polymorphism of P450-2E1 RsaI were evaluated by using logistic regression analysis. RESULTS: The frequencies of the 3 gene types P450-2E1 RsaI c1/c1, c1/c2, and c2/c2 were 75% (64/85), 20% (17/85) and 5% (4/85) respectively in patients with antituberculosis drug-induced hepatotoxicity, and 61% (61/100), 30% (30/100), and 9% (9/100) respectively in the controls. A statistical difference was found between the cases and the controls (chi(2) = 4.284, P < 0.05, OR = 2.016, 95%CI = 1.058 - 3.842). Logistic regression analysis showed that the polymorphism of P450-2E1 RsaI remained a significant independent risk factor for antituberculosis drug-induced hepatotoxicity after adjustment for age, gender and body mass index. CONCLUSION: Polymorphisms of P450-2E1 were found to be significantly associated with the risk of antituberculosis drug-induced hepatotoxicity, and the c1/c1 genotype was one of the risk factors.
Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Citocromo P-450 CYP2E1/genética , Polimorfismo de Fragmento de Restrição , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/genética , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
A sodion triethylenetetramine-bisdithiocarbamate (DTC-TETA) and its complexes with heavy metal ions were investigated by FTIR, UV, FAAS and elemental analysis, respectively. The FTIR spectrum of DTC-TETA showed strong absorption peaks at 1 461-1 388 cm(-1) and 1 174-996 cm(-1) which were attributed to partly double bonds of C-N and C-S, respectively. The UV spectrum of DTC-TETA had two absorption peaks at 265 and 290 nm, assigned to pi-pi* transition of N...C...S radical and nonbonding electron n-pi* transition of S...C...S radical to conjugated system, respectively. The elemental analysis results demonstrated that the mol ratio of C, H, N and S in DTC-TETA was about 2 : 4 : 1 : 1. As for UV spectrum of its complexes with Cu(II), Cd(II), Zn(II) and Ni(II), there were four new absorption peaks at 321, 310, 311 and 325 nm, respectively. Coupled to flow-injection, FAAS determination showed that the complexation performance of Cu2+, Cd2+, Ni2+ and Zn2+ complexes of DTC-TETA was better than that of sodium diethyldithiocarbamate (DDTC).
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A simple, environmentally friendly, cost-effective, and sensitive method was developed for the determination of trace lead in tap water by flow injection (FI) on-line unequal flow complexation preconcentration procedure coupled with flame atomic absorption spectrometry (FAAS). Compared with conventional preconcentration method, the unequal flow complexation preconcentration procedure, increased the flow rate of sample while decreased the flow rate of complexing agent. The new method decreased the dilution effect of sample caused by the chelating agent, increased the sorption preconcentration effect, and increased the enhancement factor. The decrease in the flow rate of chelating agent will not result in a deficient complex formation because the concentration of APDC is much higher than that of the sample's. Compared with other sorption preconcentration methods, such as, multiplexed sorption preconcentration procedure, the unequal flow complexation preconcentration procedure need not to prolong the preconcentration time, but received even better results. Taking lead as a model element, ammonium pyrrolidine dithiocarbamate (APDC) as the chelating agent, and ethanol as the eluent, the proposed FI on-line KR unequal flow complexation preconcentration procedure was coupled with FAAS for the determination of trace lead in tap water. With a sample loading flow rate of 10. 4 mL x min(-1) and preconcentration time of 60 s, the enhancement factor increased from 30 (conventional equal flow complexation preconcentration procedure) to 59 (unequal flow complexation preconcentration procedure), the detection limit (3sigma) of 5.6 microg x g L(-1) was obtained at a sampling frequency of 40 samples x h(-1). The relative standard deviations (n = 11) were found to be 2.1% at the level of 0.5 mg x L(-1). The recovery ranged from 98.5% to 102%. The proposed method has been successfully applied to the determination of lead in tap water samples.