Rafael de la Torre

Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial

IMPORTANCEnOxidative stress and vascular impairment are believed to partly mediate age-related cognitive decline, a strong risk factor for development of dementia. Epidemiologic studies suggest that a Mediterranean diet, an antioxidant-rich cardioprotective dietary pattern, delays cognitive decline, but clinical trial evidence is lacking.nnnOBJECTIVEnTo investigate whether a Mediterranean diet supplemented with antioxidant-rich foods influences cognitive function compared with a control diet.nnnDESIGN, SETTING, AND PARTICIPANTSnParallel-group randomized clinical trial of 447 cognitively healthy volunteers from Barcelona, Spain (233 women [52.1%]; mean age, 66.9 years), at high cardiovascular risk were enrolled into the Prevención con Dieta Mediterránea nutrition intervention trial from October 1, 2003, through December 31, 2009. All patients underwent neuropsychological assessment at inclusion and were offered retesting at the end of the study.nnnINTERVENTIONSnParticipants were randomly assigned to a Mediterranean diet supplemented with extravirgin olive oil (1 L/wk), a Mediterranean diet supplemented with mixed nuts (30 g/d), or a control diet (advice to reduce dietary fat).nnnMAIN OUTCOMES AND MEASURESnRates of cognitive change over time based on a neuropsychological test battery: Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT), Animals Semantic Fluency, Digit Span subtest from the Wechsler Adult Intelligence Scale, Verbal Paired Associates from the Wechsler Memory Scale, and the Color Trail Test. We used mean z scores of change in each test to construct 3 cognitive composites: memory, frontal (attention and executive function), and global.nnnRESULTSnFollow-up cognitive tests were available in 334 participants after intervention (median, 4.1 years). In multivariate analyses adjusted for confounders, participants allocated to a Mediterranean dietu2009plus olive oil scored better on the RAVLT (Pu2009=u2009.049) and Color Trail Test part 2 (Pu2009=u2009.04) compared with controls; no between-group differences were observed for the other cognitive tests. Similarly adjusted cognitive composites (mean z scores with 95% CIs) for changes above baseline of the memory composite were 0.04 (-0.09 to 0.18) for the Mediterranean diet plus olive oil, 0.09 (-0.05 to 0.23; Pu2009=u2009.04 vs controls) for the Mediterranean diet plus nuts, and -0.17 (-0.32 to -0.01) for the control diet. Respective changes from baseline of the frontal cognition composite were 0.23 (0.03 to 0.43; Pu2009=u2009.003 vs controls), 0.03 (-0.25 to 0.31), and -0.33 (-0.57 to -0.09). Changes from baseline of the global cognition composite were 0.05 (-0.11 to 0.21; Pu2009=u2009.005 vs controls) for the Mediterranean diet plus olive oil, -0.05 (-0.27 to 0.18) for the Mediterranean diet plus nuts, and -0.38 (-0.57 to -0.18) for the control diet. All cognitive composites significantly (Pu2009<u2009.05) decreased from baseline in controls.nnnCONCLUSIONS AND RELEVANCEnIn an older population, a Mediterranean diet supplemented with olive oil or nuts is associated with improved cognitive function.nnnTRIAL REGISTRATIONnisrctn.org Identifier: ISRCTN35739639.

Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans

SCOPEnTrisomy for human chromosome 21 results in Down syndrome (DS), which is among the most complex genetic perturbations leading to intellectual disability. Accumulating data suggest that overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), is a critical pathogenic mechanisms in the intellectual deficit.nnnMETHODS AND RESULTSnHere we show that the green tea flavonol epigallocatechin-gallate (EGCG), a DYRK1A inhibitor, rescues the cognitive deficits of both segmental trisomy 16 (Ts65Dn) and transgenic mice overexpressing Dyrk1A in a trisomic or disomic genetic background, respectively. It also significantly reverses cognitive deficits in a pilot study in DS individuals with effects on memory recognition, working memory and quality of life. We used the mouse models to ensure that EGCG was able to reduce DYRK1A kinase activity in the hippocampus and found that it also induced significant changes in plasma homocysteine levels, which were correlated with Dyrk1A expression levels. Thus, we could use plasma homocysteine levels as an efficacy biomarker in our human study.nnnCONCLUSIONnWe conclude that EGCG is a promising therapeutic tool for cognitive enhancement in DS, and its efficacy may depend of Dyrk1A inhibition.

Executive functions profile in extreme eating/weight conditions: from anorexia nervosa to obesity

Background Extreme weight conditions (EWC) groups along a continuum may share some biological risk factors and intermediate neurocognitive phenotypes. A core cognitive trait in EWC appears to be executive dysfunction, with a focus on decision making, response inhibition and cognitive flexibility. Differences between individuals in these areas are likely to contribute to the differences in vulnerability to EWC. The aim of the study was to investigate whether there is a common pattern of executive dysfunction in EWC while comparing anorexia nervosa patients (AN), obese subjects (OB) and healthy eating/weight controls (HC). Methods Thirty five AN patients, fifty two OB and one hundred thirty seven HC were compared using the Wisconsin Card Sorting Test (WCST); Stroop Color and Word Test (SCWT); and Iowa Gambling Task (IGT). All participants were female, aged between 18 and 60 years. Results There was a significant difference in IGT score (F(1.79); p<.001), with AN and OB groups showing the poorest performance compared to HC. On the WCST, AN and OB made significantly more errors than controls (F(25.73); p<.001), and had significantly fewer correct responses (F(2.71); p<.001). Post hoc analysis revealed that the two clinical groups were not significantly different from each other. Finally, OB showed a significant reduced performance in the inhibition response measured with the Stroop test (F(5.11); p<.001) compared with both AN and HC. Conclusions These findings suggest that EWC subjects (namely AN and OB) have similar dysfunctional executive profile that may play a role in the development and maintenance of such disorders.

Wine and oxidative stress: up-to-date evidence of the effects of moderate wine consumption on oxidative damage in humans.

Wine and alcohol consumption has been considered to be protective against coronary heart disease development, an oxidative stress associated disease. Wine contains polyphenols displaying antioxidant properties tested in in vitro and in vivo studies. Due to this, a general consensus exists, both among the general public and the scientific community, that wine, particularly red wine, is an antioxidant beverage. Alcohol consumption, however, is associated with oxidative damage. Several studies have been carried out on the antioxidant health benefits of wine and wine polyphenols. However, adequate scientific evidence (Level I or II) is required to be provided before recommendations or statements which can reach the general public can be formulated. Here, we summarize the state of the art of the up-to-date body of knowledge, and the extent to which there exists evidence of the benefits of moderate wine consumption on oxidative damage in humans. From the available data, there is no evidence, at present, that sustained wine consumption provides antioxidant benefits in healthy volunteers other than to counteract a possible pro-oxidative effect of the alcohol. On the contrary, data on the antioxidant protective effect of red wine in oxidative stress situations are promising. In this way, the postprandial oxidative stress after a meal, despite the diversity of biomarkers used for its evaluation, is counteracted by the ingestion of wine. Further studies are warranted.

Lifetime obesity in patients with eating disorders: increasing prevalence, clinical and personality correlates

Objectives : The aims of our study were to examine the lifetime prevalence of obesity rate in eating disorders (ED) subtypes and to examine whether there have been temporal changes among the last 10 years and to explore clinical differences between ED with and without lifetime obesity. Methods : Participants were 1383 ED female patients (DSM-IV criteria) consecutively admitted, between 2001 and 2010, to Bellvitge University Hospital. They were assessed by means of the Eating Disorders Inventory-2, the Symptom Checklist-90—Revised, the Bulimic Investigatory Test Edinburgh and the Temperament and Character Inventory—Revised. Results : The prevalence of lifetime obesity in ED cases was 28.8% (ranging from 5% in anorexia nervosa to 87% in binge-eating disorders). Over the last 10 years, there has been a threefold increase in lifetime obesity in ED patients (p < .001). People with an ED and obesity had higher levels of childhood and family obesity (p < .001), a later age of onset and longer ED duration; and had higher levels of eating, general and personality symptomatology. Conclusions : Over the last 10 years, the prevalence of obesity associated with disorders characterized by the presence of binge episodes, namely bulimic disorders, is increasing, and this is linked with greater clinical severity and a poorer prognosis. Copyright

Psychotropic drug consumption and other factors associated with heroin overdose

In clinical or forensic practice there are few studies assessing which risk factors are associated with heroin overdoses. A series of 76 consecutive non-fatal heroin overdoses were compared to 22 consecutive subjects who self-injected heroin within 1 h before admission to the emergency room. Whereas blood levels of alcohol and IgE and urinary cocaine metabolite levels were similar in both groups, higher benzodiazepine plasma levels were detected in the heroin overdose group. The assessment of methadone, dextropropoxyphene, amphetamines and cannabis in urine analysis did not show differences between both groups. The interview revealed that only 48% of subjects in the heroin overdose group self-administered the last dose of heroin before admission in the usual setting as compared to 100% of subjects in the non-overdose group. The application of a log-linear regression model identified self-injection of heroin in an unusual place and plasma concentrations of total morphine and benzodiazepines as risk factors for heroin overdose.

Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements.

Effect of the Mediterranean diet on heart failure biomarkers: a randomized sample from the PREDIMED trial

Scarce data are available on the effect of the traditional Mediterranean diet (TMD) on heart failure biomarkers. We assessed the effect of TMD on biomarkers related to heart failure in a high cardiovascular disease risk population.

Effects of repeated doses of MDMA ("ecstasy") on cell-mediated immune response in humans.

Cell-mediated immune response after the administration of two repeated doses of 100 mg 3,4-methylenedioxymethamphetamine (MDMA) at 4-hour and 24-hour intervals was evaluated in two randomised, double-blind and cross-over clinical trials conducted in healthy male MDMA consumers. MDMA produced a time-dependent decrease in the CD4/CD8 T-cell ratio due to a decrease in the number of CD4 T-helper cells, a decrease in the functional responsiveness of lymphocytes to mitogenic stimulation, and a simultaneous increase in natural killer cells. In case of two 100 mg MDMA doses given 4 hour apart, immune alterations produced by the first dose were strengthened by the second one. At 24 hours after treatment, statistically significant residual effects were observed for all the altered immune parameters after the administration of two MDMA doses if compared to single dose and placebo. In the second clinical trial, the second 100 mg MDMA dose given 24 hours after the first dose produced immunological changes significantly greater than those induced by the initial drug administration and which seemed to show a delayed onset. Significant residual effects were observed for all the immune parameters as late as 48 hours after the second dose. These results show that repeated administration of MDMA with both a short and a long time interval between doses extends the critical period following MDMA administration, already observed after a single dose, in which immunocompetence is severely compromised.

Detection of non-steroidal anti-inflammatory drugs in equine plasma and urine by gas chromatography-mass spectrometry

A gas chromatographic-mass spectrometric (GC-MS) procedure for the detection of seventeen non-steroidal anti-inflammatory drugs (NSAIDs) in equine plasma and urine samples is described. The extraction of the compounds from the biological matrix was performed at acidic pH (2-3) with diethyl ether. Ethereal extracts were washed with a saturated solution of sodium hydrogencarbonate (urine) or treated with a solid mixture of sodium carbonate and sodium hydrogencarbonate (plasma). The ethereal extracts were dried and derivatized by incubation at 60 degrees C with methyl iodide in acetone in the presence of solid potassium carbonate. Mono- or bismethyl derivatives of the NSAIDs were obtained. After derivatization kinetic studies, 90 min was the incubation time finally chosen for screening purposes for adequate methylation of all the compounds under study. For individual confirmation analyses, shorter incubation times can be used. The chromatographic analysis of the derivatives was accomplished by GC-MS with a run time of 13 min. In general, extraction recoveries ranged from 23.3 to 100% in plasma and from 37.5 to 83.8% in urine samples. Detection limits from less than 5 to 25 ng/ml were obtained for both plasma and urine samples using selected-ion monitoring. The procedure was applied to the screening and confirmation of NSAIDs in routine doping control of equine samples.