Evolution and treatment of vitamin B12 deficiency as a risk factor for (cognitive and functional) neurodegenerative diseases in institutionalized elderly = Evolución y tratamiento de la deficiencia de vitamina B12 como factor de riesgo de enfermedades neurodegenerativas (cognitivas y funcionales) en las personas mayores institucionalizadas.

Prevalence of vitamin B12 deficiency is very common in elderly people and can reach values as high as 40.5% of the population. It can be the result of the interaction among several factors. Vitamin B12 deficiencies have been associated with neurological, cognitive deterioration, haematological abnormalities and cardiovascular diseases that have an important influence on the health of the elderly and their quality of life. It is necessary to approach the problems arisen from the lack of data relative to them. The main objective of this thesis was to analyse the evolution of vitamin B12 status and related parameters, lipid and haematological profiles and their relationship to health risk factors, and to functional and cognitive status over one year and to determine the effect of an oral supplementation of 500 μg of cyanocobalamin for a short period of 28 days. An additional objective was to analyze the possible effects of medicine intakes on vitamin B status. Three studies were performed: a) a one year longitudinal follow-up with four measure points; b) an intervention study providing an oral liquid supplement of 500 μg of cyanocobalamin for a 28 days period; and c) analysis of the possible effect of medication intake on vitamin B status using the ATC classification of medicines. The participants for these studies were recruited from nursing homes for the elderly in the Region of Madrid. Sixty elders (mean age 84 _ 7y, 19 men and 41 women) were recruited for Study I and 64 elders (mean age 82 _ 7y, 24 men and 40 women) for Study II. For Study III, baseline data from the initially recruited participants of the first two studies were used. An informed consent was obtained from all participants or their mentors. The studies were approved by the Ethical Committee of the University of Granada. Blood samples were obtained at each examination date and were analyzed for serum cobalamin, holoTC, serum and RBC folate and total homocysteine according to laboratory standard procedures. The haematological parameters analyzed were haematocrit, haemoglobin and MCV. For the lipid profile TG, total cholesterol, LDL- and HDLcholesterol were analyzed. Anthropometric measures (BMI, skinfolds [triceps and subscapular], waist girth and waist to hip ratio), functional tests (hand grip, arm and leg strength tests, static balance) and MMSE were obtained or administered by trained personal. The vitamin B12 supplement of Study II was administered with breakfast and the medication intake was taken from the residents’ anamnesis. Data were analyzed by parametric and non-parametric statistics depending on the obtained data. Comparisons were done using the appropriate ANOVAs or non-parametric tests. Pearsons’ partial correlations with the variable “time” as control were used to define the association of the analyzed parameters. XIII The results showed that: A) Over one year, in relationship to vitamin B status, serum cobalamin decreased, serum folate and mean corpuscular volumen increased significantly and total homocysteine concentrations were stable. Regarding blood lipid profile, triglycerides increased and HDL-cholesterol decreased significantly. Regarding selected anthropometric measurements, waist circumference increased significantly. No significant changes were observed for the rest of parameters. B) Prevalence of hyperhomocysteinemia was high in the elderly studied, ranging from 60% to 90 % over the year depending on the cut-off used for the classification. LDL-cholesterol values were high, especially among women, and showed a tendency to increase over the year. Results of the balance test showed a deficiency and a tendency to decrease; this indicates that the population studied is at high risk for falls. Lower extremity muscular function was deficient and showed a tendency to decrease. A highly significant relationship was observed between the skinfold of the triceps and blood lipid profile. C) Low cobalamin concentrations correlated significantly with low MMSE scores in the elderly studied. No correlations were observed between vitamin B12 status and functional parameters. D) Regarding vitamin B12 status, holo-transcobalamin seems to be more sensitive for diagnosis; 5-10% of the elderly had a deficiency using serum cobalamin as a criterion, and 45-52% had a deficiency when using serum holotranscobalamin as a criterion. E) 500 μg of cyanocobalamin administered orally during 28 days significantly improved vitamin B12 status and significantly decreased total homocysteine concentrations in institutionalized elderly. No effect of the intervention was observed on functional and cognitive parameters. F) The relative change (%) of improvement of vitamin B12 status was higher when using serum holo-transcobalamin as a criterion than serum cobalamin. G) Antiaenemic drug intake normalized cobalamin, urologic drugs and corticosteroids serum folate, and psychoanaleptics holo-transcobalamin levels. Drugs treating pulmonary obstruction increased total homocysteine concentration significantly. H) The daily mean drug intake was 5.1. Fiftynine percent of the elderly took medication belonging to 5 or more different ATC groups. The most prevalent were psycholeptic (53%), antiacid (53%) and antithrombotic (47%) drugs.

Breve de beatificacion del ven. siervo de Dios F. Nicolas Factor ... del Orden de Menores Observantes y relacion de la solemnidad, con que se celebró en Roma ... el dia 27 de Agosto de ... 1786 Acompaña la carta del ... Postulador de la causa, escrita a la ... Ciudad, de cuya orden se publica

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The AtCathB3 gene, encoding a cathepsin B-like protease, is expressed during germination of Arabidopsis thaliana and transcriptionally repressed by the basic leucine zipper protein GBF1.

Protein hydrolysis plays an important role during seed germination and post-germination seedling establishment. In Arabidopsis thaliana, cathepsin B-like proteases are encoded by a gene family of three members, but only the AtCathB3 gene is highly induced upon seed germination and at the early post-germination stage. Seeds of a homozygous T-DNA insertion mutant in the AtCathB3 gene have, besides a reduced cathepsin B activity, a slower germination than the wild type. To explore the transcriptional regulation of this gene, we used a combined phylogenetic shadowing approach together with a yeast one-hybrid screening of an arrayed library of approximately 1200 transcription factor open reading frames from Arabidopsis thaliana. We identified a conserved CathB3-element in the promoters of orthologous CathB3 genes within the Brassicaceae species analysed, and, as its DNA-interacting protein, the G-Box Binding Factor1 (GBF1). Transient overexpression of GBF1 together with a PAtCathB3::uidA (β-glucuronidase) construct in tobacco plants revealed a negative effect of GBF1 on expression driven by the AtCathB3 promoter. In stable P35S::GBF1 lines, not only was the expression of the AtCathB3 gene drastically reduced, but a significant slower germination was also observed. In the homozygous knockout mutant for the GBF1 gene, the opposite effect was found. These data indicate that GBF1 is a transcriptional repressor of the AtCathB3 gene and affects the germination kinetics of Arabidopsis thaliana seeds. As AtCathB3 is also expressed during post-germination in the cotyledons, a role for the AtCathB3-like protease in reserve mobilization is also inferred.

El fitness como factor determinante en el riesgo de discapacidad, su relación con la composición corporal y el estado cognitivo en población mayor institucionalizada y de vida independiente = Fitness as a determinant factor in the risk of disability, and its relationship to body composition and cognitive status in institutionalized elderly population and independent living

La condición física, o como mejor se la conoce hoy en día el “fitness”, es una variable que está cobrando gran protagonismo, especialmente desde la perspectiva de la salud. La mejora de la calidad de vida que se ha experimentado en los últimos años en las sociedades desarrolladas, conlleva un aumento de la esperanza de vida, lo que hace que cada vez más personas vivan más años. Este rápido crecimiento de la población mayor de 60 años hace que, un grupo poblacional prácticamente olvidado desde el punto de vista de la investigación científica en el campo de la actividad física y del deporte, cobre gran relevancia, con el fin de poder ayudar a alcanzar el dicho “no se trata de aportar años a la vida sino vida a lo años”. La presente memoria de Tesis Doctoral tiene como principal objetivo valorar los niveles de fitness en población mayor española, además de analizar la relación existente entre el fitness, sus condicionantes y otros aspectos de la salud, tales como la composición corporal y el estado cognitivo. Entendemos que para poder establecer futuras políticas de salud pública en relación a la actividad física y el envejecimiento activo es necesario conocer cuáles son los niveles de partida de la población mayor en España y sus condicionantes. El trabajo está basado en los datos del estudio multicéntrico EXERNET (Estudio Multi-céntrico para la Evaluación de los Niveles de Condición Física y su relación con Estilos de Vida Saludables en población mayor española no institucionalizada), así como en los datos de dos estudios, llevados a cabo en población mayor institucionalizada. Se han analizado un total de 3136 mayores de vida independiente, procedentes de 6 comunidades autónomas, y 153 mayores institucionalizados en residencias de la Comunidad de Madrid. Los principales resultados de esta tesis son los siguientes: a) Fueron establecidos los valores de referencia, así como las curvas de percentiles, para cada uno de los test de fitness, de acuerdo a la edad y al sexo, en población mayor española de vida independiente y no institucionalizada. b) Los varones obtuvieron mejores niveles de fitness que las mujeres, excepto en los test de flexibilidad; existe una tendencia a disminuir la condición física en ambos sexos a medida que la edad aumenta. c) Niveles bajos de fitness funcional fueron asociados con un aumento en la percepción de problemas. d) El nivel mínimo de fitness funcional a partir del cual los mayores perciben problemas en sus actividades de la vida diaria (AVD) es similar en ambos sexos. e) Niveles elevados de fitness fueron asociados con un menor riesgo de sufrir obesidad sarcopénica y con una mejor salud percibida en los mayores. f) Las personas mayores con obesidad sarcopénica tienen menor capacidad funcional que las personas mayores sanas. g) Niveles elevados de fuerza fueron asociados con un mejor estado cognitivo siendo el estado cognitivo la variable que más influye en el deterioro de la fuerza, incluso más que el sexo y la edad. ABSTRACT Fitness is a variable that is gaining in prominence, especially from the health perspective. Improvement of life quality that has been experienced in the last few years in developed countries, leads to an expanded life expectancy, increasing the numbers of people living longer. This population consisting of people of over 60 years, an almost forgotten population group from the point of view of scientific research in the field of physical activity and sport, is becoming increasingly important, with the main aim of helping to achieve the saying “do not only add years to life, but also add life to years”. The principal aim of the current thesis was to assess physical fitness levels in Spanish elderly people, of over 65 years, analyzing relationship between physical fitness, its determinants, and other aspects of health such as body composition and cognitive status. In order to establish further public health policies in relation to physical activity and active ageing it is necessary to identify the starting physical fitness levels of the Spanish population and their determinants. The work is based on data from the EXERNET multi-center study ("Multi-center Study for the Evaluation of Fitness levels and their relationship to Healthy Lifestyles in noninstitutionalized Spanish elderly"), and on data from two studies conducted in institutionalized elderly people: a total of 3136 non-institutionalized elderly, from 6 Regions of Spain, and 153 institutionalized elderly in nursing homes of Madrid. The main outcomes of this thesis are: a) sex- and age-specific physical fitness normative values and percentile curves for independent and non-institutionalized Spanish elderly were established. b) Greater physical fitness was present in the elderly men than in women, except for the flexibility test, and a trend toward decreased physical fitness in both sexes as their age increased. c) Lower levels of functional fitness were associated with increased perceived problems. d) The minimum functional fitness level at which older adults perceive problems in their ADLs, is similar for both sexes e) Higher levels of physical fitness were associated with a reduced risk of suffering sarcopenic obesity and better perceived health among the elderly. f) The elderly with sarcopenic obesity have lower physical functioning than healthy counterparts. g) Higher strength values were associated with better cognitive status with cognitive status being the most influencing variable in strength deterioration even more than sex and age.

Estado actual de la Educación Física en la provincia de Castellón, a nivel de centros oficiales de B.U.P

El gran cariño que de siempre he sentido por la Educación Física, me ha llevado tras arduos y penosos esfuerzos, al estudio de la misma. El transcurrir de los años de aprendizaje en sus materias, hicieron surgir en mí, un cúmulo de interrogantes, que nunca quedaron resueltos con el conocimiento progresivo inherente a sus asignaturas. La E. Física como asignatura educativa, es factor importante en la formación pedagógica juvenil. Se basa en planteamientos teóricos como cualquier otra materia, pero su verdadero fundamento y sus incuestionables realizaciones, se dan en el campo práctico. A diferencia de las otras, en ésta, se precisa de instalaciones especiales y de material abundante. ¿Y su comprensión? Podemos decir que la forma en que ha estado estructurada la E. Física en nuestro país, la ha hecho poco comprensible para las personas ajenas o poco relacionadas con el tema. Como educador vocacional de ella, estos son problemas, que de siempre me han preocupado e intranquilizado. Buscando una posible aclaración de ellos, decidí realizar este trabajo, para dar luz en lo posible a la verdadera situación. ( Al menos en mi provincia). A medida que la idea tomaba cuerpo en mi mente, nuevas interrogantes de la misma índole, surgieron en otros compañeros. Confrontadas ideas, proyectos y encauzamientos, se llegó a crear una fórmula de trabajo común, aplicable a la situación española en general y con posteriores conclusiones particulares y concretas, en cada ámbito provincial. Con vistas a este objetivo, este trabajo, se basa en una serie de cuestionarios, dirigidos a las diversas personas implicadas en la enseñanza: directores, otros profesores, P. Educación Física, padres de alumnos y los alumnos. La meta, en definitiva, será conocer de una forma clara y palpable, el auténtico estado actual de la E. Física en la provincia de Castellón a nivel de Centros Oficiales de B.U.P.

Epitome de la vida, virtudes, y milagros del B. Nicolás Factòr ... [Texto impreso] : Sacado de la Vida, que escriviò ... Christoval Moreno, y de los Procesos hechos para su Beatificacion, y Canonizacion

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Ubiquitin-dependent degradation of IκBα is mediated by a ubiquitin ligase Skp1/Cul 1/F-box protein FWD1

Activation of the transcription factor nuclear factor kappa B (NF-κB) is controlled by proteolysis of its inhibitory subunit (IκB) via the ubiquitin-proteasome pathway. Signal-induced phosphorylation of IκBα by a large multisubunit complex containing IκB kinases is a prerequisite for ubiquitination. Here, we show that FWD1 (a mouse homologue of Slimb/βTrCP), a member of the F-box/WD40-repeat proteins, is associated specifically with IκBα only when IκBα is phosphorylated. The introduction of FWD1 into cells significantly promotes ubiquitination and degradation of IκBα in concert with IκB kinases, resulting in nuclear translocation of NF-κB. In addition, FWD1 strikingly evoked the ubiquitination of IκBα in the in vitro system. In contrast, a dominant-negative form of FWD1 inhibits the ubiquitination, leading to stabilization of IκBα. These results suggest that the substrate-specific degradation of IκBα is mediated by a Skp1/Cull 1/F-box protein (SCF) FWD1 ubiquitin-ligase complex and that FWD1 serves as an intracellular receptor for phosphorylated IκBα. Skp1/Cullin/F-box protein FWD1 might play a critical role in transcriptional regulation of NF-κB through control of IκB protein stability.

Sustained correction of bleeding disorder in hemophilia B mice by gene therapy

Mice generated by disrupting the clotting factor IX gene exhibit severe bleeding disorder and closely resemble the phenotype seen in hemophilia B patients. Here we demonstrate that a single intraportal injection of a recombinant adeno-associated virus (AAV) vector encoding canine factor IX cDNA under the control of a liver-specific enhancer/promoter leads to a long-term and complete correction of the bleeding disorder. High level expression of up to 15–20 μg/ml of canine factor IX was detected in the plasma of mice injected with 5.6 × 1011 particles of an AAV vector for >5 months. The activated partial thromboplastin time of the treated mice was fully corrected to higher than normal levels. Liver-specific expression of canine factor IX was confirmed by immunofluorescence staining, and secreted factor IX protein was identified in the mouse plasma by Western blotting. All treated mice survived the tail clip test without difficulty. Thus, a single intraportal injection of a recombinant adeno-associated virus vector expressing factor IX successfully cured the bleeding disorder of hemophilia B mice, proving the feasibility of using AAV-based vectors for liver-targeted gene therapy of genetic diseases.

Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation

Although an excitotoxic mechanism of neuronal injury has been proposed to play a role in chronic neurodegenerative disorders such as Alzheimer’s disease, and neurotrophic factors have been put forward as potential therapeutic agents, direct evidence is lacking. Taking advantage of the fact that mutations in the presenilin-1 (PS1) gene are causally linked to many cases of early-onset inherited Alzheimer’s disease, we generated PS1 mutant knock-in mice and directly tested the excitotoxic and neurotrophic hypotheses of Alzheimer’s disease. Primary hippocampal neurons from PS1 mutant knock-in mice exhibited increased production of amyloid β-peptide 42/43 and increased vulnerability to excitotoxicity, which occurred in a gene dosage-dependent manner. Neurons expressing mutant PS1 exhibited enhanced calcium responses to glutamate and increased oxyradical production and mitochondrial dysfunction. Pretreatment with either basic fibroblast growth factor or activity-dependent neurotrophic factor protected neurons expressing mutant PS1 against excitotoxicity. Both basic fibroblast growth factor and activity-dependent neurotrophic factor stabilized intracellular calcium levels and abrogated the increased oxyradical production and mitochondrial dysfunction otherwise caused by the PS1 mutation. Our data indicate that neurotrophic factors can interrupt excitotoxic neurodegenerative cascades promoted by PS1 mutations.

NF-κB-dependent inhibition of apoptosis is essential for host cell survival during Rickettsia rickettsii infection

The possibility that bacteria may have evolved strategies to overcome host cell apoptosis was explored by using Rickettsia rickettsii, an obligate intracellular Gram-negative bacteria that is the etiologic agent of Rocky Mountain spotted fever. The vascular endothelial cell, the primary target cell during in vivo infection, exhibits no evidence of apoptosis during natural infection and is maintained for a sufficient time to allow replication and cell-to-cell spread prior to eventual death due to necrotic damage. Prior work in our laboratory demonstrated that R. rickettsii infection activates the transcription factor NF-κB and alters expression of several genes under its control. However, when R. rickettsii-induced activation of NF-κB was inhibited, apoptosis of infected but not uninfected endothelial cells rapidly ensued. In addition, human embryonic fibroblasts stably transfected with a superrepressor mutant inhibitory subunit IκB that rendered NF-κB inactivatable also underwent apoptosis when infected, whereas infected wild-type human embryonic fibroblasts survived. R. rickettsii, therefore, appeared to inhibit host cell apoptosis via a mechanism dependent on NF-κB activation. Apoptotic nuclear changes correlated with presence of intracellular organisms and thus this previously unrecognized proapoptotic signal, masked by concomitant NF-κB activation, likely required intracellular infection. Our studies demonstrate that a bacterial organism can exert an antiapoptotic effect, thus modulating the host cell’s apoptotic response to its own advantage by potentially allowing the host cell to remain as a site of infection.

NF-κB activation and interleukin 6 production in fibroblasts by estrogen receptor-negative breast cancer cell-derived interleukin 1α

Several angiogenic factors and extracellular matrix-degrading enzymes that promote invasion and metastasis of cancer are produced by stromal fibroblasts that surround cancer cells. The expression of genes that code for some of these proteins is regulated by the transcription factor NF-κB. In this report, we demonstrate that conditioned medium (CM) from estrogen receptor (ER)-negative but not ER-positive breast cancer cells induces NF-κB in fibroblasts. In contrast, CM from both ER-positive and ER-negative breast cancer cells induces NF-κB in macrophages and endothelial cells. NF-κB activation in fibroblasts was accompanied by induction of interleukin 6 (IL-6) and urokinase plasminogen activator (uPA), both of which promote angiogenesis and metastasis. A survey of cytokines known for their ability to induce NF-κB identified IL-1α as the factor responsible for NF-κB activation in fibroblasts. Analysis of primary breast carcinomas revealed the presence of IL-1α transcripts in majority of lymph node-positive breast cancers. These results along with the known role of IL-1α and IL-6 in osteoclast formation provide insight into the mechanism of metastasis and hypercalcemia in advanced breast cancers.