Relationship between sex, APOE genotype, endocannabinoids and cognitive change in older adults with metabolic syndrome during a 3-year Mediterranean diet intervention.

BACKGROUND: The Mediterranean diet (MedDiet) has demonstrated efficacy in preventing age-related cognitive decline and modulating plasma concentrations of endocannabinoids (eCBs) and N-acylethanolamines (NAEs, or eCB-like compounds), which are lipid mediators involved in multiple neurological disorders and metabolic processes. Hypothesizing that eCBs and NAEs will be biomarkers of a MedDiet intervention and will be related to the cognitive response, we investigated this relationship according to sex and apolipoprotein E (APOE) genotype, which may affect eCBs and cognitive performance. METHODS: This was a prospective cohort study of 102 participants (53.9% women, 18.8% APOE-ɛ4 carriers, aged 65.6 ± 4.5 years) from the PREDIMED-Plus-Cognition substudy, who were recruited at the Hospital del Mar Research Institute (Barcelona). All of them presented metabolic syndrome plus overweight/obesity (inclusion criteria of the PREDIMED-Plus) and normal cognitive performance at baseline (inclusion criteria of this substudy). A comprehensive battery of neuropsychological tests was administered at baseline and after 1 and 3 years. Plasma concentrations of eCBs and NAEs, including 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and N-docosahexaenoylethanolamine (DHEA), were also monitored. Baseline cognition, cognitive changes, and the association between eCBs/NAEs and cognition were evaluated according to gender (crude models), sex (adjusted models), and APOE genotype. RESULTS: At baseline, men had better executive function and global cognition than women (the effect size of gender differences was - 0.49, p = 0.015; and - 0.42, p = 0.036); however, these differences became nonsignificant in models of sex differences. After 3 years of MedDiet intervention, participants exhibited modest improvements in memory and global cognition. However, greater memory changes were observed in men than in women (Cohen's d of 0.40 vs. 0.25; p = 0.017). In men and APOE-ε4 carriers, 2-AG concentrations were inversely associated with baseline cognition and cognitive changes, while in women, cognitive changes were positively linked to changes in DHEA and the DHEA/AEA ratio. In men, changes in the OEA/AEA and OEA/PEA ratios were positively associated with cognitive changes. CONCLUSIONS: The MedDiet improved participants' cognitive performance but the effect size was small and negatively influenced by female sex. Changes in 2-AG, DHEA, the OEA/AEA, the OEA/PEA and the DHEA/AEA ratios were associated with cognitive changes in a sex- and APOE-dependent fashion. These results support the modulation of the endocannabinoid system as a potential therapeutic approach to prevent cognitive decline in at-risk populations. TRIAL REGISTRATION: ISRCTN89898870.

Diet patterns associated with cognitive decline: methods to harmonize data from European and US cohort studies.

The impact of dietary intake on cognitive outcomes and dementia prevention is a topic of increasing interest. Meta-analyses of observational studies, mostly conducted within US and European populations, have reported benefits of healthy diet patterns on cognitive performance, but results from individual studies have been inconsistent. These inconsistencies are likely due to the diverse methodology used in studies, including different diet and cognitive function assessment instruments, follow-up periods, and analytical methods, which make drawing conclusions relevant to dietary guidance challenging. The objective of this project is to describe a protocol to conduct a retrospective harmonization study on dietary intake and cognitive health using data from European and US studies. The recommendations resulting from the project can be used to support evidence-based synthesis for future iterations of the Dietary Guidelines for Americans or other population-based dietary guidance. Additionally, this study will serve as a harmonization guide for future research on the relationship between diet patterns and cognition. The approach outlined ultimately aims to optimize resources and expedite research efforts for dementia prevention.

Protective effect of hydroxytyrosol and tyrosol metabolites in LPS-induced vascular barrier derangement in vitro.

Introduction: The maintenance of endothelial barrier function is essential for vasal homeostasis and prevention of cardiovascular diseases. Among the toxic stimuli involved in the initiation of atherosclerotic lesions, Gram negative lipopolysaccharide (LPS) has been reported to be able to trigger endothelial dysfunction, through the alteration of barrier permeability and inflammatory response. Hydroxytyrosol (HT) and tyrosol (Tyr), the major phenolic compounds of extra virgin olive oil (EVOO), as wells as their circulating sulphated and glucuronidated metabolites have been shown to exert anti-inflammatory effects at endothelial level. Methods: In this study we investigated the protective effects of HT and Tyr metabolites on LPS-induced alteration of permeability in Human Umbilical Vein Endothelial Cells (HUVEC) monolayers and examined underlying signaling pathways, focusing on tight junction (TJ) proteins, mitogen-activated protein kinase (MAPK) and NOD-, LRR-and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. Results: It was shown that LPS-increased permeability in HUVEC cells was due to the alteration of TJ protein level, following the activation of MAPK and NLRP3. HT and Tyr sulphated and glucuronidated metabolites were able to limit the effects exerted by LPS, acting as signaling molecules with an efficacy comparable to that of their precursors HT and Tyr. Discussion: The obtained results add a further piece to the understanding of HT and Tyr metabolites mechanisms of action in vascular protection.

Hydroxytyrosol Linoleoyl Ether Ameliorates Metabolic-Associated Fatty Liver Disease Symptoms in Obese Zucker Rats.

A main hepatic consequence of obesity is metabolic-associated fatty liver disease (MAFLD), currently treated by improving eating habits and administrating fibrates yet often yielding suboptimal outcomes. Searching for a new therapeutic approach, we aimed to evaluate the efficacy of hydroxytyrosol linoleoyl ether (HTLE), a dual Ppar-α agonist/Cb1 antagonist with inherent antioxidant properties, as an antisteatotic agent. Using lean and obese Zucker rats, they were administrated daily doses of HTLE (3 mg/kg) over a 15-day period, evaluating its safety profile, pharmacokinetics, impact on body weight, hepatic fat content, expression of key enzymes involved in lipogenesis/fatty acid oxidation, and antioxidant capacity. HTLE decreased the body weight and food intake in both rat genotypes. Biochemical analysis demonstrated a favorable safety profile for HTLE along with decreased concentrations of urea, total cholesterol, and aspartate aminotransferase AST transaminases in plasma. Notably, HTLE exhibited potent antisteatotic effects in obese rats, evidenced by a decrease in liver fat content and downregulation of lipogenesis-related enzymes, alongside increased expression of proteins controlling lipid oxidation. Moreover, HTLE successfully counteracted the redox imbalance associated with MAFLD in obese rats, attenuating lipid peroxidation and replenishing both glutathione levels and the overall antioxidant. Our findings highlight the effectiveness of triple-action strategies in managing MAFLD effectively. Based on our results in the Zucker rat model, HTLE emerges as a promising candidate with triple functionality as an anorexigenic, antisteatotic, and antioxidant agent, offering potential relief from MAFLD symptoms associated with obesity while exhibiting minimal side effects. In conclusion, our study positions HTLE as a highly promising compound for therapeutic intervention in MAFLD treatment, warranting further exploration in clinical trials.

Adolescent cannabinoid exposure rescues phencyclidine-induced social deficits through modulation of CA2 transmission.

Psychotic disorders entail intricate conditions marked by disruptions in cognition, perception, emotions, and social behavior. Notably, psychotic patients who use cannabis tend to show less severe deficits in social behaviors, such as the misinterpretation of social cues and the inability to interact with others. However, the biological underpinnings of this epidemiological interaction remain unclear. Here, we used the NMDA receptor blocker phencyclidine (PCP) to induce psychotic-like states and to study the impact of adolescent cannabinoid exposure on social behavior deficits and synaptic transmission changes in hippocampal area CA2, a region known to be active during social interactions. In particular, adolescent mice underwent 7 days of subchronic treatment with the synthetic cannabinoid, WIN 55, 212-2 (WIN) followed by one injection of PCP. Using behavioral, biochemical, and electrophysiological approaches, we showed that PCP persistently reduced sociability, decreased GAD67 expression in the hippocampus, and induced GABAergic deficits in proximal inputs from CA3 and distal inputs from the entorhinal cortex (EC) to CA2. Notably, WIN exposure during adolescence specifically restores adult sociability deficits, the expression changes in GAD67, and the GABAergic impairments in the EC-CA2 circuit, but not in the CA3-CA2 circuit. Using a chemogenetic approach to target EC-CA2 projections, we demonstrated the involvement of this specific circuit on sociability deficits. Indeed, enhancing EC-CA2 transmission was sufficient to induce sociability deficits in vehicle-treated mice, but not in animals treated with WIN during adolescence, suggesting a mechanism by which adolescent cannabinoid exposure rescues sociability deficits caused by enhanced EC-CA2 activity in adult mice.

Low TGF-ß1 plasma levels are associated with cognitive decline in Down syndrome.

Almost all individuals with Down's syndrome (DS) show the characteristic neuropathological features of Alzheimer's disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-ß1 (TGF-ß1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-ß1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19-35 years) and older DS subjects without AD (35-60 years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-ß1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-ß1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-ß1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1 µM for 24 h) were able to rescue TGF-ß1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-ß1 concentrations in DS subjects at higher risk to develop cognitive decline.

G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits.

G protein-coupled receptors (GPCRs) are sophisticated signaling machines able to simultaneously elicit multiple intracellular signaling pathways upon activation. Complete (in)activation of all pathways can be counterproductive for specific therapeutic applications. This is the case for the serotonin 2 A receptor (5-HT2AR), a prominent target for the treatment of schizophrenia. In this study, we elucidate the complex 5-HT2AR coupling signature in response to different signaling probes, and its physiological consequences by combining computational modeling, in vitro and in vivo experiments with human postmortem brain studies. We show how chemical modification of the endogenous agonist serotonin dramatically impacts the G protein coupling profile of the 5-HT2AR and the associated behavioral responses. Importantly, among these responses, we demonstrate that memory deficits are regulated by Gαq protein activation, whereas psychosis-related behavior is modulated through Gαi1 stimulation. These findings emphasize the complexity of GPCR pharmacology and physiology and open the path to designing improved therapeutics for the treatment of stchizophrenia.

Glycated hemoglobin, type 2 diabetes, and poor diabetes control are positively associated with impulsivity changes in aged individuals with overweight or obesity and metabolic syndrome.

Impulsivity has been proposed to have an impact on glycemic dysregulation. However, it remains uncertain whether an unfavorable glycemic status could also contribute to an increase in impulsivity levels. This study aims to analyze associations of baseline and time-varying glycemic status with 3-year time-varying impulsivity in older adults at high risk of cardiovascular disease. A 3-year prospective cohort design was conducted within the PREDIMED-Plus-Cognition substudy. The total population includes 487 participants (mean age = 65.2 years; female = 50.5%) with overweight or obesity and metabolic syndrome. Insulin resistance (HOMA-IR), glycated hemoglobin (HbA1c), presence of type 2 diabetes mellitus, and type 2 diabetes control were evaluated. Impulsivity was measured using the Impulsive Behavior Scale questionnaire and various cognitive measurements. Impulsivity z-scores were generated to obtain Global, Trait, and Behavioral Impulsivity domains. Linear mixed models were used to study the longitudinal associations across baseline, 1-year, and 3-year follow-up visits. HOMA-IR was not significantly related to impulsivity. Participants with higher HbA1c levels, type 2 diabetes, and poor control of diabetes showed positive associations with the Global Impulsivity domain over time, and those with higher HbA1c levels were further related to increases in the Trait and Behavioral Impulsivity domains over the follow-up visits. These results suggest a potential positive feedback loop between impulsivity and glycemic-related dysregulation.

Nueva mutación del codón 106 del gen de la rodopsina en familia con retinosis pigmentaria autosómica dominante / New mutation of the rodopsine gen 106 codon in families with dominant autosomic pigmentary retinosis

Fueron estudiados 2 pacientes con retinosis pigmentaria autosómica dominante, integrantes de una familia de 4 generaciones, en el Centro Provincial de Retinosis Pigmentaria de Santiago de Cuba, Centro Internacional de Retinosis Pigmentaria "Camilo Cienfuegos" y Laboratorio de Genética de la Universidad de Hamburgo (Alemania), en uno de los cuales se halló un polimorfismo diferente de conformación de simple cadena del producto amplificado de los exones del gen de la rodopsina, revelador de que la transversión de guanina por citosina resultó en un cambio de glicina por arginina en el codón 106 del exón 1 del gen de la rodopsina como causa de la enfermedad; hallazgo equivalente a una nueva mutación desencadenante de un cuadro clínico de retinosis pigmentaria típica y pronóstico visual reservado(AU)

Aneurisma de la orejuela de la aurícula izquierda / Aneurism of the left atrial appendage

No disponible

Muerte súbita / Sudden death

La muerte súbita definida como un hecho que acontece en forma natural, inesperada e instantánea o por lo menos dentro de la primera hora de iniciada la sintomatología, es el problema mas grave y dramático que enfrenta la cardiología. Es la primera causa de muerte de los sujetos mayores de 65 años; es tres veces mas frecuente en el hombre que en la mujer. En el 20 por ciento de los casos es la primera manifestación de cardiopatía coronaria y es la causa del fallecimiento del 50 por ciento de los pacientes coronarios.Se revisa la fisiopatología de la muerte súbita, destacando la importancia del rol que juega la cardiopatía coronaria de base la que a través de la isquemia, tanto aguda como crónica, determina disfunción ventricular sistólica y diastólica, arritmia ventriculares complejas, trastornos de conducción y depresiones del automatismo. En el desencadenamiento mismo de la muerte súbita intervienen factores modulares tales como el estrés físico y psíquico, trastornos del sistema neurovegetativo y alteraciones metabólicas y iónicas(hipocalcemia, hipomagnesemia,hipo ohiperpotasemia, etc.). Se analiza el pronóstico de la muerte súbita por fibrilación ventricular, por bradiarritmia o asistolia, reconociendo que esta última es menos frecuente pero de peor pronóstico. Los sobrevivientes de muerte súbita deben ser estudiados exhaustivamente en la Unidad de Cuidados Intensivos a fin de poder adoptar las medidas orientadas a prevenir la recurrencia del accidente.Estas consisten basicamente en corregir la isquemia miocárdica, evitar las arritmias ventriculares sea con fármacos , con la implantación de un cardioversor defibrilador o mediante la ablación de focos arritmogénicos con fulguración eléctrica o radiofrecuencia

Electrocardiografía dinámica (Holter) / Dynamic electrocardiography (Holter)

Dado, por una parte, el carácter habitualmente transitorio de las arritmias y de los síntomas asociados y, por otra, de las limitaciones que la anamnesis tiene en su estudio, la electrocardiografía dinámica o Holter se ha establecido como el método no invasivo actualmente más sensible en su detección. Para una adecuada interpretación del significado clínico de los trastornos del ritmo se requiere de una correlación en el tiempo entre los síntomas del paciente y la arritmia registrada. El Holter tiene valor en el estudio de ciertos grupos de pacientes con sospecha de cardiopatía coronaria, como son los portadores de angina de reposo o angina de Prinzmetal y aquellos con limitaciones para efectuar una prueba de esfuerzo graduada. En el postinfarto agudo del miocardio el Holter ayuda a estratificar el riesgo futuro del paciente a través de la detección de arritmias ventriculares. Por último, considerando las variaciones temporales propias de las arritmias, el Holter permite una evaluación de la respuesta terapéutica frente a las drogas antiarrítmicas, así como de la función de los marcapasos definitivos

Miocardiopatía diabética / Diabetic Myocardiopathy

Se revisan las evidencias clínicas, epidemiológicas, anatomopatológicas y de laboratorio (principalmente cardiológico no invasivo) que apoyan la existencia de una miocardiopatía específica asociada a la diabetes mellitus. Los métodos de laboratorio más útiles en este sentido han sido la ventriculografía radioisotópica y la ecocardiografía bidimensional con Doppler, los que han permitido demostrar disfunción ventricular diastólica y/o sistólica, frecuentement subclínica. Las alteraciones anatomopatológicas consisten en lesiones ubicadas en los capilares, pequeños vasos intramiocárdicos e intersticio. En su patogenia, parecen tener un rol destacado la neuropatía autonómica y la hipertensión arterial, que tan frecuentemente se asocia a la diabetes. Hay evidencias que relacionan el daño microvascular del diabético con el deterioro de su función ventricular. No existe un tratamiento específico, sino sólo el general de la insuficiencia cardíaca

Infarto del ventrículo derecho / Right ventricle infarction

El infarto del ventrículo derecho es una entidad clínica importante por su frecuencia, su gravedad y su manejo terapéutico. El 50 porciento de los infartos agudos de la pared inferior del ventrículo izquierdo se asocian a compromiso del ventrículo derecho. En todo paciente con un infarto agudo de pared inferior del miocardio en evolución, se debe sospechar la posibilidad de un compromiso concomitante del ventrículo derecho. Para ello, debe obtenerse un electrocardiograma que incluya el registro de las derivaciones precordiales derechas. La adecuada comprensión de su fisiopatología permite tratar racionalmente el infarto de ventrículo derecho. El tratamiento se basa en asegurar al ventrículo derecho una adecuada precarga y a la vez reducir su postcarga cuando ella es excesiva. Para lograr resultados favorables es necesario mantener un buen aporte de volumen, administrar fármacos de acción inotropa positiva, cuando corresponda y promover la reperfusión precoz del miocardio comprometido con trombólisis o angioplastía primaria

Algunas consideraciones acerca de las drogas bloqueadoras de los canales de calcio / Some considerations about calcium channel blockader drugs

Los bloqueadores de los canales de calcio (dihidropiridinas, verapamilo y diltiazem) son medicamentos de amplio uso en la práctica diaria. Sus principales indicaciones son la hipertensión arterial; la insuficiencia coronaria con angor crónico estable y el síndrome de raynaud. En el último tiempo algunas publicaciones han señalado que el empleo de los calcioantagonistas encerraría el riesgo de aumentar la incidencia de eventos coronarios agudos y de elevar la mortalidad, lo que ha creado inquietud en pacientes y médicos. Aparentemente el riesgo se limita sólo al nifedipino corriente cuando se administra en dosis altas (mayores de 60 mg diarios); indiscriminadamente por vía sublingual (Servicios de urgencia) y a pacientes con infartos miocárdicos agudos o angor inestable. El verapamilo, el diltiazem y los nifedipinos de liberación lenta y acción prolongada no tendrían riesgos

Algunos conceptos actuales sobre digital y otras drogas usadas en el tratamiento de la insuficiencia cardiaca / Some current concepts on digitalis and other drugs used in the treatment of cardiac failure

Se revisan en forma muy resumida algunos conceptos actuales acerca del tratamiento de la insuficiencia cardíaca y del uso e indicaciones de los digitálicos. Al respecto, existen actualmente importantes controversias. La digital sigue siendo un medicamento plenamente vigente, cuyas principales indicaciones actuales se señalan. Se destaca que su utilidad en insuficientes cardíacos con ritmo sinusal es escasa. Se sugieren los siguientes esquemas terapéuticos: Insuficiencia cardíaca CF I: ¿diurético? CF II: diurético + digital o diurético + vasodilatodor CF III y IV: dirético + digital + vasodilatador

Síndrome de Marfán: estudio de una mutación reciente en una familia / Marfan's syndrome: study of a recient motation in a family

Se presenta el caso de una niña de cuatro años de edad afecta del Síndrome de Marfan. Se muestra el estudio del arbol genealógico familiar, donde se refleja que la aparición del trastorno se debió a una mutación reciente en la madre. Se describen las alteraciones oculares y esqueléticas encontradas, sin que exista afectación del aparato cardiovascular. Se destacan los principales aspectos de la enfermedad, los que fueron tomados de la literatura revisada

Síndrome de Marfán: estudio de una mutación reciente en una familia / Marfan's syndrome: study of a recient motation in a family

Se presenta el caso de una niña de cuatro años de edad afecta del Síndrome de Marfan. Se muestra el estudio del arbol genealógico familiar, donde se refleja que la aparición del trastorno se debió a una mutación reciente en la madre. Se describen las alteraciones oculares y esqueléticas encontradas, sin que exista afectación del aparato cardiovascular. Se destacan los principales aspectos de la enfermedad, los que fueron tomados de la literatura revisada