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1.
Geroscience ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654268

RESUMO

Intestinal barrier dysfunction is hypothesized to be a contributing determinant of two prominent characteristics of aging: inflammation and decline in physical function. A relationship between microbial translocation (MT), or their biomarkers (lipopolysaccharide binding protein-1 [LBP-1], soluble cluster of differentiation [sCD]-14), and physical function has been reported in healthy older adults, rats, and invertebrates. However, it is not known whether the existence of comorbidities, or clinical interventions intended to reduce comorbidities through weight loss or exercise, alters this connection. We measured inflammation, MT, and physical function in 288 overweight/obese older patients with cardiometabolic disease and self-reported mobility limitations who were enrolled in a weight loss and lifestyle intervention study. At baseline, inflammatory cytokines and LBP-1 were positively correlated after adjustment for age, gender, and body mass index. A higher LBP-1 was significantly associated with poorer physical functional after covariate adjustment. Further, even when IL-6 levels were included in the models, 400-m walk time (p = 0.003), short physical performance battery (p = 0.07), and IL-8 (p < 0.001) remained positively associated with LBP-1. Lifestyle interventions improved body mass and some functional measures; however, MT and inflammation were unchanged. MT is reliably related to inflammation, and to poorer physical function in older adults with comorbid conditions. Intestinal barrier function did not appear to improve as a result of intervention assignment, suggesting alternative strategies are needed to target this pro-inflammatory pathway in aging.

2.
J Geriatr Oncol ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31515163

RESUMO

OBJECTIVES: This study compares health-related quality of life (HRQoL) of older patients with pancreatic ductal adenocarcinoma (PDAC) to controls without cancer, and examines the impact of medical comorbidities on HRQoL. MATERIALS AND METHODS: We conducted a case-control study using the 1998-2011 Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey (SEER-MHOS) linked dataset. Cases were Medicare beneficiaries aged 65 and older diagnosed with PDAC (N = 128) and matched controls were without a history of cancer (N = 512). We used the Short Form 36 (SF-36) and Veterans-RAND-12 (VR-12) to examine HRQoL and calculated mental (MCS) and physical (PCS) component scores. Linear regression and mixed effects models were used to examine the impact of medical comorbidities on MCS and PCS for cases and controls, respectively. RESULTS: Cases reported significantly poorer PCS (29.3 vs. 36.3) and MCS (44.8 vs. 49.9) compared to controls. Comorbidities were significantly associated with lower PCS and MCS in controls. However, neither total number of comorbidities or comorbidities grouped by organ systems (cardiopulmonary disease, musculoskeletal disease, diabetes) were significantly related to PCS or MCS for cases. Comparison of regression coefficients estimates did not indicate that lack of significance was due to differences in sample size. CONCLUSIONS: The results of this study highlight the poor HRQoL reported by older patients with PDAC. HRQoL scores were very low in this population, particularly in physical health status, which were not explained by comorbidities.

3.
Int J Hyperthermia ; 36(1): 932-937, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31535591

RESUMO

Background: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is an alternative local therapy for patients with painful bone metastasis. However, little is known about the prognostic and predictive factors of MRgFUS in treating bone metastasis. Materials and methods: This retrospective study analyzed the performance status, treated site, pretreatment pain score, pretreatment tumor volume and lesion coverage volume factor (CVF) of 31 patients who underwent MRgFUS. A numerical rating scale for pain was used at the same time to assess the clinical response. Radiographic responses were evaluated using a modified version of The University of Texas MD Anderson Cancer Center criteria and reference to the MR imaging or computed tomography scans obtained 3 months after treatment. Univariate and multivariate logistic regression analyses were conducted to examine the effect of variables on clinical and radiographic responses. Results: The overall clinical response rate was 83.9% and radiographic response rate was 67.7%. Multivariate logistic regression analysis revealed that the better pretreatment Karnofsky performance status (KPS) (odds ratio: 1.220, 95% confidence interval (CI): 1.033-1.440; p = 0.019) was significantly associated with a more positive clinical response, and that the lesion CVF (odds ratio: 1.183, 95% CI: 1.029-1.183; p = 0.0055) was an independent prognostic factor for radiographic responses. The radiographic response of patients with lesion CVF ≥70% and CVF <70% were 91.7% and 52.6%, respectively (p = 0.0235). Conclusion: The pretreatment KPS was an independent prognostic factor for clinical responses, and lesion CVF was an independent prognostic factor for radiographic responses.

5.
J Vet Intern Med ; 33(3): 1384-1391, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30990928

RESUMO

BACKGROUND: Stereotactic brain biopsy (SBB) is a technique that allows for definitive diagnosis of brain lesions. Little information is available regarding the diagnostic utility of SBB in dogs with intracranial diseases. OBJECTIVE: To investigate the diagnostic accuracy (DA) of SBB in dogs with brain tumors. ANIMALS: Thirty-one client-owned dogs that underwent SBB followed by surgical resection or necropsy examinations. METHODS: Retrospective observational study. Two pathologists blinded to SBB and reference standard diagnoses reviewed histologic specimens and typed and graded tumors according to World Health Organization and revised canine glioma classification criteria. Agreement between tumor type and grade from SBB were compared to reference standards and assessed using kappa statistics. Patient and technical factors associated with agreement also were examined. RESULTS: Stereotactic brain biopsy specimens were obtained from 24 dogs with gliomas and 7 with meningiomas. Tumor type agreement between SBB and the reference standard was observed in 30/31 cases (κ = 0.95). Diagnostic concordance was perfect for meningiomas. Grade agreement among gliomas was observed in 18/23 cases (κ = 0.47). Stereotactic brain biopsy underrepresented the reference standard glioma grade in cases with disagreement. The DA of SBB was 81%, with agreement noted in 56/69 biopsy samples. Smaller tumors and fewer SBB specimens obtained were significantly associated with diagnostic discordance. CONCLUSIONS AND CLINICAL IMPORTANCE: The DA of SBB readily allows for the diagnosis of common brain tumors in dogs. Although glioma grade discordance was frequent, diagnoses obtained from SBB are sufficient to currently inform therapeutic decisions. Multiple SBB specimens should be collected to maximize DA.


Assuntos
Neoplasias Encefálicas/veterinária , Doenças do Cão/cirurgia , Glioma/veterinária , Meningioma/veterinária , Técnicas Estereotáxicas/veterinária , Animais , Biópsia/veterinária , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/cirurgia , Doenças do Cão/diagnóstico , Cães , Feminino , Glioma/diagnóstico , Glioma/cirurgia , Masculino , Meningioma/diagnóstico , Meningioma/cirurgia , Gradação de Tumores/veterinária , Estudos Retrospectivos , Técnicas Estereotáxicas/normas
6.
Br J Anaesth ; 122(6): e146-e156, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30916003

RESUMO

BACKGROUND: The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration. METHODS: A series of behavioural and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side-effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys. RESULTS: After systemic administration, BU10038 (0.001-0.01 mg kg-1) dose-dependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e. little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10-30-fold higher dose (0.01-0.1 mg kg-1). After intrathecal administration, BU10038 (3 µg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration. CONCLUSIONS: These in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists such as BU10038 as a safe, non-addictive analgesic with fewer side-effects in primates. This study strongly supports that bifunctional MOP/NOP agonists may provide improved analgesics and an alternative solution for the ongoing prescription opioid crisis.


Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Tolerância a Medicamentos , Hiperalgesia/tratamento farmacológico , Injeções Espinhais , Macaca mulatta , Masculino , Nociceptividade/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/etiologia , Limiar da Dor/efeitos dos fármacos
7.
Nat Genet ; 51(4): 636-648, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926973

RESUMO

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.


Assuntos
Lipídeos/sangue , Lipídeos/genética , Fumar/sangue , Fumar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Estilo de Vida , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Am J Epidemiol ; 188(6): 1033-1054, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30698716

RESUMO

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

9.
Nat Commun ; 10(1): 376, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670697

RESUMO

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.


Assuntos
Exercício , Loci Gênicos/genética , Lipídeos/sangue , Lipídeos/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Brasil , Proteínas de Ligação ao Cálcio/genética , Colesterol/sangue , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hispano-Americanos/genética , Humanos , Proteínas com Homeodomínio LIM/genética , Metabolismo dos Lipídeos/genética , Masculino , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Triglicerídeos/sangue , Triglicerídeos/genética , Adulto Jovem
10.
Am J Cardiol ; 123(4): 576-581, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30553512

RESUMO

Weight management is highly recommended to patients with diabetes mellitus. However, this prescription is often characterized by weight fluctuations. It remains unclear the effects of weight fluctuations on outcomes in diabetes mellitus. We used the public use dataset from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to assess the effects of baseline weight, change in weight, and body weight variability (BWV) on outcomes. The ACCORD trial participant's weights were documented annually during the trial. Our primary predictor variables were baseline weight, change in body weight (Initial - final) and BWV defined as average successive variability in weight (average absolute difference between successive values) during the trial. Cox proportional hazards model was used. Out of the 10,251 ACCORD participants, 911(8.9%), 2985(29.1%), and 6355(62%) were normal weight, overweight, and obese. After a mean of 3.5 years of follow-up, 10.2% had the primary outcome (nonfatal MI or nonfatal stroke or CV death), 4.3% had heart failure, 7% died, and 60.7% reported a microvascular complication. BWV was associated with the primary outcome, heart failure, death, and microvascular events in our full models which included BMI [HR (95%CI): 1.25(1.15 to 1.36), 1.59(1.45 to 1.75), 1.74(1.63 to 1.85) and 1.18(1.13 to 1.22), p < 0.0001 respectively). Participants who died were in the quartile that gained the most weight. In this post hoc analysis of ACCORD trial, body weight variability was significantly associated with poor outcomes independent of CVD risk factors and BMI. Our study is consistent with significant risk associated with weight fluctuations in patients with diabetes mellitus.

11.
Exp Gerontol ; 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30508565

RESUMO

BACKGROUND: We provide the first examination of mitochondrial DNA (mtDNA) variants and pulmonary function in older persons. METHODS: Cross-sectional associations between mtDNA variants and pulmonary function were evaluated as a combined p-values meta-analysis, using data from two independent cohorts of older persons. The latter included white and black participants, aged ≥70 years, from the Lifestyle Interventions and Independence for Elders study (LIFE) (N = 1247) and the Health, Aging and Body Composition study (Health ABC) (N = 731), respectively. Pulmonary function included the forced expiratory volume in one-second as a Z-score (FEV1z) and the maximal inspiratory pressure (MIP) in cm of water. RESULTS: In black participants, significant associations were found between mtDNA variants and MIP: m.7146A > G, COI (p = 3E-5); m.7389 T > C, COI (p = 2E-4); m.15301G > A, CYB (p = 9E-5); m.16265A > G, HV1 (p = 9E-5); meta-analytical p-values <0.0002. Importantly, these mtDNA variants were unique to black participants and were not present in white participants. Moreover, in black participants, aggregate genetic effects on MIP were observed across mutations in oxidative phosphorylation complex IV (p = 0.004), complex V (p = 0.0007), and hypervariable (p = 0.003) regions. The individual and aggregate variant results were significant after adjustment for multiple comparisons. Otherwise, no significant associations were detected for MIP in whites or for FEV1z in whites or blacks. CONCLUSIONS: We have shown that mtDNA variants of African origin are cross-sectionally associated with MIP, a measure of respiratory muscle strength. Thus, our results establish the rationale for longitudinal studies to evaluate whether mtDNA variants of African origin identify those at risk of subsequently developing a respiratory muscle impairment (lower MIP values).

12.
J Am Geriatr Soc ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30452084

RESUMO

OBJECTIVES: To evaluate the effect of hospitalizations on patterns of sedentary and physical activity time in mobility-limited older adults randomized to structured physical activity or health education. DESIGN: Secondary analysis of investigator-blinded, parallel-group, randomized trial conducted at 8 U.S. centers between February 2010 and December 2013. PARTICIPANTS: Sedentary men and women aged 70 to 89 at baseline who wore a hip-fitted accelerometer 7 consecutive days at baseline and 6, 12, and 24 months after randomization (N=1,341). MEASUREMENTS: Participants were randomized to a physical activity (PA; n = 669) intervention that included aerobic, resistance, and flexibility training or to a health education (HE; n = 672) intervention that consisted of workshops on older adult health and light upper-extremity stretching. Accelerometer patterns were characterized as bouts of sedentary (<100 counts/min; ≥1, ≥10, ≥30, ≥60 minute lengths) and activity (≥100 counts/min; ≥1, ≥2, ≥5, ≥10 minute lengths) time. Each participant was categorized as having 0, 1 to 3, or 4 or more cumulative hospital days before each accelerometer assessment. RESULTS: Hospitalization increased sedentary time similarly in both intervention groups (8 min/d for 1-3 cumulative hospital days and 16 min/d for ≥4 cumulative hospital days). Hospitalization was also associated with less physical activity time across all bouts of less than 10 minutes (≥1: -7 min/d for 1-3 cumulative hospital days, -16 min/d for ≥4 cumulative hospital days; ≥2: -5 min/d for 1-3 cumulative hospital days, -11 min/d for ≥4 cumulative hospital days; ≥5: -3 min/d for 1-3 cumulative hospital days, -4 min/d for ≥4 cumulative hospital days). There was no evidence of recovery to prehospitalization levels (time effect p >.41). PA participants had less sedentary time in bouts of less than 30 minutes than HE participants (-8 to -10 min/d) and more total activity (+3 to +6 min/d), although hospital-related changes were similar between the intervention groups (interaction effect p >.26). CONCLUSION: Participating in a PA intervention before hospitalization had expected benefits, but participants remained susceptible to hospitalization's detrimental effects on their daily activity levels. There was no evidence of better activity recovery after hospitalization.

13.
BMC Med ; 16(1): 185, 2018 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30352583

RESUMO

BACKGROUND: Whether physical activity can reduce cognitive frailty-a relatively new "compound" phenotype proposed in 2013-and whether the effect of physical activity differs based on levels of inflammation are unknown. Therefore, this study aimed to evaluate the effect of physical activity on cognitive frailty and whether baseline interleukin-6 (IL-6) levels modified this effect. METHODS: We used data from the Lifestyle Interventions and Independence for Elders (LIFE) Study, a multicenter, single-blinded randomized trial conducted at eight US field centers between February 2010 and December 2013. The main outcome was cognitive frailty at 24 months, expressed as an ordinal variable based on the six combinations of its two components: frailty (non-frail, pre-frail, and frail) and mild cognitive impairment (yes, no). Frailty and cognition were assessed by the Study of Osteoporotic Fractures (SOF) index and the Modified Mini-Mental State Examination (3MSE) scale, respectively. Plasma IL-6 was measured at baseline. Of the 1635 original randomized sedentary participants (70-89 years), this study included 1298 participants with data on both cognitive frailty and IL-6 assessments at baseline. RESULTS: After adjusting for field center, sex, and baseline levels of cognitive frailty, the ordinal logistic regression model revealed that participants in the physical activity group had 21% lower odds (odds ratio, 0.79; 95% confidence interval, 0.64-0.98) of worsening cognitive frailty over 24 months than those in the health education group. The effect of physical activity on cognitive frailty did not differ according to baseline IL-6 levels (P for interaction = 0.919). The results did not change after additional adjustment for IL-6 subgroups and the inverse probability of remaining in the study. Comparable results were observed according to age, sex, ethnicity/race, and short physical performance battery score (P for interaction = 0.835, 0.536, 0.934, and 0.458, respectively). CONCLUSIONS: A 24-month structured, moderate-intensity physical activity program reduced cognitive frailty compared with a health education program in sedentary older persons, and this beneficial effect did not differ according to baseline levels of inflammatory biomarker IL-6. These findings suggest that the new cognitive frailty construct is modifiable and highlight the potential of targeting cognitive frailty for promoting healthy aging. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01072500.

14.
Geroscience ; 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30338417

RESUMO

Declines in walking speed are associated with a variety of poor health outcomes including disability, comorbidity, and mortality. While genetic factors are putative contributors to variability in walking, few genetic loci have been identified for this trait. We examined the role of mitochondrial genomic variation on walking speed by sequencing the entire mitochondrial DNA (mtDNA). Data were meta-analyzed from 1758 Lifestyle Interventions and Independence for Elders (LIFE) Study and replication data from 730 Health, Aging, and Body Composition (HABC) Study participants with baseline walking speed information. Participants were 69+ years old of diverse racial backgrounds (African, European, and other race/ethnic groups) and had a wide range of mean walking speeds [4-6 m (0.78-1.09 m/s) and 400 m (0.83-1.24 m/s)]. Meta-analysis across studies and racial groups showed that m.12705C>T, ND5 variant was significantly associated (p < 0.0001) with walking speed at both short and long distances. Replication and meta-analysis also identified statistically significant walking speed associations (p < 0.0001) between the m.5460.G>A, ND2 and m.309C>CT, HV2 variants at short and long distances, respectively. All results remained statistically significant after multiple comparisons adjustment for 499 mtDNA variants. The m.12705C>T variant can be traced to the beginnings of human global migration and that cells carrying this variant display altered tRNA expression. Significant pooled effects related to stopping during the long-distance walk test were observed across OXPHOS complexes I (p = 0.0017) and III (p = 0.0048). These results suggest that mtDNA-encoded variants are associated with differences in walking speed among older adults, potentially identifying those at risk of developing mobility impairments.

15.
BMC Proc ; 12(Suppl 9): 48, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30263049

RESUMO

Background: Triglyceride (TG) concentrations decrease in response to fenofibrate treatment, and also are associated with DNA methylation. But how interactions between fenofibrate response and DNA methylation affect TGs remains unclear. Methods: In the present study, we identified and compared differential methylation sites associated with TG concentrations in individuals before and after fenofibrate treatment. We then estimated interactions between fenofibrate treatment and methylation to identify differential methylation effects associated with fenofibrate treatment on TG concentrations using the entire longitudinal family sample. To account for within-family and within-individual corrections, the generalized estimating equations approach was used to estimate main and interaction effects between methylation sites and fenofibrate treatment, adjusting for potential confounders. Analyses were also performed with and without adjusting for high-density lipoprotein (HDL) concentrations. Results: Prior to fenofibrate treatment, 23 cytosine-phosphate-guanine (CpG) sites were significantly associated with TG concentrations, while only 13 CpG sites were identified posttreatment, adjusting for HDL. Without adjusting for HDL, pretreatment, 20 CpG sites were significantly associated with TG concentrations, while only 12 CpG sites were identified posttreatment. Among these sites, only one differential site (cg19003390 in the CPT1A gene) overlapped from pre- and posttreatment measurements regardless of HDL adjustment. Furthermore, 11 methylation sites showed substantial interaction effects (p < 1.43 × 10-7with Bonferroni correction) with or without HDL adjustment when using the whole longitudinal data. Conclusions: Our analyses suggest that DNA methylation likely modified the effect of fenofibrate on TG concentrations. Differential fenofibrate-associated methylation sites on TGs differed with and without adjusting for HDL concentrations, suggesting that these HDLs and TGs might share some common epigenetic processes.

16.
J Diabetes Complications ; 32(10): 916-921, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30042057

RESUMO

BACKGROUND: Relationships between cognitive function and brain structure remain poorly defined in African Americans with type 2 diabetes. METHODS: Cognitive testing and cerebral magnetic resonance imaging in African Americans from the Diabetes Heart Study Memory IN Diabetes (n = 480) and Action to Control Cardiovascular Risk in Diabetes MIND (n = 104) studies were examined for associations. Cerebral gray matter volume (GMV), white matter volume (WMV) and white matter lesion volume (WMLV) and cognitive performance (Mini-mental State Exam [MMSE and 3MSE], Digit Symbol Coding (DSC), Stroop test, and Rey Auditory Verbal Learning Test) were recorded. Multivariable models adjusted for age, sex, BMI, scanner, intracranial volume, education, diabetes duration, HbA1c, LDL-cholesterol, smoking, hypertension and cardiovascular disease assessed associations between cognitive tests and brain volumes by study and meta-analysis. RESULTS: Mean(SD) participant age was 60.1(7.9) years, diabetes duration 12.1(7.7) years, and HbA1c 8.3(1.7)%. In the fully-adjusted meta-analysis, lower GMV associated with poorer global performance on MMSE/3MSE (ß̂ = 7.1 × 10-3, SE 2.4 × 10-3, p = 3.6 × 10-3), higher WMLV associated with poorer performance on DSC (ß̂ = -3 × 10-2, SE 6.4 × 10-3, p = 5.2 × 10-5) and higher WMV associated with poorer MMSE/3MSE performance (ß̂ = -7.1 × 10-3, SE = 2.4 × 10-3, p = 3.6 × 10-3). CONCLUSIONS: In African Americans with diabetes, smaller GMV and increased WMLV associated with poorer performance on tests of global cognitive and executive function. These data suggest that WML burden and gray matter atrophy associate with cognitive performance independent of diabetes-related factors in this population.

17.
Stroke ; 49(8): 1812-1819, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30002152

RESUMO

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5×10-8) partially independent of known common signal ( PEA(conditional)=1.4×10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9×10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( Prs34136221=2.8×10-8). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

18.
Prev Med Rep ; 11: 169-175, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29988772

RESUMO

Sugar-sweetened beverage (SSB) consumption is a risk factor for childhood obesity. Including this measure in electronic health records (EHR) could enhance clinical care and facilitate research on this topic. We implemented a single-item, EHR screening question for SSB and 100% fruit juice at 8 pediatric practices affiliated with a North Carolina academic medical center. From March-December 2017, we evaluated SSB screening of children 6 months-17 years of age. In a sub-sample of screened patients, we also conducted a telephone-based validation survey, comparing EHR-based responses to a lengthier beverage questionnaire, using Spearman rank coefficients and Kappa statistic. 22,626 children (91% of all seen) were screened for SSB intake. The screened population was diverse - 35% non-Hispanic White, 26% African-American, and 30% Hispanic. Consistent with national estimates, reported intake was typically higher than recommended: 41% (n = 9220) reported consuming SSB or fruit juice >1×/day in the past month, and consumption was higher among race/ethnic minorities. Of 201 validation survey respondents, direct correlation between their beverage survey and EHR screener responses was moderate, with a Spearman's rank correlation coefficient of 0.41 (p < 0.001) and Kappa statistic of 0.42 (95% CI 0.24-0.60). EHR-based screening for SSBs and fruit juice was successfully implemented, generating a large volume of SSB consumption data in a diverse patient population. Inclusion of patient-reported dietary measures in the EHR is feasible and could be useful for clinical care and research. Planned modifications may improve the correlation of such a screener with lengthier dietary instruments.

19.
Artigo em Inglês | MEDLINE | ID: mdl-29948650

RESUMO

Latino farmworkers are exposed to a number of carcinogens in the workplace. Cancer survival rates for Latinos are below average. This paper describes Mexican immigrant farmworkers' knowledge of colorectal, breast, and testicular cancer, and compares farmworkers' cancer knowledge to that of other Mexican immigrants. Survey interviews for this study were conducted with 100 farmworkers and 100 non-farmworkers in 2015 in North Carolina as part of an ongoing community-based participatory research project. We found low to moderate levels of knowledge about colorectal, breast, and testicular cancer among farmworkers. Compared to non-farmworkers, farmworkers had similar levels of knowledge about breast and testicular cancer, but slightly lower knowledge about colorectal cancer (p = 0.0087). Few studies have used quantitative methods to assess farmworkers' knowledge of specific types of cancer. Our results demonstrate a need for increased dissemination of existing cancer education programs and further research to develop additional educational tools.

20.
PLoS One ; 13(6): e0198166, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29912962

RESUMO

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

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