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1.
Sci Rep ; 10(1): 901, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31965015

RESUMO

This study examines the association between aerobic capacity and biomarkers of skeletal- and cardiac muscle damage among amateur triathletes after a full distance Ironman. Men and women (N = 55) were recruited from local sport clubs. One month before an Ironman triathlon, they conducted a 20 m shuttle run test to determine aerobic capacity. Blood samples were taken immediately after finishing the triathlon, and analyzed for cardiac Troponin T (cTnT), Myosin heavy chain-a (MHC-a), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), Creatin Kinas (CK), and Myoglobin. Regression models examining the association between the biomarkers and aerobic capacity expressed in both relative terms (mLO2*kg-1*min-1) and absolute terms (LO2*min-1) controlled for weight were fitted. A total of 39 subjects (26% females) had complete data and were included in the analysis. No association between aerobic capacity and cardiac muscle damage was observed. For myoglobin, adding aerobic capacity (mLO2*kg-1*min-1) increased the adjusted r2 from 0.026 to 0.210 (F: 8.927, p = 0.005) and for CK the adjusted r2 increased from -0.015 to 0.267 (F: 13.778, p = 0.001). In the models where aerobic capacity was entered in absolute terms the adjusted r2 increased from 0.07 to 0.227 (F: 10.386, p = 0.003) for myoglobin and for CK from -0.029 to 0.281 (F: 15.215, p < 0.001). A negative association between aerobic capacity and skeletal muscle damage was seen but despite the well-known cardio-protective health effect of high aerobic fitness, no such association could be observed in this study.


Assuntos
Corrida/lesões , Adulto , Biomarcadores/sangue , Aptidão Cardiorrespiratória/fisiologia , Creatina Quinase/sangue , Feminino , Coração/fisiopatologia , Traumatismos Cardíacos/etiologia , Traumatismos Cardíacos/fisiopatologia , Humanos , Masculino , Miocárdio/metabolismo , Mioglobina/sangue , Cadeias Pesadas de Miosina/sangue , Peptídeo Natriurético Encefálico/sangue , Consumo de Oxigênio , Fragmentos de Peptídeos/sangue , Corrida/fisiologia , Troponina T/sangue
2.
J Cell Physiol ; 235(3): 2478-2491, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31489966

RESUMO

Thoracic aortic aneurysm (TAA), a serious cardiovascular disease that causes morbidity and mortality worldwide. At present, few biomarkers can accurately diagnose the appearance of TAA before dissection or rupture. Our research has the intention to investigate the developing applicable biomarkers for TAA promising clinically diagnostic biomarkers or probable regulatory targets for TAA. In our research, we built correlation networks utilizing the expression profile of peripheral blood mononuclear cell obtained from a public microarray data set (GSE9106). Furthermore, we chose the turquoise module, which has the strongest significance with TAA and was further analyzed. Fourteen genes that overlapped with differentially expressed proteins in the medial aortic layer were obtained. Subsequently, we verified the results applying quantitative polymerase chain reaction (Q-PCR) to our clinical specimen. In general, the Q-PCR results coincide with the majority of the expression profile. Fascinatingly, a notable change occurred in CLU, DES, MYH10, and FBLN5. In summary, using weighted gene coexpression analysis, our study indicates that CLU, DES, MYH10, and FBLN5 were identified and validated to be related to TAA and might be candidate biomarkers or therapeutic targets for TAA.


Assuntos
Aneurisma da Aorta Torácica/sangue , Clusterina/sangue , Desmina/sangue , Proteínas da Matriz Extracelular/sangue , Cadeias Pesadas de Miosina/sangue , Miosina não Muscular Tipo IIB/sangue , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/patologia , Biomarcadores/sangue , Proteínas da Matriz Extracelular/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Transcriptoma/genética
3.
Medicine (Baltimore) ; 97(36): e12100, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30200092

RESUMO

BACKGROUND: Both euthyroid sick syndrome and myocardial ischemia-reperfusion injury are common and have been significantly associated with morbidity and mortality after pediatric cardiac surgery with cardiopulmonary bypass. This single-center, prospective, double-blind, randomized placebo-controlled clinical pilot trial was designed to assess if preoperative oral thyroid hormone therapy could prevent the occurrence of euthyroid sick syndrome (ESS) and attenuate myocardial ischemia-reperfusion injury (IRI) after cardiac surgery with cardiopulmonary bypass (CPB) in children. METHODS: Forty children aged 3 to 12 year, scheduled for elective congenital heart disease repair surgery with CPB, were randomized into 2 groups of equal size to receive the following treatments in a double-blind manner: placebo (control group) and thyroid tablet 0.4 mg/kg (trial group) taken orally once a day for 4 days before surgery. The perioperative serum thyroid hormone levels and hemodynamic variables were determined. The extubation time, duration of intensive care unit (ICU) stay, and use of inotropic drugs in the ICU were recorded. The myocardial expressions of heat shock protein 70 (HSP70), myosin heavy chain (MHC) mRNA, and thyroid hormone receptor (TR) mRNA were detected. The serum creatine kinase-MB (CK-MB) activity and troponin I (TnI) positive ratio at 24 hour after surgery were assessed. RESULTS: There were no significant differences in hemodynamic variables at all observed points, extubation time, and duration of ICU stay between groups. As compared with baselines on administration, serum triiodothyronine (T3) and free T3 (FT3) levels on the first, second, and fourth postoperative day, and serum thyrotropic-stimulating hormone (TSH), tetraiodothyronine (T4), and free T4 (FT4) levels on the first postoperative day were significantly decreased in the 2 groups. Serum T3, FT3, and T4 levels on the first and second postoperative day, and serum FT4 level on the first postoperative day were significantly higher in the trial group than in control group. As compared with the control group, the number of patients requiring inotropic drugs in the ICU, serum CK-MB activity, serum positive TnI ratio, and myocardial expression of MHCß mRNA were significantly decreased, and myocardial expressions of both HSP70 and MHCα mRNA were significantly increased in the trial group. CONCLUSIONS: In children undergoing cardiac surgery with CPB, preoperative oral small-dose thyroid hormone therapy reduces severity of postoperative ESS and provides a protection against myocardial IRI by increasing HSP70 and MHCα expression.


Assuntos
Ponte Cardiopulmonar , Síndromes do Eutireóideo Doente/prevenção & controle , Cuidados Intraoperatórios , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Hormônios Tireóideos/administração & dosagem , Administração Oral , Biomarcadores/sangue , Criança , Pré-Escolar , Método Duplo-Cego , Procedimentos Cirúrgicos Eletivos , Síndromes do Eutireóideo Doente/sangue , Feminino , Proteínas de Choque Térmico HSP70/sangue , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/cirurgia , Humanos , Tempo de Internação , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Cadeias Pesadas de Miosina/sangue , Projetos Piloto , Hormônios Tireóideos/sangue , Resultado do Tratamento
4.
Am J Physiol Heart Circ Physiol ; 315(4): H1012-H1018, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30004237

RESUMO

Abdominal aortic aneurysm (AAA) is a life-threatening disease, and no disease-specific circulating biomarkers for AAA screening are currently available. We have identified a smooth muscle cell (SMC)-specific biomarker for AAA. We cultured aneurysmal tunica media that were collected from eight patients undergoing elective open-repair surgeries. Secreted proteins in culture medium were subjected to liquid chromatography/tandem mass spectrometry. Myosin heavy chain 11 (myosin-11) was identified as a SMC-specific protein in the tunica media-derived secretions of all patients. We then examined myosin-11 protein concentrations by ELISA in plasma samples from patients with AAA ( n = 35) and age-matched healthy control subjects ( n = 34). Circulating myosin-11 levels were significantly higher in patients with AAA than control subjects. The area under the receiver-operating characteristic curve (AUC) of myosin-11 was 0.77, with a specificity of 65% at a sensitivity of 91%. Multivariate logistic regression analysis showed a significant association between the myosin-11 level and presence of AAA. When the myosin-11 level was combined with hypertension, it improved the prediction of AAA (AUC 0.88) more than hypertension per se. We then investigated the correlation between aortic diameter and circulating myosin-11 levels using AAA serum samples from patients undergoing endovascular aneurysm repair ( n = 20). Circulating myosin-11 levels were significantly correlated with maximum aortic diameter. Furthermore, changes in myosin-11 concentrations from the baseline 12 mo after endovascular aneurysm repair were associated with those in aortic diameter. These data suggest that circulating levels of myosin-11, which is a SMC-specific myosin isoform, may be useful as a biomarker for AAA. NEW & NOTEWORTHY Extensive studies have revealed that inflammation- or proteolysis-related proteins are proposed as biomarkers for abdominal aortic aneurysm (AAA). Changes in these protein concentrations are not specific for smooth muscle, which is a major part of AAA pathologies. Hence, no disease-specific circulating markers for AAA are currently available. We found, using secretome-based proteomic analysis on human AAA tunica media, that myosin heavy chain 11 was associated with AAA. Circulating myosin heavy chain 11 may be a new tissue-specific AAA marker.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Proteômica/métodos , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/patologia , Biomarcadores/sangue , Estudos de Casos e Controles , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Cadeias Pesadas de Miosina/sangue , Espectrometria de Massas em Tandem , Técnicas de Cultura de Tecidos
5.
Platelets ; 29(8): 793-800, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29090586

RESUMO

MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (döhle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if döhle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.


Assuntos
Plaquetas/metabolismo , Perda Auditiva Neurossensorial/genética , Mutação , Cadeias Pesadas de Miosina/genética , Púrpura Trombocitopênica Idiopática/genética , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/congênito , Trombopoetina/uso terapêutico , Adulto , Australásia , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Tamanho Celular , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Genes Dominantes , Perda Auditiva Neurossensorial/sangue , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Corpos de Inclusão/efeitos dos fármacos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Masculino , Volume Plaquetário Médio , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/sangue , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/genética
6.
Res Sports Med ; 24(3): 287-97, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27379471

RESUMO

We investigated alternatives to commonly used biomarkers of exercise-induced tissue damage. Over 5 days following two bouts of 100 drop-to-vertical jumps (inter-bout rest period of 3 weeks), myosin heavy chain 1, hydroxylysine (HYL), hydroxyproline (HYP), spermine (SPM) and spermine synthase (SMS) were measured in the serum of 10 participants. HYL significantly increased from 5.92 ± 1.49 ng/mL to 6.48 ± 1.47 ng/mL at 24 h. A similar trend was observed for bout 2, but without reaching significance. SPM significantly increased only after bout 1 from 0.96 ± 0.19 ng/mL at pretest to a peak level of 1.12 ± 0.26 ng/mL at 24 h, while B2 increments remained non-significant. Myosin heavy chain 1, HYP and SMS values remained below the detection limit of the applied enzyme-linked immunosorbent assay (ELISA) kit. Though HYL and SM increased after the intervention, both markers showed a large standard deviation (SD) combined with small increments. Therefore, none of the investigated biomarkers provides a meaningful alternative to commonly used damage markers.


Assuntos
Exercício Físico/fisiologia , Músculo Esquelético/patologia , Neutrófilos , Adulto , Biomarcadores/sangue , Humanos , Hidroxilisina/sangue , Hidroxiprolina/sangue , Contagem de Leucócitos , Masculino , Mialgia/sangue , Mialgia/etiologia , Cadeias Pesadas de Miosina/sangue , Espermina/sangue , Espermina Sintase/sangue , Adulto Jovem
8.
PLoS One ; 10(8): e0133132, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26241864

RESUMO

Familial hypertrophic cardiomyopathy (HCM) is attributed to mutations in genes that encode for the sarcomere proteins, especially Mybpc3 and Myh7. Genotype-phenotype correlation studies show significant variability in HCM phenotypes among affected individuals with identical causal mutations. Morphological changes and clinical expression of HCM are the result of interactions with modifier genes. With the exceptions of angiotensin converting enzyme, these modifiers have not been identified. Although mouse models have been used to investigate the genetics of many complex diseases, natural murine models for HCM are still lacking. In this study we show that the DBA/2J (D2) strain of mouse has sequence variants in Mybpc3 and Myh7, relative to widely used C57BL/6J (B6) reference strain and the key features of human HCM. Four-month-old of male D2 mice exhibit hallmarks of HCM including increased heart weight and cardiomyocyte size relative to B6 mice, as well as elevated markers for cardiac hypertrophy including ß-myosin heavy chain (MHC), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and skeletal muscle alpha actin (α1-actin). Furthermore, cardiac interstitial fibrosis, another feature of HCM, is also evident in the D2 strain, and is accompanied by up-regulation of type I collagen and α-smooth muscle actin (SMA)-markers of fibrosis. Of great interest, blood pressure and cardiac function are within the normal range in the D2 strain, demonstrating that cardiac hypertrophy and fibrosis are not secondary to hypertension, myocardial infarction, or heart failure. Because D2 and B6 strains have been used to generate a large family of recombinant inbred strains, the BXD cohort, the D2 model can be effectively exploited for in-depth genetic analysis of HCM susceptibility and modifier screens.


Assuntos
Cardiomiopatia Hipertrófica Familiar/genética , Proteínas de Transporte/genética , Modelos Animais de Doenças , Camundongos Endogâmicos DBA/genética , Cadeias Pesadas de Miosina/genética , Actinas/sangue , Animais , Biomarcadores , Pressão Sanguínea , Cardiomiopatia Hipertrófica Familiar/sangue , Cardiomiopatia Hipertrófica Familiar/diagnóstico por imagem , Cardiomiopatia Hipertrófica Familiar/patologia , Fibrose , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/patologia , Miofibroblastos/patologia , Cadeias Pesadas de Miosina/sangue , Peptídeos Natriuréticos/sangue , Fenótipo , RNA Mensageiro/biossíntese , Ultrassonografia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia
9.
Europace ; 17(10): 1563-70, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25851726

RESUMO

AIM: Long-term right ventricular apical (RVA) pacing may lead to left ventricular (LV) remodelling and heart failure. This study assessed changes in the expression of genes regulating LV contractile function and hypertrophy, after permanent RVA pacing and investigated whether such changes proceed or even predict LV remodelling. METHODS AND RESULTS: We enrolled 52 consecutive patients (age 79.1 ± 7.7 years, 34 males) who underwent pacemaker implantation for bradycardic indications: Group A, 24 individuals with atrioventricular conduction disturbances and group B, 28 patients with sinus node disease. In group A, peripheral blood mRNA levels of gene sarcoplasmic reticulum calcium ATPase decreased at 3, 6, and 12 months' follow-up, while α-myosin heavy chain (MHC) decreased and ß-MHC increased until 6 months follow-up. In this group, 25% of patients demonstrated significant LV remodelling. At 4 years, LV end-systolic diameter increased from 29.67 ± 3.39 mm at baseline to 35.38 ± 4.22 mm, LV end-diastolic diameter increased from 50 ± 4.95 to 56.71 ± 5.52 mm, and ejection fraction declined from 63.04 ± 10.22 to 52.83 ± 10.81%. Early alterations in gene expression were associated with a deterioration in LV function and geometry that became apparent months later. In group B, echocardiographic indexes and mRNA levels of the evaluated genes demonstrated no statistically significant changes. CONCLUSIONS: Permanent RVA pacing in patients with preserved ejection fraction is associated with alterations in the expression of genes regulating LV contractile function and hypertrophy, measured in the peripheral blood. These alterations are traceable at an early stage, before echocardiographic changes are apparent and are associated with LV remodelling that becomes evident in the long term.


Assuntos
Miosinas Cardíacas/sangue , Ventrículos do Coração/fisiopatologia , Cadeias Pesadas de Miosina/sangue , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/sangue , Síndrome do Nó Sinusal/complicações , Função Ventricular Esquerda/genética , Remodelação Ventricular/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Bradicardia/terapia , Estimulação Cardíaca Artificial/métodos , Ecocardiografia , Feminino , Insuficiência Cardíaca/terapia , Humanos , Masculino , Marca-Passo Artificial , Estudos Prospectivos , Volume Sistólico
10.
Clin Chim Acta ; 446: 132-40, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25892673

RESUMO

BACKGROUND: Hypertrophic cardiomyopathy is a common genetic cardiac disease. Prevention and early diagnosis of this disease are very important. Because of the large number of causative genes and the high rate of mutations involved in the pathogenesis of this disease, traditional methods of early diagnosis are ineffective. METHODS: We developed a custom AmpliSeq panel for NGS sequencing of the coding sequences of ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TPM1, and CASQ2. A genetic analysis of student cohorts (with and without cardiomyopathy risk in their medical histories) and patients with cardiomyopathies was performed. For the statistical and bioinformatics analysis, Polyphen2, SIFT, SnpSift and PLINK software were used. To select genetic markers in the patients with cardiomyopathy and in the students of the high risk group, four additive models were applied. RESULTS: Our AmpliSeq custom panel allowed us to efficiently explore targeted sequences. Based on the score analysis, we detected three substitutions in the MYBPC3 and CASQ2 genes and six combinations between loci in the MYBPC3, MYH7 and CASQ2 genes that were responsible for cardiomyopathy risk in our cohorts. We also detected substitutions in the TNNT2 gene that can be considered as protective against cardiomyopathy. CONCLUSION: We used NGS with AmpliSeq libraries and Ion PGM sequencing to develop improved predictive information for patients at risk of cardiomyopathy.


Assuntos
Calsequestrina/genética , Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/diagnóstico , Proteínas de Transporte/genética , Dor no Peito/diagnóstico , Cadeias Pesadas de Miosina/genética , Software , Troponina T/genética , Adolescente , Adulto , Idoso , Calsequestrina/sangue , Miosinas Cardíacas/sangue , Cardiomiopatia Hipertrófica/sangue , Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/sangue , Dor no Peito/sangue , Dor no Peito/genética , Estudos de Coortes , Diagnóstico Precoce , Feminino , Expressão Gênica , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Cadeias Pesadas de Miosina/sangue , Fases de Leitura Aberta , Risco , Troponina T/sangue
11.
Toxicol Pathol ; 42(7): 1117-29, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24713317

RESUMO

This investigation examined microRNA-208a (miR-208a) as a potential biomarker of isoproterenol (ISO)-induced cardiac injury in superoxide dismutase-2 (Sod2(+/-) ) and the wild-type mice, and the potential sensitivity of Sod2(+/-) mice to ISO-induced toxicity. A single intraperitoneal injection of ISO was administered to age-matched wild-type and Sod2(+/-) mice at 0, 80, or 160 mg/kg. Plasma miR-208a, cardiac troponin I (cTnI), and ISO systemic exposure were measured at various time points postdose. Hearts were collected for histopathology examination and for tissue expression of miR-208a and myosin heavy chain 7. ISO administration caused increases in cTnI and miR-208a plasma levels that correlated with myocardial damage; however, the magnitude of increase differed according to the types of mice. At similar ISO systemic exposure, the magnitude of cTnI was greater in wild-type mice compared to Sod2(+/) (-) mice; however, the magnitude of miR-208a was greater in Sod2(+/-) mice than that of the wild-type mice. Myocardial degeneration occurred at ≥3 hr in the wild-type and ≥6 hr in Sod2(+/) (-) mice. At ≥24 hr after ISO administration, miR-208a appeared superior to cTnI in indicating myocardial injury in both wild-type and Sod2(+/-) mice. Sod2(+/-) mice were not more sensitive than wild-type mice to ISO-induced toxicity.


Assuntos
Biomarcadores/sangue , Coração/efeitos dos fármacos , Isoproterenol/toxicidade , MicroRNAs/sangue , Animais , Miosinas Cardíacas/sangue , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/patologia , Caspase 3/metabolismo , Feminino , Coração/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cadeias Pesadas de Miosina/sangue , Superóxido Dismutase/metabolismo , Troponina I/sangue
12.
Am J Respir Cell Mol Biol ; 49(5): 866-74, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23795611

RESUMO

Preterm birth is associated with inflammation of the fetal membranes (chorioamnionitis). We aimed to establish how chorioamnionitis affects the contractile function and phenotype of the preterm diaphragm. Pregnant ewes received intra-amniotic injections of saline or 10 mg LPS, 2 days or 7 days before delivery at 121 days of gestation (term = 150 d). Diaphragm strips were dissected for the assessment of contractile function after terminal anesthesia. The inflammatory cytokine response, myosin heavy chain (MHC) fibers, proteolytic pathways, and intracellular molecular signaling were analyzed using quantitative PCR, ELISA, immunofluorescence staining, biochemical assays, and Western blotting. Diaphragm peak twitch force and maximal tetanic force were approximately 30% lower than control values in the 2-day and 7-day LPS groups. Activation of the NF-κB pathway, an inflammatory response, and increased proteasome activity were observed in the 2-day LPS group relative to the control or 7-day LPS group. No inflammatory response was evident after a 7-day LPS exposure. Seven-day LPS exposure markedly decreased p70S6K phosphorylation, but no effect on other signaling pathways was evident. The proportion of MHC IIa fibers was lower than that for control samples in the 7-day LPS group. MHC I fiber proportions did not differ between groups. These results demonstrate that intrauterine LPS impairs preterm diaphragmatic contractility after 2-day and 7-day exposures. Diaphragm dysfunction, resulting from 2-day LPS exposure, was associated with a transient activation of proinflammatory signaling, with subsequent increased atrophic gene expression and enhanced proteasome activity. Persistently impaired contractility for the 7-day LPS exposure was associated with the down-regulation of a key component of the protein synthetic signaling pathway and a reduction in the proportions of MHC IIa fibers.


Assuntos
Corioamnionite/fisiopatologia , Diafragma/fisiopatologia , Lipopolissacarídeos , Contração Miocárdica , Animais , Corioamnionite/sangue , Corioamnionite/induzido quimicamente , Corioamnionite/imunologia , Citocinas/metabolismo , Diafragma/imunologia , Diafragma/metabolismo , Modelos Animais de Doenças , Feminino , Idade Gestacional , Mediadores da Inflamação/sangue , Fibras Musculares Esqueléticas/imunologia , Fibras Musculares Esqueléticas/metabolismo , Força Muscular , Atrofia Muscular/sangue , Atrofia Muscular/imunologia , Atrofia Muscular/fisiopatologia , Cadeias Pesadas de Miosina/sangue , NF-kappa B/metabolismo , Gravidez , Complexo de Endopeptidases do Proteassoma/metabolismo , Ovinos , Transdução de Sinais , Fatores de Tempo
13.
Proteomics ; 13(15): 2324-34, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23713052

RESUMO

In-depth proteomic analyses offer a systematic way to investigate protein alterations in disease and, as such, can be a powerful tool for the identification of novel biomarkers. Here, we analyzed proteomic data from a transgenic mouse model with cardiac-specific overexpression of activated calcineurin (CnA), which results in severe cardiac hypertrophy. We applied statistically filtering and false discovery rate correction methods to identify 52 proteins that were significantly different in the CnA hearts compared to controls. Subsequent informatic analysis consisted of comparison of these 52 CnA proteins to another proteomic dataset of heart failure, three available independent microarray datasets, and correlation of their expression with the human plasma and urine proteome. Following this filtering strategy, four proteins passed these selection criteria, including myosin heavy chain 7, insulin-like growth factor-binding protein 7, annexin A2, and desmin. We assessed expression levels of these proteins in mouse plasma by immunoblotting, and observed significantly different levels of expression between healthy and failing mice for all four proteins. We verified antibody cross-reactivity by examining human cardiac explant tissue by immunoblotting. Finally, we assessed protein levels in plasma samples obtained from four unaffected and four heart failure patients and demonstrated that all four proteins increased between twofold and 150-fold in heart failure. We conclude that MYH7, IGFBP7, ANXA2, and DESM are all excellent candidate plasma biomarkers of heart failure in mouse and human.


Assuntos
Anexina A2/sangue , Desmina/sangue , Insuficiência Cardíaca/sangue , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Cadeias Pesadas de Miosina/sangue , Animais , Biomarcadores/sangue , Calcineurina/genética , Calcineurina/metabolismo , Análise por Conglomerados , Bases de Dados Factuais , Modelos Animais de Doenças , Ventrículos do Coração/química , Humanos , Camundongos , Camundongos Transgênicos , Miocárdio/química , Neoplasias/metabolismo , Projetos Piloto , Proteômica
14.
Immunopharmacol Immunotoxicol ; 35(1): 71-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23083320

RESUMO

CONTEXT: Neutrophils are the primary effector cells in the pathogenesis of transfusion-related acute lung injury or multiple organ failure after blood transfusion. OBJECTIVE: We aimed to investigate the effect of fresh (1 day preparation) and aged (42 day preparation) PRBC-derived plasma on neutrophil morphology, migration and phagocytosis. MATERIALS AND METHODS: We evaluated the production of reactive oxygen species (ROS) and the expression of non-muscle myosin heavy chain IIA (MYH9) in neutrophils treated with PRBC-derived plasma. We used western blots and antibody arrays to evaluate changes in signal transduction pathways in plasma-treated neutrophils. RESULTS: Aged PRBC-derived plasma elicited a stronger oxidative burst in neutrophils when compared with fresh PRBC-derived plasma (p < 0.05). Antibody arrays showed increased phosphorylation of NF-ĸB proteins (p105, p50 and Ikk) in aged PRBC-derived plasma-treated neutrophils. The expression of non-muscle myosin IIA (MYH9), a cytoskeleton protein involved in immune cell migration and morphological change, was also significantly upregulated in neutrophils treated with aged PRBC-derived plasma compared to fresh plasma (p < 0.05). Pretreatment of neutrophils with blebbistatin (a specific type II myosin inhibitor), ascorbic acid (an antioxidant), or staurosporine (a protein tyrosine kinase inhibitor), effectively abrogated the morphological changes, neutrophil migration, and phagocytosis induced by aged PRBC-derived plasma. CONCLUSION: Upregulation of MYH9 in neutrophils treated with aged PRBC-derived plasma and abrogation of neutrophil migration in blebbistatin-treated neutrophils suggested a functional role of MYH9 in the directional migration of immune cells. Our data help elucidate the cellular and molecular mechanisms of transfusion-related injury.


Assuntos
Movimento Celular/fisiologia , Eritrócitos/metabolismo , Proteínas Motores Moleculares/sangue , Cadeias Pesadas de Miosina/sangue , Neutrófilos/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Movimento Celular/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Eritrócitos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Proteínas Motores Moleculares/antagonistas & inibidores , Cadeias Pesadas de Miosina/antagonistas & inibidores , NF-kappa B/metabolismo , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Miosina não Muscular Tipo IIA/antagonistas & inibidores , Miosina não Muscular Tipo IIA/sangue , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Explosão Respiratória/efeitos dos fármacos , Explosão Respiratória/fisiologia , Transdução de Sinais/efeitos dos fármacos , Estaurosporina/farmacologia
15.
J Thromb Haemost ; 10(8): 1653-61, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22672365

RESUMO

BACKGROUND: Inherited thrombocytopenias (ITs) are heterogeneous genetic disorders that frequently represent a diagnostic challenge. The requirement of highly specialized tests for diagnosis represents a particular problem in resource-limited settings. To overcome this difficulty, we applied a diagnostic algorithm and developed a collaboration program with a specialized international center in order to increase the diagnostic yield in a cohort of patients in Argentina. METHODS: Based on the algorithm, initial evaluation included collection of clinical data, platelet size, blood smear examination and platelet aggregation tests. Confirmatory tests were performed according to diagnostic suspicion, which included platelet glycoprotein expression, immunofluorescence for myosin-9 in granulocytes and platelet thrombospondin-1 and molecular screening of candidate genes. RESULTS: Thirty-one patients from 14 pedigrees were included; their median age was 32 (4-72) years and platelet count 72 (4-147)×10(9) L(-1). Autosomal dominant inheritance was found in nine (64%) pedigrees; 10 (71%) had large platelets and nine (29%) patients presented with syndromic forms. A definitive diagnosis was made in 10 of 14 pedigrees and comprised MYH9-related disease in four, while classic and monoallelic Bernard-Soulier syndrome, gray platelet syndrome, X-linked thrombocytopenia, thrombocytopenia 2 (ANKRD26 mutation) and familial platelet disorder with predisposition to acute myelogenous leukemia were diagnosed in one pedigree each. CONCLUSIONS: Adoption of an established diagnostic algorithm and collaboration with an expert referral center proved useful for diagnosis of IT patients in the setting of a developing country. This initiative may serve as a model to develop international networks with the goal of improving diagnosis and care of patients with these rare diseases.


Assuntos
Comportamento Cooperativo , Países em Desenvolvimento , Testes Genéticos , Testes Hematológicos , Cooperação Internacional , Trombocitopenia/diagnóstico , Adolescente , Adulto , Idoso , Algoritmos , Argentina , Biomarcadores/sangue , Criança , Pré-Escolar , Análise Mutacional de DNA , Estudos de Viabilidade , Feminino , Citometria de Fluxo , Imunofluorescência , Predisposição Genética para Doença , Testes Genéticos/métodos , Acessibilidade aos Serviços de Saúde , Testes Hematológicos/métodos , Hereditariedade , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Proteínas Motores Moleculares/sangue , Cadeias Pesadas de Miosina/sangue , Linhagem , Fenótipo , Contagem de Plaquetas , Testes de Função Plaquetária , Valor Preditivo dos Testes , Prognóstico , Encaminhamento e Consulta , Trombocitopenia/sangue , Trombocitopenia/congênito , Trombospondina 1/sangue , Adulto Jovem
16.
Clin Obstet Gynecol ; 55(2): 418-23, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22510623

RESUMO

Unless an ectopic pregnancy is visible by ultrasound, diagnosis can be a challenge. Differentiating ectopic pregnancies from intrauterine pregnancies can be impossible without intervention or follow-up. This poses a clinical dilemma to the practitioner given the inherent danger to the mother of tubal rupture of an ectopic pregnancy versus the fear of intervening in the case of a desired pregnancy without certainty of diagnosis. Early diagnostic modalities are clearly lacking, and serum biomarkers are currently being investigated as a solution to need for a rapid and accurate test for ectopic pregnancy.


Assuntos
Gravidez Ectópica/sangue , Gravidez Ectópica/diagnóstico , Proteínas ADAM/sangue , Proteína ADAM12 , Ativinas/sangue , Biomarcadores/sangue , Antígeno Ca-125/sangue , Gonadotropina Coriônica/sangue , Creatina Quinase/sangue , Estradiol/sangue , Feminino , Glicodelina , Glicoproteínas/sangue , Humanos , Inibinas/sangue , Interleucina-6/sangue , Interleucina-8/sangue , Fator Inibidor de Leucemia/sangue , Proteínas de Membrana/sangue , Mioglobina/sangue , Cadeias Pesadas de Miosina/sangue , Lactogênio Placentário/sangue , Gravidez , Proteínas da Gravidez/sangue , Proteína Plasmática A Associada à Gravidez/análise , Glicoproteínas beta 1 Específicas da Gravidez/análise , Progesterona/sangue , Proteoma , Relaxina/sangue , Renina/sangue , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/sangue
17.
Rev Med Interne ; 33(2): 99-102, 2012 Feb.
Artigo em Francês | MEDLINE | ID: mdl-22217922

RESUMO

INTRODUCTION: The MYH9 syndrome is a group of rare autosomal dominant platelet disorders associating in most of the cases a macrothrombocytopenia and characteristic leukocyte inclusions. Clinical features may include renal, visual, or hearing impairment. The bleeding tendency is usually moderate. CASE REPORT: We report a 28-year-old-man, with an auto-immune haemolytic anaemia associated with a MYH9 syndrome. CONCLUSION: To our knowledge, this is the first report of such an association.


Assuntos
Anemia Hemolítica Autoimune/genética , Proteínas Motores Moleculares/sangue , Proteínas Motores Moleculares/genética , Cadeias Pesadas de Miosina/sangue , Cadeias Pesadas de Miosina/genética , Adulto , Anemia Hemolítica Autoimune/sangue , Biomarcadores/sangue , Cromossomos Humanos Par 22/genética , Éxons , Regulação da Expressão Gênica , Humanos , Masculino , Mutação , Síndrome
18.
Arch Oral Biol ; 56(12): 1646-54, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21741618

RESUMO

OBJECTIVE: We studied adaptation of diaphragm and orofacial muscles as well as hormonal responses to forced oral breathing (lasting for only 4 days) following reversible bilateral nasal obstruction performed on day 8 post-natal male rats. DESIGN: Muscle myosin heavy chain (MHC) composition and hormone levels were analysed during two periods: 1 and 3 days after obstruction (days 9 and 11 post-natal), and following 3 months recovery with nasal breathing (90 days, adult). RESULTS: Diaphragm muscle showed significant increases in adult isoforms (MHC 1, 2a) in oral breathing group versus control. We observed increases in MHC neonatal and adult type 1 isoforms in muscles involved with oral breathing, masseter superficialis and anterior digastric. No changes were observed in the levator nasolabialis muscle involved with nasal breathing. Reversible nasal obstruction was associated with reduced growth of the olfactory bulbs lasting into adulthood, and an initial decrease in lung growth followed by recovery at 90 days. Adrenal hypertrophy was observed after 1 day of nasal obstruction and lasted into adulthood. The "stress" hormone response was variable, increased (over 1000%) during the obstruction but normal by adulthood. An increase in plasma testosterone was observed during the obstruction, and a decrease in thyroid hormone levels throughout. CONCLUSIONS: Very short term nasal obstruction, i.e. forced oral breathing, leads to long term hormonal changes and respiratory muscle fibre adaptation.


Assuntos
Adaptação Fisiológica , Diafragma/fisiopatologia , Músculos Faciais/fisiopatologia , Respiração Bucal , Cadeias Pesadas de Miosina/sangue , Bulbo Olfatório/fisiopatologia , Testosterona/sangue , Hormônios Tireóideos/sangue , Análise de Variância , Animais , Eletroforese em Gel de Ágar , Masculino , Obstrução Nasal , Ratos , Ratos Wistar
20.
J Am Coll Cardiol ; 56(19): 1535-41, 2010 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-21029872

RESUMO

Acute aortic syndromes have an incidence of >30 per million per annum and a high mortality without definitive treatment. Survival may relate to the speed of diagnosis. Although pain is the most common symptom, there is a large fraction of patients in whom the diagnosis may be mistaken or overlooked. Currently, a high index of clinical suspicion is the chief prompt that diverts a patient into a definitive algorithm of imaging investigations. Although there is no point-of-care biochemical test that can be reliably used to positively identify dissection, biomarkers are available that could accelerate the diagnostic pathway and thereby expedite treatment.


Assuntos
Aneurisma Aórtico/sangue , Aneurisma Aórtico/diagnóstico , Dissecção Aórtica/sangue , Dissecção Aórtica/diagnóstico , Doença Aguda , Dissecção Aórtica/terapia , Animais , Aneurisma Aórtico/terapia , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Elastina/sangue , Humanos , Cadeias Pesadas de Miosina/sangue
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