Effects of a Carbohydrate-restricted Diet on Emerging Plasma Markers for Cardiovascular Disease

BACKGROUND : Increasing evidence supports carbohydrate restricted diets (CRD) for weight loss and improvement in traditional markers for cardiovascular disease (CVD); less is known regarding emerging CVD risk factors. We previously reported that a weight loss intervention based on a CRD (% carbohydrate:fat:protein = 13:60:27) led to a mean weight loss of 7.5 kg and a 20% reduction of abdominal fat in 29 overweight men. This group showed reduction in plasma LDL-cholesterol and triglycerides and elevations in HDL-cholesterol as well as reductions in large and medium VLDL particles and increases in LDL particle size. In this study we report on the effect of this intervention with and without fiber supplementation on plasma homocysteine, lipoprotein (a) [Lp(a)], C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha). METHODS : Twenty nine overweight men [body mass index (BMI) 25-35 kg/m2] aged 20-69 years consumed an ad libitum CRD (% carbohydrate:fat:protein = 13:60:27) including a standard multivitamin every other day for 12 wk. Subjects were matched by age and BMI and randomly assigned to consume 3 g/d of either a soluble fiber supplement (n = 14) or placebo (n = 15). RESULTS : There were no group or interaction (fiber x time) main effects, but significant time effects were observed for several variables. Energy intake was spontaneously reduced (-30.5%). This was accompanied by an increase in protein intake (96.2 +/- 29.8 g/d to 107.3 +/- 29.7 g/d) and methionine intake (2.25 +/- 0.7 g/d, to 2.71 +/- 0.78 g/d; P < 0.001). Trans fatty acid intake was significantly reduced (-38.6%) while dietary folate was unchanged, as was plasma homocysteine. Bodyweight (-7.5 +/- 2.5 kg) was reduced as was plasma Lp(a) (-11.3%). Changes in plasma Lp(a) correlated with reductions in LDL-cholesterol (r = .436, P < 0.05) and fat loss (r = .385, P < 0,05). At wk 12, both CRP (-8.1%) and TNF-alpha (-9.3%) were reduced (P < 0.05) independently of weight loss. IL-6 concentrations were unchanged. CONCLUSION : A diet based on restricting carbohydrates leads to spontaneous caloric reduction and subsequent improvement in emerging markers of CVD in overweight/obese men who are otherwise healthy.

The relationship between supermarket nutrient movements and the mortality rates from fat-associated and non-fat-associated cardiovascular disease: Development of an ecologic method for determining community food patterns

Supermarket nutrient movement, a community food consumption measure, aggregated 1,023 high-fat foods, representing 100% of visible fats and approximately 44% of hidden fats in the food supply (FAO, 1980). Fatty acid and cholesterol content of foods shipped from the warehouse to 47 supermarkets located in the Houston area were calculated over a 6 month period. These stores were located in census tracts with over 50% of a given ethnicity: Hispanic, black non-Hispanic, or white non-Hispanic. Categorizing the supermarket census tracts by predominant ethnicity, significant differences were found by ANOVA in the proportion of specific fatty acids and cholesterol content of the foods examined. Using ecological regression, ethnicity, income, and median age predicted supermarket lipid movements while residential stability did not. No associations were found between lipid movements and cardiovascular disease mortality, making further validation necessary for epidemiological application of this method. However, it has been shown to be a non-reactive and cost-effective method appropriate for tracking target foods in populations of groups, and for assessing the impact of mass media nutrition education, legislation, and fortification on community food and nutrient purchase patterns. ^

The effects of omega -3 fatty acid -enriched fish on C -reactive protein levels in postmenopausal women

Coronary heart disease (CHD) is the leading cause of death in women and rates markedly increase among women after 65 years of age. C-reactive protein (CRP) is a new clinical indicator of atherosclerotic-related inflammation with a direct pathogenic role. Studies show lifestyle factors can modulate CRP. Omega-3 fatty acids have anti-inflammatory properties and studies suggest that eating fish high in omega-3 fatty acids may lower CHD risk in women. This study sought to assess the possible role of omega-3 fatty acids in the reduction of CHD-related inflammation by investigating the effect of fish consumption on CRP levels. Methods. Twenty-four healthy postmenopausal women were randomly assigned to a fish group (usual diet plus two servings per week of enriched fish) or control group (usual diet with no fatty fish) for eight weeks. Omega-3 fatty acid-enriched fish developed by the West Virginia University Aquaculture Division was used. Serum CRP, serum interleukin-6 (IL-6), and the fatty acid content of red blood cells (RBC) were measured before and after the study. Women also completed food records. RESULTS: Baseline levels of CRP were low (85% of the fish group had normal levels) and few changes in CRP risk category were observed. Mean IL-6 levels were reduced by 27% and 35% in the fish and control groups, respectively (p for between-group difference = 0.60). Changes in RBC fatty acid composition were not statistically significant. Compared to control women, women in the fish group had greater reductions in mean triglycerides (p = 0.08), total cholesterol (P = 0.04), and LDL cholesterol levels (p = 0.06). Baseline dietary intake of total and monounsaturated fatty acids tended to be positively associated with baseline CRP, while vitamin E intake was inversely related. Saturated fat intake tended to have a positive association with IL-6. Conclusions. Findings regarding the effect of two servings of fish on CRP and IL-6 levels are inconclusive due to low baseline levels of CRP and IL-6. However, results indicate two servings of fatty fish have favorable effects on blood lipids. The relationship of dietary components with CRP and IL-6 is complex and further research is needed to determine the varying roles of diet on the inflammatory process. ^

Subjective well -being as predictor of mortality, heart disease, and obesity: Prospective evidence from the Alameda County Study

Based on the World Health Organization's (1965) definition of health, understanding of health requires understanding of positive psychological states. Subjective Well-being (SWB) is a major indicator of positive psychological states. Up to date, most studies of SWB have been focused on its distributions and determinants. However, study of its consequences, especially health consequences, is lacking. This dissertation research examined Subjective Well-being, as operationally defined by constructs drawn from the framework of Positive Psychology, and its sub-scores (Positive Feelings and Negative Feelings) as predictors of three major health outcomes—mortality, heart disease, and obesity. The research used prospective data from the Alameda County Study over 29 years (1965–1994), based on a stratified, randomized, representative sample of the general public in Alameda County, California (Baseline N = 6928). ^ Multivariate analyses (Survival analyses using sequential Cox Proportional Hazard models in the cases of mortality and heart disease, and sequential Logistic Regression analyses in the case of obesity) were performed as the main methods to evaluate the associations of the predictors and the health outcomes. The results revealed that SWB reduced risks of all-cause mortality, natural-cause mortality, and cardiovascular mortality. Positive feelings not only had an even stronger protective effect against all-cause, natural-cause and cardiovascular mortality, but also predicted decreased unnatural-cause mortality which includes deaths from suicide, homicide, accidents, mental disorders, drug dependency, as well as alcohol-related liver diseases. These effects were significant even after adjusted for age, gender, education, and various physical health measures, and, in the case of cardiovascular mortality, obesity and health practices (alcohol consumption, smoking, and physical activities). However, these two positive psychological indicators, SWB and positive feelings, did not predict obesity. And negative feelings had no significant effect on any of the health outcomes evaluated, i.e., all-cause mortality, natural- and unnatural-cause mortality, cardiovascular mortality, or obesity, after covariates were controlled. These findings were discussed (1) in comparison with relevant existing studies, (2) in terms of their implications in health research and promotion, (3) in terms of the independence of positive and negative feelings, and (4) from a Positive Psychology perspective and its significance in Public Health research and practice. ^

Liver proteome profiling of juvenile Chinese sturgeon (Acipenser sinensis) using GeLC-MS/MS approach

Chinese sturgeon (Acipenser sinensis), mainly distributed in the Yangtze River, has been listed as a grade I protected animal in China because of a dramatic decline in population owing to loss of natural habitat for reproduction and interference by human activities. Understanding the proteome profile of Chinese sturgeon liver would provide an invaluable resource for protecting and increasing the stocks of this species. In this study, we have analyzed proteome profiles of juvenile Chinese sturgeon liver using a one-dimensional gel electrophoresis coupled to LC-MS/MS approach. A total of 1059 proteins and 2084 peptides were identified. The liver proteome was found to be associated with diverse biological processes, cellular components and molecular functions. The proteome profile identified a variety of significant pathways including carbohydrate metabolism, fatty acid metabolism and amino acid metabolism pathways. It also established a network for protein biosynthesis, folding and catabolic processes. The proteome profile established in this study can be used for understanding the development of Chinese sturgeon and studying the molecular mechanisms of action under environmental or chemical stress, providing very useful omics information that can be applied to preserve this species.

Functional response of Ulmus minor Mill. to drought, flooding and dutch elm disease

Ulmus minor es una especie arbórea originaria de Europa cuyas poblaciones han sido diezmadas por el hongo patógeno causante de la enfermedad de la grafiosis. La conservación de los olmos exige plantearse su propagación a través de plantaciones y conocer mejor su ecología y biología. Ulmus minor es un árbol de ribera, pero frecuentemente se encuentra alejado del cauce de arroyos y ríos, donde la capa freática sufre fuertes oscilaciones. Por ello, nuestra hipótesis general es que esta especie es moderadamente resistente tanto a la inundación como a la sequía. El principal objetivo de esta tesis doctoral es entender desde un punto de vista funcional la respuesta de U. minor a la inundación, la sequía y la infección por O. novo-ulmi; los factores que posiblemente más influyen en la distribución actual de U. minor. Con este objetivo se persigue dar continuidad a los esfuerzos de conservación de esta especie que desde hace años se dedican en varios centros de investigación a nivel mundial, ya que, entender mejor los mecanismos que contribuyen a la resistencia de U. minor ante la inoculación con O. novo-ulmi y factores de estrés abiótico ayudará en la selección y propagación de genotipos resistentes a la grafiosis. Se han planteado tres experimentos en este sentido. Primero, se ha comparado la tolerancia de brinzales de U. minor y U. laevis – otro olmo ibérico – a una inmersión controlada con el fin de evaluar su tolerancia a la inundación y comprender los mecanismos de aclimatación. Segundo, se ha comparado la tolerancia de brinzales de U. minor y Quercus ilex – una especie típica de ambientes Mediterránea secos – a la falta de agua en el suelo con el fin de evaluar el grado de tolerancia y los mecanismos de aclimatación a la sequía. El hecho de comparar dos especies contrastadas responde al interés en entender mejor cuales son los procesos que conducen a la muerte de una planta en condiciones de sequía – asunto sobre el que hay una interesante discusión desde hace algunos años. En tercer lugar, con el fin de entender mejor la resistencia de algunos genotipos de U. minor a la grafiosis, se han estudiado las diferencias fisiológicas y químicas constitutivas e inducidas por O. novo-ulmi entre clones de U. minor seleccionados a priori por su variable grado de resistencia a esta enfermedad. En el primer experimento se observó que los brinzales de U. minor sobrevivieron 60 días inmersos en una piscina con agua no estancada hasta una altura de 2-3 cm por encima del cuello de la raíz. A los 60 días, los brinzales de U. laevis se sacaron de la piscina y, a lo largo de las siguientes semanas, fueron capaces de recuperar las funciones fisiológicas que habían sido alteradas anteriormente. La conductividad hidráulica de las raíces y la tasa de asimilación de CO2 neta disminuyeron en ambas especies. Por el contrario, la tasa de respiración de hojas, tallos y raíces aumentó en las primeras semanas de la inundación, posiblemente en relación al aumento de energía necesario para desarrollar mecanismos de aclimatación a la inundación, como la hipertrofia de las lenticelas que se observó en ambas especies. Por ello, el desequilibrio del balance de carbono de la planta podría ser un factor relevante en la mortalidad de las plantas ante inundaciones prolongadas. Las plantas de U. minor (cultivadas en envases de 16 litros a media sombra) sobrevivieron por un prolongado periodo de tiempo en verano sin riego; la mitad de las plantas murieron tras 90 días sin riego. El cierre de los estomas y la pérdida de hojas contribuyeron a ralentizar las pérdidas de agua y tolerar la sequía en U. minor. Las obvias diferencias en tolerancia a la sequía con respecto a Q. ilex se reflejaron en la distinta capacidad para ralentizar la aparición del estrés hídrico tras dejar de regar y para transportar agua en condiciones de elevada tensión en el xilema. Más relevante es que las plantas con evidentes síntomas de decaimiento previo a su muerte exhibieron pérdidas de conductividad hidráulica en las raíces del 80% en ambas especies, mientras que las reservas de carbohidratos apenas variaron y lo hicieron de forma desigual en ambas especies. Árboles de U. minor de 5 y 6 años de edad (plantados en eras con riego mantenido) exhibieron una respuesta a la inoculación con O. novo-ulmi consistente con ensayos previos de resistencia. La conductividad hidráulica del tallo, el potencial hídrico foliar y la tasa de asimilación de CO2 neta disminuyeron significativamente en relación a árboles inoculados con agua, pero solo en los clones susceptibles. Este hecho enlaza con el perfil químico “más defensivo” de los clones resistentes, es decir, con los mayores niveles de suberina, ácidos grasos y compuestos fenólicos en estos clones que en los susceptibles. Ello podría restringir la propagación del hongo en el árbol y preservar el comportamiento fisiológico de los clones resistentes al inocularlos con el patógeno. Los datos indican una respuesta fisiológica común de U. minor a la inundación, la sequía y la infección por O. novo-ulmi: pérdida de conductividad hidráulica, estrés hídrico y pérdida de ganancia neta de carbono. Pese a ello, U. minor desarrolla varios mecanismos que le confieren una capacidad moderada para vivir en suelos temporalmente anegados o secos. Por otro lado, el perfil químico es un factor relevante en la resistencia de ciertos genotipos a la grafiosis. Futuros estudios deberían examinar como este perfil químico y la resistencia a la grafiosis se ven alteradas por el estrés abiótico. ABSTRACT Ulmus minor is a native European elm species whose populations have been decimated by the Dutch elm disease (DED). An active conservation of this species requires large-scale plantations and a better understanding of its biology and ecology. U. minor generally grows close to water channels. However, of the Iberian riparian tree species, U. minor is the one that spread farther away from rivers and streams. For these reasons, we hypothesize that this species is moderately tolerant to both flooding and drought stresses. The main aim of the present PhD thesis is to better understand the functional response of U. minor to the abiotic stresses – flooding and drought – and the biotic stress – DED – that can be most influential on its distribution. The overarching goal is to aid in the conservation of this emblematic species through a better understanding of the mechanisms that contribute to resistance to abiotic and biotic stresses; an information that can help in the selection of resistant genotypes and their expansion in large-scale plantations. To this end, three experiments were set up. First, we compared the tolerance to experimental immersion between seedlings of U. minor and U. laevis – another European riparian elm species – in order to assess their degree of tolerance and understand the mechanisms of acclimation to this stress. Second, we investigated the tolerance to drought of U. minor seedlings in comparison with Quercus ilex (an oak species typical of dry Mediterranean habitats). Besides assessing and understanding U. minor tolerance to drought at the seedling stage, the aim was to shed light into the functional alterations that trigger drought-induced plant mortality – a matter of controversy in the last years. Third, we studied constitutive and induced physiological and biochemical differences among clones of variable DED resistance, before and following inoculation with Ophiostoma novo-ulmi. The goal is to shed light into the factors of DED resistance that is evident in some genotypes of U. minor, but not others. Potted seedlings of U. minor survived for 60 days immersed in a pool with running water to approximately 2-3 cm above the stem collar. By this time, U. minor seedlings died, whereas U. laevis seedlings moved out of the pool were able to recover most physiological functions that had been altered by flooding. For example, root hydraulic conductivity and leaf photosynthetic CO2 uptake decreased in both species; while respiration initially increased with flooding in leaves, stems and roots possibly to respond to energy demands associated to mechanisms of acclimation to soil oxygen deficiency; as example, a remarkable hypertrophy of lenticels was soon observed in flooded seedlings of both species. Therefore, the inability to maintain a positive carbon balance somehow compromises seedling survival under flooding, earlier in U. minor than U. laevis, partly explaining their differential habitats. Potted seedlings of U. minor survived for a remarkable long time without irrigation – half of plants dying only after 90 days of no irrigation in conditions of high vapour pressure deficit typical of summer. Some mechanisms that contributed to tolerate drought were leaf shedding and stomata closure, which reduced water loss and the risk of xylem cavitation. Obviously, U. minor was less tolerant to drought than Q. ilex, differences in drought tolerance resulting mostly from the distinct capacity to postpone water stress and conduct water under high xylem tension among species. More relevant was that plants of both species exhibited similar symptoms of root hydraulic failure (i.e. approximately 80% loss of hydraulic conductivity), but a slight and variable depletion of non-structural carbohydrate reserves preceding dieback. Five- and six-year-old trees of U. minor (planted in the field with supplementary watering) belonging to clones of contrasted susceptibility to DED exhibited a different physiological response to inoculation with O. novo-ulmi. Stem hydraulic conductivity, leaf water potential and photosynthetic CO2 uptake decreased significantly relative to control trees inoculated with water only in DED susceptible clones. This is consistent with the “more defensive” chemical profile observed in resistant clones, i.e. with higher levels of saturated hydrocarbons (suberin and fatty acids) and phenolic compounds than in susceptible clones. These compounds could restrict the spread of O. novo-ulmi and contribute to preserving the near-normal physiological function of resistant trees when exposed to the pathogen. These results evidence common physiological responses of U. minor to flooding, drought and pathogen infection leading to xylem water disruption, leaf water stress and reduced net carbon gain. Still, seedlings of U. minor develop various mechanisms of acclimation to abiotic stresses that can play a role in surviving moderate periods of flood and drought. The chemical profile appears to be an important factor for the resistance of some genotypes of U. minor to DED. How abiotic stresses such as flooding and drought affect the capacity of resistant U. minor clones to face O. novo-ulmi is a key question that must be contemplated in future research.

Extracción de conocimientos de la diabetes tipo 1 utilizando la metodología de "Data Mining"

La diabetes mellitus es un trastorno en la metabolización de los carbohidratos, caracterizado por la nula o insuficiente segregación de insulina (hormona producida por el páncreas), como resultado del mal funcionamiento de la parte endocrina del páncreas, o de una creciente resistencia del organismo a esta hormona. Esto implica, que tras el proceso digestivo, los alimentos que ingerimos se transforman en otros compuestos químicos más pequeños mediante los tejidos exocrinos. La ausencia o poca efectividad de esta hormona polipéptida, no permite metabolizar los carbohidratos ingeridos provocando dos consecuencias: Aumento de la concentración de glucosa en sangre, ya que las células no pueden metabolizarla; consumo de ácidos grasos mediante el hígado, liberando cuerpos cetónicos para aportar la energía a las células. Esta situación expone al enfermo crónico, a una concentración de glucosa en sangre muy elevada, denominado hiperglucemia, la cual puede producir a medio o largo múltiples problemas médicos: oftalmológicos, renales, cardiovasculares, cerebrovasculares, neurológicos… La diabetes representa un gran problema de salud pública y es la enfermedad más común en los países desarrollados por varios factores como la obesidad, la vida sedentaria, que facilitan la aparición de esta enfermedad. Mediante el presente proyecto trabajaremos con los datos de experimentación clínica de pacientes con diabetes de tipo 1, enfermedad autoinmune en la que son destruidas las células beta del páncreas (productoras de insulina) resultando necesaria la administración de insulina exógena. Dicho esto, el paciente con diabetes tipo 1 deberá seguir un tratamiento con insulina administrada por la vía subcutánea, adaptado a sus necesidades metabólicas y a sus hábitos de vida. Para abordar esta situación de regulación del control metabólico del enfermo, mediante una terapia de insulina, no serviremos del proyecto “Páncreas Endocrino Artificial” (PEA), el cual consta de una bomba de infusión de insulina, un sensor continuo de glucosa, y un algoritmo de control en lazo cerrado. El objetivo principal del PEA es aportar al paciente precisión, eficacia y seguridad en cuanto a la normalización del control glucémico y reducción del riesgo de hipoglucemias. El PEA se instala mediante vía subcutánea, por lo que, el retardo introducido por la acción de la insulina, el retardo de la medida de glucosa, así como los errores introducidos por los sensores continuos de glucosa cuando, se descalibran dificultando el empleo de un algoritmo de control. Llegados a este punto debemos modelar la glucosa del paciente mediante sistemas predictivos. Un modelo, es todo aquel elemento que nos permita predecir el comportamiento de un sistema mediante la introducción de variables de entrada. De este modo lo que conseguimos, es una predicción de los estados futuros en los que se puede encontrar la glucosa del paciente, sirviéndonos de variables de entrada de insulina, ingesta y glucosa ya conocidas, por ser las sucedidas con anterioridad en el tiempo. Cuando empleamos el predictor de glucosa, utilizando parámetros obtenidos en tiempo real, el controlador es capaz de indicar el nivel futuro de la glucosa para la toma de decisones del controlador CL. Los predictores que se están empleando actualmente en el PEA no están funcionando correctamente por la cantidad de información y variables que debe de manejar. Data Mining, también referenciado como Descubrimiento del Conocimiento en Bases de Datos (Knowledge Discovery in Databases o KDD), ha sido definida como el proceso de extracción no trivial de información implícita, previamente desconocida y potencialmente útil. Todo ello, sirviéndonos las siguientes fases del proceso de extracción del conocimiento: selección de datos, pre-procesado, transformación, minería de datos, interpretación de los resultados, evaluación y obtención del conocimiento. Con todo este proceso buscamos generar un único modelo insulina glucosa que se ajuste de forma individual a cada paciente y sea capaz, al mismo tiempo, de predecir los estados futuros glucosa con cálculos en tiempo real, a través de unos parámetros introducidos. Este trabajo busca extraer la información contenida en una base de datos de pacientes diabéticos tipo 1 obtenidos a partir de la experimentación clínica. Para ello emplearemos técnicas de Data Mining. Para la consecución del objetivo implícito a este proyecto hemos procedido a implementar una interfaz gráfica que nos guía a través del proceso del KDD (con información gráfica y estadística) de cada punto del proceso. En lo que respecta a la parte de la minería de datos, nos hemos servido de la denominada herramienta de WEKA, en la que a través de Java controlamos todas sus funciones, para implementarlas por medio del programa creado. Otorgando finalmente, una mayor potencialidad al proyecto con la posibilidad de implementar el servicio de los dispositivos Android por la potencial capacidad de portar el código. Mediante estos dispositivos y lo expuesto en el proyecto se podrían implementar o incluso crear nuevas aplicaciones novedosas y muy útiles para este campo. Como conclusión del proyecto, y tras un exhaustivo análisis de los resultados obtenidos, podemos apreciar como logramos obtener el modelo insulina-glucosa de cada paciente. ABSTRACT. The diabetes mellitus is a metabolic disorder, characterized by the low or none insulin production (a hormone produced by the pancreas), as a result of the malfunctioning of the endocrine pancreas part or by an increasing resistance of the organism to this hormone. This implies that, after the digestive process, the food we consume is transformed into smaller chemical compounds, through the exocrine tissues. The absence or limited effectiveness of this polypeptide hormone, does not allow to metabolize the ingested carbohydrates provoking two consequences: Increase of the glucose concentration in blood, as the cells are unable to metabolize it; fatty acid intake through the liver, releasing ketone bodies to provide energy to the cells. This situation exposes the chronic patient to high blood glucose levels, named hyperglycemia, which may cause in the medium or long term multiple medical problems: ophthalmological, renal, cardiovascular, cerebrum-vascular, neurological … The diabetes represents a great public health problem and is the most common disease in the developed countries, by several factors such as the obesity or sedentary life, which facilitate the appearance of this disease. Through this project we will work with clinical experimentation data of patients with diabetes of type 1, autoimmune disease in which beta cells of the pancreas (producers of insulin) are destroyed resulting necessary the exogenous insulin administration. That said, the patient with diabetes type 1 will have to follow a treatment with insulin, administered by the subcutaneous route, adapted to his metabolic needs and to his life habits. To deal with this situation of metabolic control regulation of the patient, through an insulin therapy, we shall be using the “Endocrine Artificial Pancreas " (PEA), which consists of a bomb of insulin infusion, a constant glucose sensor, and a control algorithm in closed bow. The principal aim of the PEA is providing the patient precision, efficiency and safety regarding the normalization of the glycemic control and hypoglycemia risk reduction". The PEA establishes through subcutaneous route, consequently, the delay introduced by the insulin action, the delay of the glucose measure, as well as the mistakes introduced by the constant glucose sensors when, decalibrate, impede the employment of an algorithm of control. At this stage we must shape the patient glucose levels through predictive systems. A model is all that element or set of elements which will allow us to predict the behavior of a system by introducing input variables. Thus what we obtain, is a prediction of the future stages in which it is possible to find the patient glucose level, being served of input insulin, ingestion and glucose variables already known, for being the ones happened previously in the time. When we use the glucose predictor, using obtained real time parameters, the controller is capable of indicating the future level of the glucose for the decision capture CL controller. The predictors that are being used nowadays in the PEA are not working correctly for the amount of information and variables that it need to handle. Data Mining, also indexed as Knowledge Discovery in Databases or KDD, has been defined as the not trivial extraction process of implicit information, previously unknown and potentially useful. All this, using the following phases of the knowledge extraction process: selection of information, pre- processing, transformation, data mining, results interpretation, evaluation and knowledge acquisition. With all this process we seek to generate the unique insulin glucose model that adjusts individually and in a personalized way for each patient form and being capable, at the same time, of predicting the future conditions with real time calculations, across few input parameters. This project of end of grade seeks to extract the information contained in a database of type 1 diabetics patients, obtained from clinical experimentation. For it, we will use technologies of Data Mining. For the attainment of the aim implicit to this project we have proceeded to implement a graphical interface that will guide us across the process of the KDD (with graphical and statistical information) of every point of the process. Regarding the data mining part, we have been served by a tool called WEKA's tool called, in which across Java, we control all of its functions to implement them by means of the created program. Finally granting a higher potential to the project with the possibility of implementing the service for Android devices, porting the code. Through these devices and what has been exposed in the project they might help or even create new and very useful applications for this field. As a conclusion of the project, and after an exhaustive analysis of the obtained results, we can show how we achieve to obtain the insulin–glucose model for each patient.

Natural trans-splicing in carnitine octanoyltransferase pre-mRNAs in rat liver

Carnitine octanoyltransferase (COT) transports medium-chain fatty acids through the peroxisome. During isolation of a COT clone from a rat liver library, a cDNA in which exon 2 was repeated, was characterized. Reverse transcription-PCR amplifications of total RNAs from rat liver showed a three-band pattern. Sequencing of the fragments revealed that, in addition to the canonical exon organization, previously reported [Choi, S. J. et al. (1995) Biochim. Biophys. Acta 1264, 215–222], there were two other forms in which exon 2 or exons 2 and 3 were repeated. The possibility of this exonic repetition in the COT gene was ruled out by genomic Southern blot. To study the gene expression, we analyzed RNA transcripts by Northern blot after RNase H digestion of total RNA. Three different transcripts were observed. Splicing experiments also were carried out in vitro with different constructs that contain exon 2 plus the 5′ or the 3′ adjacent intron sequences. Our results indicate that accurate joining of two exons 2 occurs by a trans-splicing mechanism, confirming the potential of these structures for this process in nature. The trans-splicing can be explained by the presence of three exon-enhancer sequences in exon 2. Analysis by Western blot of the COT proteins by using specific antibodies showed that two proteins corresponding to the expected Mr are present in rat peroxisomes. This is the first time that a natural trans-splicing reaction has been demonstrated in mammalian cells.

Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression

The signal transducer and activator of transcription, STAT5b, has been implicated in signal transduction pathways for a number of cytokines and growth factors, including growth hormone (GH). Pulsatile but not continuous GH exposure activates liver STAT5b by tyrosine phosphorylation, leading to dimerization, nuclear translocation, and transcriptional activation of the STAT, which is proposed to play a key role in regulating the sexual dimorphism of liver gene expression induced by pulsatile plasma GH. We have evaluated the importance of STAT5b for the physiological effects of GH pulses using a mouse gene knockout model. STAT5b gene disruption led to a major loss of multiple, sexually differentiated responses associated with the sexually dimorphic pattern of pituitary GH secretion. Male-characteristic body growth rates and male-specific liver gene expression were decreased to wild-type female levels in STAT5b−/− males, while female-predominant liver gene products were increased to a level intermediate between wild-type male and female levels. Although these responses are similar to those observed in GH-deficient Little mice, STAT5b−/− mice are not GH-deficient, suggesting that they may be GH pulse-resistant. Indeed, the dwarfism, elevated plasma GH, low plasma insulin-like growth factor I, and development of obesity seen in STAT5b−/− mice are all characteristics of Laron-type dwarfism, a human GH-resistance disease generally associated with a defective GH receptor. The requirement of STAT5b to maintain sexual dimorphism of body growth rates and liver gene expression suggests that STAT5b may be the major, if not the sole, STAT protein that mediates the sexually dimorphic effects of GH pulses in liver and perhaps other target tissues. STAT5b thus has unique physiological functions for which, surprisingly, the highly homologous STAT5a is unable to substitute.

Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1

SOCS-1, a member of the suppressor of cytokine signaling (SOCS) family, was identified in a genetic screen for inhibitors of interleukin 6 signal transduction. SOCS-1 transcription is induced by cytokines, and the protein binds and inhibits Janus kinases and reduces cytokine-stimulated tyrosine phosphorylation of signal transducers and activators of transcription 3 and the gp130 component of the interleukin 6 receptor. Thus, SOCS-1 forms part of a feedback loop that modulates signal transduction from cytokine receptors. To examine the role of SOCS-1 in vivo, we have used gene targeting to generate mice lacking this protein. SOCS-1−/− mice exhibited stunted growth and died before weaning with fatty degeneration of the liver and monocytic infiltration of several organs. In addition, the thymus of SOCS-1−/− mice was reduced markedly in size, and there was a progressive loss of maturing B lymphocytes in the bone marrow, spleen, and peripheral blood. Thus, SOCS-1 is required for in vivo regulation of multiple cell types and is indispensable for normal postnatal growth and survival.

Lipotoxic heart disease in obese rats: Implications for human obesity

To determine the mechanism of the cardiac dilatation and reduced contractility of obese Zucker Diabetic Fatty rats, myocardial triacylglycerol (TG) was assayed chemically and morphologically. TG was high because of underexpression of fatty acid oxidative enzymes and their transcription factor, peroxisome proliferator-activated receptor-α. Levels of ceramide, a mediator of apoptosis, were 2–3 times those of controls and inducible nitric oxide synthase levels were 4 times greater than normal. Myocardial DNA laddering, an index of apoptosis, reached 20 times the normal level. Troglitazone therapy lowered myocardial TG and ceramide and completely prevented DNA laddering and loss of cardiac function. In this paper, we conclude that cardiac dysfunction in obesity is caused by lipoapoptosis and is prevented by reducing cardiac lipids.

Infusion of α-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease

Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (α-gal A). This enzymatic defect results in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3; also referred to as ceramidetrihexoside) throughout the body. To investigate the effects of purified α-gal A, 10 patients with Fabry disease received a single i.v. infusion of one of five escalating dose levels of the enzyme. The objectives of this study were: (i) to evaluate the safety of administered α-gal A, (ii) to assess the pharmacokinetics of i.v.-administered α-gal A in plasma and liver, and (iii) to determine the effect of this replacement enzyme on hepatic, urine sediment and plasma concentrations of Gb3. α-Gal A infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified α-gal A in several cell types, including sinusoidal endothelial cells, Kupffer cells, and hepatocytes, suggesting diffuse uptake via the mannose 6-phosphate receptor. The tissue half-life in the liver was greater than 24 hr. After the single dose of α-gal A, nine of the 10 patients had significantly reduced Gb3 levels both in the liver and shed renal tubular epithelial cells in the urine sediment. These data demonstrate that single infusions of α-gal A prepared from transfected human fibroblasts are both safe and biochemically active in patients with Fabry disease. The degree of substrate reduction seen in the study is potentially clinically significant in view of the fact that Gb3 burden in Fabry patients increases gradually over decades. Taken together, these results suggest that enzyme replacement is likely to be an effective therapy for patients with this metabolic disorder.

Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease

For many inborn errors of metabolism, early treatment is critical to prevent long-term developmental sequelae. We have used a gene-therapy approach to demonstrate this concept in a murine model of mucopolysaccharidosis type VII (MPS VII). Newborn MPS VII mice received a single intravenous injection with 5.4 × 106 infectious units of recombinant adeno-associated virus encoding the human β-glucuronidase (GUSB) cDNA. Therapeutic levels of GUSB expression were achieved by 1 week of age in liver, heart, lung, spleen, kidney, brain, and retina. GUSB expression persisted in most organs for the 16-week duration of the study at levels sufficient to either reduce or prevent completely lysosomal storage. Of particular significance, neurons, microglia, and meninges of the central nervous system were virtually cleared of disease. In addition, neonatal treatment of MPS VII mice provided access to the central nervous system via an intravenous route, avoiding a more invasive procedure later in life. These data suggest that gene transfer mediated by adeno-associated virus can achieve therapeutically relevant levels of enzyme very early in life and that the rapid growth and differentiation of tissues does not limit long-term expression.

Regulation of fatty acid homeostasis in cells: Novel role of leptin

It is proposed that an important function of leptin is to confine the storage of triglycerides (TG) to the adipocytes, while limiting TG storage in nonadipocytes, thus protecting them from lipotoxicity. The fact that TG content in nonadipocytes normally remains within a narrow range, while that of adipocytes varies enormously with food intake, is consistent with a system of TG homeostasis in normal nonadipocytes. The facts that when leptin receptors are dysfunctional, TG content in nonadipocytes such as islets can increase 100-fold, and that constitutively expressed ectopic hyperleptinemia depletes TG, suggest that leptin controls the homeostatic system for intracellular TG. The fact that the function and viability of nonadipocytes is compromised when their TG content rises above or falls below the normal range suggests that normal homeostasis of their intracellular TG is critical for optimal function and to prevent lipoapoptosis. Thus far, lipotoxic diabetes of fa/fa Zucker diabetic fatty rats is the only proven lipodegenerative disease, but the possibility of lipotoxic disease of skeletal and/or cardiac muscle may require investigation, as does the possible influence of the intracellular TG content on autoimmune and neoplastic processes.

Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice

Fabry disease is an X-linked metabolic disorder caused by a deficiency of α-galactosidase A (α-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with α-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated α-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of α-Gal A −/0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of α-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease.