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Postprandial TAG-rich lipoproteins (TRL) can be taken up by macrophages, leading to the formation of foam cells, probably via receptor-mediated pathways. The present study was conducted to investigate whether the postprandial time point at which TRL are collected modulates this process. A meal containing refined olive oil was given to nine healthy young men and TRL were isolated from their serum at 2, 4 and 6 h postprandially. The lipid class and apoB compositions of TRL were determined by HPLC and SDS-PAGE, respectively. The accumulation of lipids in macrophages was determined after the incubation of THP-1 macrophages with TRL. The gene expression of candidate receptors was measured by real-time PCR. The highest concentrations of TAG, apoB48 and apoB100 in TRL were observed at 2 h after the consumption of the test meal. However, excessive intracellular TAG accumulation in THP-1 macrophages was observed in response to incubation with TRL isolated at 4 h, when their particle size (estimated as the TAG:apoB ratio) was intermediate. The abundance of mRNA transcripts in macrophages in response to incubation with TRL was down-regulated for LDL receptor (LDLR), slightly up-regulated for VLDL receptor and remained unaltered for LDLR-related protein, but no effect of the postprandial time point was observed. In contrast, the mRNA expression of scavenger receptors SRB1, SRA2 and CD36 was higher when cells were incubated with TRL isolated at 4 h after the consumption of the test meal. In conclusion, TRL led to excessive intracellular TAG accumulation in THP-1 macrophages, which was greater when cells were incubated with intermediate-sized postprandial TRL isolated at 4 h and was associated with a significant increase in the mRNA expression of scavenger receptors.
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Lipoproteínas/sangue , Macrófagos/metabolismo , Período Pós-Prandial/fisiologia , Triglicerídeos/sangue , Adulto , Antígenos CD36/genética , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Cinética , Macrófagos/química , Masculino , Tamanho da Partícula , RNA Mensageiro/sangue , Receptores de LDL/genética , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe B/genética , Fatores de TempoRESUMO
INTRODUCTION: The objective of this study is to develop a clinical tool for the evaluation and follow-up of adolescent and adult patients with 5q spinal muscular atrophy (SMA) and to design its validation. METHODS: This prospective, non-interventional study will be carried out at five centres in Spain and will include patients aged 16 years or older with a confirmed diagnosis of 5q SMA (biallelic mutation of the survival motor neuron 1 [SMN1] gene). A panel of experts made up of neurologists, physiatrists and Spanish patients' association (FundAME), participated in the design of the clinical tool. Physicians will administer the tool at three time points (baseline, 12 months and 24 months). Additionally, data from other questionnaires and scales will be collected. Once recruitment is achieved, an interim statistical analysis will be performed to assess its psychometric properties by applying Rasch analysis and classical statistical tests. RESULTS: The tool will consist of up to 53 items to assess functional status from a clinical perspective in seven key dimensions (bulbar, respiratory, axial, lower, upper, fatigability and other symptoms), which will be collected together with objective clinical measures (body mass index, forced vital capacity, pinch strength and 6-minute walk test). CONCLUSIONS: The validation of this tool will facilitate the clinical evaluation of adult and adolescent patients with SMA and the quantification of their response to new treatments in both clinical practice and research.
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INTRODUCTION: Outcome measures traditionally used in spinal muscular atrophy (SMA) clinical trials are inadequate to assess the full range of disease severity. The aim of this study was to assess the psychometric properties of a set of existing questionnaires and new items, gathering information on the impact of SMA from the patient and caregiver perspectives. METHODS: This was a multicenter, prospective, noninterventional study including patients with a confirmed diagnosis of 5q-autosomal-recessive SMA aged 8 years and above, or their parents (if aged between 2 and 8 years). The set of outcome measurements included the SMA Independence Scale (SMAIS) patient and caregiver versions, the Neuro-QoL Fatigue Computer Adaptive Test (CAT), the Neuro-QoL Pain Short Form-Pediatric Pain, the PROMIS adult Pain Interference CAT, and new items developed by Fundación Atrofia Muscular España: perceived fatigability, breathing and voice, sleep and rest, and vulnerability. Reliability, construct validity, discriminant validity, and sensitivity to change (4 months from baseline) were measured. RESULTS: A total of 113 patients were included (59.3% 2-17 years old, 59.3% male, and 50.4% with SMA type II). Patients required moderate assistance [mean patient and caregiver SMAIS (SD) scores were 31.1 (12.8) and 7.6 (11.1), respectively]. Perceived fatigability was the most impacted domain, followed by vulnerability. Cronbach's alpha coefficient for perceived fatigability, breathing and voice, and vulnerability total scores were 0.92, 0.88, and 0.85, respectively. The exploratory factor analysis identified the main factors considered in the design, except in the sleep and rest domain. All questionnaires were able to discriminate between the Clinical Global Impression-Severity scores and SMA types. Sensitivity to change was only found for the SMAIS caregiver version and vulnerability items. CONCLUSIONS: This set of outcome measures showed adequate reliability, construct validity, and discriminant validity and may constitute a valuable option to measure symptom severity in patients with SMA.
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INTRODUCTION: There are many uncertainties about treatment selection and expectations regarding therapeutic goals and benefits in the new landscape of spinal muscular atrophy (SMA). Our aim was to assess treatment preferences and expectations of pediatric neurologists caring for patients with SMA. METHODS: DECISIONS-SMA is a non-interventional, cross-sectional pilot study that assessed pediatric neurologists with expertise in SMA from across Spain. Participants were presented with 11 simulated case scenarios of common encounters of patients with SMA type 1 and 2 to assess treatment initiation, escalation, or switches. We also asked for the expected benefit with new therapies for four simulated case scenarios. Participants completed a behavioral battery to address their tolerance to uncertainty and aversion to ambiguity. The primary outcome was therapeutic inertia (TI), defined as the number of simulated scenarios with lack of treatment initiation or escalation when warranted over the total (11) presented cases. RESULTS: A total of 35 participants completed the study. Participants' mean (SD) expectation for achieving an improvement by starting a new therapy for SMA type 1 (case 1, a 5-month-old) and SMA type 2 (case 6, a 1-year-old) were both 59.6% (± 21.8), but declined to 20.2% (± 12.2) for a case scenario of a 16-year-old treatment-naïve patient with long-standing SMA type 2 with severe disability. The mean (SD) TI score was 4.2 (1.7), and 3.29 (1.5) for treatment initiation. Of a total 385 individual responses, TI was observed in 147 (38.2%) of treatment choices. The multivariable analysis showed that lower aversion to ambiguity (p = 0.019) and lower expectation of treatment response (p = 0.007) were associated with higher TI after adjustment for participants' age and years of experience. Older age (p = 0.019), lower years of experience (p = 0.035), lower aversion to ambiguity (p = 0.015), and lower expectation of treatment benefits (p = 0.006) were associated with inertia for treatment initiation. CONCLUSIONS: Pediatric neurologists managing patients with SMA were optimistic regarding treatment improvement in cases with early diagnosis, but had lower expectations when treatment delays and advanced patient age were present. Low aversion to ambiguity, low expectation of treatment benefits, and lower clinical experience were more likely to make suboptimal decisions, resulting in lack of treatment initiation, escalation, and TI.
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PURPOSE: Patients with multiple sclerosis (MS) are increasingly demanding access to reliable information regarding their disease. The objective of the INFOSEEK-MS study was to assess what are the strategies people with MS use when searching for information on their disease, including sources, frequency, reliability, and preferred content. PATIENTS AND METHODS: A non-interventional, cross-sectional study was conducted. Patients with a diagnosis of MS according to the 2010 McDonald criteria were included. The InfoSeek questionnaire was used to assess patients' strategies when seeking information about the disease. Clinical characteristics and other variables, including disability, quality of life, fatigue, cognition, anxiety and depression, were analysed using the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale (MSIS-29), 5-item Modified Fatigue Scale (MFIS-5), Symbol Digit Modalities Test (SDMT), and Hospital Anxiety and Depression Scale (HADS), respectively. RESULTS: Three hundred and two patients were studied (mean age: 42.3 ± 10 years, 64% female, mean disease duration: 9.6 ± 7.0 years, 90% with relapsing-remitting MS, and mean EDSS score: 2.6 ± 1.9). The internet (either via mobile or computer) is a frequently reported source of information. Lifestyle-related information (67.2%), research and emerging treatments (63.6%), symptom control (49.7%), sharing experiences with other patients (46.4%), and disease prognosis (46.4%) were the most searched topics. Neurologists and nurses were the most trusted source of information. Younger patients and higher SDMT scores were associated with all search resources (M = 37.7 and M = 49.97, respectively). The frequency of searches was related to the number of relapses (R2 = 0.07), EDSS (R2 = 0.14), MSIS-29 physical and psychological components (R2 = 0.132) and inversely with depression (R2 = 0.132). CONCLUSION: Although healthcare professionals are considered the most reliable source of information for people with MS, searching for information on the Internet is very frequent. An individualized information strategy considering the different factors involved is needed.
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The endothelium is involved in many of the processes related to the development of atherosclerosis, which is considered an inflammatory disease. Actually, traditional risk factors for atherosclerosis predispose to endothelial dysfunction, which is manifested as an increase in the expression of specific cytokines and adhesion molecules. There are firm evidence supporting the beneficial effects of olive oil, the most genuine component of the Mediterranean diet. Although the effects of olive oil and other oleic acid-rich dietary oils on atherosclerosis and plasma lipids are well known, the roles of minor components have been less investigated. Minor components constitute only 1-2% of virgin olive oil (VOO) and are composed of hydrocarbons, polyphenols, tocopherols, sterols, triterpenoids and other components usually found in traces. Despite their low concentration, non-fatty acid constituents may be of importance because studies comparing monounsaturated dietary oils have reported different effects on cardiovascular disease. Most of these compounds have demonstrated antioxidant, anti-inflammatory and hypolipidemic properties. In this review, we summarize current knowledge on the effects of these compounds contained in VOO on vascular dysfunction and the mechanisms by which they modulate endothelial activity. Such mechanisms involve the release of nitric oxide, eicosanoids (prostaglandins and leukotrienes) and adhesion molecules, in most cases by activation of nuclear factor kappaB by reactive oxygen species.
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Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Óleos de Plantas/farmacologia , Animais , Doenças Cardiovasculares/etiologia , Dieta Mediterrânea , Gorduras Insaturadas na Dieta/farmacologia , Humanos , Hipercolesterolemia/complicações , Olea/química , Ácido Oleico/farmacologia , Azeite de Oliva , Óleos de Plantas/química , Espécies Reativas de Oxigênio/farmacologiaRESUMO
Postprandial triglyceride-rich lipoproteins (TRLs) are recognized as atherogenic particles whose lipid composition and function can be modified by the composition of dietary oils. This study was designed to test the hypothesis that minor components of pomace olive oil (POMACE) can not only change the composition of postprandial TRL but also affect the clearance of triglyceride (TG) molecular species of postprandial TRL. Meals enriched in either POMACE or refined olive oil (OLIVE) were administered to 10 healthy young men. TRL were isolated from serum at 2, 4, and 6 hours postprandially, and their fatty acid and TG molecular species compositions were analyzed by gas chromatography. The apolipoprotein B concentration was determined by immunoturbidimetry. POMACE and OLIVE, differing mainly in their unsaponifiable fraction, led to similar fatty acid and TG molecular species profiles in postprandial TRL. However, POMACE-TRL presented a higher particle size, estimated as TG to apolipoprotein B ratio, which was also found for the main TG molecular species (trioleoyl-glycerol, palmitoyl-dioleoyl-glycerol, palmitoyl-oeloyl-linoleoyl-glycerol, and dioleoyl-linoleoyl-glycerol). TG from POMACE-TRL also showed higher clearance rates. In this regard, apolar TG (with a higher equivalent carbon number) disappeared more rapidly from TRL particles obtained after the ingestion of either POMACE or OLIVE. In conclusion, minor components of POMACE facilitated TG clearance from TRL by modifying their particle size and the hydrolysis of the most apolar species.
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Lipoproteínas/sangue , Óleos de Plantas/administração & dosagem , Óleos de Plantas/química , Período Pós-Prandial , Triglicerídeos/sangue , Adulto , Apolipoproteínas B/sangue , Índice de Massa Corporal , Ácidos Graxos/análise , Ácidos Graxos/sangue , Humanos , Masculino , Refeições , Taxa de Depuração Metabólica , Azeite de Oliva , Tamanho da PartículaRESUMO
The first results of the PREDIMED (PREvencion con Dieta MEDiterranea) randomized trial, after 3-month intervention, showed that the Mediterranean Diet (MD), supplemented with either virgin olive oil (VOO) or nuts, reduced systolic blood pressure, serum cholesterol and triacylglycerol (TG) concentrations and increased high-density lipoprotein (HDL)-cholesterol when compared to a control (low-fat diet) group. Serum TG levels are an independent risk factor for coronary heart disease and are strongly determined by very low-density lipoprotein (VLDL) composition, which can be specifically modified by dietary lipid source. Within the context of the PREDIMED study, we assessed the VLDL composition in 50 participants after 3 months of intake of two MD, supplemented with VOO or nuts, compared with a low-fat diet. Total and low-density lipoprotein cholesterol concentrations were reduced in subjects on the MD+nuts, whereas HDL-cholesterol increased after consumption of the MD+VOO. Serum TG concentrations were significantly lowered in both intervention groups (either the MD+nuts or MD+VOO). However, only the MD+VOO reduced the VLDL-cholesterol and VLDL-TG content and the TG/apolipoprotein B ratio in VLDL, which was used to estimate particle size. Although VLDL-TG fatty acids were very slightly modified, VLDL-TG molecular species in VLDL after consumption of the MD+nuts were characterized by a higher presence of linoleic acid (18:2, n-6), whereas after the intake of MD+VOO, they were rich in oleic acid (18:1, n-9). Therefore, we conclude that the reduction in systemic TG concentrations observed after consumption of the MD may be explained by reduction of the lipid core of VLDL and a selective modification of the molecular species composition in the particle.
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Doenças Cardiovasculares/etiologia , Dieta Mediterrânea , Gorduras na Dieta/farmacologia , Lipoproteínas VLDL/sangue , Triglicerídeos/sangue , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nozes , Azeite de Oliva , Óleos de Plantas/farmacologia , Fatores de RiscoRESUMO
OBJECTIVE: This study was designed to determine the composition of postprandial triglyceride-rich lipoproteins (TRL) after the intake of pomace olive oil (POO), which is a subproduct of the extraction of virgin olive oil (VOO) and presents a high concentration of minor components with biological activity. METHODS: Meals enriched in POO and refined olive oil (ROO) were administrated to 9 healthy young men and blood was extracted every hour during a postprandial period of 7 hours. Serum and TRL lipid composition were measured by enzymatic and chromatographic methods and apolipoprotein B composition by SDS-PAGE. RESULTS: POO and ROO showed a very similar fatty acid composition but differed in their unsaponifiable fraction. The content of phytosterols, tocopherols, terpenic acids and alcohols and fatty alcohols was much higher in POO than in ROO. Serum lipids were not affected by the administration of the oils but the triglyceride concentration in TRL and the size of the particles (p < 0.05) after POO was higher at time point 2 h and lower at time point 4 h compared with ROO. In contrast, the number of TRL particles was lower after POO, although the rate of clearance was similar. CONCLUSION: We suggest that the unsaponifiable fraction between the two olive oils affect the size and composition of postprandial TRL, which might have a relevant impact on their atherogenicity.