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BACKGROUND: Avocado intake improves dietary fat quality, but the subsequent impact on red blood cell (RBC) saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA) and trans fatty acid (TFA) composition and association with cardiometabolic health, has not been elucidated. OBJECTIVES: To compare the effect of consuming one avocado/day relative to habitual diet on RBC-FA profiles, and their association with visceral adiposity and cardiometabolic risk factors (CMRFs) in individuals with abdominal obesity. METHODS: RBC-FA profiling at baseline, 3- and 6-months was conducted in participants (n=994) from the Habitual Diet and Avocado Trial (HAT). HAT was a multi-site, free-living, parallel-arm intervention study in which participants were randomized to either the Avocado Supplemented group (AVO, usual diet with one avocado/day), or the Habitual Diet group (HAB, usual diet with limited avocado intake) for 6-months. Changes in RBC-FA profiles, a secondary outcome measure, were determined within and between groups using linear regression and mixed effect models, adjusting for age, sex, BMI, clinical site, smoking status and % energy intake from fat at baseline. Association between changes in RBC-FAs with visceral adiposity and CMRFs was assessed after covariate and FDR (<0.05) adjustment. RESULTS: No major differences in RBC-FA profiles were observed between groups, with the exception of MUFA cis-vaccenic [18:1n-7c], which was significantly higher in AVO (ß=0.11 [0.05, 0.17]) compared to the HAB (ß=0.03 [-0.03, 0.08]) participants. In the HAB but not AVO group, increases in MUFA cis (18:1n-7c, oleic [18;1n-9c], erucic [22:1n-9c]) and MUFA trans (palmitelaidic [16:1n-7t], vaccenic [18:1n-7t], elaidic [18:1n-9t] and petroselaidic [18;1n-10-12t), as well as PUFA γ-linolenic [18:3n-6], dihomo-γ-linolenic [20:3n-6], arachidonic [20:4n-6] and α-linolenic [18:3n-3] were associated with unfavorable changes in visceral adiposity measures, lipid profiles, glucose, insulin and hsCRP concentrations. CONCLUSION: Daily avocado intake over 6-months modified RBC-MUFA composition, notably 18:1n-7c, and potentially mitigated some of the unfavorable individual RBC FA-CMRF associations observed over time in the HAB group. CLINICAL TRIAL REGISTRY: https://clinicaltrials.gov/study/NCT03528031.
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INTRODUCTION: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans. METHODS: U.S. POINTER was planned as a 2-year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well-established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER. RESULTS: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing. DISCUSSION: U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies.
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Disfunção Cognitiva , Humanos , Idoso , Disfunção Cognitiva/psicologia , Estilo de Vida , Cognição , Exercício Físico , EncéfaloRESUMO
Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([18F]MK6240), beta-amyloid (Aß)-PET ([18F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aß and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aß+> Aß- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.
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Doença de Alzheimer , Disfunção Cognitiva , Idoso , Humanos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/metabolismo , Pessoa de Meia-IdadeRESUMO
BACKGROUND: U.S. POINTER is a Phase 3, multicenter, randomized 2-year clinical trial of two multidomain lifestyle interventions in 2111 older adults who are at increased risk of cognitive decline and dementia due sedentary lifestyle, poor diet, and other factors such as family history of memory impairment and suboptimum cardiovascular health. METHOD: Enrollment took place at five geographically diverse sites, beginning in 2019 and completing in early 2023. Participants are randomly assigned to one of two lifestyle intervention groups that differ in format, intensity, and accountability. Those randomized to the Self-Guided Lifestyle Intervention receive annual medical monitoring and health education information, tools, and support to encourage increased physical and cognitive activity and a healthier diet through 2-3 annual group meetings. Those randomized to the Structured Lifestyle Intervention receive frequent medical monitoring of cardiovascular health and a structured program of exercise (primarily aerobic), nutritional counseling, cognitive training and social engagement initially through weekly and then monthly group meetings. U.S. POINTER includes partnerships with local chapters of the Alzheimer's Association and lifestyle specialists to assist with intervention delivery. The primary outcome is 2-year change in cognitive function measured with a global cognition composite score that permits harmonization with FINGER and other trials. Secondary and tertiary outcomes include measures of executive function and episodic memory, physical activity, diet, cognitive and physical activity, cardiometabolic disease risks, mood, quality of life, health care costs, and health care utilization. RESULT: U.S. POINTER is generating a richly phenotyped cohort that will provide a rigorous comparison of two lifestyle interventions designed to preserve cognitive function. It has nurtured 4 ancillary studies to assess intervention effects on outcomes related to sleep quality, brain structure and pathology, peripheral and neurovascular function, and the microbiome. It also partners with clinical trials within the World-Wide FINGERS international network. The study is generating an archive of biospecimens and de-identified public use data. Plans for a post-intervention observational study of the U.S. POINTER cohort are underway. CONCLUSION: U.S. POINTER provides an important national resource to advance the field in understanding the role of nonpharmacological interventions in reducing risk for cognitive decline and Alzheimer's disease and related dementia.
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Disfunção Cognitiva , Humanos , Disfunção Cognitiva/terapia , Demência/prevenção & controle , Exercício Físico , Idoso , Estilo de Vida , Masculino , Feminino , Comportamento SedentárioRESUMO
Background Excess visceral adiposity is associated with increased risk of cardiometabolic disorders. Short-term well-controlled clinical trials suggest that regular avocado consumption favorably affects body weight, visceral adiposity, and satiety. Methods and Results The HAT Trial (Habitual Diet and Avocado Trial) was a multicenter, randomized, controlled parallel-arm trial designed to test whether consuming 1 large avocado per day for 6 months in a diverse group of free-living individuals (N=1008) with an elevated waist circumference compared with a habitual diet would decrease visceral adiposity as measured by magnetic resonance imaging. Secondary and additional end points related to risk factors associated with cardiometabolic disorders were assessed. The primary outcome, change in visceral adipose tissue volume during the intervention period, was not significantly different between the Avocado Supplemented and Habitual Diet Groups (estimated mean difference (0.017 L [-0.024 L, 0.058 L], P=0.405). No significant group differences were observed for the secondary outcomes of hepatic fat fraction, hsCRP (high-sensitivity C-reactive protein), and components of the metabolic syndrome. Of the additional outcome measures, modest but nominally significant reductions in total and low-density lipoprotein cholesterol were observed in the Avocado Supplemented compared with the Habitual Diet Group. Changes in the other additional and post hoc measures (body weight, body mass index, insulin, very low-density lipoprotein concentrations, and total cholesterol:high-density lipoprotein cholesterol ratio) were similar between the 2 groups. Conclusions Addition of 1 avocado per day to the habitual diet for 6 months in free-living individuals with elevated waist circumference did not reduce visceral adipose tissue volume and had minimal effect on risk factors associated with cardiometabolic disorders. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT03528031.
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Doenças Cardiovasculares , Dieta , Obesidade Abdominal , Persea , Adiposidade , Índice de Massa Corporal , Peso Corporal , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Frutas , Humanos , Obesidade Abdominal/complicaçõesRESUMO
BACKGROUND: In the SPRINT (Systolic Blood Pressure Intervention Trial), intensive BP treatment reduced acute decompensated heart failure (ADHF) events. Here, we report the effect on HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF) and their subsequent outcomes. METHODS: Incident ADHF was defined as hospitalization or emergency department visit, confirmed, and formally adjudicated by a blinded events committee using standardized protocols. HFpEF was defined as EF ≥45%, and HFrEF was EF <45%. RESULTS: Among the 133 participants with incident ADHF who had EF assessment, 69 (52%) had HFpEF and 64 (48%) had HFrEF (P value: 0.73). During average 3.3 years follow-up in those who developed incident ADHF, rates of subsequent all-cause and HF hospital readmission and mortality were high, but there were no significant differences between those who developed HFpEF versus HFrEF. Randomization to the intensive arm had no effect on subsequent mortality or readmissions after the initial ADHF event, irrespective of EF subtype. During follow-up among participants who developed HFpEF, although relatively modest number of events limited statistical power, age was an independent predictor of all-cause mortality, and Black race independently predicted all-cause and HF hospital readmission. CONCLUSIONS: In SPRINT, intensive BP reduction decreased both acute decompensated HFpEF and HFrEF events. After initial incident ADHF, rates of subsequent hospital admission and mortality were high and were similar for those who developed HFpEF or HFrEF. Randomization to the intensive arm did not alter the risks for subsequent all-cause, or HF events in either HFpEF or HFrEF. Among those who developed HFpEF, age and Black race were independent predictors of clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.
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Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/cirurgia , Resultado do Tratamento , Disfunção Ventricular Esquerda/cirurgia , Idoso , Idoso de 80 Anos ou mais , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/estatística & dados numéricos , Fatores de Risco , Volume Sistólico/fisiologia , Fatores de Tempo , Disfunção Ventricular Esquerda/epidemiologia , Função Ventricular Esquerda/fisiologiaRESUMO
BACKGROUND: Elevated interleukine-6 (IL-6) and C-reactive protein (CRP) are associated with aging-related reductions in physical function, but little is known about their independent and combined relationships with major mobility disability (MMD), defined as the self-reported inability to walk a quarter mile. METHODS: We estimated the absolute and relative effect of elevated baseline IL-6, CRP, and their combination on self-reported MMD risk among older adults (≥68 years; 59% female) with slow gait speed (<1.0 m/s). Participants were MMD-free at baseline. IL-6 and CRP were assessed using a central laboratory. The study combined a cohort of community-dwelling high-functioning older adults (Health ABC) with 2 trials of low-functioning adults at risk of MMD (LIFE-P, LIFE). Analyses utilized Poisson regression for absolute MMD incidence and proportional hazards models for relative risk. RESULTS: We found higher MMD risk per unit increase in log IL-6 (hazard ratio [HR] = 1.26; 95% confidence interval [95% CI] 1.13-1.41). IL-6 meeting predetermined threshold considered to be high (>2.5 pg/mL) was similarly associated with higher risk of MMD (HR = 1.31; 95% CI 1.12-1.54). Elevated CRP (CRP >3.0 mg/L) was also associated with increased MMD risk (HR = 1.38; 95% CI 1.10-1.74). The CRP effect was more pronounced among participants with elevated IL-6 (HR = 1.62; 95% CI 1.12-2.33) compared to lower IL-6 levels (HR = 1.19; 95% CI 0.85-1.66). CONCLUSIONS: High baseline IL-6 and CRP were associated with an increased risk of MMD among older adults with slow gait speed. A combined biomarker model suggests CRP was associated with MMD when IL-6 was elevated.
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Proteína C-Reativa/análise , Interleucina-6 , Limitação da Mobilidade , Velocidade de Caminhada , Idoso , Feminino , Humanos , Interleucina-6/sangue , Masculino , Autorrelato , CaminhadaRESUMO
BACKGROUND: Observational studies have documented lower risks of coronary heart disease and diabetes among moderate alcohol consumers relative to abstainers, but only a randomized clinical trial can provide conclusive evidence for or against these associations. AIM: The purpose of this study was to describe the rationale and design of the Moderate Alcohol and Cardiovascular Health Trial, aimed to assess the cardiometabolic effects of one alcoholic drink daily over an average of six years among adults 50 years or older. METHODS: This multicenter, parallel-arm randomized trial was designed to compare the effects of one standard serving (â¼11-15 g) daily of a preferred alcoholic beverage to abstention. The trial aimed to enroll 7800 people at high risk of cardiovascular disease. The primary composite endpoint comprised time to the first occurrence of non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalized angina, coronary/carotid revascularization, or total mortality. The trial was designed to provide >80% power to detect a 15% reduction in the risk of the primary outcome. Secondary outcomes included diabetes. Adverse effects of special interest included injuries, congestive heart failure, alcohol use disorders, and cancer. RESULTS: We describe the design, governance, masking issues, and data handling. In three months of field center activity until termination by the funder, the trial randomized 32 participants, successfully screened another 70, and identified â¼400 additional interested individuals. CONCLUSIONS: We describe a feasible design for a long-term randomized trial of moderate alcohol consumption. Such a study will provide the highest level of evidence for the effects of moderate alcohol consumption on cardiovascular disease and diabetes, and will directly inform clinical and public health guidelines.
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Consumo de Bebidas Alcoólicas , Doenças Cardiovasculares/epidemiologia , Síndrome Metabólica/epidemiologia , Medição de Risco/métodos , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Estudos de Viabilidade , Feminino , Seguimentos , Saúde Global , Humanos , Masculino , Síndrome Metabólica/etiologia , Pessoa de Meia-Idade , Morbidade , Fatores de TempoRESUMO
The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34-0.72), whereas no benefit was observed for other genotypes (P interaction = 3.7 × 10-4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11-a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.
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Diabetes Mellitus Tipo 2/genética , Dislipidemias/tratamento farmacológico , Fenofibrato/uso terapêutico , Hipolipemiantes/uso terapêutico , PPAR alfa/genética , Polimorfismo de Nucleotídeo Único , Quimiocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/genética , Feminino , Genótipo , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Farmacogenética , Resultado do TratamentoRESUMO
OBJECTIVES: Our aim was to examine the impacts of baseline fatigue on the effectiveness of a physical activity (PA) intervention to prevent major mobility disability (MMD) and persistent major mobility disability (PMMD) in participants from the Lifestyle Interventions and Independence for Elders (LIFE) study. DESIGN: Prospective cohort of individuals aged 65 years or older undergoing structured PA intervention or health education (HE) for a mean of 2.6 years. SETTING: LIFE was a multicenter eight-site randomized trial that compared the efficacy of a structured PA intervention with an HE program in reducing the incidence of MMD. PARTICIPANTS: Study participants (N = 1591) at baseline were 78.9 ± 5.2 years of age, with low PA and at risk for mobility impairment. MEASUREMENTS: Self-reported fatigue was assessed using the modified trait version of the Exercise-Induced Feelings Inventory, a six-question scale rating energy levels in the past week. Responses ranged from 0 (none of the time) to 5 (all of the time). Total score was calculated by averaging across questions; baseline fatigue was based on the median split: 2 or higher = more fatigue (N = 856) and lower than 2 = less fatigue (N = 735). Participants performed a usual-paced 400-m walk every 6 months. We defined incident MMD as the inability to walk 400-m at follow-up visits; PMMD was defined as two consecutive walk failures. Cox proportional hazard models quantified the risk of MMD and PMMD in PA vs HE stratified by baseline fatigue adjusted for covariates. RESULTS: Among those with higher baseline fatigue, PA participants had a 29% and 40% lower risk of MMD and PMMD, respectively, over the trial compared with HE (hazard ratio [HR] for MMD = .71; 95% confidence interval [CI] = .57-.90; P = .004) and PMMD (HR = .60; 95% CI = .44-.82; P = .001). For those with lower baseline fatigue, no group differences in MMD (P = .36) or PMMD (P = .82) were found. Results of baseline fatigue by intervention interaction was MMD (P = .18) and PMMD (P = .05). CONCLUSION: A long-term moderate intensity PA intervention was particularly effective at preserving mobility in older adults with higher levels of baseline fatigue. J Am Geriatr Soc 68:619-624, 2020.
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Exercício Físico/fisiologia , Fadiga , Educação em Saúde , Limitação da Mobilidade , Idoso , Feminino , Humanos , Masculino , Estudos Prospectivos , Autorrelato , CaminhadaRESUMO
OBJECTIVES: This study assessed the potential role of differential diuretic drugs in preventing incident acute decompensated heart failure (ADHF) in the SPRINT (Systolic Blood Pressure Intervention Trial) study. BACKGROUND: SPRINT showed that intensive blood pressure reduction in older patients (50 to 97 years of age) resulted in 36% fewer incident cases of ADHF. However, some investigators have questioned whether this was due merely to intergroup differences in diuretic medications. METHODS: Detailed use of medication data prospectively collected throughout the trial were examined. RESULTS: ADHF events occurred in 173 of 9,361 participants. Diuretic medication increased in both arms from screening to baseline visit (from 45% to 50% in the standard arm; and from 43% to 63% in the intensive arm) and then remained steady. The lowest use of diuretic agents was among participants in the standard arm who never had an ADHF event. Withdrawal of diuretic agents at the baseline visit occurred in 6.1% (n = 284) of participants in the standard arm and 2.3% (n = 107) of participants in the intensive arm. Of these, only 11 developed ADHF during the trial (10 in the standard arm, 1 in the intensive arm), and only 1 occurred ≤1 month after diuretic withdrawal. The benefit of ADHF reduction remained significant even after excluding those 11 participants (hazard ratio [HR]: 0.69; 95% confidence interval [CI]: 0.5 to 0.94; p = 0.02). Most ADHF events occurred in participants who were taking prescribed diuretic therapy at the last visit, prior to the ADHF event. There was limited use of loop (<6%) and potassium-sparing diuretic agents (2%). Diuretic use was not a predictor of ADHF (HR: 0.96; 95% CI: 0.66 to 1.40; p = 0.83). CONCLUSIONS: No evidence was found to suggest that the reduction in new ADHF events in SPRINT was due to differential diuretic use. (Systolic Blood Pressure Intervention Trial [SPRINT]; NCT01206062).
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Diuréticos/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Método Simples-CegoRESUMO
BACKGROUND: High dietary sodium intake may induce a small, yet physiologically relevant rise in serum sodium concentration, which associates with increased systolic blood pressure. Cellular data suggest that this association is mediated by increased endothelial cell stiffness. We hypothesized that higher serum sodium levels were associated with greater arterial stiffness in participants in the Systolic Blood Pressure Intervention Trial (SPRINT). METHODS: Multivariable linear regression was used to examine the association between baseline serum sodium level and (i) pulse pressure (PP; n = 8,813; a surrogate measure of arterial stiffness) and (ii) carotid-femoral pulse wave velocity (CFPWV; n = 591 in an ancillary study to SPRINT). RESULTS: Baseline mean ± SD age was 68 ± 9 years and serum sodium level was 140 ± 2 mmol/L. In the PP analysis, higher serum sodium was associated with increased baseline PP in the fully adjusted model (tertile 3 [≥141 mmol] vs. tertile 2 [139-140 mmol]; ß = 0.87, 95% CI = 0.32 to 1.43). Results were similar in those with and without chronic kidney disease. In the ancillary study, higher baseline serum sodium was not associated with increased baseline CFPWV in the fully adjusted model (ß = 0.35, 95% CI = -0.14 to 0.84). CONCLUSIONS: Among adults at high risk for cardiovascular events but free from diabetes, higher serum sodium was independently associated with baseline arterial stiffness in SPRINT, as measured by PP, but not by CFPWV. These results suggest that high serum sodium may be a marker of risk for increased PP, a surrogate index of arterial stiffness.
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Pressão Sanguínea , Hipertensão/sangue , Hipertensão/fisiopatologia , Sódio/sangue , Rigidez Vascular , Idoso , Biomarcadores/sangue , Velocidade da Onda de Pulso Carótido-Femoral , Estudos Transversais , Feminino , Humanos , Hipertensão/diagnóstico , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Estados Unidos , Regulação para CimaRESUMO
Osteoarthritis (OA) is one of the most common causes of chronic disability in adults due to pain and altered joint function. Although most patients report pain and functional limitation, symptoms, age of onset and disease progression are extremely variable. While inflammation could play a central role in the OA pathogenesis and progression, many underpinning mechanisms are still unclear. A number of proinflammatory mediators have been found in OA joints and could play a role, such as IL-1, IL-6, IL-7, IL-8, IL-15, IL-17, IL-18, TNF-alpha, macrophage chemotactic protein (MCP)-1, interferon-induced protein (IP)-10, monokine induced by interferon (MIG), oncostatin M (OSM), growth-related oncogene (GRO)-alpha, chemokine (C-C-motif) ligand 19 (CCL19), macrophage inflammatory protein (MIP)-1beta, and TGF-alpha. Biological approaches have recently got increasing interest due to their anti-inflammatory and immunomodulatory properties, regenerative potential, and high tolerability. The primary aim of this paper is to report the current concepts on regenerative medicine for knee OA with a particular focus on Autologous Protein solution (APS). APS is a blood derived product obtained by using a proprietary device, made of APS Separator, which isolates WBCs and platelets in a small volume of plasma, and APS Concentrator, which further concentrates platelets, WBCs and plasma proteins. The result is a peculiar formulation differing from other biologic products as it contains high levels of growth factors (EGF, IGF-1, PDGF-AB, PDGF-BB, VEGF, TGF-ß1) along with high concentrations of anti-inflammatory mediators (IL-1ra, sIL-1RII, sTNF-RI, sTNF-RII) and low levels of pro-inflammatory cytokines (Il-1ß and TNF-α). While emerging evidence supports the use of APS, as confirmed by in vitro studies and preliminary clinical results, the real clinical potential of APS and its benefits are still under investigation.
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BACKGROUND: Low-grade chronic inflammation, characterized by elevations in plasma Interleukin-6 (IL-6), is an independent risk factor of impaired mobility in older persons. Angiotensin receptor blockers and omega-3 polyunsaturated fatty acids (ω-3) may reduce IL-6 and may potentially improve physical function. To assess the main effects of the angiotensin receptor blocker losartan and ω-3 as fish oil on IL-6 and 400 m walking speed, we conducted the ENRGISE Pilot multicenter randomized clinical trial. METHODS: The ENRGISE Pilot enrolled participants between April 2016 and June 2017, who participated for 12 months. Participants were aged ≥70 years with mobility impairment, had IL-6 between 2.5 and 30 pg/mL, and were able to walk 400 m at baseline. Participants were randomized in three strata 2 × 2 factorial to: (i) losartan 50-100 mg/d or placebo (n = 43), (ii) fish oil 1,400-2,800 mg/d or placebo (n = 180), and (iii) with both (n = 66). RESULTS: Two hundred eighty-nine participants were randomized (mean age 78.3 years, 47.4% women, 17.0% black). There was no effect of losartan (difference of means = -0.065 ± 0.116 [SE], 95% confidence interval [CI]: -0.293-0.163, p = .58) or fish oil (-0.020 ± 0.077, 95% CI: -0.171-0.132, p = .80) on the log of IL-6. Similarly, there was no effect of losartan (-0.025 ± 0.026, 95% CI: -0.076-0.026, p = .34) or fish oil (0.010 ± 0.017, 95% CI: -0.025-0.044, p = .58) on walking speed (m/s). CONCLUSIONS: These results do not support the use of these interventions to prevent mobility loss in older adults at risk of disability with low-grade chronic inflammation. REGISTRATION: Clinicaltrials.gov NCT02676466.
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Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Interleucina-6/sangue , Losartan/uso terapêutico , Limitação da Mobilidade , Velocidade de Caminhada/fisiologia , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Masculino , Projetos PilotoRESUMO
BACKGROUND: The Enabling Reduction of Low-grade Inflammation in Seniors (ENRGISE) Pilot Study is a multicenter randomized clinical trial examining the feasibility of testing whether omega-3 fish oil (ω-3) and the angiotensin receptor blocker losartan alone or in combination can reduce inflammation and improve walking speed in older adults with mobility impairment. We describe recruitment methods and results. METHODS: Eligible participants were 70 years and older, had elevated interleukin-6 levels (2.5-30 pg/mL) and mobility impairment. RESULTS: Of those who responded to recruitment, 83% responded to mailings. A total of 5,424 telephone screens were completed; of these, 2,011 (37.1%) were eligible for further screening. The most common reasons for ineligibility at the telephone screens were lack of mobility impairment or use of angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (n=1.789). Of the 1,305 initial screening visits, 1,087 participants had slow gait speed (<1 m/s). Of these, 701 (64%) had elevated interleukin-6 and were eligible for second screening visits. Of the 582 second screening visits, 335 (57.6%) were eligible to be randomized. A total of 289 participants (96% of goal) were randomized: 180 in the ω-3 stratum (240% of goal); 43 in the losartan (57% of goal), and 66 in the combination (44% of goal). The telephone screen and first screening visit to randomization ratio was 19 to 1 and 4.5 to 1, respectively. The estimated cost of recruitment per randomized participant was $1,782. CONCLUSION: Recruitment for ω-3 exceeded goals, but goals for the losartan and combination strata were not met due to the high proportion of participants taking angiotensin receptor blockers or angiotensin-converting enzyme inhibitors.
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Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Inflamação/prevenção & controle , Losartan/uso terapêutico , Limitação da Mobilidade , Velocidade de Caminhada , Idoso , Estudos de Viabilidade , Feminino , Humanos , Interleucina-6/sangue , Masculino , Projetos Piloto , Estados UnidosRESUMO
PURPOSE: Osteochondral implants are currently adopted for the treatment of symptomatic full-thickness chondral and osteochondral defects. Agili-C™ is a cell-free aragonite-based scaffold which aims to reproduce the original structure and function of the articular joint while directing the growth and regeneration of both cartilage and its underlying subchondral bone. The goal of the present study was to investigate the ex vivo mechanisms of action (MOA) of the Agili-C™ implant in the repair of full-thickness cartilage defects. In particular, we tested whether Agili-C™ implant has the potential to stimulate cartilage ingrowth through chondrocytes migration into the 3D interconnected porous structure of the scaffold, along with maintaining their viability and phenotype and the deposition of hyaline cartilage matrix. METHODS: Articular cartilage samples were collected through the Gift of Hope Organ and Tissue Donor Network (Itasca, IL) within 24 h from death. For this study, cartilage from a total of 14 donors was used. To model a chondral defect, donut-shaped cartilage explants were prepared from each tissue specimen. The chondral phase of the Agili-C™ implant was placed inside the tissue in full contact and press fit manner. Cartilage explants with the Agili-C™ implant inside were cultured for 60 days. As a control, the same donut-shaped cartilage explants were cultured without Agili-C™, under the same culture conditions. RESULTS: Using fresh human cadaveric articular cartilage tissue in a 60-day culture, it was demonstrated that chondrocytes were able to migrate into the Agili-C™ scaffold and contribute to the deposition of the extracellular matrix (ECM) rich in collagen type II and aggrecan, and lacking collagen type I. Additionally, we were able to show the formation of a layer populated by progenitor-like cells on the articular surface of the implant. CONCLUSIONS: The analysis of samples taken from knee and ankle joints of human donors with a wide age range and both genders supports the potential of Agili-C™ scaffold to stimulate cartilage regeneration and repair. Based on these results, the present scaffold can be used in the clinical practice as a one-step procedure to treat full-thickness chondral defects.
Assuntos
Doenças das Cartilagens/cirurgia , Cartilagem Articular/citologia , Condrócitos/transplante , Articulação do Joelho/cirurgia , Próteses e Implantes , Adulto , Idoso , Animais , Doenças das Cartilagens/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Cultura de Tecidos , Alicerces TeciduaisRESUMO
Biological studies on in vitro cell cultures are of fundamental importance to investigate cell response to external stimuli, such as new drugs for the treatment of specific pathologies, or to study communication between electrogenic cells. Although three-dimensional (3D) nanostructures brought tremendous improvements on biosensors used for various biological in vitro studies, including drug delivery and electrical recording, there is still a lack of multifunctional capabilities that could help gain deeper insights in several bio-related research fields. In this work, the electrical recording of large cell ensembles and the intracellular delivery of few selected cells are combined on the same device by integrating microfluidic channels on the bottom of a multi-electrode array decorated with 3D hollow nanostructures. The novel platform allows the recording of intracellular-like action potentials from large ensembles of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and from the HL-1 line, while different molecules are selectively delivered into single/few targeted cells. The proposed approach shows high potential for enabling new comprehensive studies that can relate drug effects to network level cell communication processes.
Assuntos
Técnicas Biossensoriais/instrumentação , Espaço Intracelular/metabolismo , Linhagem Celular , Fenômenos Eletrofisiológicos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Microeletrodos , Miócitos Cardíacos/citologiaRESUMO
OBJECTIVES: To explore whether baseline scores on the Mobility Assessment Tool-short form (MAT-sf), a brief, animated, computer-based means of assessing mobility that predicts mobility disability, are associated with number of hospitalizations and time to first hospitalization over a median follow-up of 2.7 years. DESIGN: Post hoc analysis of prospectively gathered data from the Lifestyle Interventions and Independence for Elders (LIFE) Study, a randomized clinical trial of lifestyle interventions to preserve mobility in older adults. SETTING: Eight U.S. academic medical centers. PARTICIPANTS: Of 1,635 sedentary community-dwelling older adults enrolled in LIFE, 1,574 completed baseline physical function screening including the MAT-sf, with baseline scores ranging from 30.2 (low function) to 69.8 (high function) on a scale from 30 to 80. MEASUREMENTS: Number of hospitalizations and time to first hospitalization, adjusted for age, sex, race, living alone, clinical site, baseline comorbidities, number of prescription medications, and cognition. RESULTS: Of the 1,557 participants with data regarding hospitalization status, 726 (47%) had at least 1 hospitalization; 78% of these had 1 or 2 hospitalizations. For every 10-point lower MAT-sf score, the rate of all hospitalizations was 19% higher in those with lower scores (adjusted rate ratio=1.20, 95% confidence interval (CI)=1.08-1.32, p<.001). Lower baseline MAT-sf scores were also associated with greater risk of first hospitalization (adjusted hazard ratio=1.20, 95% CI=1.09-1.32, p<.01, per 10-point lower MAT-sf score). CONCLUSION: Low MAT-sf scores identify older adults at risk of hospitalization; further study is needed to test interventions to reduce hospitalizations in these individuals.