Oral phytate supplementation on the progression of mild cognitive impairment, brain iron deposition and diabetic retinopathy in patients with type 2 diabetes: a concept paper for a randomized double blind placebo controlled trial (the PHYND trial).

Type 2 diabetes mellitus has a worldwide prevalence of 10.5% in the adult population (20-79 years), and by 2045, the prevalence is expected to keep rising to one in eight adults living with diabetes. Mild cognitive impairment has a global prevalence of 19.7% in adults aged 50 years. Both conditions have shown a concerning increase in prevalence rates over the past 10 years, highlighting a growing public health challenge. Future forecasts indicate that the prevalence of dementia (no estimations done for individuals with mild cognitive impairment) is expected to nearly triple by 2050. Type 2 diabetes mellitus is a risk factor for the development of cognitive impairment, and such impairment increase the likelihood of poor glycemic/metabolic control. High phytate intake has been shown to be a protective factor against the development of cognitive impairment in observational studies. Diary phytate intake might reduce the micro- and macrovascular complications of patients with type 2 diabetes mellitus through different mechanisms. We describe the protocol of the first trial (the PHYND trial) that evaluate the effect of daily phytate supplementation over 56 weeks with a two-arm double-blind placebo-controlled study on the progression of mild cognitive impairment, cerebral iron deposition, and retinal involvement in patients with type 2 diabetes mellitus. Our hypothesis proposes that phytate, by inhibiting advanced glycation end product formation and chelating transition metals, will improve cognitive function and attenuate the progression from Mild Cognitive Impairment to dementia in individuals with type 2 diabetes mellitus and mild cognitive impairment. Additionally, we predict that phytate will reduce iron accumulation in the central nervous system, mitigate neurodegenerative changes in both the central nervous system and retina, and induce alterations in biochemical markers associated with neurodegeneration.

[Neurophysiology and ageing. Definition and pathophysiological foundations of cognitive impairment]. / Neurofisiología y envejecimiento. Concepto y bases fisiopatológicas del deterioro cognitivo.

Brain ageing is produced by various morphological, biochemical, metabolic and circulatory changes, which are reflected in functional changes, whose impact depends on the presence or absence of cognitive impairment. Because of brain plasticity, together with redundancy of the distinct cerebral circuits, age- related deterioration of the brain at various levels does not always translate into loss of brain function. However, when the damage exceeds certain thresholds, there is age-related cognitive impairment, which increases the risk of developing various neurodegenerative diseases such as Alzheimer disease. Genetics, together with lifestyle, diet, and environmental factors, etc, can trigger the development of these diseases, which provoke cognitive impairment. This article discusses the most important age-related changes in the brain, as well as the pathophysiological foundations of cognitive impairment.

Neurofisiología y envejecimiento. Concepto y bases fisiopatológicas del deterioro cognitivo / Neurophysiology and ageing. Definition and pathophysiological foundations of cognitive impairment

El envejecimiento cerebral se produce por diversos cambios morfológicos, bioquímicos, metabólicos y circulatorios, que se traducen en cambios funcionales, de cuyo alcance depende el desarrollo o no de deterioro cognitivo. La plasticidad cerebral, junto con la redundancia de los distintos circuitos cerebrales, hace que, aun habiendo deterioro del cerebro a distintos niveles con el envejecimiento, estos no se traduzcan en pérdida de las capacidades funcionales del mismo. Sin embargo, cuando el daño supera unos determinados límites aparece el deterioro cognitivo asociado a la edad, que aumenta el riesgo de desarrollo de diversas enfermedades neurodegenerativas, como la enfermedad de Alzheimer. La genética, junto con el estilo de vida, la alimentación, factores ambientales, etc. pueden precipitar la aparición de estas enfermedades que cursan con deterioro cognitivo. En este capítulo se comentan los cambios cerebrales más importantes asociados al envejecimiento, así como las bases fisiopatológicas del deterioro cognitivo (AU)

Brain ageing is produced by various morphological, biochemical, metabolic and circulatory changes, which are reflected in functional changes, whose impact depends on the presence or absence of cognitive impairment. Because of brain plasticity, together with redundancy of the distinct cerebral circuits, agerelated deterioration of the brain at various levels does not always translate into loss of brain function. However, when the damage exceeds certain thresholds, there is age-related cognitive impairment, which increases the risk of developing various neurodegenerative diseases such as Alzheimer disease. Genetics, together with lifestyle, diet, and environmental factors, etc, can trigger the development of these diseases, which provoke cognitive impairment. This article discusses the most important age-related changes in the brain, as well as the pathophysiological foundations of cognitive impairment (AU)

El estrés oxidativo como predictor de longevidad; estudio de casos y controles / Oxidative stress and longevity; a case-control study

Introducción. La longevidad humana es un fenómeno complejo en el que influyen factores genéticos y ambientales. El estrés oxidativo (EO) puede jugar un papel importante en este proceso. El envejecimiento exitoso podría relacionarse con la habilidad del organismo para hacer frente al EO. Nuestro objetivo es comparar los niveles en plasma de malondialdehído (MDA) y proteínas oxidadas (PO) entre sujetos mayores de 97 años y con edad entre 70 y 80 años, para comprender mejor los efectos del estrés oxidativo en la longevidad humana. Material y métodos. Estudio de casos y controles de base poblacional. Se consideraron casos todas aquellas personas nacidas y residentes en la comarca de la Ribera (Valencia), con edad superior a 97 años y que aceptaron participar en el mismo. Los controles son sujetos de la misma base poblacional, elegidos al azar, y con edad entre 70 y 80 años. Se realiza un análisis descriptivo de variables sociodemográficas, clínicas y funcionales; se calcula la razón de odds (OR) de ser centenario en función del cuartil de los niveles de PO y MDA; y la significación estadística de la tendencia mediante el test Mantel-Haenszel. Resultados. Fueron incluidos 28 casos y 31 controles. La situación funcional, así como el porcentaje de individuos robustos, fue menor en el grupo de casos que en los controles. Los niveles de MDA fueron menores en los casos (1,44 ± 0,45 vs. 1,84 ± 0,59, p = 0,005), al igual que los niveles de PO (64,29 ± 15,73 vs. 76,52 ± 13,44, p = 0,002). Al comparar a los sujetos con niveles de MDA y PO en el cuartil inferior respecto al superior, la OR de ser centenario es de 3,8 para el MDA y de 5,7 para las PO, con una p = 0,029 y p = 0,044, respectivamente, en la significación de la tendencia. Conclusiones. En los sujetos de nuestro estudio los niveles plasmáticos de MDA y PO son menores en centenarios que en ancianos más jóvenes, y se observa que a menor grado de EO mayor es la probabilidad de ser centenario (AU)

Introduction. Human longevity is a complex issue influenced by genetic and environmental factors. Oxidative stress (OE) could play an important role in this process. Succesful aging could be related with the organism ability facing OE. In the present study we compared malondialdehyde (MDA) and oxidized proteins (OP) plasma levels, in elderly people older than 97 years and 70-80 years old, to better understand the effects of OE on human longevity. Material and methods. Population-based case control study. We considered as cases patients who were born and live on la Ribera county in Valencia (Spain) older than 97 years old and who accepted to participate in the study. Controls were from the same poblational base, chosen randomly, and 70-80 years old. We made a descriptive analysis of sociodemographic, clinic and functional variables; an odds ratio (OR) estimation of being centenarian by OP and MDA quartiles; and a tendency analysis by Mantel-Haenszel test. Results. Twenty eight cases and 31 controls were included. Functional state and robust percentage were worse in cases. MDA (1,44 ± 0,45 vs 1,84 ± 0,59, p = 0,005), and OP (64,29 ± 15,73 vs. 76,52 ± 13,44, p = 0,002) levels, were significantly lower in cases. The OR of being centenarian in lower/higher quartile were 3,8 for MDA and 5,7 for OP, with a Mantel-Haenszel signification of 0,029 and 0,044 respectively. Conclusions. In our study OE level were lower in centenarians than in younger elderly, and the lower the OE grade, the higher were the likelihood of being centenarian (AU)

[Oxidative stress and longevity; a case-control study]. / El estrés oxidativo como predictor de longevidad; estudio de casos y controles.

INTRODUCTION: Human longevity is a complex issue influenced by genetic and environmental factors. Oxidative stress (OE) could play an important role in this process. Succesful aging could be related with the organism ability facing OE. In the present study we compared malondialdehyde (MDA) and oxidized proteins (OP) plasma levels, in elderly people older than 97 years and 70-80 years old, to better understand the effects of OE on human longevity. MATERIAL AND METHODS: Population-based case control study. We considered as cases patients who were born and live on la Ribera county in Valencia (Spain) older than 97 years old and who accepted to participate in the study. Controls were from the same poblational base, chosen randomly, and 70-80 years old. We made a descriptive analysis of sociodemographic, clinic and functional variables; an odds ratio (OR) estimation of being centenarian by OP and MDA quartiles; and a tendency analysis by Mantel-Haenszel test. RESULTS: Twenty eight cases and 31 controls were included. Functional state and robust percentage were worse in cases. MDA (1,44±0,45 vs 1,84±0,59, p=0,005), and OP (64,29±15,73 vs. 76,52±13,44, p=0,002) levels, were significantly lower in cases. The OR of being centenarian in lower/higher quartile were 3,8 for MDA and 5,7 for OP, with a Mantel-Haenszel signification of 0,029 and 0,044 respectively. CONCLUSIONS: In our study OE level were lower in centenarians than in younger elderly, and the lower the OE grade, the higher were the likelihood of being centenarian.

Early biomarkers of acute kidney failure after heart angiography or heart surgery in patients with acute coronary syndrome or acute heart failure.

BACKGROUND: Acute kidney injury (AKI) is a common complication in cardiac surgery and coronary angiography, which worsens patients' prognosis. The diagnosis is based on the increase in serum creatinine, which is delayed. It is necessary to identify and validate new biomarkers that allow for early and effective interventions. AIMS: To assess the sensitivity and specificity of neutrophil gelatinase-associated lipocalin in urine (uNGAL), interleukin-18 (IL-18) in urine and cystatin C in serum for the early detection of AKI in patients with acute coronary syndrome or heart failure, and who underwent cardiac surgery or catheterization. METHODS: The study included 135 patients admitted to the intensive care unit for acute coronary syndrome or heart failure due to coronary or valvular pathology and who underwent coronary angiography or cardiac bypass surgery or valvular replacement. The biomarkers were determined 12 hours after surgery and serum creatinine was monitored during the next six days for the diagnosis of AKI. RESULTS: The area under the ROC curve (AUC) for NGAL was 0.983, and for cystatin C and IL-18 the AUCs were 0.869 and 0.727, respectively. At a cut-off of 31.9 ng/ml for uNGAL the sensitivity was 100% and the specificity was 91%. CONCLUSIONS: uNGAL is an early marker of AKI in patients with acute coronary syndrome or heart failure and undergoing cardiac surgery and coronary angiography, with a higher predictive value than cystatin C or IL-18.

Upper-extremity deep vein thrombosis in a patient on clozapine therapy carrying the prothrombin G20210A mutation.

Clozapine treatment for resistant schizophrenic disorders has been associated to venous thromboembolic events. We report the case of a patient who developed upper-extremity deep vein thrombosis just 2 months after starting on clozapine in whom the thrombophilia work-up revealed the presence of the prothrombin G20210A mutation.

Implicaciones genéticas en la longevidad: análisis multigénico en el macho y en la hembra / Genetic implications in longevity: a multigenic analysis in males and females

Introducción: las hembras viven más que los machos. Hemos demostrado que los estrógenos son capaces de aumentar la expresión de genes asociados a la longevidad. Sin embargo, nos hemos centrado en el estudio de genes cuya relación con la longevidad está muy bien establecida. Por esto, nos planteamos el estudio de 9.000 genes mediante el método del Genechip. Estudiamos la expresión de estos genes en machos y los comparamos con la expresión en las hembras. Material y método: la expresión de los genes se estudió mediante la tecnología Affymetrix. En esencia, aislamos ARN total y lo pasamos a ADNc de doble cadena por retrotranscripción. Obtenemos ARN marcado con biotina a partir del ADNc y lo purificamos. La muestra se introduce en un bioarray U34A y se procesa en la estación de fluidos Affymetrix. Los resultados se escanean y analizan con el programa Microarray Suite 3.0. Resultados: encontramos 33 genes cuya expresión es significativamente mayor en el macho que en la hembra y 53 genes que se sobrexpresan en la hembra comparada con el macho. Estudiamos en particular los genes cuya expresión cambiaba más de 2 veces, y vemos que todos estos genes están relacionados con el envejecimiento. Por tanto, encontramos genes que se sobrexpresan en la hembra respecto del macho y previamente no habían sido identificados como relacionados con el sexo. Conclusiones: el análisis multigénico es una herramienta útil para identificar genes sobrexpresados en las hembras en relación con los machos y que sean relevantes en el proceso de envejecimiento

Introduction: females live longer than males. We have traced the gender-associated advantage to the up-regulation of longevity-associated genes by oestrogens. However, we restricted our analysis to the well-known longevity-associated genes. A more general approach can be adopted through the use of Genechip analysis, which allows the expression of 9,000 genes to be studied. We studied the expression of these genes in the brains of male rats and compared the results with those in females. Material and method: genome-wide expression was studied using Affymetrix technology. Essentially, total ARN was extracted and double-stranded cDNA was obtained by reverse transcription. New biotinylated complementary ARN was obtained and purified. The sample was hybridised and introduced into an Affymetrix fluidics station. The results were scanned and analysed by a Microarray Suite 3.0. Results: we found 33 genes whose expression was significantly increased in males versus females and 53 genes that were over-expressed in females in comparison with males. In particular, we studied genes whose expression was twofold higher or more in males than in females and found that these genes were all related to ageing. Thus, we identified age-related genes that are over-expressed in females when compared with males and whose expression was not previously identified as being gender-specific. Conclusions: genome-wide analysis is a powerful tool to identify genes that are over-expressed in females versus males and to determine which of these genes are relevant to the study of ageing

Estudio de toxicidad del péptido beta-amiloide en linfocitos humanos / Beta amyloid peptide toxicity in human lymphocytes

Introducción: la enfermedad de Alzheimer (EA) es uno de los problemas sociosanitarios más importantes actualmente. Se considera la toxicidad del péptido beta-amiloide la clave de su patogenia. Cada vez es más importante conseguir marcadores periféricos de la enfermedad para avanzar en su conocimiento y de sus posibles dianas terapéuticas. Con este estudio pretendemos valorar la idoneidad de los linfocitos como modelo en el que estudiar la toxicidad del beta-amiloide. Material y métodos: se reclutó a 6 voluntarios sanos, 3 varones y 3 mujeres, con edades comprendidas entre los 25 y 35 años, sin antecedentes familiares de EA. Se les realizó una extracción sanguínea de donde se aislaron los linfocitos que posteriormente se incubaron con beta-amiloide 1-42 durante 6 h. Se utilizó la microscopia confocal y la citometría de flujo para estudiar, como marcadores de toxicidad celular, la apoptosis, el potencial de membrana mitocondrial y el número de mitocondrias. Resultados: encontramos un aumento de muerte celular en sus distintos estadios (apoptosis temprana y tardía) así como una disminución de mitocondrias en los linfocitos incubados con el péptido beta-amiloide. Observamos un mayor daño celular en los linfocitos de los varones que en las mujeres, probablemente por el efecto protector de los estrógenos. Conclusiones: los linfocitos son un buen modelo para estudiar la toxicidad celular del péptido beta-amiloide

Introduction: Alzheimer's disease is a major health concern. The toxicity of the beta amyloid peptide is a key pathogenic event in the development of this disease. Finding peripheral markers for Alzheimer's disease is an important step for the early detection and treatment of this disease. The aim of the present study was to evaluate the utility of lymphocytes as a peripheral model for the study of beta amyloid toxicity. Material and methods: six healthy volunteers (three men and three women), aged 25-35 years, without a family history of Alzheimer's disease were recruited. Peripheral blood lymphocytes were obtained and incubated with 10 micromolar beta amyloid peptide for 6 hours. Confocal microscopy and flow cytometry were used to determine the rate of apoptosis, mitochondrial membrane potential, and the number of mitochondria. Results: incubation of lymphocytes with beta amyloid peptide caused an increase in cell death (apoptosis plus necrosis) as well as a decrease in the number of mitochondria. The peptide caused more damage to cells from men than to those from women, probably due to the protective effect of estrogens. Conclusions: lymphocytes are a good model for studying cellular susceptibility to beta amyloid peptide