BACKGROUND: Obesity is a global health problem that is associated with wide range of diseases, including atherosclerosis and Nonalcoholic fatty liver (NAFL) disease. Hepatic inflammation can cause cirrhosis, hepatic decompensation (liver failure) and cancer. Recent research now looks at the chronic systemic effects and inter-organ communication between atherosclerosis potentially promoting the development of NAFL. The resolution of inflammation is regulated naturally in the body by specialized pro-resolving mediators (SPMs). Immunoresolvents like ⍹6-derived Lipoxin A4 are suggested as a therapeutic strategy to overcome chronic inflammation and disease. In this study we investigated the therapeutic potential of Lipoxin A4 (LXA4) in cholesterol fed rabbit model of hypercholesterolemia, with atherosclerotic plaques and confined vascular endothelial injury and its effect on the progression of NAFL. OBJECTIVE: This is a continuation of studies pioneered in the Hamilton lab and an extension of the recent study by Taylor et. al in 201811 linking aortic plaque and liver disease. We will now investigate the therapeutic potential of Lipoxin A4 on lipid-rich atherosclerotic plaques in cholesterol fed rabbits and its effect on the progression of NAFL to NASH. METHODS: In vivo magnetic resonance imaging (MRI) measured aortic atherosclerotic inflammation (with plaque Gd-enhancement), plaque size (vessel wall area), and composition, within rabbits fed normal chow or a 1% cholesterol-enriched diet. Biomarkers in the blood were monitored in the rabbits, with follow-up by histology, which included Masson’s trichrome staining. Light Microscopy was used for liver imaging. Ex vivo MRI, T1W imaging was used to quantify VWA (vessel wall area), with Image J programming. RESULTS: Cholesterol-fed rabbits with and without aortic injury developed hypercholesterolemia, NAFL, and atherosclerotic plaques in the aorta. Elevated plasma gamma-glutamyl transferase (GGT; p =0.014) and the ratio of liver enzymes aspartate and alanine aminotransferases (AST/ALT; p = 0.033) confirmed the progression of steatosis to non-alcoholic steatohepatitis (NASH). Histological images showed less fibrosis in those rabbits fed 1% CHOL diet with injury treated with LipoxinA4, when compared to 1% CHOL diet and injury alone. The plasma biomarkers showed a decrease in cholesterol (79%) and triglycerides (49.9%) in those rabbits given LXA4 therapy. The LXA4 treated 1% CHOL diet with injury group showed a marked decrease in the aorta vessel wall area when compared to the 1% CHOL diet with injury, without treatment; as seen in ex vivo, MRI T1W imaging. CONCLUSION: Lipoxin implementation in cholesterol fed rabbits that have localized regions of highly inflamed aortic atherosclerotic plaques, may contribute to the attenuation on the progression of NAFL to NASH as seen in histology and plasma biomarkers including; cholesterol and triglycerides. Lipoxin as a therapeutic has an effect on treating atherosclerotic plaques and attenuating atherosclerosis progression.

A Dissertation submitted to the Faculty of Arts, UNIVERSITY OF ZULULAND In partial fulfilment for the degree MASTER OF ARTS IN CLINICAL PSYCHOLOGY in the Department of Psychology, 1988. / The researcher's aim in this study was to identify and compare the attitudes of adolescents, parents and grandparents towards three adolescent problem variables. The researcher's point of departure was to review relevant literature on the generation gap phenomenon, adolescent premarital sexual relations, delinquent behaviour and the use of alcoholic beverages. A. Likert-type scale was constructed to measure the attitudes of adolescents, parents and grandparents towards adolescent premarital sexual relations) delinquent behaviour and use of alcoholic beverages. Three samples comprising 30 adolescents, 30 parents and 30 grandparents were randomly selected from the seven wards/ sections of the 42 Hill Location, Harrismith. Respondents were from the Zulu, South-Sotho, Tswana .and Xhosa ethnic groups. Illiterate and educated subjects were included in the study. The t-test and Chi-Square (ifi test results highlighted significant differences between the attitudes of adolescents and parents towards premarital sexual relations. The differences between the attitudes of adolescents and those of grandparents towards this variable were also significant:. The attitudes of parents and grandparents towards premarital sexual relations were not significantly different. These findings tended to support previous research studies which stated that parents and grandparents were traditionally more conservative in their attitude towards sexuality than were adolescents. Modern adolescents who lived in a society where sex was discussed more openly seemed to feel that they should engage in premarital sexual relations. It seemed the generation gap between adolescents and parents,and to a greater extent between adolescent and grandparent, had increased. Results indicated insignificant differences between the attitudes of adolescents, parents and grandparents towards adolescent delinquent behaviour. All three generations seemed to agree that modern adolescents acquired much information from their friends. In a modern rapidly changing South African society, traditional authority seemed to have lost most of its impact on the adolescent's bahaviour. Adolescents seemed to believe that parents had failed to change the socio¬political situation hence they had to take the lead. Parents themselves seemed to be puzzled and confused by the rapidly changing, contemporary, technocratic and violently divided society. Significant differences between the adolescent and parent attitudes and between adolescent and grandparent attitudes towards adolescent use of alcoholic beverages were indicated in this study. The insignificant differences between the attitudes of parents and grandparents towards this variable seemed to indicate that parents and grandparents were against adolescent use of alcoholic beverages. On the other hand, adolescents seemed to feel that they should indulge in drinking alcoholic beverages. In the modern South African society, adolescents saw liquor advertised on television and in literature and thus indulged in drinking alcoholic beverages. It was recommended that whatever the desired politico-social change, both parents and adolescents could be made aware that communication and dialogue between them are a sine-qua-non towards the solution and alleviation of their problems. Parents may be motivated to discuss with adolescents their views and feelings about premarital sexual relations and vice versa. The dialogue could be encouraged in public meetings, seminars, on television and radio. Parents could be encouraged to listen to the views of adolescents in order to guide them. Parents may be made to accept the fact that adolescents live during a time and in a society where they may express both their positive and negative opinions regarding certain issues. Community programmes such as therapeutic groups, youth clubs and recreation clubs could provide adolescents with an opportunity of expressing their views, developing their social skills and improving relationships with others. Information concerning problems that are associated with the use of alcoholic beverages could be made available to adolescents during the discussions and advertisements. The aim could be to assist adolescents to cope with problems and to feel happy without indulging in drinking alcoholic beverages.

Actualmente en Lima Metropolitana, 7 de cada 10 personas consumen bebidas alcohólicas como la cerveza y el trago corto. Este hecho origina que casi el 90% de estas personas padezcan resaca por alcohol, producto de la ingesta excesiva y/o la mezcla de estas bebidas, originando malestar general acompañado de dolor de cabeza, náuseas, mareos y dolor estomacal. Los momentos más frecuentes de consumo que se presentan son los fines de semana, festividades, feriados y fines de mes. Los consumos de las bebidas alcohólicas se presentan en su mayoría en reuniones, fiestas, integraciones familiares, amicales y de trabajo. Para solucionar esta problemática identificada hemos creado R-BORN, una Bebida hecha a base de insumos naturales, teniendo como propuesta de valor principal aliviar el malestar y mitigar los síntomas de la resaca con productos naturales. Esta bebida está hecha a base de tres frutas, las cuales son la tuna, piña y coco, debido a sus componentes y propiedades que permiten contrarrestar los efectos del alcohol. Nuestro producto va dirigido para hombres y mujeres mayores de 18 años hasta los 39 años de edad, que pertenezcan a un nivel socioeconómico A y B, que padezcan el malestar de resaca producto de la ingesta excesiva de bebidas alcohólicas y prefieran combatirla con un producto hecho a base de insumos naturales. Nuestro tamaño de mercado estimado es de 390,378 personas. Asimismo, este producto será comercializado a través de los siguientes canales de ventas: bodegas, ferias saludables, sitio web, redes sociales y venta directa. / Currently in Lima Metropolitan 7 out of 10 people, consume alcoholic beverages such as beer and short drink. This fact results in almost 90% of these people developing alcohol hangover caused by an excessive intake and/or the mixture of these drinks, producing general discomfort accompanied by headache, nausea, dizziness and stomach pain. The most frequent times of consumption that occur are weekends, holidays and weekends. Consumption of alcoholic beverages are the mostly presented in meetings, parties, and family, amical and work integrations. To solve this identified problem we have created R-BORN, a drink made from natural inputs having as its main value proposition to alleviate the discomfort and mitigate hangover symptoms with natural products. This drink is made from three fruits, which are tuna, pineapple and coconut because of its components, and properties that counteract the effects of alcohol. Our product is aimed at men and women over the age of 18 up to the age of 39 who belong to a socioeconomic level A and B who suffer from hangover discomfort resulting from excessive alcoholic beverages and preferring to fight it with a product made from natural supplies. Our estimated market size is 390,378 people. In addition, this product will be marketed through the following sale’s channels: grocery stores, healthy food fairs, website, social networks and direct selling. / Trabajo de investigación

Actualmente, el consumo de bebidas alcohólicas es cada vez más frecuente, ya que se pronostican incrementos en 10% para los próximos años en la industria. Asimismo, este mercado posee una gran acogida en horarios nocturnos. Sin embargo, las licorerías como tiendas retail no pueden abastecer en horarios de madrugada, ya que la venta de estas se encuentra prohibida pasada las 11:00 pm, según norma legal, por lo que muchos clientes deben comprar estos productos horas previas a iniciar un evento o bien se les hace imposible encontrar un establecimiento abierto con disponibilidad de vender estas bebidas. Lo que puede generar incomodidad por no continuar la reunión como esperaban. Es así que el presente proyecto, aborda esta problemática enfocándose en personas jóvenes entre las edades de 18 – 39 años de los NSE A y B que residan en Lima Metropolitana. Mediante un servicio de entrega de bebidas alcohólicas en los horarios de jueves a sábado de 09:00 pm a 04:00 am. El equipo de trabajo escoge este público objetivo, ya que este posee la capacidad adquisitiva para pagar los precios establecidos por Sr. Shot y se encuentra a la vanguardia de la tecnología del comercio electrónico para estar en contacto con alguno de los canales de venta del negocio. Para la inversión inicial se requerirá del aporte de S/ 42,396 por parte de los accionistas, donde se recibirá un COK del 14.73% con un retorno de la inversión a partir del tercer año. / Nowadays, the consumption of alcoholic drinks are more frequently, as increases of 10% were predicted for the coming years in the industry. In addition, this market has a great reception at night hours. However, liquor stores such as retail stores cannot supply at dawn hours because the sale of them are prohibited after 11:00 pm, according to legal regulations, so many customers must buy those products before starting an event or they find it impossible to find an open establishment with availability to sell these drinks. What it can generate discomfort for not continuing the meeting how people expected. Thus, this project takes in consideration this problem focusing in young people between the ages of 18 - 39 years of socioeconomic level A and B residing in Metropolitan Lima. Through a service delivery of alcoholic drinks in the hours from Thursday to Saturday from 09:00 pm to 04:00 am. The work team chooses this target because it has the purchasing power to pay established prices of “Sr. Shot” and is at the forefront of E-commerce technology to be in contact with any of the sales channels of the business. For the initial investment, a contribution of S/. 137,722 will be required from the shareholders, where a COK of 14.73% will be received with a return on investment from the third year. / Trabajo de investigación

Indiana University-Purdue University Indianapolis (IUPUI) / CXXC finger protein 1 (CFP1) is an epigenetic regulator of H3K4 and cytosine methylation. Due to its role in establishing and maintaining methylation patterns, CFP1 determines whether DNA is found in its euchromatin or heterochromatin state and as such whether genes are transcriptionally active or inactive. In stem cells, deficiency of CFP1 results in inability to differentiate and in murine embryos it results in periimplantation death. Despite the demonstrated importance in developing tissue, the role of CFP1 in mature tissues, such as the liver, has yet to be elucidated. This study examined the role of CFP1 in maintaining liver homeostasis under conditions involving hepatocellular stress by examining liver regeneration, pregnancy-induced hepatomegaly, and non-alcoholic steatohepatitis (NASH) disease progression. The liver’s ability to recover was analyzed through liver:body mass ratios, blood serum analysis, liver histology, and qualitative observations. Deficiency of CFP1 in the livers of animals subjected to partial hepatectomies (PH) resulted in decreased liver regeneration capacity with liver mass restoration becoming significantly different starting at 48H post-PH and remaining so until 10D post-PH. This decreased regeneration appeared to be the result of reduced hepatocyte mitosis. Mouse dams lacking hepatic CFP1 mated with males expressing CFP1 displayed a proclivity for dystocia. Mice subjected to a fast food diet resulting in NASH while lacking hepatic CFP1 experienced decreased weight gain and hepatic lipid accumulation compared to their CFP1 expressing counterparts. Through these three studies, the critical role of CFP1 for the maintenance of liver homeostasis was demonstrated.

Indiana University-Purdue University Indianapolis (IUPUI) / This thesis explores a minimally invasive approach of diagnosing Non-Alcoholic Fatty Liver disease (NAFLD) on mice and humans which can be useful for pathologists while performing their diagnosis. NAFLD is a spectrum of diseases going from least severe to most severe – steatosis, steatohepatitis, fibrosis and finally cirrhosis. This disease primarily results from fat deposition in the liver which is unrelated to alcohol or viral causes. In general, it affects individuals having a combination of at least three of the five metabolic syndromes namely, obesity, hypertension, diabetes, hypertriglyceridemia, and hyperlipidemia. Given how common these metabolic syndromes have become, the rate of NAFLD has increased dramatically over the years affecting about three-quarters of all obese individuals including many children, making it one of the most common diseases in United States. Our study focuses on building various computational models which help identify different histological features in a liver biopsy image, thereby analyzing if a person is affected by NAFLD or not. Here, we develop and validate the performance of automated classifiers built using image processing and machine learning methods for detection of macro- and microsteatosis, lobular and portal inflammation and also categorize different types fibrosis in murine and human fatty liver disease and study the correlation of automated quantification of macrosteatosis, lobular and portal inflammation, and fibrosis (amount of collagen) with expert pathologist’s semi-quantitative grades. Our research for macrosteatosis and microsteatosis prediction shows the model’s precision and sensitivity as 94.2%, 95% for macrosteatosis and 79.2%, 77% for microsteatosis. Our models detect lobular and portal inflammation(s) with a precision, sensitivity of 79.6%, 77.1% for lobular inflammation and 86%, 90.4% for portal inflammation. We also present the first study on identification of the six different types of fibrosis having a precision of 85.6% for normal fibrosis and >70% for portal fibrosis, periportal fibrosis, pericellular fibrosis, bridging fibrosis and cirrhosis. We have also quantified the amount of collagen in a liver biopsy and compared it to the pathologist semi-quantitative fibrosis grade.

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No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Risk of coronary artery disease (CAD), the leading cause of death, greatly increases in metabolic syndrome. Metabolic syndrome (MetS; obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension) is increasing in prevalence with sedentary lifestyles and poor nutrition. Non-alcoholic steatohepatitis (NASH; i.e. MetS liver) is progressive and decreases life expectancy, with CAD as the leading cause of death. Pathogenic Ca2+ regulation transforms coronary artery smooth muscle from a healthy, quiescent state to a diseased, proliferative phenotype thus majorly contributing to the development of CAD. In particular, store-operated Ca2+ entry (SOCE) in vascular smooth muscle is associated with atherosclerosis. Genetic predisposition may render individuals more susceptible to Ca2+ dysregulation, CAD, NASH, and MetS. However, the metabolic and cellular mechanisms underlying these disease states are poorly understood. Accordingly, the goal of this dissertation was to investigate the role of dyslipidemia within MetS in the development of Ca2+ dysregulation, CAD, and NASH. The overarching hypothesis was that dyslipidemia within MetS would be necessary for induction of NASH and increased SOCE that would primarily mediate development of CAD. To test this hypothesis we utilized the Ossabaw miniature swine model of MetS. Swine were fed one of five diets for different lengths of time to induce varying severity of MetS. Lean swine were fed normal maintenance chow diet. F/MetS swine were fed high Fructose (20% kcal) diet that induced normolipidemic MetS. TMetS were fed excess high Trans-fat/cholesterol atherogenic diet that induced mildly dyslipidemic MetS and CAD. XMetS were TMetS swine with eXercise. DMetS (TMetS + high fructose) were moderately dyslipidemic and developed MetS and extensive CAD. sDMetS (Short-term DMetS) developed MetS with mild dyslipidemia, but no CAD. MMetS (Mixed-source-fat/cholesterol/fructose) were severely dyslipidemic, exhibited NASH, and developed severe CAD. Dyslipidemia in MetS predicted NASH severity (all groups < DMetS << MMetS), CAD severity (i.e. Lean, F/MetS, sDMetS < XMetS < TMetS < DMetS < MMetS), and was necessary for STIM1/TRPC1-mediated SOCE, which preceded CAD. Exercise ameliorated SOCE and CAD compared to TMetS. In conclusion, dyslipidemia elicits TRPC1/STIM1 SOCE that mediates CAD, is necessary for and predictive of NASH and CAD, and whose affects are attenuated by exercise.

Resistance exercise (RE) training is a well-known and effective method for promoting increases in muscle mass and strength. A single bout of RE induces physiological disturbances that require coordinated activation of the immune system and intramuscular signaling in order to return the tissue to homeostasis and adapt to the RE challenge. On the other hand, acute binge alcohol consumption can affect the immune response to an inflammatory challenge, intramuscular anabolic signaling, and muscle protein synthesis, and the effects of alcohol on these processes are opposite that of RE. Furthermore, individuals who report more frequent exercise also report a greater frequency of binge drinking. However, few investigations exist regarding the effects of binge alcohol consumed after a bout of RE on RE-induced physiological changes and performance recovery. Therefore, the overarching purpose of the investigations contained within this dissertation was to investigate the effect of alcohol consumed after RE on the RE-induced changes in mTOR pathway signaling, muscle protein synthesis, inflammatory capacity, strength recovery, and power recovery. Although RE increased mTOR pathway signaling and inflammatory capacity after exercise and reduced maximal strength and explosive power the day after exercise, we observed no effects of alcohol (1.09 g ethanol∙kg-1 lean body mass, designed to result in a peak blood alcohol concentration of approximately 0.12 g∙dl-1) consumed after RE on mTOR pathway signaling, 24-hour rates of muscle protein synthesis, inflammatory capacity, or strength and power recovery in resistance-trained individuals.