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2.
Rev Cardiovasc Med ; 22(1): 231-238, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33792267

RESUMO

Trimethylamine N-oxide (TMAO) is reported to accelerate atherosclerosis and the development of adverse cardiac outcomes. Relationship between coronary atherosclerotic burden and TMAO has been examined in stable coronary artery disease and ST-segment elevation myocardial infarction, but not in non-ST-segment elevation myocardial infarction (NSTEMI). We examined the association between TMAO and coronary atherosclerotic burden in NSTEMI. In this prospective cohort study, two groups including NSTEMI (n = 73) and age-sex matched Healthy (n = 35) individuals were enrolled between 2019 and 2020. Coronary atherosclerotic burden was stratified based on the number of diseased coronary vessels and clinical risk scores including SYNTAX and GENSINI. Fasting plasma TMAO was measured by isotope dilution high-performance liquid chromatography. The median plasma TMAO levels were significantly higher in the NSTEMI group than in the Healthy group, respectively (0.59 µM; interquartile range [IQR]: 0.43-0.78 versus 0.42 µM; IQR: 0.33-0.64; P = 0.006). Within the NSTEMI group, higher TMAO levels were observed in the multivessel disease (MVD) versus single vessel disease (P = 0.002), and intermediate-high risk (score ≥ 23) versus low risk (score < 23) of SYNTAX (P = 0.003) and GENSINI (P = 0.005). TMAO level remained an independent predictor of MVD (odds ratio [OR]: 5.94, P = 0.005), intermediate-high risk SYNTAX (OR: 3.61, P = 0.013) and GENSINI scores (OR: 4.60, P = 0.008) following adjustment for traditional risk factors. Receiver operating characteristic curve (AUC) analysis for TMAO predicted MVD (AUC: 0.73, 95% confidence interval [Cl]: 0.60-0.86, P = 0.002), intermediate-high SYNTAX score (AUC: 0.70, 95% Cl: 0.58-0.82, P = 0.003) and GENSINI score (AUC: 0.70, 95% Cl: 0.57-0.83, P = 0.005). In all, TMAO levels are independently associated with high coronary atherosclerotic burden in NSTEMI.


Assuntos
Aterosclerose , Infarto do Miocárdio sem Supradesnível do Segmento ST , Humanos , Metilaminas , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio sem Supradesnível do Segmento ST/terapia , Estudos Prospectivos
3.
Medicine (Baltimore) ; 99(27): e20794, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629663

RESUMO

BACKGROUND: Recently, trimethylamine N-oxide (TMAO) unexplained gut microbe has been proposed as a promising risk factor for atherosclerotic cardiovascular disease (CVD) pathogenesis and adverse events. The relationship of TMAO with coronary atherosclerotic burden has been evaluated in patients with stable coronary artery disease and ST-segment elevation myocardial infarction, but still needs to be explored in newly diagnosed non-ST-segment elevation myocardial infarction (NSTEMI) patients. MATERIAL AND METHODS: A prospective, single-center, SZ-NSTEMI trial (ChiCTR1900022366) is underway to investigate the relationship of TMAO with the severity and prognosis of coronary atherosclerosis in newly diagnosed NSTEMI patients who will undergo coronary angiography with primary percutaneous coronary intervention (pPCI). The primary endpoint of the study will be assessed the association of TMAO with coronary atherosclerotic severity quantify by the number of diseased coronary arteries and SYNTAX score after the coronary angiography. The secondary endpoints will be identified the TMAO as a prognostic biomarker for the short (1 month) and long-term (12 months) major cardiovascular and cerebrovascular events (MACCEs) rate including myocardial infarction, target vessel revascularization, stroke, heart failure, all-cause rehospitalization, and all-cause mortality after the pPCI. The blood samples will be collected from each patient before the procedure to measure the TMAO by isotope dilution high-performance liquid chromatography. In conclusion, SZ-NSTEMI will be the first cohort that will be investigated the association of TMAO with the severity and prognosis of coronary atherosclerotic burden in NSTEMI patients, aiming to identify TMAO as a predictor and a prognostic biomarker.


Assuntos
Aterosclerose/patologia , Doença da Artéria Coronariana/patologia , Metilaminas/sangue , Infarto do Miocárdio sem Supradesnível do Segmento ST/patologia , Adolescente , Adulto , Idoso , Biomarcadores , Doenças Cardiovasculares/patologia , Doença da Artéria Coronariana/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto Jovem
4.
Rev. colomb. cardiol ; 27(2): 84-89, mar.-abr. 2020. tab, graf
Artigo em Inglês | LILACS, COLNAL | ID: biblio-1138760

RESUMO

Abstract Background: percutaneous transmitral commissurotomy has become an ideal treatment option for mitral stenosis due to its less adverse events and more favorable outcomes. Patients improve symptomatically after percutaneous transmitral commissurotomy but we have minimal available data about the quality of life after percutaneous transmitral commissurotomy. Objective: to assess the quality of life after percutaneous transmitral commissurotomy through WHOQol scoring covering different aspects of life, to determine its correlation with a net gain in mitral valve area (MVA) and to ascertain its association with gender. Methods: it was a prospective cohort study carried out for a period of 15 months. A total of 100 patients with mitral stenosis who had successful percutaneous transmitral commissurotomy done were enrolled in the study. Among the total included, 4 patients were lost to follow up and data were collected from 96 patients. Quality of life was assessed before the procedure, at 1 month and 3 months follow up after percutaneous transmitral commissurotomy using WHOQol scoring questionnaire. Results: among 96 patients, 64 (67%) were females and 32 (33%) were males. WHOQol scoring improved significantly after percutaneous transmitral commissurotomy from 32.8±8.9 to 54.6±11.2 and 62.8± 9.7, after one month and 3 months respectively. There was a significant association between net gain of MVA and WHOQol scoring with an R value of 0.46 and p value of 0.03. There was no difference in group comparison of all the six domains between male and female patients. Conclusion: successful percutaneous transmitral commissurotomy improves the quality of life in mitral stenosis patients regardless of their gender and has a positive correlation with a net gain in mitral valve area.


Resumen Antecedentes: La comisurotomía mitral percutánea se ha convertido en una opción terapéutica ideal para la estenosis mitral, debido a efectos menos adversos y a resultados más favorables. Los pacientes mejoran sintomáticamente tras la realización de esta técnica, aunque se dispone de escasos datos acerca de la calidad de vida tras su puesta en práctica. Objetivo: Evaluar la calidad de vida tras la comisurotomía mitral percutánea mediante la puntuación WHOQol, que cubre diferentes aspectos de la vida, para determinar su correlación con la ganancia neta del área valvular mitral (AVM), y determinar su asociación con el sexo. Métodos: Estudio prospectivo de cohorte durante un periodo de 15 meses, en el que se incluyeron 100 pacientes con estenosis mitral a quienes se les practicó con éxito comisurotomía mitral percutánea. De entre el total incluido, se perdieron 4 pacientes durante el estudio, por lo que se recolectaron datos de los 96 pacientes restantes. La calidad de vida se evaluó antes del procedimiento, y transcurridos un mes y tres meses de seguimiento, utilizando el cuestionario de puntuación WHOQol. Resultados: De los 96 pacientes, 64 (67%) eran mujeres y 32 (33%) varones. La puntuación WHOQol mejoró considerablemente tras la realización de la comisurotomía mitral percutánea, con valores de 32,8±8,9 a 54,6±11,2 y 62,8± 9,7, transcurridos uno y 3 meses, respectivamente. Se produjo una asociación significativa entre la ganancia neta de AVM y la puntuación WHOQol, con un valor R de 0,46 y un valor p de 0,03. No se produjo diferencia alguna en cuanto a la comparación grupal de los seis dominios entre varones y mujeres. Conclusión: La comisurotomía mitral percutánea exitosa mejora la calidad de vida de los pacientes de estenosis mitral, independientemente del sexo, y tiene una correlación positiva con la ganancia neta del área valvular mitral.


Assuntos
Humanos , Masculino , Feminino , Qualidade de Vida , Estenose da Valva Mitral , Inquéritos e Questionários , Identidade de Gênero , Valva Mitral
5.
J Pak Med Assoc ; 69(12): 1794-1799, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31853105

RESUMO

OBJECTIVE: To compare efficacy and safety of indapamide-furosemide combination against metolazone-furosemide combination in refractory heart failure patients. METHODS: The randomised controlled trial was conducted at Rehman Medical Institute, Peshawar, Pakistan, from January 1 to June 30, 2018, and comprised refractory heart failure patients who were randomised into two groups using lottery method Group 1 received intravenous furosemide 40mg Q12hr with metolazone 5mg Q24hr, while group 2 received intravenous furosemide 40mg Q12hr with indapamide 2.5mg Q24hr. Both groups were assessed for urinary sodium excretion, total urine output and decrease in weight on day one, day three and day five of admission. SPSS 22 was used for data analysis. RESULTS: Of the 150 patients, there were 75(50%) in each of the two groups. Mean age in group 1 was 64.8}11.2 years, while it was 66.3}12.9 years in group 2. Both groups showed increased urinary sodium excretion and total urine output (p>0.05). Hypokalaemia was the most common adverse event 66%. Mean hospital stay was not significantly different between the groups (p>0.05). CONCLUSIONS: There was no significant differences between adverse events and efficacy between patients receiving either indapamide-furosemide combination or metolazone-furosemide combination.


Assuntos
Diuréticos , Furosemida , Insuficiência Cardíaca/tratamento farmacológico , Indapamida , Metolazona , Sódio/urina , Administração Intravenosa , Administração Oral , Idoso , Peso Corporal , Diuréticos/administração & dosagem , Diuréticos/efeitos adversos , Diuréticos/uso terapêutico , Quimioterapia Combinada , Feminino , Furosemida/administração & dosagem , Furosemida/efeitos adversos , Furosemida/uso terapêutico , Humanos , Indapamida/administração & dosagem , Indapamida/efeitos adversos , Indapamida/uso terapêutico , Masculino , Metolazona/administração & dosagem , Metolazona/efeitos adversos , Metolazona/uso terapêutico , Pessoa de Meia-Idade , Paquistão
6.
Pak J Med Sci ; 35(5): 1349-1354, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31489005

RESUMO

OBJECTIVE: There is very limited data about gender based differences in Acute Coronary Syndrome (ACS) in Asian population. This study was therefore aimed to ascertain gender based differences in clinical and angiographic characteristics and clinical outcomes in patient admitted with ACS. METHODS: This was a cross sectional, observational study including patients admitted with diagnosis of ACS. Patients were divided into two groups (Males and Females) and their clinical characteristics were noted. Gender based assessment was done following coronary angiography. RESULTS: A total of 386 patients were included, with 210 males and 176 females. Anterior wall myocardial infarction (AWMI) was present in 177(45.86%) patients. Mean age was 72.8±12.9 years in females and 66.8±11.2 years in males. Diabetes was present in 38.1% females and 31% males. Patients from rural population were 225(58.3%), while from urban 161(41.7%). Mean ejection fraction was 43.9±7.9% in women and 38.2±8.68% in males. CONCLUSION: ACS was more common in males, rural population and AWMI was most common cause. Women were more elderly and had more adverse events as compared to males. Impaired renal dynamics were more commonly observed in males. Women were less aggressively treated with coronary interventions and radial approach was better tolerated regardless of gender.

7.
J Nepal Health Res Counc ; 17(2): 158-162, 2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31455927

RESUMO

BACKGROUND: Cardiac pacemaker infections have increased globally due to increase in demand and lack of adequate knowledge about its significantly contributing risk factors. This study was therefore aimed to determine the prevailing causative microbes and risk factors of both single and dual chamber permanent pacemaker infections. METHODS: This was a retrospective case control study. Cases were selected as culture positive swab, Temporary pacemaker wire or catheter were matched with three controls for each variable using chi square test. Multivariate regression analysis was done to determine risk factors. RESULTS: Among 47 cases, 23.4% cases were infected by methicillin resistant staph aureus, 14.9% by methicilin susceptible Staphylococcus aureus, 10.6% by pseudomonas, 8.5% by escherichia coli and 6.4% by klebsiella. Temporary pacemaker/Central line placed >24 hours ago before permanent pacemaker implantation, remnant pacemaker leads, corticosteroid use, no antibiotic prophylaxis, diabetes, smoking and non-absorbable stitches had statistically significant association with permanent pacemaker infection using multivariate regression model analysis. Chronic obstructive pulmonary disease and non-absorbable stitches had a non-significant association. CONCLUSIONS: Temporary pacemaker/Central line placed >24hours before permanent pacemaker implantation, remnant pacemaker leads, corticosteroid use, no antibiotic prophylaxis, diabetes, smoking and use of non-absorbable stitches are risk factors for permanent pacemaker infection. Staph aureus is the most prevalent microorganism causing infection.


Assuntos
Marca-Passo Artificial/efeitos adversos , Infecções Relacionadas à Prótese/microbiologia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco
8.
J Tehran Heart Cent ; 14(3): 134-137, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31998390

RESUMO

Air inside the pericardial cavity is called "pneumopericardium", which is a rare complication of pericardiocentesis. Pneumopericardium may resolve spontaneously or can complicate into tension pericardium, requiring urgent aspiration. We herein describe a 55-year-old man with pericardial effusion who underwent pericardiocentesis. The patient was completely asymptomatic after the procedure. Chest radiograph and computed tomography scan accidentally detected pneumopericardium, which was subsequently complicated by atrial fibrillation and necessitated pharmacological cardioversion. We found no case of asymptomatic pneumopericardium complicated by atrial fibrillation after pericardiocentesis in our literature review. Clinicians and cardiologists should do a post pericardiocentesis chest X-ray to diagnose pneumopericardium and prevent the catastrophic complications of tension pneumopericardium.

9.
J Saudi Heart Assoc ; 30(4): 305-310, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30069136

RESUMO

OBJECTIVE: Coronary artery disease is major cause of mortality and morbidity. Homocysteine has long been postulated as an underlying factor for atherosclerosis leading to coronary artery disease, yet its role in young patients is uncertain. This study was aimed to analyze the correlation between plasma homocysteine and coronary artery disease among young adults in the absence of conventional risk factors. METHODS: It was a case-control study carried out at Rehman Medical Institute, Peshawar, Pakistan from October 1, 2016, to September 30, 2017. Universal sampling technique was adopted and 158 participants were included. A total of 30 participants were in the control group and 128 were in the patient group, who had moderate to severe stenosis in either single or multiple major coronary arteries on coronary angiography and aged <40 years. RESULTS: Cases and controls had similar characteristics but differed significantly in serum homocysteine concentration. In the control group, the mean plasma homocysteine concentration of 6.3 (±2.05) µmol/L and in the patient group a mean plasma homocysteine concentration of 44.5 (±14.01) µmol/L was observed. All the patients with moderate to severe stenosis in single or major coronary arteries had raised plasma homocysteine concentrations. Among 128 patients, 15 (11.7%) had moderate increase, 109 (85.2%) had intermediate increase, and four (3.1%) had severe increase in plasma homocysteine levels. Single vessel coronary artery disease was observed in 118 (92.2%) patients, whereas 10 (7.8%) had more than one major coronary artery involvement. CONCLUSION: Hyper-homocysteinemia has positive correlation with coronary artery disease among young adults in the absence of conventional risk factors.

10.
Cureus ; 10(6): e2857, 2018 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-30148010

RESUMO

Objectives The aim of this study was to assess the prognosis in patients with left main coronary artery stenosis one year after percutaneous coronary intervention (PCI). Methods Our study included 40 patients who underwent PCI for left main coronary artery stenosis without the use of intravascular ultrasound (IVUS). Patients were followed for a year, and the prognostic effect of PCI on a composite end-point of revascularization, new myocardial infarction, cardiac death, and on all-cause mortality was assessed in multivariable Cox analysis. Results The multivariable analysis showed a good prognosis in patients receiving PCI with a total event rate of 7.5%. The independent predictors for major adverse cardiac events (MACE) were diabetes (p = 0.02). Other prognostic factors included in the model were gender, age, smoking, body mass index (BMI), hypertension, the complexity of the vessel, and ejection fraction. Conclusion PCI for left main coronary artery stenosis without the use of IVUS has a good prognosis after one year of clinical follow-up.

11.
Med J Islam Repub Iran ; 32: 129, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30815424

RESUMO

Background: Hypertension was considered as a disease of the elderly but due to unhealthy dietary and lifestyle changes its incidence has increased in younger population. Smoking and obesity are emerging concerns the world is facing globally in younger age groups. This study is therefore aimed to identify these cardiovascular risk factors among Pathan and Persian young adults. Methods: It was a cross-sectional study carried out at multiple undergraduate, postgraduate educational institutes and hospitals using non-probability convenient sampling among young adults aged between 15 to 40 years for a period of six months from Apr 1st, 2017 to Sep 30th, 2017. Mean±SD was calculated for continuous variables and categorical variables were expressed as frequencies. Chi-square test and Fisher exact test were used for statistical analysis. Results: A total of 708 subjects were included. Mean±SD age was 26.12±3.7 years. Out of 708, 300(42.37%) were smokers with 209 (29.52%) active and 91 (12.85%) passive smokers. Among smokers, 216 (30.5%) were males while 84 (11.87%) were females. A total of 432 (61.02%) subjects were not doing any exercise, and 636 (89.83%) were consuming junk food. A total of 165 (23.3%) subjects were overweight, and 15 (2.1%) were obese. Stage-1 hypertension was present in 72 (10.2%), while 16 (2.25%) subjects had stage-2 hypertension. Conclusion: There is an increased prevalence of cardiovascular risk factors which includes hypertension, smoking, and obesity among Pathan and Persian young adults.

12.
Coron Artery Dis ; 26(5): 409-21, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25946654

RESUMO

OBJECTIVES: Despite recent advances in the understanding of the role of NLRP3 inflammasomes in coronary atherosclerosis, further work on their activation and clinical implications remains to be performed. In this study, we aimed to evaluate the effect of the dose of rosuvastatin on NLRP3 and cathepsin-B expression in peripheral blood monocytes in patients with acute coronary syndrome. METHODS: A total of 123 participants were enrolled in this study; these included acute myocardial infarction (AMI) patients (n=53), unstable angina patients (UA, n=40), and normal controls (n=30). AMI and UA patients were divided into high-dose rosuvastatin (20 mg) and low-dose rosuvastatin (5 mg) groups. NLRP3, cathepsin-B, and downstream cytokine expressions were appropriately evaluated using real-time PCR, flow cytometry, western blotting and enzyme-linked immunosorbent assay. The concentrations of serum inflammatory markers were also evaluated for correlation with NLRP3 levels. RESULTS: AMI and UA patients had higher NLRP3, cathepsin-B, interleukin-18 (IL-18), pro-IL-18, IL-1ß, and pro-IL-1ß expressions as compared with the control group (P<0.05). This corresponded with higher levels of serum total cholesterol, serum low-density lipoprotein cholesterol, and oxidized low-density lipoprotein in UA and AMI patients (P<0.05). Rosuvastatin at a concentration of 20 mg led to a significant decrease (P<0.05) in the expressions of NLRP3, cathepsin-B, and their downstream cytokines as compared with 5 mg rosuvastatin (P>0.05) from baseline to 4 weeks. This study also showed a positive correlation between NLRP3, cathepsin-B, and downstream inflammatory mediators. CONCLUSION: NLRP3 is involved in inflammation that leads to atherosclerosis. A high dose of rosuvastatin can modulate the inflammatory process of atherosclerosis by downregulating the expression of NLRP3, cathepsin-B, and their downstream mediators. These findings provide insight into the pathogenesis and management of acute coronary syndrome, with NLRP3 as the potential target.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Angina Instável/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Proteínas de Transporte/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inflamassomos/sangue , Mediadores da Inflamação/sangue , Monócitos/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Rosuvastatina Cálcica/administração & dosagem , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/imunologia , Adulto , Idoso , Angina Instável/sangue , Angina Instável/diagnóstico , Angina Instável/genética , Angina Instável/imunologia , Biomarcadores/sangue , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Catepsina B/sangue , China , Citocinas/sangue , Feminino , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Mediadores da Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Infarto do Miocárdio/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fatores de Tempo , Adulto Jovem
13.
Int J Mol Med ; 35(5): 1179-88, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25761252

RESUMO

Purinergic 2X7 receptor (P2X7R) and nucleotide­binding oligomerization domain-like receptor protein 3 (NLRP3) are expressed in macrophages in atherosclerotic lesions. However, the mechanisms through which P2X7R participates in the inflammatory response in atherosclerosis remain largely unknown. The aim of the present study was to investigate the role of P2X7R in atherosclerosis and the mechanisms of action of the NLRP3 inflammasome following stimulation with oxidized low-density lipoprotein (oxLDL). We observed the expression and distribution of P2X7R in the atherosclerotic plaque in the coronary arteries from an autopsy specimen and in that of the aortic sinuses of apoE(-/-) mice by immunohistochemistry and immunofluorescence staining. The specificity of short interfering RNA (siRNA) was used to suppress P2X7R and NLRP3 mRNA expression. RT-qPCR and western blot analysis were used to analyze mRNA and protein expression, respectively. Co-immunoprecipitation was used to examine the interaction between protein kinase R (PKR) phosphorylation and NLRP3. P2X7R and NLRP3 were expressed at high levels in the atherosclerotic plaque in the coronary arteries. Stimulation with oxLDL upregulated P2X7R, NLRP3 and interleukin (IL)-1ß expression. P2X7R knockdown by siRNA suppressed NLRP3 inflammasome activation by inhibiting the PKR phosphorylation mediated by oxLDL. In the atherosclerotic lesions in the aortic sinuses of apoE(-/-) mice, P2X7R expression was found at high levels. Moreover, P2X7R siRNA attenuated the development of atherosclerosis in the apoE(-/-) mice. In conclusion, our results demonstrate that P2X7R plays a significant role in the development of atherosclerosis and regulates NLRP3 inflammasome activation by promoting PKR phosphorylation.


Assuntos
Aterosclerose/genética , Aterosclerose/metabolismo , Proteínas de Transporte/metabolismo , Inflamassomos/metabolismo , Receptores Purinérgicos P2X7/genética , Animais , Apolipoproteínas E/deficiência , Aterosclerose/patologia , Proteínas de Transporte/genética , Linhagem Celular , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Modelos Animais de Doenças , Progressão da Doença , Células Espumosas/metabolismo , Células Espumosas/patologia , Expressão Gênica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Receptores Purinérgicos P2X7/metabolismo
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