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1.
Mod Pathol ; 32(7): 943-956, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30737471

RESUMO

Patients with head and neck squamous cell carcinoma are at increased risk of developing a second primary malignancy, which is associated with poor prognosis and early death. To help improve clinical outcome, we aimed to identify biomarkers for second primary malignancy risk prediction using the routinely obtained formalin-fixed paraffin-embedded tissues of the index head and neck cancer. Liquid chromatography-tandem mass spectrometry was initially performed for candidate biomarker discovery in 16 pairs of primary cancer tissues and their matched normal mucosal epithelia from head and neck squamous cell carcinoma patients with or without second primary malignancy. The 32 candidate proteins differentially expressed between head and neck cancers with and without second primary malignancy were identified. Among these, 30 selected candidates and seven more from literature review were further studied using NanoString nCounter gene expression assay in an independent cohort of 49 head and neck cancer patients. Focusing on the p16-negative cases, we showed that a multivariate logistic regression model comprising the expression levels of ITPR3, KMT2D, EMILIN1, and the patient's age can accurately predict second primary malignancy occurrence with 88% sensitivity and 75% specificity. Furthermore, using Cox proportional hazards regression analysis and survival analysis, high expression levels of ITPR3 and DSG3 were found to be significantly associated with shorter time to second primary malignancy development (log-rank test P = 0.017). In summary, we identified a set of genes whose expressions may serve as the prognostic biomarkers for second primary malignancy occurrence in head and neck squamous cell carcinomas. In combination with the histopathologic examination of index tumor, these biomarkers can be used to guide the optimum frequency of second primary malignancy surveillance, which may lead to early diagnosis and better survival outcome.

2.
Am J Hum Genet ; 103(5): 691-706, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388399

RESUMO

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

3.
BMC Complement Altern Med ; 18(1): 258, 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30249222

RESUMO

BACKGROUND: For decades, various cardiovascular symptoms have been relieved by the use of Ya-Hom Navakot, which is a formulation comprising 54 herbal medicines. The Thailand Ministry of Public Health listed Ya-Hom Navakot's nine active principle and nomenclative herbal ingredients and termed them 'Phikud Navakot' (PN). Several reports have confirmed that PN has cardiovascular benefits similar to Ya-Hom Navakot. However, whether PN facilitates lipid-lowering activity remains unclear. METHODS: The present study investigated an in vitro model for examining the gene expression levels of 3-hydroxyl-3-methylglutaryl-CoA reductase (HMGCR) and low-density lipoprotein receptor (LDL-R) in HepG2 cells using qRT-PCR. The ethanol and water extractions of Ya-Hom Navakot, PN and Ya-Hom Navakot without PN were compared. RESULTS: One mg/ml of both NYEF and NYWF were found to significantly lower cholesterol by either the up-regulation of LDL-R or down-regulation of HMGCR compared with negative controls and 1 mg/ml simvastatin (p < 0.05). PNEF also up-regulated LDL-R gene expression, even more than NYEF (p < 0.05). In addition, the ethanol and water extracts of PN significantly down-regulated HMGCR gene expression compared with those of Ya-Hom Navakot without PN (p < 0.05). CONCLUSION: The use of Ya-Hom Navakot or PN may provide an alternative treatment to lower cholesterol through HMGCR gene inhibition and LDL-R gene enhancement.


Assuntos
Anticolesterolemiantes/farmacologia , Expressão Gênica/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/metabolismo , Extratos Vegetais/farmacologia , Receptores de LDL/metabolismo , Anticolesterolemiantes/toxicidade , Colesterol/sangue , Células Hep G2 , Humanos , Hidroximetilglutaril-CoA Redutases/análise , Hidroximetilglutaril-CoA Redutases/genética , Extratos Vegetais/toxicidade , Receptores de LDL/análise , Receptores de LDL/genética , Sinvastatina/farmacologia
4.
BMC Med Genet ; 19(1): 23, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29439659

RESUMO

BACKGROUND: Imputation involves the inference of untyped single nucleotide polymorphisms (SNPs) in genome-wide association studies. The haplotypic reference of choice for imputation in Southeast Asian populations is unclear. Moreover, the influence of SNP annotation on imputation results has not been examined. METHODS: This study was divided into two parts. In the first part, we applied imputation to genotyped SNPs from Southeast Asian populations from the Pan-Asian SNP database. Five percent of the total SNPs were removed. The remaining SNPs were applied to imputation with IMPUTE2. The imputed outcomes were verified with the removed SNPs. We compared imputation references from Chinese and Japanese haplotypes from the HapMap phase II (HMII) and the complete set of haplotypes from the 1000 Genomes Project (1000G). The second part was imputation accuracy and yield in Thai patient dataset. Half of the autosomal SNPs was removed to create Set 1. Another dataset, Set 2, was then created where we switched which half of the SNPs were removed. Both Set 1 and Set 2 were imputed with HMII to create a complete imputed SNPs dataset. The dataset was used to validate association testing, SNPs annotation and imputation outcome. RESULTS: The accuracy was highest for all populations when using the HMII reference, but at the cost of a lower yield. Thai genotypes showed the highest accuracy over other populations in both HMII and 1000G panels, although accuracy and yield varied across chromosomes. Imputation was tested in a clinical dataset to compare accuracy in gene-related regions, and coding regions were found to have a higher accuracy and yield. CONCLUSIONS: This work provides the first evidence of imputation reference selection for Southeast Asian studies and highlights the effects of SNP locations respective to genes on imputation outcome. Researchers will need to consider the trade-off between accuracy and yield in future imputation studies.

5.
PLoS One ; 12(7): e0180056, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28704380

RESUMO

INTRODUCTION: Sudden unexpected death syndrome (SUDS) is an important cause of death in young healthy adults with a high incident rate in Southeast Asia; however, there are no molecular autopsy reports about these victims. We performed a combination of both a detailed autopsy and a molecular autopsy by whole exome sequencing (WES) to investigate the cause of SUDS in Thai sudden death victims. MATERIALS AND METHODS: A detailed forensic autopsy was performed to identify the cause of death, followed by a molecular autopsy, in 42 sudden death victims who died between January 2015 and August 2015. The coding sequences of 98 SUDS-related genes were sequenced using WES. Potentially causative variants were filtered based on the variant functions annotated in the dbNSFP database. Variants with inconclusive clinical significance evidence in ClinVar were resolved with a variant prediction algorithm, metaSVM, and the frequency data of the variants found in public databases, such as the 1000 Genome Project, ESP6500 project, and the Exome Aggregation Consortium (ExAc) project. RESULTS: Combining both autopsy and molecular autopsy enabled the potential identification of cause of death in 81% of the cases. Among the 25 victims with WES data, 72% (18/25) were found to have potentially causative SUDS mutations. The majority of the victims had at a mutation in the TTN gene (8/18 = 44%), and only one victim had an SCN5A mutation. CONCLUSIONS: WES can help to identify the genetic causes in victims of SUDS and may help to further guide investigations into their relatives to prevent additional SUDS victims.


Assuntos
Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Conectina/genética , Estudo de Associação Genômica Ampla/métodos , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Polimorfismo de Nucleotídeo Único , Adulto , Algoritmos , Autopsia , Exoma , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Tailândia , Adulto Jovem
6.
PLoS One ; 12(4): e0176342, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28437431

RESUMO

BACKGROUND: The clinical syndrome of disseminated nontuberculous mycobacterial (NTM) infection in patients who were previously healthy is now well recognized to be associated with an acquired autoantibody to Interferon gamma (Anti IFN- γ autoantibody). However, the risk factors of this syndrome remain unknown. METHOD: We performed an unmatched case control study among patients with NTM diseases who were diagnosed and treated at Siriraj Hospital, Bangkok, Thailand. Anti-IFN autoantibody was detected by enzyme-linked immunosorbent assay (ELISA) method. Cases were patients with NTM diseases and detectable anti IFN- γ autoantibody. Controls were randomly selected from those with undetectable anti IFN- γ autoantibody. Data from both groups including demographic data, clinical presentation, laboratory results, other risk factors and HLA genotypes were collected. Univariate and multivariate analyses were performed to identify independent risk factors for this syndrome. RESULTS: 70 cases (mean age 50 ± 11 years) and 70 controls (mean age 58 ± 18 years) were enrolled into the study. Mycobacterial abscessus was the most common NTM pathogen found in both groups (72.9% in cases and 41.4% in controls respectively). However, disseminated NTM disease was significantly more common in cases (92.9%) than in the controls (14.3%, p<0.001). Binary logistic regression analysis showed that previous OIs (adjusted OR14.87, 95% CI 2.36-93.86), birthplace outside Central region (adjusted OR 19.19, 95% CI 3.86-95.35), lack of comorbidities lead to immunosuppression, such as HIV infection or diabetes mellitus (adjusted OR 23.68, 95% CI 4.01-139.94), and presence of HLA DRB1*15/16 (adjusted OR 153.28, 95% CI 16.87-139.88) were independent factors associated with this syndrome. CONCLUSION: Patients with NTM disease associated with anti IFN- γ autoantibody are almost always previously healthy and HIV negative. Most of these patients presented with disseminated NTM disease with generalized lymphadenitis and often with reactive skin lesions. Factors associated with detectable anti IFN- γ autoantibody are HLA-DRB1 and DQB1 alleles, and history of previous OIs in patients without comorbidity that leads to immunosuppression. Further studies are needed to better understand these associations and to improve the treatment outcome.


Assuntos
Autoanticorpos/imunologia , Interferon gama/imunologia , Infecções por Micobactéria não Tuberculosa/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Micobactéria não Tuberculosa/genética
7.
PLoS One ; 10(5): e0128481, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26011559

RESUMO

Recently a newly identified clinical syndrome of disseminated non-tuberculous mycobacterial diseases (with or without other opportunistic infections in adult patients who were previously healthy, has been recognized in association with an acquired autoantibody to interferon-gamma. This syndrome is emerging as an important cause of morbidity and mortality, especially among people of Asian descent. Trigger for the production of this autoantibody remains unknown, but genetic factors are strongly suspected to be involved. We compared HLA genotyping between 32 patients with this clinical syndrome, and 38 controls. We found that this clinical syndrome was associated with very limited allele polymorphism, with HLA-DRB1 and DQB1 alleles, especially HLA-DRB1*15:01, DRB1*16:02, DQB1*05:01 and DQB1*05:02. Odds ratio of DRB1*15:01, DRB1*16:02, DQB1*05:01 and DQB1*05:02 were 7.03 (95% CI, 2.18-22.69, P<0.0001, 9.06 (95% CI, 2.79-29.46, P<0.0001), 6.68 (95% CI, 2.29-19.52, P = 0.0004), and 6.64 (95% CI, 2.30-19.20, P = 0.0004), respectively. Further investigation is warranted to provide better understanding on pathogenesis of this association.


Assuntos
Autoanticorpos/sangue , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Interferon gama/imunologia , Infecções por Micobactéria não Tuberculosa/genética , Adulto , Idade de Início , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Micobactéria não Tuberculosa/sangue , Infecções por Micobactéria não Tuberculosa/imunologia , Polimorfismo Genético , Tailândia
8.
BMC Genet ; 16: 58, 2015 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-26024889

RESUMO

BACKGROUND: We have previously shown that platelet aggregation has higher heritability in African Americans than European Americans. However, a genome-wide association study (GWAS) of platelet aggregation in African Americans has not been reported. We measured platelet aggregation in response to arachidonic acid, ADP, collagen, or epinephrine by optical aggregometry. The discovery cohort was 825 African Americans from the GeneSTAR study. Two replication cohorts were used: 119 African Americans from the Platelet Genes and Physiology Study and 1221 European Americans from GeneSTAR. Genotyping was conducted with Illumina 1 M arrays. For each cohort, age- and sex-adjusted linear mixed models were used to test for association between each SNP and each phenotype under an additive model. RESULTS: Six SNPs were significantly associated with platelet aggregation (P<5×10(-8)) in the discovery sample. Of these, three SNPs in three different loci were confirmed: 1) rs12041331, in PEAR1 (platelet endothelial aggregation receptor 1), replicated in both African and European Americans for collagen- and epinephrine-induced aggregation, and in European Americans for ADP-induced aggregation; 2) rs11202221, in BMPR1A (bone morphogenetic protein receptor type1A), replicated in African Americans for ADP-induced aggregation; and 3) rs6566765 replicated in European Americans for ADP-induced aggregation. The rs11202221 and rs6566765 associations with agonist-induced platelet aggregation are novel. CONCLUSIONS: In this first GWAS of agonist-induced platelet aggregation in African Americans, we discovered and replicated, novel associations of two variants with ADP-induced aggregation, and confirmed the association of a PEAR1 variant with multi-agonist-induced aggregation. Further study of these genes may provide novel insights into platelet biology.


Assuntos
Afro-Americanos/genética , Estudo de Associação Genômica Ampla , Agregação Plaquetária/genética , Difosfato de Adenosina/farmacologia , Adulto , Alelos , Ácido Araquidônico/farmacologia , Colágeno/metabolismo , Colágeno/farmacologia , Epinefrina/farmacologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , Polimorfismo de Nucleotídeo Único
9.
Genet Epidemiol ; 39(5): 385-94, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25663376

RESUMO

Genome-wide association studies (GWAS) for nonsyndromic cleft lip with or without cleft palate (CL/P) have identified multiple genes as important in the etiology of this common birth defect. We performed a candidate gene/pathway analysis explicitly considering gene-gene (G × G) interaction to further explore the etiology of CL/P. Animal models have shown the WNT signaling pathway plays an important role in mid-facial development, and various genes in this pathway have been associated with nonsyndromic CL/P in previous studies. We propose a combined approach to search for possible G × G interactions using machine learning and regression-based methods to test for interactions between genes in the WNT family, and between these genes and other genes identified by GWAS in case-parent trios. Using this combined approach of regression-based and machine learning methods in CL/P case-parent trios, we found robust evidence of G × G interaction between markers in WNT5B and MAFB (empiric P-values = 0.0076 among Asian trios and P-values = 0.018 among European trios). Additional evidence for epistatic interaction between markers in WNT5A, IRF6, and C1orf107 was seen among Asian trios, and markers in the 8q24 region and WNT5B among European trios.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Fatores Reguladores de Interferon/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Wnt/metabolismo , Inteligência Artificial , Grupo com Ancestrais do Continente Asiático/genética , Epistasia Genética , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Humanos , Fatores Reguladores de Interferon/genética , Modelos Genéticos , Pais , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Wnt/genética , Proteína Wnt-5a
10.
Cell Cycle ; 13(18): 2889-900, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25486477

RESUMO

Overexpression of cyclin D1 and its catalytic partner, CDK4, is frequently seen in human cancers. We constructed cyclin D1 and CDK4 protein interaction network in a human breast cancer cell line MCF7, and identified novel CDK4 protein partners. Among CDK4 interactors we observed several proteins functioning in protein folding and in complex assembly. One of the novel partners of CDK4 is FKBP5, which we found to be required to maintain CDK4 levels in cancer cells. An integrative analysis of the extended cyclin D1 cancer interactome and somatic copy number alterations in human cancers identified BAIAPL21 as a potential novel human oncogene. We observed that in several human tumor types BAIAPL21 is expressed at higher levels as compared to normal tissue. Forced overexpression of BAIAPL21 augmented anchorage independent growth, increased colony formation by cancer cells and strongly enhanced the ability of cells to form tumors in vivo. Lastly, we derived an Aggregate Expression Score (AES), which quantifies the expression of all cyclin D1 interactors in a given tumor. We observed that AES has a prognostic value among patients with ER-positive breast cancers. These studies illustrate the utility of analyzing the interactomes of proteins involved in cancer to uncover potential oncogenes, or to allow better cancer prognosis.


Assuntos
Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Oncogenes , Mapas de Interação de Proteínas , Animais , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Nus , Proteínas dos Microfilamentos/metabolismo , Prognóstico , Ligação Proteica , Receptores Estrogênicos/metabolismo , Análise de Sobrevida , Proteínas de Ligação a Tacrolimo/metabolismo
11.
PLoS One ; 9(10): e110188, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25329996

RESUMO

Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75-325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65-5.26; p<0.001) and 11.26 (95%CI, 2.47-51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70-1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98 × 10(-6)). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.


Assuntos
Arildialquilfosfatase/genética , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Citocromo P-450 CYP2C19/genética , Inibidores da Agregação de Plaquetas/farmacologia , Polimorfismo Genético , Ticlopidina/análogos & derivados , Difosfato de Adenosina/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Clopidogrel , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/fisiopatologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticlopidina/farmacologia , Ticlopidina/uso terapêutico
12.
PLoS One ; 9(8): e104355, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25118596

RESUMO

Copy number variation (CNV) is a major genetic polymorphism contributing to genetic diversity and human evolution. Clinical application of CNVs for diagnostic purposes largely depends on sufficient population CNV data for accurate interpretation. CNVs from general population in currently available databases help classify CNVs of uncertain clinical significance, and benign CNVs. Earlier studies of CNV distribution in several populations worldwide showed that a significant fraction of CNVs are population specific. In this study, we characterized and analyzed CNVs in 3,017 unrelated Thai individuals genotyped with the Illumina Human610, Illumina HumanOmniexpress, or Illumina HapMap550v3 platform. We employed hidden Markov model and circular binary segmentation methods to identify CNVs, extracted 23,458 CNVs consistently identified by both algorithms, and cataloged these high confident CNVs into our publicly available Thai CNV database. Analysis of CNVs in the Thai population identified a median of eight autosomal CNVs per individual. Most CNVs (96.73%) did not overlap with any known chromosomal imbalance syndromes documented in the DECIPHER database. When compared with CNVs in the 11 HapMap3 populations, CNVs found in the Thai population shared several characteristics with CNVs characterized in HapMap3. Common CNVs in Thais had similar frequencies to those in the HapMap3 populations, and all high frequency CNVs (>20%) found in Thai individuals could also be identified in HapMap3. The majorities of CNVs discovered in the Thai population, however, were of low frequency, or uniquely identified in Thais. When performing hierarchical clustering using CNV frequencies, the CNV data were clustered into Africans, Europeans, and Asians, in line with the clustering performed with single nucleotide polymorphism (SNP) data. As CNV data are specific to origin of population, our population-specific reference database will serve as a valuable addition to the existing resources for the investigation of clinical significance of CNVs in Thais and related ethnicities.


Assuntos
Variações do Número de Cópias de DNA , Algoritmos , Bases de Dados Genéticas , Variação Genética , Genoma Humano , Genótipo , Humanos , Cadeias de Markov , Tailândia
13.
J Am Coll Clin Wound Spec ; 6(1-2): 9-13, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26442206

RESUMO

Hyperbaric Oxygen (HBO, HBO2) Therapy is a non-invasive therapy. It has been applied as adjuvant treatment in many medical conditions over the past 50 years. Different treatment protocols have been proven effective for specifically indicated conditions. To evaluate the clinical effectiveness of Hyperbaric Oxygen (HBO) Therapy as an adjunctive treatment for patients with complex wounds. In this prospective cohort study, 40 patients with complex wounds were included. All patients received HBO. HBO was delivered with 100% oxygen for 90 min at 2.0-2.4 ATA. Wound sizes were assessed by one wound surgeon before, during, and every 2 weeks for a total of 12 months after HBO. An analysis of demographic data, wound size and wound photography was performed. Over the 22-month period ending October 31, 2013, 40 patients (21 men and 19 women) with a mean age of 59.73 (range, 29-88) with complex wounds were included. All complex wounds studied were at least 6 months old. The mean wound size was 16.72 cm(2) in diameter. Thirty-one patients with complex wounds healed after the completion of a series of HBO treatments (77.5%). Two orocutaneous fistulas were completely closed without further surgery. After 5 HBO treatments, the wound size reduced by 29.7% on average (p = 1.24 × 10(-6)). After 10 HBO treatments, the wound size statistically significantly reduced by an additional 16.9% (p = 0.0002). There were no complications in this study. Wound healing process was accelerated by HBO. Significant wound size reduction was noted after 5 HBO treatments. Because the biggest reduction in wound size occurred within the first 10 HBO treatments, it is important to conduct these first treatments without interruption. HBO is an effective and safe treatment modality for complex wounds.

14.
PLoS One ; 8(5): e64179, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23704978

RESUMO

Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1) gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13) selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate). Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5%) were noted in African Americans compared to European Americans (108 vs. 45). The common intronic GWAS-identified variant (rs12041331) demonstrated the most significant association signal in African Americans (p = 4.020×10(-4)); no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331). Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965) supports the results noted in the sequenced discovery sample: p = 3.56×10(-4), 2.27×10(-7), 5.20×10(-5) for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans, and show that exonic variants play an additional role in platelet aggregation in European Americans.


Assuntos
Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Fases de Leitura Aberta/genética , Agregação Plaquetária/genética , Polimorfismo de Nucleotídeo Único/genética , Afro-Americanos/genética , Alelos , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Éxons/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular/genética
15.
PLoS One ; 8(12): e85053, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24386444

RESUMO

Mangosteen extracts (ME) contain high levels of polyphenolic compounds and antioxidant activity. Protective effects of ME against ß-amyloid peptide (Aß), induced cytotoxicity have been reported. Here, we further studied the protective effects of ME against oxidative stress induced by hydrogen peroxide (H2O2) and polychlorinated biphenyls (PCBs), and demonstrated the protection against memory impairment in mice. The cytoprotective effects of ME were measured as cell viability and the reduction in ROS activity. In SK-N-SH cell cultures, 200 µg/ml ME could partially antagonize the effects of 150 or 300 µM H2O2 on cell viability, ROS level and caspase-3 activity. At 200, 400 or 800 µg/ml, ME reduced AChE activity of SK-N-SH cells to about 60% of the control. In vivo study, Morris water maze and passive avoidance tests were used to assess the memory of the animals. ME, especially at 100 mg/kg body weight, could improve the animal's memory and also antagonize the effect of scopolamine on memory. The increase in ROS level and caspase-3 activity in the brain of scopolamine-treated mice were antagonized by the ME treatment. The study demonstrated cytoprotective effects of ME against H2O2 and PCB-52 toxicity and having AChE inhibitory effect in cell culture. ME treatment in mice could attenuate scopolamine-induced memory deficit and oxidative stress in brain.


Assuntos
Citotoxinas/farmacologia , Garcinia mangostana/química , Peróxido de Hidrogênio/farmacologia , Transtornos da Memória , Antagonistas Muscarínicos/efeitos adversos , Extratos Vegetais/farmacologia , Escopolamina/efeitos adversos , Animais , Humanos , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Endogâmicos ICR , Antagonistas Muscarínicos/farmacologia , Oxidantes/farmacologia , Extratos Vegetais/química , Escopolamina/farmacologia
16.
Hum Hered ; 74(1): 17-26, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23038411

RESUMO

Variance components analysis (VCA), the traditional method for handling correlations within families in genetic association studies, is computationally intensive for genome-wide analyses, and the computational burden of VCA increases with family size and the number of genetic markers. Alternative approaches that do not require the computation of familial correlations are preferable, provided that they do not inflate type I error or decrease power. We performed a simulation study to evaluate practical alternatives to VCA that use regression with generalized estimating equations (GEE) in extended family data. We compared the properties of linear regression with GEE applied to an entire extended family structure (GEE-EXT) and GEE applied to nuclear family structures split from these extended families (GEE-SPL) to variance components likelihood-based methods (FastAssoc). GEE-EXT was evaluated with and without robust variance estimators to estimate the standard errors. We observed similar average type I error rates from GEE-EXT and FastAssoc compared to GEE-SPL. Type I error rates for the GEE-EXT method with a robust variance estimator were marginally higher than the nominal rate when the minor allele frequency (MAF) was <0.1, but were close to the nominal rate when the MAF was ≥0.2. All methods gave consistent effect estimates and had similar power. In summary, the GEE framework with the robust variance estimator, the computationally fastest and least data management-intensive approach, appears to work well in extended families and thus provides a reasonable alternative to full variance components approaches for extended pedigrees in a genome-wide association study setting.


Assuntos
Simulação por Computador , Bases de Dados Factuais , Análise de Variância , Família , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Funções Verossimilhança , Modelos Estatísticos
17.
Blood ; 118(12): 3367-75, 2011 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-21791418

RESUMO

Genetic variation is thought to contribute to variability in platelet function; however, the specific variants and mechanisms that contribute to altered platelet function are poorly defined. With the use of a combination of fine mapping and sequencing of the platelet endothelial aggregation receptor 1 (PEAR1) gene we identified a common variant (rs12041331) in intron 1 that accounts for ≤ 15% of total phenotypic variation in platelet function. Association findings were robust in 1241 persons of European ancestry (P = 2.22 × 10⁻8) and were replicated down to the variant and nucleotide level in 835 persons of African ancestry (P = 2.31 × 10⁻²7) and in an independent sample of 2755 persons of European descent (P = 1.64 × 10⁻5). Sequencing confirmed that variation at rs12041331 accounted most strongly (P = 2.07 × 10⁻6) for the relation between the PEAR1 gene and platelet function phenotype. A dose-response relation between the number of G alleles at rs12041331 and expression of PEAR1 protein in human platelets was confirmed by Western blotting and ELISA. Similarly, the G allele was associated with greater protein expression in a luciferase reporter assay. These experiments identify the precise genetic variant in PEAR1 associated with altered platelet function and provide a plausible biologic mechanism to explain the association between variation in the PEAR1 gene and platelet function phenotype.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Plaquetas/metabolismo , Doença da Artéria Coronariana/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Agregação Plaquetária/genética , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Alelos , Aspirina/administração & dosagem , Plaquetas/citologia , Linhagem Celular , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Expressão Gênica , Genes Reporter , Variação Genética , Genótipo , Humanos , Íntrons , Luciferases/análise , Fenótipo , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismo , Análise de Sequência de DNA , Transfecção
18.
BMC Genet ; 12: 50, 2011 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-21599946

RESUMO

BACKGROUND: Arachidonic acid (AA) is a long-chain omega-6 polyunsaturated fatty acid (PUFA) synthesized from the precursor dihomo-gamma-linolenic acid (DGLA) that plays a vital role in immunity and inflammation. Variants in the Fatty Acid Desaturase (FADS) family of genes on chromosome 11q have been shown to play a role in PUFA metabolism in populations of European and Asian ancestry; no work has been done in populations of African ancestry to date. RESULTS: In this study, we report that African Americans have significantly higher circulating levels of plasma AA (p = 1.35 × 10(-48)) and lower DGLA levels (p = 9.80 × 10(-11)) than European Americans. Tests for association in N = 329 individuals across 80 nucleotide polymorphisms (SNPs) in the Fatty Acid Desaturase (FADS) locus revealed significant association with AA, DGLA and the AA/DGLA ratio, a measure of enzymatic efficiency, in both racial groups (peak signal p = 2.85 × 10(-16) in African Americans, 2.68 × 10(-23) in European Americans). Ancestry-related differences were observed at an upstream marker previously associated with AA levels (rs174537), wherein, 79-82% of African Americans carry two copies of the G allele compared to only 42-45% of European Americans. Importantly, the allelic effect of the G allele, which is associated with enhanced conversion of DGLA to AA, on enzymatic efficiency was similar in both groups. CONCLUSIONS: We conclude that the impact of FADS genetic variants on PUFA metabolism, specifically AA levels, is likely more pronounced in African Americans due to the larger proportion of individuals carrying the genotype associated with increased FADS1 enzymatic conversion of DGLA to AA.


Assuntos
Afro-Americanos/genética , Ácidos Graxos Ômega-6/metabolismo , Polimorfismo de Nucleotídeo Único , Estearoil-CoA Dessaturase/genética , Ácido 8,11,14-Eicosatrienoico/sangue , Ácido Araquidônico/sangue , Cromossomos Humanos Par 11 , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Humanos
19.
Invest Ophthalmol Vis Sci ; 52(7): 4742-8, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21398275

RESUMO

PURPOSE: To investigate the role of mitochondrial DNA (mt DNA) background on the expression of Leber hereditary optic neuropathy (LHON) in Southeast Asian carriers of the G11778A mutation. METHODS: Complete mtDNA sequences were analyzed from 53 unrelated Southeast Asian G11778A LHON pedigrees in Thailand and 105 normal Thai controls, and mtDNA haplogroups were determined. Clinical phenotypes were tested for association with mtDNA haplogroup, with adjustment for potential confounders such as sex and age at onset. RESULTS: mtDNA subhaplogroup B was significantly associated with LHON. Follow-up analysis narrowed the association down to subhaplogroup B5a1 (P = 0.008). Survival analyses with Cox's proportional hazards modeling on 469 samples (91 affected and 378 unaffected), adjusted for sex and heteroplasmy, revealed that haplogroup B5a1 tended to increase the risk of visual loss, but the trend was not statistically significant. Conversely, haplogroup F, the second most common haplogroup in the control population, was the least frequent haplogroup in LHON. This negative association was narrowed down to subhaplogroup F1 (P = 0.00043), suggesting that haplogroup F1 confers a protective effect. The distributions of sex, age at onset and heteroplasmy were not significantly different among haplogroups. CONCLUSIONS: The specific mtDNA background B5a1 was significantly associated with Southeast Asian G11778A LHON and appeared to modify the risk of visual loss.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , DNA Mitocondrial/genética , Mutação , NADH Desidrogenase/genética , Atrofia Óptica Hereditária de Leber/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Seguimentos , Predisposição Genética para Doença , Haploidia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Atrofia Óptica Hereditária de Leber/etnologia , Atrofia Óptica Hereditária de Leber/fisiopatologia , Linhagem , Fenótipo , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Tailândia/epidemiologia , Acuidade Visual/genética , Adulto Jovem
20.
J Hum Genet ; 56(3): 224-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21270820

RESUMO

A 58 kb region on chromosome 9p21.3 has consistently shown strong association with coronary artery disease (CAD) in multiple genome-wide association studies in populations of European and East Asian ancestry. In this study, we sought to further characterize the role of genetic variants in 9p21.3 in African American individuals. Apparently healthy African American siblings (n = 548) of patients with documented CAD < 60 years of age were genotyped and followed for incident CAD for up to 17 years. Tests of association for 86 single-nucleotide polymorphisms (SNPs) across the 9p21.3 region in a generalized estimating equation logistic framework under an additive model adjusting for traditional risk factors, family, follow-up time and population stratification were performed. A single SNP within the CDKN2B gene met stringent criteria for statistical significance, including permutation-based evaluations. This variant, rs3217989, was common (minor allele (G) frequency 0.242), conveyed protection against CAD (odds ratio (OR) = 0.19, 95% confidence interval (CI): 0.07 to 0.50, P = 0.0008) and was replicated in a combined analysis of two additional case/control studies of prevalent CAD/MI in African Americans (n = 990, P = 0.024, OR = 0.779, 95% CI: 0.626-0.968). This is the first report of a CAD association signal in a population of African ancestry with a common variant within the CDKN2B gene, independent from previous findings in European and East Asian ancestry populations. The findings demonstrate a significant protective effect against incident CAD in African American siblings of persons with premature CAD, with replication in a combination of two additional African American cohorts.


Assuntos
Afro-Americanos/genética , Cromossomos Humanos Par 9 , Doença da Artéria Coronariana/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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