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Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites. It is caused by defects in the HSD11B2 gene, encoding the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone. To date, over 50 deleterious HSD11B2 mutations have been identified worldwide. Multiple molecular mechanisms function in the lowering of 11ß-HSD2 activity, including damaging protein stability, lowered affinity for the substrate and cofactor, and disrupting the dimer interface. Genetic polymorphism, environmental factors as well as epigenetic modifications may also offer an implicit explanation for the molecular pathogenesis of AME. A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage. In this review, we provide insights into the molecular genetics of classic and non-classic apparent mineralocorticoid excess and aim to offer a comprehensive overview of this monogenic disease.
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Cortisona , Hipertensão , Humanos , Cortisona/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Hidrocortisona/metabolismo , Biologia Molecular , Síndrome de Excesso Aparente de MinerolocorticoidesRESUMO
INTRODUCTION: Liddle syndrome (LS), an autosomal dominant and inherited monogenic hypertension syndrome caused by pathogenic mutations in the epithelial sodium channel (ENaC) genes SCNN1A, SCNN1B, and SCNN1G. OBJECTIVE: This study was designed to identify a novel SCNN1B missense mutation in a Chinese family with a history of stroke, and to confirm that the identified mutation is responsible for LS in this family. METHODS: DNA samples were collected from the proband and 11 additional relatives. Next-generation sequencing was performed in the proband to find candidate variants. In order to exclude genetic polymorphism, the candidate variantin SCNN1B was verified in other family members, 100 hypertensives, and 100 healthy controls by Sanger sequencing. RESULTS: Genetic testing revealeda novel and rare heterozygous variant in SCNN1B in the proband. This variant resulted in a substitution of threonine instead of proline at codon 617, altering the PY motif of ß-ENaC. The identified mutation was only verified in 5 relatives. In silico analyses indicated that this variant was highly pathogenic. In this family, phenotypic heterogeneity was present among 6 LS patients. Tailored medicine with amiloride was effective in controlling hypertension and improving the serum potassium concentration in patients with LS. CONCLUSIONS: We identified a novel SCNN1B mutation (c.1849C>A) in a family affected by LS. Patients with LS, especially those with severe hypertension, should be alert for the occurrence of premature stroke. Timely diagnosis using genetic testing and tailored treatment with amiloride can help LS patients to avoid severe complications.
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Canais Epiteliais de Sódio/genética , Hipertensão/complicações , Síndrome de Liddle/complicações , Síndrome de Liddle/genética , Mutação de Sentido Incorreto , Acidente Vascular Cerebral/complicações , Adolescente , Adulto , Povo Asiático/genética , Criança , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Acidente Vascular Cerebral/genética , Adulto JovemRESUMO
Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions.
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Movimento Celular , Proliferação de Células , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Cátion TRPM/metabolismo , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Transdução de SinaisRESUMO
OBJECTIVES: To investigate the value of CCKBRfl/fl villin-Cre mice as a mouse model of salt-sensitive hypertension (SSH). METHODS: In the first part, 2-month-old CCKBRfl/fl villin-Cre mice (CKO) and control CCKBRfl/fl mice (WT) were fed with normal diet (0.4% NaCl) or high salt diet (4% NaCl), separately for 6 weeks. In the rescue study, one week of hydrochlorothiazide or saline injection were treated with the CKO mice fed high salt diet. The blood pressure, biochemical indexes, and the expression of small intestinal sodium transporters (NHE3, NKCC1, eNaC) was detected. The organ injury markers (MMP2/MMP9) and the histopathological changes of kidneys were observed, whereas the changes of duodenal sodium absorption were detected by small intestinal perfusion in vivo. RESULTS: The CCKBRfl/fl villin-Cre mice with high salt intake exhibited high blood pressure, increased duodenal sodium absorption and urinary sodium excretion, and with renal injury. The protein expression of NHE3, NKCC1 and eNaC were also significant increase in the intestine of CKO-HS mice. Treatment with hydrochlorothiazide remarkably attenuated the elevated blood pressure by high salt absorption in the CCKBRfl/fl villin-Cre mice, but no significant histopathological changes were observed. CONCLUSIONS: These results support a crucial role of intestinal Cckbr deficiency on SSH development and the diuretic antihypertension effect in CCKBRfl/fl villin-Cre mice. The CCKBRfl/fl villin-Cre mice with the high salt intake may serve as a stable model of salt-sensitive hypertensive induced by sodium overloading.
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Objective: To evaluate the long-term prognosis of patients with ST-segment elevation myocardial infarction (STEMI) treated with different reperfusion strategies in Chinese county-level hospitals. Methods: A total of 2,514 patients with STEMI from 32 hospitals participated in the China Acute Myocardial Infarction registry between January 2013 and September 2014. The success of fibrinolysis was assessed according to indirect measures of vascular recanalization. The primary outcome was 2-year mortality. Results: Reperfusion therapy was used in 1,080 patients (42.9%): fibrinolysis ( n= 664, 61.5%) and primary percutaneous coronary intervention (PCI) ( n= 416, 38.5%). The most common reason for missing reperfusion therapy was a prehospital delay > 12 h (43%). Fibrinolysis [14.5%, hazard ratio ( HR): 0.59, 95% confidence interval ( CI) 0.44-0.80] and primary PCI (6.8%, HR= 0.32, 95% CI: 0.22-0.48) were associated with lower 2-year mortality than those with no reperfusion (28.5%). Among fibrinolysis-treated patients, 510 (76.8%) achieved successful clinical reperfusion; only 17.0% of those with failed fibrinolysis underwent rescue PCI. There was no difference in 2-year mortality between successful fibrinolysis and primary PCI (8.8% vs. 6.8%, HR = 1.53, 95% CI: 0.85-2.73). Failed fibrinolysis predicted a similar mortality (33.1%) to no reperfusion (33.1% vs. 28.5%, HR= 1.30, 95% CI: 0.93-1.81). Conclusion: In Chinese county-level hospitals, only approximately 2/5 of patients with STEMI underwent reperfusion therapy, largely due to prehospital delay. Approximately 30% of patients with failed fibrinolysis and no reperfusion therapy did not survive at 2 years. Quality improvement initiativesare warranted, especially in public health education and fast referral for mechanical revascularization in cases of failed fibrinolysis.
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Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , População do Leste Asiático , Resultado do Tratamento , Reperfusão Miocárdica , Sistema de Registros , HospitaisRESUMO
OBJECTIVE: To study the chemical constituents, antimicrobial activity and antitumor activity of the essential oil from Zanthoxylum avicennae. METHODS: The essential oil from the leaves of Zanthoxylum avicennae was extracted by steam distillation. The components of the essential oil were separated and identified by GC-MS. RESULTS: 72 components were identified and accounted for 98.15% of the all peak area. The essential oil exhibited strong antitumor activity against K-562 human tumor cell lines with IC50 of 1.76 microg/mL. It also exhibited moderate antimicrobial activity against three bacteria. CONCLUSION: The essential oil of Zanthoxylum avicennae contains various active constituents. This result provides scientific reference for the pharmacological further research of Zanthoxylum avicennae.
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Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Óleos Voláteis/análise , Óleos Voláteis/farmacologia , Folhas de Planta/química , Zanthoxylum/química , Monoterpenos Acíclicos , Anti-Infecciosos/química , Antineoplásicos Fitogênicos/química , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Concentração Inibidora 50 , Monoterpenos/análise , Monoterpenos/farmacologia , Óleos Voláteis/química , Sesquiterpenos Policíclicos , Sesquiterpenos/análise , Sesquiterpenos/farmacologiaRESUMO
BACKGROUND: Left ventricular noncompaction (LVNC) is an increasingly recognised cardiomyopathy of which a significant percentage are genetic in origin. The purpose of the present study was to identify potential pathogenic mutation leading to disease in a Chinese LVNC family. METHODS: A 3-generation family affected by LVNC was recruited. Clinical assessments were performed on available family members, with clinical examination, ECG, echocardiography and cardiac MRI. The proband (I-2), the proband's daughter (II-1, affected) and mother (III-1, unaffected) were selected for WGS. Sanger sequencing were performed in all of the 4 surviving family members. RESULTS: Combined whole genome sequencing with linkage analysis identified a novel missense mutation in the giant protein obscurin (OBSCN NM_001098623, c.C19063T), as the only plausible disease-causing variant that segregates with disease among the four surviving individuals, with interrogation of the entire genome excluding other potential causes. This c.C19063T missense mutation resulted in p.R6355W in the encoded OBSCN protein. It affected a highly conserved residue in the C terminus of the obscurin-B-like isoform between the PH and STKc domains, which was predicted to affect the function of the protein by different bioinformatics tools. CONCLUSIONS: Here we present clinical and genetic evidence implicating the novel R6355W missense mutation in obscurin as the cause of familial LVNC. This expands the spectrum of obscurin's roles in cardiomyopathies. It furthermore highlights that rare obscurin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identiï¬ed by the approach presented here. This study also provided new insights into the molecular basis of OBSCN mutation positive LVNC.
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In 1939, Robinson and Brucer first proposed the concept of prehypertension (PHTN), which was defined as a systolic blood pressure of 120-139 mmHg and/or diastolic blood pressure of 80-89 mmHg. PHTN is a major global health risk that adversely affects human health, especially the cardiovascular system. People with PHTN have a higher risk of developing cardiovascular diseases, including stroke, coronary heart disease, myocardial infarction and total cardiovascular events. However, there are few systematic summaries of the relationship between PHTN and the cardiovascular system. Furthermore, because the definition of 'normal BP' and the advantages of more intensive BP control remain unclear, there is no consensus on optimal interventions. In an attempt to provide information for clinicians or professionals who are interested in reducing the risk associated with PHTN, we review the existing studies to provide references for them with the effects of PHTN on the cardiovascular system and the potential pathogenic mechanisms of PHTN, including inflammatory responses, insulin resistance, endothelial dysfunction, sympathovagal imbalance, activation of the renin-angiotensin system and others. PHTN is highly prevalent and has adverse effects on health. An effective public health strategy is important to prevent the progression of PHTN. We envisage that this information will increase the public attention of PHTN and help to provide more strategies to reduce the risk of cardiovascular events.
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Background: Neurofibromatosis type 1 (NF-1) is a common autosomal dominant disorder caused by mutations in the NF1 gene. It is characterized by multiple café-au-lait macules, cutaneous neurofibromas, optic glioma, Lisch nodules, and axillary and inguinal freckling. The aim of this study was to investigate NF1 mutations in two Chinese families with NF-1 who presented with early-onset hypertension, and to determine the prevalence of hypertension associated with NF-1 to better understand this complication. Methods: Whole-exome sequencing was performed for the probands with NF-1 from two unrelated families. Possible pathogenic mutation was predicted by bioinformatic tools. Sanger sequencing was used to confirm candidate variants in all available individuals for familial co-segregation analysis. We also performed a systematic literature review of studies that reported the prevalence of hypertension in patients with NF-1. Results: In family 1, a recurrent mutation c.6789_6792delTTAC in NF1 was identified in the proband but in no other family members, indicating that this is a de novo mutation. In family 2, a novel mutation c.6934_6936delGCAinsTGCT in NF1 was detected in the proband and two other family members, which co-segregated with the disease phenotype within the family. Both mutations were predicted to be pathogenic by bioinformatic analysis. We found hypertension was a relatively common complication of NF-1, with a prevalence range of 6.1-23.4%. Ambulatory blood pressure monitoring is a stable method for detecting initial alterations of the blood pressure pattern, particularly for pre-hypertension. Conclusions: We identified one recurrent (c.6789_6792delTTAC) and one novel frame-shift mutation (c.6934_6936delGCAinsTGCT) in two unrelated families with NF-1 using whole-exome sequencing. In consideration of phenotypic heterogeneity in NF-1, genetic testing is a robust tool which helps early and accurate diagnosis. Because hypertension is not a rare complication of NF-1, routine screening for hypertension in patients with NF-1, especially children and adolescents, is important to avoid serious cardiovascular events.
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OBJECTIVE: To determine the prognostic role of big endothelin-1 (ET-1) in left ventricular non-compaction cardiomyopathy (LVNC). METHODS: We prospectively enrolled patients whose LVNC was diagnosed by cardiac MRI and who had big ET-1 data available. Primary end point was a composite of all-cause mortality, heart transplantation, sustained ventricular tachycardia/fibrillation and implanted cardioverter defibrillator discharge. Secondary end point was cardiac death or heart transplantation. RESULTS: Altogether, 203 patients (median age 44 years; 70.9% male) were divided into high-level (≥0.42 pmol/L) and low-level (<0.42 pmol/L) big ET-1 groups according to the median value of plasma big ET-1 levels. Ln big ET-1 was positively associated with Ln N-terminal pro-brain natriuretic peptide, left ventricular diameter, but negatively related to age and Ln left ventricular ejection fraction. Median follow-up was 1.9 years (IQR 0.9-3.1 years). Kaplan-Meier analysis showed that, compared with patients with low levels of big ET-1, those with high levels were at greater risk for meeting both primary (p<0.001) and secondary (p<0.001) end points. The C-statistic estimation of Ln big ET-1 for predicting the primary outcome was 0.755 (95% CI 0.685 to 0.824, p<0.001). After adjusting for confounding factors, Ln big ET-1 was identified as an independent predictor of the composite primary outcome (HR 1.83, 95% CI 1.27 to 2.62, p=0.001) and secondary outcome (HR 1.93, 95% CI 1.32 to 2.83, p=0.001). CONCLUSIONS: Plasma big ET-1 may be a valuable index to predict the clinical adverse outcomes in patients with LVNC.
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Endotelina-1/sangue , Miocárdio Ventricular não Compactado Isolado/complicações , Miocárdio Ventricular não Compactado Isolado/mortalidade , Adulto , Biomarcadores/sangue , Morte Súbita Cardíaca/epidemiologia , Desfibriladores Implantáveis/estatística & dados numéricos , Feminino , Transplante de Coração/estatística & dados numéricos , Ventrículos do Coração/diagnóstico por imagem , Humanos , Miocárdio Ventricular não Compactado Isolado/terapia , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Prognóstico , Estudos Prospectivos , Volume Sistólico , Taquicardia Ventricular/epidemiologia , Fibrilação Ventricular/epidemiologiaRESUMO
Hypertension is an important risk factor in many conditions and creates a heavy burden of disease and mortality globally. Polygenic hypertension is the most common form; however, it is increasingly recognized that monogenic hypertension is not rare, especially in patients with electrolyte disorders. Single genetic alterations are associated with plasma volume expansion and catecholamines/sympathetic excess with simultaneously increased potassium excretion in the urine and potassium intracellular shift. Early-onset refractory hypertension and profound hypokalemia are characteristics of monogenic hypertension. However, accumulated evidence shows the existence of phenotypic heterogeneity in monogenic hypertension meaning that, even for mild symptoms, clinicians cannot easily exclude the possibility of monogenic hypertension. Genetic, epigenetic and non-genetic factors are all possible mechanisms influencing phenotypic diversity. Genetic sequencing is a precise and efficient method that can broaden the mutant gene spectrum of the disease and is very helpful for understanding the pathophysiology of monogenic hypertension. Genetic sequencing, along with biochemical tests and imaging modalities, is essential for the early diagnosis and targeted management of monogenic hypertension to avoid long-term catastrophic complications.
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BACKGROUND: Hypertension and brachydactyly syndrome (HTNB), also called Bilginturan syndrome, is a rare autosomal dominant disorder characterized by severe salt-independent hypertension, a short stature, brachydactyly, and death from stroke before the age of 50 years when untreated. The purpose of the present study was to identify a PDE3A mutation leading to HTNB associated with vertebral artery malformation in a Chinese family. METHODS: Peripheral blood samples were collected from all subjects for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the PDE3A mutation. A comparative overview was performed in the probands with HTNB caused by PDE3A mutations. RESULTS: Genetic analysis identified a missense mutation in PDE3A, c.1346G>A, in the proband with HTNB. This mutation, resulting in p.Gly449Asp, was located in a highly conserved domain and predicted to be damaging by different bioinformatics tools. Cosegregation analyses showed that the proband inherited the identified mutation from her father. Antihypertensive therapy was effective for the proband. Comparative overview of HTNB probands with 9 different PDE3A mutations revealed phenotypic heterogeneity. CONCLUSIONS: Genetic screening can significantly improve the diagnosis of HTNB patients at an early age. Our study not only adds to the spectrum of PDE3A mutations in the Chinese population and extends the phenotype of HTNB patients to include vertebral malformation but also improves the awareness of pathogenesis in HTNB patients. We emphasize the importance of antihypertensive treatment and long-term follow-up to prevent stroke and adverse cardiovascular events.
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Pressão Sanguínea/genética , Braquidactilia/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Hipertensão/congênito , Mutação de Sentido Incorreto , Artéria Vertebral/anormalidades , Braquidactilia/diagnóstico , Braquidactilia/fisiopatologia , Braquidactilia/terapia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , Hipertensão/fisiopatologia , Hipertensão/terapia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Artéria Vertebral/diagnóstico por imagem , Adulto JovemRESUMO
Objective@#To analyze knowledge, attitudes and practice regarding protection against COVID-19 among primary and middle school students in Hangzhou and to provide a scientific basis for schools to carry out targeted prevention and control measures.@*Methods@#Anonymous network sampling survey was carried out through the questionnaire star, and a total of 14 216 subjects from primary and middle school in Hangzhou were recruited to fill in the questionnaire regarding knowledge, attitudes and practice of COVID-19 from March 3 to March 7, 2020.@*Results@#Primary and middle school students showed high awareness rate of transmission (85.83%) and incubation period (77.44%), but lower awareness on symptoms (44.70%) of COVID-19. The practice of wearing masks, cough etiquette and correct hand washing were 97.27%, 88.01% and 91.82%, respectively. The protective practice among primary and middle school students were generally good, 91.21% of them were at moderate level or above. 83.91% of primary and secondary school students reported worries about infection of COVID-19, and 55.42% of primary and secondary school students were anxious about returning to school. Primary school students and rural students were more anxious about returning to school(χ 2=46.66, 26.70, P<0.05).@*Conclusion@#The primary and middle school students in Hangzhou have a relatively good level of knowledge and practice concerning COVID-19. Yet, it is necessary to carry out targeted health education and strengthen mental health education for primary and middle school students.