Pgc1a is responsible for the sex differences in hepatic Cidec/Fsp27ß mRNA expression in hepatic steatosis of mice fed a Western diet.

Hepatic fat-specific protein 27 [cell death-inducing DNA fragmentation effector protein C (Cidec)/Fsp27] mRNA levels have been associated with hepatic lipid droplet extent under certain circumstances. To address its hepatic expression under different dietary conditions and in both sexes, apolipoprotein E (Apoe)-deficient mice were subjected to different experimental conditions for 11 wk to test the influence of cholesterol, Western diet, squalene, oleanolic acid, sex, and surgical castration on Cidec/Fsp27 mRNA expression. Dietary cholesterol increased hepatic Cidec/Fsp27ß expression, an effect that was suppressed when cholesterol was combined with saturated fat as represented by Western diet feeding. Using the latter diet, neither oleanolic acid nor squalene modified its expression. Females showed lower levels of hepatic Cidec/Fsp27ß expression than males when they were fed Western diets, a result that was translated into a lesser amount of CIDEC/FSP27 protein in lipid droplets and microsomes. This was also confirmed in low-density lipoprotein receptor (Ldlr)-deficient mice. Incubation with estradiol resulted in decreased Cidec/Fsp27ß expression in AML12 cells. Whereas male surgical castration did not modify the expression, ovariectomized females did show increased levels compared with control females. Females also showed increased expression of peroxisome proliferator-activated receptor-γ coactivator 1-α (Pgc1a), suppressed by ovariectomy, and the values were significantly and inversely associated with those of Cidec/Fsp27ß. When Pgc1a-deficient mice were used, the sex differences in Cidec/Fsp27ß expression disappeared. Therefore, hepatic Cidec/Fsp27ß expression has a complex regulation influenced by diet and sex hormonal milieu. The mRNA sex differences are controlled by Pgc1a.

The Search for Dietary Supplements to Elevate or Activate Circulating Paraoxonases.

Low levels of paraoxonase 1 (PON1) have been associated with the development of several pathological conditions, whereas high levels have been shown to be anti-atherosclerotic in mouse models. These findings suggest that PON1 could be a good surrogate biomarker. The other members of the family, namely PON2 and PON3, the role of which has been much less studied, deserve more attention. This paper provides a systematic review of current evidence concerning dietary supplements in that regard. Preliminary studies indicate that the response to dietary supplements may have a nutrigenetic aspect that will need to be considered in large population studies or in clinical trials. A wide range of plant preparations have been found to have a positive action, with pomegranate and some of its components being the best characterized and Aronia melanocarpa one of the most active. Flavonoids are found in the composition of all active extracts, with catechins and genistein being the most promising agents for increasing PON1 activity. However, some caveats regarding the dose, length of treatment, bioavailability, and stability of these compounds in formulations still need to be addressed. Once these issues have been resolved, these compounds could be included as nutraceuticals and functional foods capable of increasing PON1 activity, thereby helping with the long-term prevention of atherosclerosis and other chronic ailments.

Societal Preferences for Meningococcal B Vaccination in Children: A Discrete Choice Experiment in Spain.

INTRODUCTION: Immunization is the most effective strategy for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB); however, parents need to weigh the risk-benefit and financial impact of immunizing their children against MenB in the absence of a national immunization program (NIP). This study aimed to explore societal preferences (of parents and pediatricians) regarding the attributes of a MenB vaccine in Spain. METHODS: A discrete choice experiment (DCE) based on cross-sectional surveys was carried out to determine preferences. A literature review and scientific committee determined the six attributes related to the MenB vaccine included in the DCE: vaccination age, cost, duration, percentage of protection, adverse events probability, and expert/authority recommendation. Data were analyzed using a mixed logit model. Relative importance (RI) of attributes was calculated and compared between parents and pediatricians. RESULTS: A total of 278 parents [55.8% female, mean age 40.4 (standard deviation, SD 7.3) years] and 200 pediatricians [73.0% female, mean age 45.8 (SD 12.9) years] answered the DCE. For parents, the highest RI was attributed to vaccine cost, expert/authority recommendation, and percentage of protection (26.4%, 26.1%, and 22.9%, respectively), while for pediatricians the highest RI was assigned to percentage of protection, expert/authority recommendation, and vaccination age (27.2%, 23.7%, and 22.6%, respectively). Significant differences between parents and pediatricians were found in the RI assigned to all attributes (p < 0.001), except for vaccine recommendation. CONCLUSION: In the decision regarding MenB vaccination, cost was a driver in parental decision-making but had a low RI for pediatricians and, conversely, vaccination age was highly valued by pediatricians but was the attribute with least importance for parents. Despite these differences, expert/authority recommendation and percentage of protection were essential criteria for both groups. These results provide relevant information about MenB vaccination, highlighting the importance of considering societal preferences for NIP inclusion.

Preferences for Renal Cell Carcinoma Pharmacological Treatment: A Discrete Choice Experiment in Patients and Oncologists.

INTRODUCTION: The purpose of this investigation was to explore patients' and oncologists' preferences for the characteristics of a pharmacological regimen for patients with advanced renal cell carcinoma (aRCC). MATERIAL AND METHODS: Cross-sectional observational study based on a discrete choice experiment (DCE) conducted in Spain. A literature review, a focus group with oncologists and interviews with patients informed the DCE design. Five attributes were included: progression survival gain, risk of serious adverse events (SAEs), health-related quality of life (HRQoL), administration mode, and treatment cost. Preferences were analyzed using a mixed-logit model to estimate relative importance (RI) of attributes (importance of an attribute in relation to all others), which was compared between aRCC patients and oncologists treating aRCC. Willingness to pay (WTP, payer: health system) for a benefit in survival or in risk reduction and maximum acceptable risk (MAR) in SAEs for improving survival were estimated from the DCE. Subgroup analyses were performed to identify factors that influence preference. RESULTS: A total of 105 patients with aRCC (77.1% male, mean age 65.9 years [SD: 10.4], mean time since RCC diagnosis 6.3 years [SD: 6.1]) and 67 oncologists (52.2% male, mean age 41.9 years [SD: 8.4], mean duration of experience in RCC 10.2 years [SD: 7.5]) participated in the study. The most important attribute for patients and oncologists was survival gain (RI: 43.6% vs. 54.7% respectively, p<0.05), followed by HRQoL (RI: 35.5% vs. 18.0%, respectively, p<0.05). MAR for SAEs was higher among oncologists than patients, while WTP (for the health system) was higher for patients. Differences in preferences were found according to time since diagnosis and education level (patients) or length of professional experience (oncologists). CONCLUSION: Patients' and oncologists' preferences for aRCC treatment are determined mainly by the efficacy (survival gain) but also by the HRQoL provided. The results of the study can help to inform decision-making in the selection of appropriate aRCC treatment.

Patient-physician discrepancy in the perception of immune-mediated inflammatory diseases: rheumatoid arthritis, psoriatic arthritis and psoriasis. A qualitative systematic review of the literature.

INTRODUCTION: Recommendations on chronic diseases management emphasise the need to consider patient perspectives and shared decision-making. Discrepancies between patients and physicians' perspectives on treatment objectives, disease activity, preferences and treatment have been described for immune-mediate inflammatory diseases. These differences could result on patient dissatisfaction and negatively affect outcomes. OBJECTIVE: To describe the degree of patient-physician discrepancy in three chronic immune-mediated inflammatory diseases (rheumatoid arthritis [RA], psoriatic arthritis [PsA] and psoriasis [Ps]), identifying the main areas of discrepancy and possible predictor factors. METHODS: Qualitative systematic review of the available literature on patient and physician discrepancies in the management of RA, PsA and Ps. The search was performed in international (Medline/PubMed, Cochrane Library, ISI-WOK) and Spanish electronic databases (MEDES, IBECS), including papers published from April 1, 2008 to April 1, 2018, in English or Spanish, and conducted in European or North American populations. Study quality was assessed by the Oxford Centre for Evidence-Based Medicine criteria. RESULTS: A total of 21 studies were included (13 RA; 3 PsA; 4 Ps; 1 RA, Ps, and Axial Spondyloarthritis). A significant and heterogeneous degree of discrepancy between patients and physicians was found, regarding disease activity, treatment, clinical expectations, remission concept, and patient-physician relationship. In RA and PsA, studies were mainly focused on the evaluation of disease activity, which is perceived as higher from the patient's than the physician's perspective, with the discrepancy determined by factors such as patient's perception of pain and fatigue. In Ps, studies were focused on treatment satisfaction and patient-physician relationship, showing a lower degree of discrepancy in the satisfaction regarding these aspects. CONCLUSIONS: There is a significant degree of patient-physician discrepancy regarding the management of RA, PA, and Ps, what can have a major impact on shared decision-making. Future research may help to show whether interventions considering discrepancy improve shared decision-making.

Dietary Squalene Induces Cytochromes Cyp2b10 and Cyp2c55 Independently of Sex, Dose, and Diet in Several Mouse Models.

SCOPE: To investigate the effects of squalene, the main hydrocarbon present in extra virgin olive oil, on liver transcriptome in different animal models and to test the influence of sex on this action and its relationship with hepatic lipids. METHODS AND RESULTS: To this purpose, male C57BL/6J Apoe-deficient mice are fed a purified Western diet with or without squalene during 11 weeks and hepatic squalene content is assessed, so are hepatic lipids and lipid droplets. Hepatic transcriptomic changes are studied and confirmed by RT-qPCR. Dietary characteristics and influence of squalene doses are tested in Apoe-deficient on purified chow diets with or without squalene. These diets are also given to Apoa1 and wild-type mice on C57BL/6J background and to C57BL/6J xOla129 Apoe-deficient mice. Squalene supplementation increases its hepatic content without differences among sexes and hormonal status. The Cyp2b10 and Cyp2c55 gene expressions are significantly up-regulated by the squalene intake in all models, with independence of sex, sexual hormones, dietary fat content, genetic background and dose, and in Apoe-deficient mice consuming extra-virgin olive oil. CONCLUSION: Hepatic squalene increases the expression of these cytochromes and their changes in virgin olive oil diets may be due to their squalene content.

Treatment decision-making in chronic lymphocytic leukaemia: Key factors for healthcare professionals. PRELIC study.

OBJECTIVE: To explore the preferences of Spanish healthcare professionals (haematologists and hospital pharmacists) for the treatment selection of active Chronic Lymphocytic Leukaemia (CLL) patients at first relapse, condition that mainly afflicts older adults. METHODS: A discrete choice experiment (DCE) was conducted among haematologists and hospital pharmacists. A literature review and a focus group informed the DCE design. CLL treatment settings were defined by seven attributes: four patient/disease-related attributes (age, functional status, comorbidities, and risk of the disease) and three treatment-related attributes (efficacy [hazard ratio of progression-free survival, HR-PFS], rate of discontinuations due to adverse events and cost). A mixed-logit model was used to determine choice-based preferences. Relative importance (RI) of attributes was calculated and compared between stakeholders. Willingness-to-pay (WTP) was estimated through the DCE. Besides, nine ad-hoc questions were posed, to explore more in depth CLL treatment decision making. RESULTS: A total of 130 participants (72 haematologists and 58 hospital pharmacists) answered the DCE. All attributes were significant predictors of preferences (p < 0.05) in the multinomial model. Higher RI was obtained for treatment-related attributes: the highest rated being 'cost' (23.8%) followed by 'efficacy' (20.9%). Regarding patient-related attributes, the highest RI was obtained for 'age' (18.1%). No significant differences (p > 0.05) in RI between haematologists and pharmacists were found. WTP for the treatment was higher for younger CLL patients. Ad-hoc questions showed that patient age and functional status influence treatment decisions. CONCLUSIONS: For healthcare professionals, 'cost' and 'efficacy' (treatment-related attributes) and age (patient-related attribute) are the main factors that determine CLL treatment selection at first relapse. WTP decreases as patient's age increases.

Diet and sexual hormones regulate hepatic synaptotagmin 1 mRNA in mice.

The expression of Synaptotagmin 1 (Syt1) has been found to be associated with the lipid droplets in liver. Here, we studied the expression of Syt1 in Apoe-deficient mice receiving cholesterol, Western diet, squalene, and oleanolic acid. We also studied the influence of sex and impact of surgical castration. Dietary cholesterol increased hepatic Syt1 expression, an effect that was enhanced when cholesterol was combined with saturated fat present in a Western diet. This potentiation was modified by the administration of 10 mg/kg oleanolic acid or 1 g/kg squalene. Females fed chow or Western diet showed higher levels of hepatic Syt1 expression as compared to male mice on the same diet. Surgical castration of males did not modify the Syt1 expression; however, ovariectomy led to decreased levels. The data show that hepatic Syt1 expression is influenced by diet and hormonal milieu.

PON1 and Mediterranean Diet.

The Mediterranean diet has been proven to be highly effective in the prevention of cardiovascular diseases. Paraoxonase 1 (PON1) has been implicated in the development of those conditions, especially atherosclerosis. The present work describes a systematic review of current evidence supporting the influence of Mediterranean diet and its constituents on this enzyme. Despite the differential response of some genetic polymorphisms, the Mediterranean diet has been shown to exert a protective action on this enzyme. Extra virgin olive oil, the main source of fat, has been particularly effective in increasing PON1 activity, an action that could be due to low saturated fatty acid intake, oleic acid enrichment of phospholipids present in high-density lipoproteins that favor the activity, and increasing hepatic PON1 mRNA and protein expressions induced by minor components present in this oil. Other Mediterranean diet constituents, such as nuts, fruits and vegetables, have been effective in modulating the activity of the enzyme, pomegranate and its compounds being the best characterized items. Ongoing research on compounds isolated from all these natural products, mainly phenolic compounds and carotenoids, indicates that some of them are particularly effective, and this may enhance the use of nutraceuticals and functional foods capable of potentiating PON1 activity.

Dietary squalene increases high density lipoprotein-cholesterol and paraoxonase 1 and decreases oxidative stress in mice.

BACKGROUND AND PURPOSE: Squalene, the main hydrocarbon in the unsaponifiable fraction of virgin olive oil, is involved in cholesterol synthesis and it has been reported to own antiatherosclerotic and antiesteatosic effects. However, the squalene's role on lipid plasma parameters and the influence of genotype on this effect need to be addressed. EXPERIMENTAL APPROACHES: Three male mouse models (wild-type, Apoa1- and Apoe- deficient) were fed chow semisynthetic diets enriched in squalene to provide a dose of 1 g/kg during 11 weeks. After this period, their plasma parameters and lipoprotein profiles were analyzed. KEY RESULTS: Squalene administration at a dose of 1 g/kg showed decreased reactive oxygen species in lipoprotein fractions independently of the animal background and caused an specific increase in high density lipoprotein (HDL)-cholesterol levels, accompanied by an increase in phosphatidylcholine and paraoxonase 1 and no changes in apolipoproteins A1 and A4 in wild-type mice. In these mice, the cholesterol increase was due to its esterified form and associated with an increased hepatic expression of Lcat. These effects were not observed in absence of apolipoprotein A1. The increases in HDL- paraoxonase 1 were translated into decreased plasma malondialdehyde levels depending on the presence of Apolipoprotein A1. CONCLUSIONS AND IMPLICATIONS: Dietary squalene promotes changes in HDL- cholesterol and paraoxonase 1 and decreases reactive oxygen species in lipoproteins and plasma malondialdehyde levels, providing new benefits of its intake that might contribute to explain the properties of virgin olive oil, although the phenotype related to apolipoproteins A1 and E may be particularly relevant.

Dietary oleanolic acid mediates circadian clock gene expression in liver independently of diet and animal model but requires apolipoprotein A1.

Oleanolic acid is a triterpene widely distributed throughout the plant kingdom and present in virgin olive oil at a concentration of 57 mg/kg. To test the hypotheses that its long-term administration could modify hepatic gene expression in several animal models and that this could be influenced by the presence of APOA1-containing high-density lipoproteins (HDLs), diets including 0.01% oleanolic acid were provided to Apoe- and Apoa1-deficient mice and F344 rats. Hepatic transcriptome was analyzed in Apoe-deficient mice fed long-term semipurified Western diets differing in the oleanolic acid content. Gene expression changes, confirmed by reverse transcriptase quantitative polymerase chain reaction, were sought for their implication in hepatic steatosis. To establish the effect of oleanolic acid independently of diet and animal model, male rats were fed chow diet with or without oleanolic acid, and to test the influence of HDL, Apoa1-deficient mice consuming the latter diet were used. In Apoe-deficient mice, oleanolic acid intake increased hepatic area occupied by lipid droplets with no change in oxidative stress. Bmal1 and the other core component of the circadian clock, Clock, together with Elovl3, Tubb2a and Cldn1 expressions, were significantly increased, while Amy2a5, Usp2, Per3 and Thrsp were significantly decreased in mice receiving the compound. Bmal1 and Cldn1 expressions were positively associated with lipid droplets. Increased Clock and Bmal1 expressions were also observed in rats, but not in Apoa1-deficient mice. The core liver clock components Clock-Bmal1 are a target of oleanolic acid in two animal models independently of the diets provided, and this compound requires APOA1-HDL for its hepatic action.