Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 89
Filtrar
1.
Heart ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608305

RESUMO

Metabolomics, the comprehensive measurement of low-molecular-weight molecules in biological fluids used for metabolic phenotyping, has emerged as a promising tool to better understand pathways underlying cardiovascular disease (CVD) and to improve cardiovascular risk stratification. Here, we present the main methodologies for metabolic phenotyping, the methodological steps to analyse these data in epidemiological settings and the associated challenges. We discuss evidence from epidemiological studies linking metabolites to coronary heart disease and stroke. These studies indicate the systemic nature of CVD and identify associated metabolic pathways such as gut microbial cometabolism, branched-chain amino acids, glycerophospholipid and cholesterol metabolism, as well as activation of inflammatory processes. Integration of metabolomic with genomic data can provide new evidence for involved biochemical pathways and potential for causality using Mendelian randomisation. The clinical utility of metabolic biomarkers for cardiovascular risk stratification in healthy individuals has not yet been established. As sample sizes with high-dimensional molecular data increase in epidemiological settings, integration of metabolomic data across studies and platforms with other molecular data will lead to new understanding of the metabolic processes underlying CVD and contribute to identification of potentially novel preventive and pharmacological targets. Metabolic phenotyping offers a powerful tool in the characterisation of the molecular signatures of CVD, paving the way to new mechanistic understanding and therapies, as well as improving risk prediction of CVD patients. However, there are still challenges to face in order to contribute to clinically important improvements in CVD.

2.
Ann Vasc Surg ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33508452

RESUMO

BACKGROUND: The study aimed to assess the effects of serum YKL-40 level on patency at the repair site in patients who underwent arterial repair at the level of the forearm. METHODS: The study included 58 subjects, including 29 patients (aged 18-50 years) who had ulnar or radial artery injury secondary to cut injury to wrist between June 2015 and November 2019 and no comorbid disease and 29 age- and sex-matched healthy controls. The vascular patency was assessed using Doppler sonography in patients who underwent arterial repair at the level of the forearm. The patients were defined as flow failure if the blood flow was ≤50%, and sufficient flow if the blood flow was >50% of those in the synonymous artery on the intact extremity. The YKL-40 level differences in the patient and control groups were compared to those in the sufficient and insufficient flow groups. RESULTS: The patients were stratified into 2 groups based on the presence of sufficient flow. The mean YKL level was 11.96 ± 8.87 in the sufficient flow groups, whereas it was 32.22 ± 15.43 in the insufficient flow groups (p= 0.038). Besides, it was found that each unit of increase in the YKL-40 level increased the likelihood of having flow failure by 1.128. CONCLUSION: Based on our results, it was observed that over-expression of the YKL-40 level has adverse effects on patency following arterial repair.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33374093

RESUMO

Objective: We aimed to evaluate the clinical, radiological and pathological findings of children and adolescents with thyroid nodules. Method: Data of 121 children and adolescent with thyroid nodule and had fine needle aspiration (FNA) were examined retrospectively. Concomitant thyroid disease, ultrasound (US) features of the nodule, FNA and histopathological results were recorded. FNA results were assessed according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Results: Median age of the cases was 14 years (range 3-18 years) and 81% were female. FNA results of patients were insufficient in 1 (0.8%), benign in 68 (56.2 %), indeterminate in 44 (36.4%) and malignant in 8 (6.6%) patients. Among 39 patients who were directed to surgery, 10 patients had differentiated thyroid cancer (DTC). The total malignancy rate was 10.0% (10/100). Control FNA results showed progress according to TBSRTC in 18.7% of benign results and 4 of 75 patients had DTC in surgical excision. 2 of 22 patients with atypia of undetermined significance (AUS) who continued follow-up was diagnosed with DTC. Male gender, presence of Hashimoto thyroiditis and US findings of uninodularity; hypoechogenicity; increased blood flow; irregular margins; solid structure; microcalcification and presence of abnormal cervical lymph nodes were associated with malignancy. Conclusion: Our results revealed that, thyroid nodules are 10% malignant in children and adolescents. Patients with AUS has 9% potential for malignancy and patients with initially benign FNA result may have changes in TBSTRC findings in repeat FNA with a 5.3% false negative rate.

4.
J Pediatr Urol ; 16(5): 635.e1-635.e7, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32891575

RESUMO

INTRODUCTION: Epididymal anomalies are common in boys with undescended testis. Epididymo-testicular non-union with a nubbin in the scrotum is a rare anomaly and may be confusing during management of cryptorchidism. The non-fused epididymis and vas deferens which are descended to the scrotum, may be regarded as nubbin tissue secondary to testicular atrophy and proximal testis may be overlooked. OBJECTIVE: To evaluate a relatively rare anomaly of epididymo-testicular non-union in which vas deferens and epididymis are descended to the scrotum resembling a nubbin tissue, while a separate testis remains in a proximal peritoneal fold (hernia or processus vaginalis)which could potentially be missed during the management of patients with undescended testis. STUDY DESIGN: The charts of the fourteen patients with epididymo-testicular non-union and a scrotal nubbin are retrospectively evaluated. RESULTS: Median age of the patiens was 1.5 years (0.5-12), 11 were left and 3 were right. No connection could be demonstrated between the testis and vaso-epididymal unit in any of the patients. Orchidopexy was performed in 13 patients while orchidectomy in1 patient. The scrotal nubbin tissue is excised in 4 patients and histological examination revealed sections of vas deferens and epididymis. One of the patients underwent inguinal exploration and orchidectomy for assumed testicular atrophy elsewhere but histological examination revealed vas deferens and epididymis without any sign suggesting an atrophic testis. An intrabdominal testis was found incidentally in this patient and he underwent 2 additional procedures for orchidopexy. DISCUSSION: Although epididymo-testicular anomalies are common in boys with undescended testis, nonunion is the rarest type of this anomaly. Similar cases are reported in the literature as simple fusion anomalies with indefinite clinical significance or even polyorchidism although no accessory testis could be demonstrated. However, the scrotal nubbin tissue which actually contains epididymis and vas is a potential decoy and may result in missing of the proximal testis if regarded as a sign of testicular atrophy and further evaluation is obviated. As this is retrospective study, actual incidence of the condition is yet to be determined. CONCLUSION: A scrotal nubbin tissue may be secondary to epididymo-testicular nonunion as well as testicular atrophy. As feasibility of radiological imaging studies are limited, a laparoscopic exploration may be considered to confirm or to exclude a separate testis in patients with scrotal nubbin. Prospective studies are needed to evaluate the actual incidence of the condition and gain-loss analysis of laparoscopic exploration.

5.
Acta Orthop Traumatol Turc ; 54(3): 320-329, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32544068

RESUMO

OBJECTIVE: This study aimed to determine the effects of a natural diterpenoid, kirenol, on fracture healing in vivo in an experimental rat model of femur fracture and investigate its potential mechanism of action via the Wnt/ß-catenin pathway. METHODS: In this study, 64 male Wistar albino rats aged 5-7 weeks and weighing 261-348 g were randomly divided into 8 groups from A to L, with eight rats in each group. Standardized fractures were created in the right femurs of the rats and then fixed with an intramedullary Kirschner wire. Four experimental groups were administered 2 mg/kg/day kirenol (Groups C and G) and 4 mg/kg/day (Groups D and H) kirenol by oral gavage.Thereafter, the animals were sacrificed at two time points as follows: on the 10th day (Groups B, C and D) and on the 21st day (Groups F, G and H) after the surgery; fracture healing in each group was assessed radiologically and histopathologically. The Radiographic Union scale of tibia fracture scoring system was used in the radiological examination; callus volume and density were measured using computed tomography. In the histopathologic examination, the scoring system described by Huo et al. was used. Additionally, the mechanism of action was evaluated based on the analyses of protein expression of Wnt3a, LRP5, TCF-LEF1, ß-catenin, and Runx-2 proteins using western blot analysis. RESULTS: Among the animals sacrificed on the 10th day after the surgery, the highest histopathological and radiological scores were observed in Group D (p<0.05). Furthermore, the callus density (p<0.05) was highest in Group D. Among the animals sacrificed on the 21st day, the highest histopathological and radiological scores were found in Group H, although the differences among the groups were not significant (p>0.05). The callus volume and density were the highest in Groups G and H, respectively, although the differences among groups were not significant. CONCLUSION: Kirenol may improve fracture healing in a dose-dependent manner with the early activation of the Wnt/ß-catenin pathway and the activation of the Runx-2 pathway.


Assuntos
Calo Ósseo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Diterpenos/farmacologia , Fraturas do Fêmur , Consolidação da Fratura , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Antirreumáticos/farmacologia , Calo Ósseo/diagnóstico por imagem , Calo Ósseo/efeitos dos fármacos , Calo Ósseo/metabolismo , Fraturas do Fêmur/metabolismo , Fraturas do Fêmur/cirurgia , Fixação Intramedular de Fraturas/métodos , Consolidação da Fratura/efeitos dos fármacos , Consolidação da Fratura/fisiologia , Masculino , Ratos , Ratos Wistar , Resultado do Tratamento
6.
Pediatr Surg Int ; 36(8): 959-963, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32405765

RESUMO

PURPOSE: Perinatal testicular torsion is a rare condition in which testicular salvage rates are significantly low and management is controversial. We retrospectively evaluated our patients and aimed to go through our management approach. METHODS: The newborn patients who underwent surgery for testicular torsion in two tertiary referral centers between 2000 and 2019 are enrolled. Radiological and clinical findings are retrospectively evaluated. RESULTS: Thirty-two newborns are enrolled in the study. All of the cases were unilateral and 30 ended up with immediate orchidectomy while 2 received orchidopexy but both underwent atrophy on follow-up. No bilateral torsion is demonstrated neither in 16 patients with bilateral exploration nor in the follow up of the rest 16 with unilateral exploration. Intravaginal torsion was encountered in five patients (16%). No morbidity or mortality related to anesthesia is documented. No malignancy is encountered in any of the patients. CONCLUSION: Although ipsilateral testicular salvage rates are low, urgent bilateral exploration in a multidisciplinary center seems reasonable to give a chance to the ipsilateral testis and to avoid the rare but catastrophic bilateral torsion, after discussing with the family.

7.
Aging Cell ; 19(6): e13149, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32363781

RESUMO

Markers of biological aging have potential utility in primary care and public health. We developed a model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry in urine and serum, within a large sample (N = 2,239) from the UK Airwave cohort. We validated a subset of model predictors in a Finnish cohort including repeat measurements from 2,144 individuals. We investigated the determinants of accelerated aging, including lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (mean r = .86 across independent test sets). Increased metabolomic age acceleration (mAA) was associated after false discovery rate (FDR) correction with overweight/obesity, diabetes, heavy alcohol use and depression. DNA methylation age acceleration measures were uncorrelated with mAA. Increased DNA methylation phenotypic age acceleration (N = 1,110) was associated after FDR correction with heavy alcohol use, hypertension and low income. In conclusion, metabolomics is a promising approach for the assessment of biological age and appears complementary to established epigenetic clocks.

8.
Jt Dis Relat Surg ; 31(1): 20-7, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160489

RESUMO

OBJECTIVES: This study aims to evaluate the effects of local adipose stem cell injection on non-union and diabetic non-union of rat femurs. MATERIALS AND METHODS: Forty-eight female Wistar albino rats (weighing mean 200 g and aged 8 weeks) were used in this study. The rats were divided into six groups. Group 1 was chosen as a reference for receptor activator of nuclear factor-kappa (κ) B (RANK), receptor activator of nuclear factor-κ B ligand (RANKL) and osteoprotegerin (OPG) genes and no femur osteotomy was performed in this group. Group 2 underwent femur osteotomy, the osteotomy was fixed with a 1.5 mm K-wire as retrograde from the knee joint, and no gap was left in the osteotomy line. In order to induce non-union, femurs underwent osteotomy fixed with K-wires in groups 3, 4, 5 and 6. In addition, the osteotomy line was measured as 1.8 mm gap with electronic calipers and the gap was fixed with U staple. Before osteotomy, streptozocin was injected intraperitoneally at a dose of 60 mg/kg in 0.1 mol/L citrate buffer solution (Ph 4.4) in groups 4 and 6, in order to induce diabetes mellitus. Left femur anteroposterior and lateral X-rays were taken 10 weeks after the operation and the union in group 2 and non-union in groups 3, 4, 5, and 6 were confirmed. To see if injection of adipose stem cells into the non-union site increases bone union, 2 mL 0.9% sodium chloride (NaCl) in groups 3 and 4 and 2×106 adipose stem cell in groups 5 and 6 were locally injected into the non-union area with fluoroscopy. Femur X-rays were taken eight weeks after the injection and all rats were sacrificed. Femurs of rats were removed for histopathological and gene expression evaluation. RESULTS: There were significant differences between the groups injected 0.9% NaCI and adipose stem cells in terms of bone healing according to radiological and histopathological evaluations (p<0.05). No statistically significant difference was observed between the groups in terms of gene expression levels. CONCLUSION: According to the results of our study, local adipose stem cell injection has positive radiological and histopathological effects in diabetic and non-diabetic femoral non-unions, independently of RANK, RANKL, or OPG gene expression pathways.


Assuntos
Adipócitos , Fêmur , Consolidação da Fratura/fisiologia , Fraturas não Consolidadas , Transplante de Células-Tronco/métodos , Adipócitos/metabolismo , Adipócitos/transplante , Animais , Feminino , Fêmur/lesões , Fêmur/metabolismo , Fêmur/cirurgia , Fraturas não Consolidadas/diagnóstico por imagem , Fraturas não Consolidadas/terapia , Osteoprotegerina/análise , Osteotomia/métodos , Osteotomia/estatística & dados numéricos , Ligante RANK/metabolismo , Ratos , Ratos Wistar , Receptor Ativador de Fator Nuclear kappa-B/análise
9.
Bioinformatics ; 36(9): 2862-2871, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31950989

RESUMO

MOTIVATION: Liquid chromatography-mass spectrometry (LC-MS) is a standard method for proteomics and metabolomics analysis of biological samples. Unfortunately, it suffers from various changes in the retention times (RT) of the same compound in different samples, and these must be subsequently corrected (aligned) during data processing. Classic alignment methods such as in the popular XCMS package often assume a single time-warping function for each sample. Thus, the potentially varying RT drift for compounds with different masses in a sample is neglected in these methods. Moreover, the systematic change in RT drift across run order is often not considered by alignment algorithms. Therefore, these methods cannot effectively correct all misalignments. For a large-scale experiment involving many samples, the existence of misalignment becomes inevitable and concerning. RESULTS: Here, we describe an integrated reference-free profile alignment method, neighbor-wise compound-specific Graphical Time Warping (ncGTW), that can detect misaligned features and align profiles by leveraging expected RT drift structures and compound-specific warping functions. Specifically, ncGTW uses individualized warping functions for different compounds and assigns constraint edges on warping functions of neighboring samples. Validated with both realistic synthetic data and internal quality control samples, ncGTW applied to two large-scale metabolomics LC-MS datasets identifies many misaligned features and successfully realigns them. These features would otherwise be discarded or uncorrected using existing methods. The ncGTW software tool is developed currently as a plug-in to detect and realign misaligned features present in standard XCMS output. AVAILABILITY AND IMPLEMENTATION: An R package of ncGTW is freely available at Bioconductor and https://github.com/ChiungTingWu/ncGTW. A detailed user's manual and a vignette are provided within the package. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Metabolômica , Espectrometria de Massas em Tandem , Algoritmos , Cromatografia Líquida , Proteômica , Software
10.
Eklem Hastalik Cerrahisi ; 30(3): 289-95, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31650927

RESUMO

OBJECTIVES: This study aims to assess the effects of the hematopoietic stem cells and endothelial progenitor cells in peripheral blood and monocyte cluster of differentiation (CD) 34, CD133 and CD309 expression levels on maturation at the repair site in patients who underwent forearm arterial repair. PATIENTS AND METHODS: This prospective study included 30 patients (23 males, 7 females; mean age 28.9±1.8 years; range, 18 to 49 years) with a well-defined cut at the wrist due to a stabbing injury but no comorbid condition who presented to the emergency department of our hospital between November 2014 and November 2017. Vascular patency was assessed by Doppler sonography in patients who underwent forearm arterial repair via micro-vascular techniques. The relationships between patency and hematopoietic stem and endothelial progenitor cell markers such as CD34, CD133 and CD309 were assessed by flow cytometry. RESULTS: The patients were divided into two groups according to presence of sufficient flow in the arteries repaired. The mean CD34 expression level was 72.09±3.00 in the group with maturation whereas it was 54.64±7.34 in the group without maturation, indicating a statistically significant difference (p<0.05). In addition, the likelihood of sufficient flow was increased by 1.075 per one unit increase in CD34 level. Resistive index values were significantly lower in the group with maturation and CD34 level was predictive for maturation of arterial repair. CONCLUSION: In the present study, the findings demonstrated that high CD34 expression level has favorable effects on maturation after arterial repair.


Assuntos
Células Progenitoras Endoteliais/fisiologia , Antebraço/irrigação sanguínea , Células-Tronco Hematopoéticas/fisiologia , Artéria Radial/lesões , Adolescente , Adulto , Biomarcadores , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Artéria Radial/fisiopatologia , Artéria Radial/cirurgia , Ferimentos Perfurantes/fisiopatologia , Traumatismos do Punho/fisiopatologia , Adulto Jovem
12.
Nat Commun ; 10(1): 3653, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409800

RESUMO

Urinary sodium and potassium excretion are associated with blood pressure (BP) and cardiovascular disease (CVD). The exact biological link between these traits is yet to be elucidated. Here, we identify 50 loci for sodium and 13 for potassium excretion in a large-scale genome-wide association study (GWAS) on urinary sodium and potassium excretion using data from 446,237 individuals of European descent from the UK Biobank study. We extensively interrogate the results using multiple analyses such as Mendelian randomization, functional assessment, co localization, genetic risk score, and pathway analyses. We identify a shared genetic component between urinary sodium and potassium expression and cardiovascular traits. Ingenuity pathway analysis shows that urinary sodium and potassium excretion loci are over-represented in behavioural response to stimuli. Our study highlights pathways that are shared between urinary sodium and potassium excretion and cardiovascular traits.


Assuntos
Doenças Cardiovasculares/genética , Estudo de Associação Genômica Ampla , Potássio/urina , Sódio/urina , Pressão Sanguínea , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/urina , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
13.
Methods Mol Biol ; 2037: 453-470, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31463860

RESUMO

NMR data from large studies combining multiple cohorts is becoming common in large-scale metabolomics. The data size and combination of cohorts with diverse properties leads to special problems for data processing and analysis. These include alignment, normalization, detection and removal of outliers, presence of strong correlations, and the identification of unknowns. Nonetheless, these challenges can be addressed with suitable algorithms and techniques, leading to enhanced data sets ripe for further data mining.


Assuntos
Algoritmos , Biomarcadores/análise , Espectroscopia de Ressonância Magnética/métodos , Redes e Vias Metabólicas , Metabolômica/métodos , Estudos de Coortes , Humanos
14.
Nat Hum Behav ; 3(9): 950-961, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358974

RESUMO

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Genes/genética , Predisposição Genética para Doença/genética , Transtornos Mentais/genética , Adulto , Idoso , Alcoolismo/genética , Encéfalo/fisiopatologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genes/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Esquizofrenia/genética
15.
Ann Ital Chir ; 90: 264-268, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354154

RESUMO

AIMS: This study aimed to examine the correlation between DTI, clinical assessment, and electromyography results in patients who underwent primary median nerve repair. METHODS: Ten patients who underwent primary repair of the complete median nerve transection were included. Study assessments were performed on both the traumatized and non-traumatized extremities and patients were followed up for a minimum duration of 11 months. Clinical assessments, (Tinnel test, static 2-point discrimination test, motor and quality of life assessments), electromyography and DTI were performed. RESULTS: None of the clinical or electromyographic parameters correlated significantly with any of the diffusion tensor imaging parameters, i.e. fractional anisotropy (FA) or apparent diffusion coefficient (ADC) (p>0.05 for all). In addition, The Disabilities of the Arm, Shoulder and Hand (DASH) scores did not correlate with either FA (r=0.55, p=0.098) or ADC (r=0.40, p=0.260) values. However, Tinnel positive cases (n=3) had lower relative FA when compared to Tinnel negative cases (n=7) (-0.11±0.19 vs. 0.05±0.04, p=0.033). CONCLUSION: Our findings do not support the presence of relations between DTI parameters and electromyographic or most of the clinical parameters. Further MRI studies with larger numbers of patients with complete transection of the median nerve using the novel imaging parameters are warranted. KEY WORDS: Diffusion Tensor Imaging (DTI), Electromyography (EMG), Median nerve, Nerve injury, Nerve repair.


Assuntos
Imagem de Tensor de Difusão , Nervo Mediano/diagnóstico por imagem , Nervo Mediano/lesões , Adulto , Correlação de Dados , Feminino , Humanos , Masculino , Ferimentos e Lesões/diagnóstico por imagem , Ferimentos e Lesões/cirurgia , Adulto Jovem
16.
Eur Heart J ; 40(34): 2883-2896, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31102408

RESUMO

AIMS: To characterize serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease (CVD). METHODS AND RESULTS: We used untargeted one-dimensional (1D) serum metabolic profiling by proton nuclear magnetic resonance spectroscopy (1H NMR) among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 participants from the Rotterdam and LOLIPOP studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 1H NMR measured metabolites were associated with CAC and/or IMT, P = 1.3 × 10-14 to 1.0 × 10-6 (discovery) and P = 5.6 × 10-10 to 1.1 × 10-2 (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine, and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide, and lactate as well as apolipoprotein B (P < 0.05). CONCLUSION: Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclerosis.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/metabolismo , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/metabolismo , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças das Artérias Carótidas/sangue , Doença da Artéria Coronariana/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Espectroscopia de Prótons por Ressonância Magnética
17.
J Am Heart Assoc ; 8(9): e010810, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31017036

RESUMO

Background Identifying associations between serum metabolites and visceral adipose tissue ( VAT ) could provide novel biomarkers of VAT and insights into the pathogenesis of obesity-related diseases. We aimed to discover and replicate metabolites reflecting pathways related to VAT . Methods and Results Associations between fasting serum metabolites and VAT area (by computed tomography or magnetic resonance imaging) were assessed with cross-sectional linear regression of individual-level data from participants in MESA (Multi-Ethnic Study of Atherosclerosis; discovery, N=1103) and the NEO (Netherlands Epidemiology of Obesity) study (replication, N=2537). Untargeted 1H nuclear magnetic resonance metabolomics profiling of serum was performed in MESA, and metabolites were replicated in the NEO study using targeted 1H nuclear magnetic resonance spectroscopy. A total of 30 590 metabolomic spectral variables were evaluated. After adjustment for age, sex, race/ethnicity, socioeconomic status, smoking, physical activity, glucose/lipid-lowering medication, and body mass index, 2104 variables representing 24 nonlipid and 49 lipid/lipoprotein subclass metabolites remained significantly associated with VAT ( P=4.88×10-20-1.16×10-3). These included conventional metabolites, amino acids, acetylglycoproteins, intermediates of glucose and hepatic metabolism, organic acids, and subclasses of apolipoproteins, cholesterol, phospholipids, and triglycerides. Metabolites mapped to 31 biochemical pathways, including amino acid substrate use/metabolism and glycolysis/gluconeogenesis. In the replication cohort, acetylglycoproteins, branched-chain amino acids, lactate, glutamine (inversely), and atherogenic lipids remained associated with VAT ( P=1.90×10-35-8.46×10-7), with most associations remaining after additional adjustment for surrogates of VAT (glucose level, waist circumference, and serum triglycerides), reflecting novel independent associations. Conclusions We identified and replicated a metabolite panel associated with VAT in 2 community-based cohorts. These findings persisted after adjustment for body mass index and appear to define a metabolic signature of visceral adiposity.


Assuntos
Gordura Intra-Abdominal/metabolismo , Metabolômica , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/sangue , Aminoácidos de Cadeia Ramificada/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Gluconeogênese , Glutamina/sangue , Glicólise , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Ácido Láctico/sangue , Modelos Lineares , Imagem por Ressonância Magnética , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Tamanho do Órgão , Espectroscopia de Prótons por Ressonância Magnética , Tomografia Computadorizada por Raios X , Triglicerídeos/sangue
18.
Gigascience ; 8(2)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535405

RESUMO

BACKGROUND: Metabolomics is the comprehensive study of a multitude of small molecules to gain insight into an organism's metabolism. The research field is dynamic and expanding with applications across biomedical, biotechnological, and many other applied biological domains. Its computationally intensive nature has driven requirements for open data formats, data repositories, and data analysis tools. However, the rapid progress has resulted in a mosaic of independent, and sometimes incompatible, analysis methods that are difficult to connect into a useful and complete data analysis solution. FINDINGS: PhenoMeNal (Phenome and Metabolome aNalysis) is an advanced and complete solution to set up Infrastructure-as-a-Service (IaaS) that brings workflow-oriented, interoperable metabolomics data analysis platforms into the cloud. PhenoMeNal seamlessly integrates a wide array of existing open-source tools that are tested and packaged as Docker containers through the project's continuous integration process and deployed based on a kubernetes orchestration framework. It also provides a number of standardized, automated, and published analysis workflows in the user interfaces Galaxy, Jupyter, Luigi, and Pachyderm. CONCLUSIONS: PhenoMeNal constitutes a keystone solution in cloud e-infrastructures available for metabolomics. PhenoMeNal is a unique and complete solution for setting up cloud e-infrastructures through easy-to-use web interfaces that can be scaled to any custom public and private cloud environment. By harmonizing and automating software installation and configuration and through ready-to-use scientific workflow user interfaces, PhenoMeNal has succeeded in providing scientists with workflow-driven, reproducible, and shareable metabolomics data analysis platforms that are interfaced through standard data formats, representative datasets, versioned, and have been tested for reproducibility and interoperability. The elastic implementation of PhenoMeNal further allows easy adaptation of the infrastructure to other application areas and 'omics research domains.


Assuntos
Metabolômica/métodos , Software , Computação em Nuvem , Humanos , Fluxo de Trabalho
20.
Nat Genet ; 50(10): 1412-1425, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224653

RESUMO

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.


Assuntos
Pressão Sanguínea/genética , Locos de Características Quantitativas , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Células Cultivadas , Feminino , Loci Gênicos , Predisposição Genética para Doença , Testes Genéticos/métodos , Genética Populacional/métodos , Estudo de Associação Genômica Ampla , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/genética , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA