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1.
J Atheroscler Thromb ; 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39443133

RESUMO

AIMS: Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), and its level is genetically determined. Although guidelines and consensuses in various cardiovascular fields have emphasized the importance of Lp(a), screening for Lp(a) in China has not been well studied. METHODS: A cross-sectional study was conducted using a random sample of 30,000 medical examiners from each of the five health check-up centres. The distribution of Lp(a) was described for those who completed Lp(a) testing, and logistic regression modelling was used to evaluate the relationship between Lp(a) levels and vascular structure and function in the population who underwent carotid ultrasound and brachial‒ankle pulse wave velocity (baPWV) measurements. RESULTS: Lp(a) was measured in only 4400 (3.02%) of the 150,000 participants. Among those tested for Lp(a), the median concentration was 15.85 mg/dL. The proportion of participants with Lp(a) levels ≥ 30 mg/dL was 15.00%. Multiple logistic regression analysis revealed a significant correlation between Lp(a) and cIMT ≥ 1.0 mm (OR: 1.008, 95% CI: 1.001-1.014, P=0.020) and carotid artery plaques (OR: 1.010, 95% CI: 1.004-1.016, P=0.001) but no correlation with baPWV ≥ 1400 (OR: 0.999, 95% CI: 0.993-1.005, P=0.788) or baPWV ≥ 1800 (OR: 1.002, 95% CI: 0.993-1.011, P=0.634). CONCLUSIONS: The detection rate of Lp(a) at health checkups is low, and Lp(a) is positively associated with cervical vascular sclerosis and plaque but not with baPWV. Therefore, the testing rate of Lp(a) and the awareness of the risk of vascular structural changes due to Lp(a) should be further improved.

2.
Sci Rep ; 14(1): 9037, 2024 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-38641617

RESUMO

We aimed to identify different trajectories of remnant cholesterol (RC) and investigate the association of RC trajectories with vascular endothelial function and atherosclerosis progression in a longitudinal cohort of the Chinese population. A total of 521 participants were included in the flow-mediated vasodilation (FMD) subcohort study, and 7775 participants were included in the brachial-ankle pulse wave velocity (baPWV) subcohort study. All participants had ≥ 3 medical examinations during the 10-year follow-up period. In the FMD subcohort study, three distinct RC trajectories were identified according to the RC range and changing pattern over time: "low" (57.58%), "moderate" (30.90%) and "high" (11.52%). The proportion of the three groups with vascular endothelial dysfunction (FMD < 7.0%) was 20.00%, 39.75% and 60.00% respectively. Taking the low group as a reference, participants in the moderate and high groups had over 1.88 and 2.94 times the odds of vascular endothelial dysfunction (P = 0.048). In the baPWV subcohort study, three distinct RC trajectories were also identified: "low" (54.29%), "moderate" (38.97%) and "high" (6.74%). The proportion of the three groups with atherosclerosis (baPWV > 1400 cm/s) was 38.79%, 51.26% and 59.01% respectively. Taking the low group as a reference, participants in the moderate and high groups had over 1.46 and 2.16 times the odds of atherosclerosis (P < 0.001). The findings indicated that distinct RC trajectories are significantly associated with vascular endothelial function and atherosclerosis. Regular monitoring to identify persistent increases in RC may be more helpful in identifying individuals with a high risk of cardiovascular disease.


Assuntos
Aterosclerose , Rigidez Vascular , Adulto , Humanos , Estudos Longitudinais , Índice Tornozelo-Braço , Endotélio Vascular , Análise de Onda de Pulso , Aterosclerose/epidemiologia , Colesterol , China/epidemiologia , Fatores de Risco
3.
J Affect Disord ; 347: 414-421, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38000470

RESUMO

BACKGROUND: Youth mental health problems are a public health priority. Multiple healthy lifestyle behaviors may cluster into healthy lifestyle behavioral patterns (HLBPs) that increase mental health risks in adolescents and older adults, but little is known regarding young adults. This study aimed to explore the associations between cluster HLBPs and mental health problems in young adults. METHODS: We selected 161,744 young adults aged 20-39 as participants from the database of a Chinese general hospital health management center for the years 2015-2020. The latent class analysis was used to identify HLBPs. RESULTS: A total of 15.0 % of young adults have at least one mental health problem. Five clusters of HLBPs were identified, characterized as low-risk class (1.6 %), moderate-risk class 1 (12.0 %), moderate-risk class 2 (2.1 %), moderate-risk class 3 (56.8 %), and high-risk class (27.4 %). The odds ratios (ORs) for young adults with two mental health problems increased with the risk grade of HLBPs, while the ORs for young adults with one or three mental health problems ranged from high to low according to the risk grade of HLBPs: high-risk class, moderate-risk class 2, moderate-risk class 3, moderate-risk class 1. LIMITATIONS: Cross-sectional design and no causal conclusions could be drawn. CONCLUSION: Young adults demonstrated a cluster phenomenon of healthy lifestyle behaviors and significant associations between HLBPs and mental health problems. Young adults with a higher risk grade for HLBPs were more likely to have mental health problems. Different HLBPs should be taken into account when implementing mental health interventions.


Assuntos
Estilo de Vida Saudável , Saúde Mental , Adolescente , Humanos , Adulto Jovem , Idoso , Análise de Classes Latentes , Estudos Transversais , China/epidemiologia
4.
Front Cardiovasc Med ; 10: 1148353, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37621562

RESUMO

Sedentary behavior is a risk factor for several diseases, and previous studies have mostly reported the effects of acute sedentary behavior on vascular endothelial function. Data on the relationship between sedentary lifestyle habits and vascular function in large sample populations are lacking. Therefore, the aim of this study was to assess the correlation between self-reported sedentary behavior and peripheral vascular function in a check-up population from real-world data. Methods: We recruited 13,220 participants from two health management centers of general tertiary hospitals located in northern and southern China between 2017 and 2021. All participants had undergone both questionnaires and brachial artery flow-mediated dilation (FMD) measurements. Results: In total, 3,205 participants with FMD ≤ 5.0% were identified to have endothelial dysfunction. In a multivariable regression model including lifestyle habits such as sedentary behavior and cardiovascular risk factors, taking leisure sedentary time <2 h/day as a reference, the risk of vascular endothelial dysfunction gradually increased with time: 2-4 h/day (OR = 1.182, 95% CI: 1.058-1.321, P = 0.003), 4-6 h/day (OR = 1.248, 95% CI: 1.100-1.414, P = 0.001) and >6 h/day (OR = 1.618, 95% CI: 1.403-1.866, P < 0.001). Conclusion: Longer leisure sedentary time is associated with a higher prevalence of vascular endothelial dysfunction. These findings suggest that leisure sedentary behavior is a risk factor for the occurrence of vascular endothelial dysfunction in the Chinese check-up population.

5.
J Atheroscler Thromb ; 30(6): 684-697, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-36104205

RESUMO

AIM: Vascular endothelial function and atherosclerosis are known to be important risk factors for cardiovascular disease. However, it remains unknown whether remnant cholesterol (RC) correlates with vascular endothelial function and atherosclerosis as represented by flow-mediated vasodilation (FMD) and brachial-ankle pulse wave velocity (baPWV). Therefore, in this study, we aimed to investigate this in the general population. METHODS: In this study, we examined 13,237 subjects who have undergone blood lipid, FMD, and baPWV measurements. Participants were divided into four groups based on RC quartiles. Multivariable linear regression models were used to calculate odds ratios for FMD and baPWV according to the RC levels. RESULTS: A significant negative relationship was found between RC and FMD (ß=-0.14, p=0.014), whereas RC was positively associated with baPWV (ß=21.42, p<0.001), especially in the male and without chronic disease medication populations. The population was divided into three groups according to their lipids: dyslipidemia group, nondyslipidemia but RC increased group (RC >0.78 mmol/L), and nondyslipidemia and RC normal group (RC ≤ 0.78 mmol/L). The FMD of the three groups was 7.09%±3.36%, 7.39%±3.38%, and 7.57%±3.54%, respectively. The baPWV of the three groups was 1445.26±261.56 cm/s, 1425.04±265.24 cm/s, and 1382.73±267.75 cm/s. Significant differences were noted between the groups. CONCLUSIONS: The findings indicated that a higher RC was an independent predictive factor for participants with endothelial function and atherosclerosis. It is important to use RC as a risk management indicator of vascular function, especially for those with normal conventional lipid parameters but increased RC.


Assuntos
Aterosclerose , Rigidez Vascular , Humanos , Masculino , Índice Tornozelo-Braço , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Colesterol , Lipídeos , Análise de Onda de Pulso , Fatores de Risco , Feminino
6.
Chin Med J (Engl) ; 133(8): 892-898, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32187053

RESUMO

BACKGROUND: Despite the recent advances in treatments for rheumatoid arthritis (RA), there are still unmet needs in disease outcomes. This study aimed to analyze the satisfaction with drug therapies for RA according to the levels of disease severity (patient-assessed) and proportions of treatment cost to household income. METHODS: This was a subgroup study of a cross-sectional study in patients with RA and their physicians. The patients were subdivided into different subgroups based on their self-assessed severity of RA and on the proportions of treatment cost to household income (<10%, 10-30%, 31-50%, and >50%). The Treatment Satisfaction Questionnaire for Medication version II was used to assess patients' treatment satisfaction. RESULTS: When considering all medications, effectiveness, convenience, and global satisfaction scores were lower in the severe and moderate RA subgroups than those in the mild and extremely mild RA subgroups (all P < 0.001). Effectiveness, side effects, and convenience scores were higher in the <10% subgroup compared to those in the >50% subgroup (all P < 0.05). Global satisfaction score was higher in the <10% subgroup than that in the 31% to 50% subgroup (F = 13.183, P = 0.004). For biological disease-modifying anti-rheumatic drugs, effectiveness and convenience scores were lower in the severe RA subgroup than those in the extremely mild RA subgroup (both P < 0.05). Convenience score was higher in the <10% subgroup compared to that in the 31% to 50% and >50% subgroups (F = 12.646, P = 0.005). Global satisfaction score was higher in the <10% subgroup than that in the 31% to 50% subgroup (F = 8.794, P = 0.032). CONCLUSION: Higher disease severity and higher financial burden were associated with lower patient satisfaction.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Adulto , Antirreumáticos/uso terapêutico , China , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Índice de Gravidade de Doença , Inquéritos e Questionários
7.
Endocrine ; 68(1): 71-80, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31940133

RESUMO

PURPOSE: Previous studies revealed that high serum uric acid (SUA) levels correlated with increased triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio. However, evidence is lacking regarding whether TG/HDL-C is an independent risk factor or just a simple marker of hyperuricemia. We aimed to investigate the relationship between TG/HDL-C and the risk of hyperuricemia in Chinese population. METHODS: This retrospective cohort study involved 15,198 subjects (43.14 ± 13.13 years, 54.9% men) who were free of hyperuricemia at baseline. The association between TG/HDL-C and the risk of hyperuricemia, in the total sample and stratified by subgroups, was examined by multiple logistic regression analyses. RESULTS: During 4 years follow-up, hyperuricemia occurred in 2365 (15.6%) participants. The cumulative incidence of hyperuricemia was significantly elevated with increasing TG/HDL-C quartiles (5.9, 10.8, 18.4, and 27.5%, respectively). After multivariate adjustment, the odds ratio for hyperuricemia in the highest compared with the lowest quartile of TG/HDL-C was 1.80 (95% confidence interval [CI] 1.49, 2.18), and each SD increment of TG/HDL-C ratio caused a 10% additional risk for hyperuricemia. Moreover, subgroup analyses showed that the association between TG/HDL-C and the risk of hyperuricemia was more pronounced in women and normal-weight adults. The results were consistent when analyses were restricted to participants without metabolic syndrome. CONCLUSIONS: TG/HDL-C ratio was positively related to the risk of hyperuricemia in Chinese population, particularly in women and normal-weight individuals. These findings suggested the potential of TG/HDL-C ratio to serve as an independent risk indicator in the prevention of hyperuricemia.


Assuntos
Hiperuricemia , Adulto , China/epidemiologia , HDL-Colesterol , Estudos de Coortes , Feminino , Humanos , Hiperuricemia/epidemiologia , Masculino , Estudos Retrospectivos , Fatores de Risco , Triglicerídeos , Ácido Úrico
8.
Eat Weight Disord ; 25(6): 1651-1661, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31728924

RESUMO

PURPOSE: Vitamin D insufficiency and obesity are recognized as worldwide concerns and have been linked with each other. New anthropometric indices reflect visceral obesity better than traditional anthropometric indices. Our aim was to identify the specific correlations of novel and traditional anthropometric indices with 25-hydroxyvitamin D (25(OH)D) concentrations by sex and age. METHODS: Cross-sectional data on sociodemographic characteristics, lifestyle factors, clinical characteristics and biochemical measurements were collected for 12,617 Chinese adults. Four traditional anthropometric indices, body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR), and two novel anthropometric indices, body roundness index (BRI) and body shape index (ABSI), were calculated. RESULTS: In both sexes, the mean values of BMI, WC, WHtR and BRI tended to increase with 25(OH)D insufficiency, regardless of adjustment (all P < 0.05). Males with insufficient 25(OH)D had increased odds of obesity (assessed by BMI, WC, WHtR, BRI and ABSI) compared to the odds of males with sufficient 25(OH)D. Females with insufficient 25(OH)D had a higher chance of general obesity (assessed by BMI). Low 25(OH)D status was associated with indicators of obesity only in participants aged 45-64 years in both sexes. CONCLUSION: A inverse association between obesity and lower vitamin D levels was found. Moreover, in addition to BMI, novel indicators of visceral adiposity, such as BRI and ABSI, were associated with lower 25(OH)D serum concentrations in males. The effects of optimizing vitamin D levels in obese Chinese adults need further examination, particularly in middle-aged males. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study.


Assuntos
Vitamina D , Adulto , Antropometria , Índice de Massa Corporal , China , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Circunferência da Cintura , Relação Cintura-Quadril
9.
J Thorac Dis ; 7(5): 790-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26101634

RESUMO

AIMS: Many epidemiological studies have shown that low bone mineral density (BMD) and atherosclerosis appear to be related. However, their precise correlation is not completely understood after full adjustment the shared confounders of atherosclerosis and bone metabolism. The aim of this cross-sectional study was to investigate the relationship between BMD and subclinical atherosclerosis in a healthy Chinese population and the difference in gender. METHODS: The study population consisted of 2,487 subjects (1,467 men, 1,020 women) who participated in health check-up programs and were selected to be free of major diseases which might affect atherosclerosis and bone metabolism. Bone status was assessed by BMD in lumbar spine. The brachial-ankle PWV (baPWV) was assessed as a functional marker of atherosclerosis. The ankle-brachial index (ABI), carotid artery intima-media thickness (CIMT), estimated glomerular filtration rate (eGRF) and microalbuminuria were evaluated as indexes of structural markers of atherosclerosis. RESULTS: After adjustment for risk factors, significant association was shown between baPWV and BMD in both genders (male: r=-0.084, P=0.035; female: r=-0.088, P=0.014). The correlation was stronger in females than in males, and in females, the correlation was stronger after menopause. Similarly, mean baPWV differed significantly according to the decreased BMD (normal BMD, Osteopenia, Osteoporosis). In contrast, no significant differences were observed for ABI, CIMT, eGFR or microalbuminuria with BMD. CONCLUSIONS: Independent of confounding factors, low BMD is associated with the functional marker of subclinical atherosclerosis (increased baPWV), but not with structural markers (ABI, CIMT, eGFR or microalbuminuria) among healthy females and males.

10.
J Thorac Dis ; 6(10): 1441-51, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25364521

RESUMO

OBJECTIVE: We examined the relationship of several cardiovascular risk factors (CVRF) to brachial artery flow-mediated dilatation (FMD) in Chinese subjects. METHODS: This was a cross-sectional study. In 2,511 Chinese adults (age 46.86±9.52 years, 1,891 men and 620 women) recruited from people who underwent health screening at The Third Xiangya Hospital, patients' CVRF [age, body mass index (BMI), waist circumference (WC), blood pressure (BP), cholesterol parameters, creatinine (Cr), uric acid (UA), glucose level and smoking] and prevalence of present disease (hypertension, diabetes mellitus, coronary heart disease and hyperlipidemia) were investigated. RESULTS: Multivariate analysis revealed that FMD negative correlated with age (ß=-0.29, P<0.001), gender (ß=-0.12, P<0.001), BMI (ß=-0.12, P=0.001), WC (ß=-0.10, P=0.011), systolic BP (SBP) (ß=-0.12, P<0.001), fasting glucose (ß=-0.04, P=0.009), total cholesterol (TC) (ß=-0.04, P=0.014), smoking (ß=-0.05, P=0.003), and baseline brachial artery diameter (ß=-0.35, P<0.001). FMD decreased with increasing age in both genders. In women, FMD was higher than men and age-related decline in FMD was steepest after age 40; FMD was similar in men above 55 years old. CONCLUSIONS: In Chinese subjects, FMD may be a usefully marker of CVRF. Age, gender, BMI, WC, SBP, fasting glucose, TC, smoking, and baseline brachial artery diameter were independent variables related to the impairment of FMD. The influence of CVRF on endothelial function is more in women than men.

11.
Clin Rheumatol ; 33(8): 1161-4, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24691584

RESUMO

The aim of this study is to investigate the serum levels and clinical significance of nerve grow factor (NGF) and brain-derived neurotrophic factor (BDNF) in Sjogren's syndrome (SS) with interstitial lung disease (ILD). Fifty two untreated patients with SS were enrolled in the study. Of them, 25 patients only displayed salivary glands damage and/or lacrimal gland injury (simple SS group). The other 27 patients were lacrimal and/or salivary gland involvement as well as being concomitant only with intestinal lung disease (ILD group). Twenty-five serum samples from healthy volunteers were examined as controls. We measure serum NGF and BDNF levels by ELISA and correlate them with clinical data. Serum NGF levels were significantly higher in ILD patients (372 ± 129 pg/ml) and simple SS patients (293 ± 72 pg/ml) when compared with healthy controls (187 ± 47 pg/ml) (both p < 0.01). Significant difference were also found between the two patient groups (p < 0.01). In contrast, BDNF were significantly decreased in ILD patients (1,005 ± 143 pg/ml) when compared with either simple SS patients (1,204 ± 176 pg/ml, p < 0.01) or healthy controls (1,217 ± 155 pg/ml, p < 0.01). Correlation analysis showed NGF levels in ILD patient were positively correlated with serum levels of C-reactive protein and IgG (both p < 0.05). The abnormal NGF and BDNF in sera may be a potential character of ILD secondary to pSS.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Doenças Pulmonares Intersticiais/sangue , Fator de Crescimento Neural/sangue , Síndrome de Sjogren/sangue , Adulto , Idoso , Feminino , Humanos , Doenças Pulmonares Intersticiais/complicações , Masculino , Pessoa de Meia-Idade , Síndrome de Sjogren/complicações
12.
Immunobiology ; 215(12): 956-62, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20163887

RESUMO

OBJECTIVE: High mobility group box chromosomal protein 1 (HMGB1) is a lately discovered candidate molecule identified as an important extracellular mediator in systemic inflammation. Systemic inflammation results in endothelial cell activation and microvascular injury. In the present study, we investigated the effects of HMGB1 on the activation of human umbilical vein endothelial cells (HUVECs) and defined pathways activated by HMGB1. METHODS: HUVECs obtained by collagenase treatment of umbilical cord veins were stimulated in vitro with HMGB1. The activation of HUVECs was studied regarding (i) the kinetics of tumor necrosis factor-α (TNF-α) production in HUVECs, (ii) HMGB1-induced up-regulation of receptor for advanced glycation end products (RAGE), (iii) HMGB1-induced nuclear translocation of nuclear factor kappa B (NF-κB) in HUVECs, (iv) the activation of signalling transduction pathways. RESULTS: HUVECs activation was stimulated by HMGB1 partially in a RAGE-dependent manner. Additionally, the HMGB1-induced activation of HUVECs was significantly inhibited by anti-RAGE monoclonal antibody and Ethyl pyruvate (EP) that had been shown to be an effective anti-inflammatory agent. Short-term prestimulation of HUVECs with HMGB1 caused a time-dependent increase in the secretion of TNF-α and expression of RAGE. Furthermore, HMGB1 stimulation resulted in nuclear translocation of transcription factor NF-κB. Most importantly, pretreatment with anti-RAGE monoclonal antibody significantly decreased the amounts of TNF-α and inhibited the nuclear translocation of NF-κB. Additionally in HUVECs cultures, EP specifically inhibited activation of NF-κB signaling pathway that are critical for TNF-α release. CONCLUSIONS: In conclusion, Our data present a link between HMGB1and RAGE function of endothelial cells and demonstrate the pathway activated by HMGB1. These findings may provide a novel therapeutic strategy to improve the endothelial cells function.


Assuntos
Células Endoteliais/efeitos dos fármacos , Proteína HMGB1/farmacologia , NF-kappa B/metabolismo , Receptores Imunológicos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Anticorpos/imunologia , Anticorpos/farmacologia , Núcleo Celular/metabolismo , Células Cultivadas , Citoplasma/metabolismo , Células Endoteliais/metabolismo , Feminino , Citometria de Fluxo , Proteína HMGB1/genética , Humanos , Imuno-Histoquímica , Microscopia de Fluorescência , Transporte Proteico/efeitos dos fármacos , Piruvatos/farmacologia , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/imunologia , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Veias Umbilicais/citologia
13.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 21(6): 748-50, 2005 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-16256040

RESUMO

AIM: To understand the effect of neutralizing anti-vascular endothelial growth factor (VEGF) antibody on the genesis of murine type II collagen (CO II)-induced arthritis (CIA). METHODS: mice DBA/1J (8-10 weeks) were given intradermal injection chick tape II collagen to set up the murine CIA model. The incidence of CIA and arthritis index were measured and the pathologic changes of articular tissue were observed after the injection of neutralizing anti-VEGF antibody. RESULTS: The anti-VEGF antibody could notably inhibit the genesis and severity of arthritis (P<0.05) at the early stage of CIA formation; while it made no difference after CIA was completely formed. CONCLUSION: Anti-VEGF neutralizing antibody can significantly inhibit synovial fibroblast proliferation, neovascularization and angeitis genesis, which made it a promising agent for RA treatment.


Assuntos
Anticorpos/farmacologia , Artrite Experimental/tratamento farmacológico , Colágeno Tipo II/farmacologia , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/imunologia , Animais , Anticorpos/administração & dosagem , Artrite Experimental/patologia , Proliferação de Células/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Masculino , Camundongos , Membrana Sinovial/citologia
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