Body weight in mammals is defended so that small changes in weight evoke neuroendocrine and metabolic responses that encourage a return to one’s previous weight. While these homeostatic responses have been more commonly studied in the case of weight loss, our lab has developed a mouse model of overfeeding to study the physiology of defense against weight gain. In response to overfeeding-induced weight gain, the return to previous body weight is mediated primarily by a striking reduction in food intake, which persists until pre-overfeeding body weight is restored. However, preliminary data do not suggest activation of anorectic POMC neurons which reduce food intake or inhibition of the appetite stimulating AgRP or NPY neurons in the arcuate nucleus of the hypothalamus. Furthermore, we found that adipose tissue from overfed mice does not show the same inflammatory response as mice that have become obese slowly due to ad libitum high-fat diet (HFD) consumption. Paradoxically, despite the existence of mammalian systems that defend against weight gain, average body weight in humans has been on the rise over the last half century. Concomitant with the rise in obesity rates, has been increasing availability and consumption of processed and fast foods which are generally high in sugar, salt, and fat making them extremely palatable and calorically dense. Both the caloric density and enticing taste of the foods have been implicated in causing overconsumption and contributing to a rise in average body weight and prevalence of obesity. Thus, while controlling for caloric density we have investigated whether diet palatability can increase body weight and suppress defense against weight gain in mice. We designed our studies so that all diets were of the same caloric density and therefore varied only proportion of calories derived from fats, carbohydrates, and protein. Palatability is the relative subjective preference of one food over another; in our mouse studies we equated preference, when given, a choice with palatability. We confirmed that liquid diets sweetened with sucrose or the non-nutritive sweeteners sucralose and saccharin were preferred over non-sweetened diets. In 12 day feeding studies, although we found that sweetened diets were more palatable than unsweetened diets, they did not increase caloric intake or body weight. Next, we tested whether increasing percent calories from fat leads to increases in palatability or caloric intake. In a similar 12 day feeding preference study, we found diets higher in percent calories from fat (high-fat diet = HFD) were preferred to diets with lower percent calories from fat (low-fat diet = LFD) and that the access to a HFD increased caloric intake and body weight. Employing a four-week single diet feeding study, we also found a linear relationship between percent calories from fat and caloric intake consistent with our hypothesis that percent calories from fat is sensed and modulates caloric intake. To test whether HFD can suppress defense of body weight, we used an overfeeding paradigm which I help develop, to test whether ad libitum access to a HFD prevented a return to the original body weight following overfeeding. HFD did attenuate the hypophagic response to overfeeding and prevented a return to each mouse’s initial weight with the mice having access to the HFD mice stabilizing at a higher body weight. Palatability has traditionally been ascribed to sensing of smell and taste, however, macronutrients can also be sensed within intestinal tract. To determine whether the effects of percent calories from fat require naso-oral sensing to modulate feeding behavior, we used an intragastric feeding system to bypass taste and smell and deliver HFD directly into the stomach of mice. Even in the absence of oropharyngeal sensing, HFD in the gut was sufficient to increase ad libitum caloric intake of a low-fat diet and increase body weight. Finally, based on our findings of post-oral fat sensing driving caloric intake, we tested whether post-oral sensing of percent calories from fat was sufficient to condition a flavor preference. However, we found that when caloric density was controlled, a high percent calories from fat was not sufficient to condition a flavor preference.

Contexte : Le tabagisme actif et passif, la pollution atmosphérique, le radon, les expositions professionnelles à certains agents chimiques tels que l’amiante, la silice cristalline, les hydrocarbures aromatiques polycycliques sont des facteurs de risque établis du cancer du poumon. De plus, certains facteurs alimentaires comme la faible consommation de fruits et de légumes ont été associés à une augmentation de risque de cancer du poumon. Des études épidémiologiques antérieures consacrées à l’étude de l’association entre le cancer du poumon et d’autres expositions comme la consommation de café et l’indice de masse corporelle (IMC) ont été peu concluantes.Objectif : L’objectif de ce travail est d’étudier l’association entre la consommation de café, l’IMC et le risque de cancer du poumon.Matériels et Méthodes : L’étude du rôle du café dans la survenue du cancer du poumon s’est basée sur les données d’une étude cas-témoins en population générale de grande envergure, l’étude ICARE. Les analyses concernaient 2 684 cas de cancer du poumon et 3 481 témoins. Une description détaillée de la consommation de café a été recueillie à l’aide de questionnaires standardisés réalisés au cours d’entretiens en face à face. L’étude de l’association entre l’IMC et le risque de cancer du poumon s’est basée sur une étude cas-témoins nichée dans quatre cohortes aux Etats-Unis, en Europe, en Chine et à Singapour, incluant 4 172 cas de cancer du poumon et 8 471 témoins. L’IMC a été calculé à partir de du poids et de la taille mesurés ou auto-déclarés à l’inclusion. Les Odds ratios (ORs) et les intervalles de confiance à 95% (IC) ont été estimés à l’aide de la régression logistique non conditionnelle, en ajustant sur les facteurs de confusion potentiels.Résultats : Nous n’avons pas observé d’association entre la consommation de café et le risque de cancer du poumon. Les ORs ajustés étaient de l’ordre de 1,07 (0,77-1,48) pour une consommation ≥ 5 tasses/jour, de 1,02 (0,72-1,43) pour une durée de consommation ≥ 49 ans et de 1,02 (0,73-1,42) pour une consommation cumulée vie entière ≥ 184 tasses-années par rapport aux non consommateurs. L’étude cas-témoins nichée dans les 4 cohortes a montré une association inverse significative entre l’IMC et le risque de cancer du poumon. Les ORs ajustés pour les sujets en surpoids (IMC, 25-30 kg/m2) et les sujets obèses (IMC ≥30 kg/m2) étaient respectivement de 0,77 (0,68-0,86) et de 0.69 (0,59-0,82) en comparaison avec les par rapport aux/comparés aux sujets de poids normal (IMC, 18,5-24,9 kg/m2). Cette association était accentuée chez les anciens et actuels fumeurs.Conclusions : La consommation de café ne semble pas être associée au risque de cancer du poumon. L’obésité est associée à une réduction de risque de cancer du poumon, particulièrement chez les anciens et les actuels fumeurs. / Context: Smoking, second-hand smoke, air pollution, radon, and occupational exposure to chemical agents such as asbestos, silica and polycyclic aromatic hydrocarbons are well-known risk factors for lung cancer. In addition, dietary factors involving low intake of vegetables and fruits has been associated with an increased risk of lung cancer. Previous epidemiological studies on the association between lung cancer with other exposures such as coffee intake and body mass index (BMI) have been inconclusive.Objective: The aim of the present work is to investigate the association between coffee consumption and BMI and risk of lung cancer.Materials and Methods: The work on coffee was based on a large French population based case-control study, the ICARE study. Analyses involved 2,684 lung cancer cases and 3,481 controls. Detailed information on coffee was collected using standardized questionnaires through face-to-face interviews. For BMI, a case-control study was nested within four cohorts in USA, Europe, China and Singapore, which included 4,172 lung cancer cases and 8,471 controls. BMI was calculated based on the measured/self-reported height and weight at the baseline. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression, adjusting for potential confounders.Results: We found no significant association between coffee consumption and lung cancer risk. The adjusted OR was 1.07 (95%-CI: 0.77-1.48) for ≥ 5 cups /day, 1.02 (95%-CI: 0.72-1.43) for duration of consumption ≥49 years and 1.02 (95%-CI: 0.73-1.42) for life time cumulative consumption ≥184 cup-years compared with never consumers. In the analysis of nested case-control study, we found statistically significant inverse association between BMI and lung cancer risk. Compared with normal weight subjects (BMI, 18.5-24.9 kg/m2), the adjusted OR for overweight (BMI, 25-30 kg/m2) and obese subjects (BMI, ≥30 kg/m2) were 0.77 (95% CI: 0.68-0.86) and 0.69 (95% CI: 0.59-0.82) respectively. This association was strengthened in both current and former smokers.Conclusions: Coffee consumption does not appear to be associated to the risk of lung cancer. Obesity is associated with decreased lung cancer risk, particularly in former and current smokers.

v AJ: This thesis deals with the subject of anemia. The theoretical part of the Master's thesis is concerned with an overview of the well-known types of anemia, their etiology, diagnostics, symptoms and treatment. The practical part observes the awareness of the issue within the non-medical sanitary staff working at the intensive care units without professional supervision. The data will be collected in the form of structured questionnaires filled by a selected group of respondents. The thesis is, in the outcome, an educational material that can be used for comprehensive understanding of this issue in the adaptation process. The results of the research will be processed into tables with graphs. They will be summarized in the discussion as well as in the conclusion.

The diploma thesis focuses on the elaboration of proposals for materials for clients of the Aphasia Club, which were used in group therapy. The diploma thesis is divided into theoretical and practical part. The theoretical part contains three main chapters, in which the concept of aphasia is defined, the symptomatology and etiology of this imaired communication ability are described. Then are listed possible classifications of aphasia, available tests for diagnosis and directions in the therapy of aphasia. The practical parts sets the main goal of the thesis, together with three research questions. As research methods were chosen case studies, which were prepared on the basis of medical reports of individual clients of the Aphasia Club. With information of medical reports were created materials for group therapies of Aphasia Club. The materials were used in group therapies. Using method of observation, research questions focused on the use of materials, their modification and practical signifikance in the development of impaired communication functions were subsequently answered.

This thesis records a series of experiments conducted to gain further insight into factors which influence the expression, ligand binding and functional activity of the beta-2 adrenergic receptor. These studies were prompted by previous reports that the postulated beta-2 adrenergic receptor abnormality in allergic asthma could be induced, induced by autoantibodies. I established and optimised beta-2 adrenergic receptor ligand binding and functional assays in guinea pig lung membranes and then conducted an original study of beta adrenergic receptor expression in the guinea pig foetal lung. I found that beta adrenergic receptor expression in the foetal lung was dormant for 80% of the gestation period. After day 53 there was a surge in receptor expression which increased beyond term.

Amyloids are fibrous protein aggregates associated with age-related diseases, such as Alzheimer’s disease and Parkinson’s disease. The role of amyloids in the etiology of neurodegeneration is debatable, but genetic and molecular evidence supports a causative relationship between amyloidogenesis and disease. Amyloidogenic proteins are constitutively expressed throughout the lifespan of an organism, and yet only become pathogenic in certain situations. This led to a hunt to understand how amyloidogenic proteins could be modified in order to become aggregation-prone. One possibility that has garnered attention is phosphorylation, primarily because several amyloid aggregates such as tau and α-synuclein are often highly phosphorylated in disease. However, the contribution of phosphorylation to disease progression remains unclear.While amyloid aggregates are typically described as irreversible and pathogenic, some cells utilize reversible amyloid-like structures that serve important functions. One example is the RNA-binding protein Rim4 which forms amyloid-like assemblies that are essential for translational control during S. cerevisiae meiosis. If Rim4 is unable to translationally repress its mRNA targets, cells mis-segregate chromosomes during meiosis resulting in aneuploid gametes. Importantly, Rim4 amyloid-like assemblies are disassembled in a phosphorylation-dependent manner at meiosis II onset which allows previously repressed transcripts to become translated. In Chapter 1, I describe the significance and complexity of protein phosphorylation as it relates to disease-associated amyloids and why Rim4 is an ideal model for studying this phenomenon. The objective of this thesis is to examine the mechanisms underlying clearance of Rim4 amyloid-like assemblies. The work described in Chapter 2 focuses on identifying co-factors that mediate clearance of amyloid-like assemblies in a physiological setting. I demonstrate that yeast 14-3-3 proteins, Bmh1 and Bmh2, bind to Rim4 assemblies and facilitate their subsequent phosphorylation and timely clearance. Furthermore, distinct 14-3-3 proteins play non-redundant roles in facilitating phosphorylation and clearance of amyloid-like Rim4. In Chapter 3, I explore the mechanism underlying 14-3-3 contribution to Rim4 amyloid-like disassembly. I find that 14-3-3 proteins are critical for the interaction between Rim4 and its primary kinase Ime2, thus facilitating downstream multi-site phosphorylation of Rim4. In Chapter 4, I explore additional roles for 14-3-3 proteins in general protein aggregate homeostasis. I find that 14-3-3 mutants exhibit greater protein aggregate burdens. Additionally, 14-3-3 mutants accumulate ubiquitinated proteins and are sensitized to proteasome mutations, suggesting a role for 14-3-3 proteins in proteasome function. Collectively, the studies described in this thesis support a protective role for 14-3-3 proteins in protein aggregation that may have implications for amyloid biology in human disease.

Abstract Views of addiction etiology predict religious individuals’ willingness to help. Emily Brady, Valerie Hoots, Joseph Barnet, and Andrea Clements, Department of Psychology, East Tennessee State University. Addiction to drugs and alcohol is an accrescent societal problem. Individuals with substance addiction face stigma in their daily lives, specifically from religious individuals as explored in this study. The stigma these religious individuals might portray could be related to their ideas on addiction etiology. The purpose of this project is to evaluate if different views of addiction etiology predict religious individuals’ willingness to help individuals with substance addition. Our hypothesis for this sample consists of two parts. (1) Religious individuals who hold the belief of a moral etiology of addiction will be less willing to help individuals with substance addiction. (2) Religious individuals who hold the ideology of a physical etiology of addiction will be less willing to help individuals with substance addiction. A survey, which contained the Addiction Attitudes and Beliefs Scale (AABS) and the Tobacco, Alcohol, Prescription medication, and other Substance use Tool (TAPS), was administered to a sample of 215 individuals recruited through social media advertising via Facebook and Reddit platforms, email, and East Tennessee State University’s SONA research portal. Results showed significance in beliefs of moral etiology and willingness to help across religious individuals. One limitation for this project is a lack of generalizability due to the majority of participants being female (73.6%) and white (92.1%). Another limitation is that the measure is based on self-report, and given the sensitivity on the topic, individuals may not be willing to report accurately.

Gastric aspirate specimens were collected from patients w~th clinically diagnosed gastric carcinoma and from non-carcinoma patients. The nitrite concentration and pH values of the aspirates were measured, the microorganisms present in selected specimens were isolated and identified, and the mutagenicity ratios of the aspirates were determined. The median nitrite concentration of the gastric aspirates from the carcinoma patients was significantly higher than that obtained for the non-carcinoma patients. A positive correlation was found between the nitrite concentration and the pH values of all the specimens tested, and a marked increase in nitrite levels at pH values above 6,0 was evident in specimens from the coloured ethnic "normal" subgroup. Gastric aspirate nitrite concentrations did not correlate with salivary values. The presence of microorganisms in gastric aspirates was shown to be pH dependent. Gastric aspirates with a pH < 2,0 were sterile, below pH 4,0 only acidophilic bacteria survived, whereas above pH 4,0, numerous species, predominantly members of the oral microflora, were isolated. The mean mutagenicity ratio of the gastric aspirates from the carcinoma patients was found to be significantly higher than that found for the control group. There was a positive correlation between the mutagenicity ratios of all the gastric specimens and pH with a maximum at a pH value of approximately 6,0.

The incidence and causes of diarrhoea among critically ill patients receiving enteral tube feeding were investigated. Sixty acutely ill surgical or medical intensive care patients who had had a minimum of 48 hrs bowel rest were entered into the study. They were randomly assigned to receive one of two lactose free liquid formula diets - "Ensure", a commercially available feed containing 825 kCal/L and 34 g/L of protein with an osmolality of 441mOsm/1 or "Casilan Oil", a home-made feed containing 840 kCal /L and 45g/L of protein with an osmolality of 383 mOsm/1. The feeds were administered by constant nasogastric infusion. Patients received 1000ml at a rate of 40ml per hour for the first day and up to 2000ml at 80 ml per hour for the remainder of the study period. Investigations included documentation of medical history, medications administered and clinical details for each patient. Serum albumin was measured and the nutritional status of each patient was assessed using anthropometric measurements. Feeds were tested for bacterial contamination on the three days following the start of feeding and small intestinal bacterial overgrowth was assessed by the 1 g-¹⁴C Xylose breath test of Toskes and King. Twelve of the sixty patients had to be withdrawn from the trial within 24 hours of the start of enteral feeding for medical reasons. The remaining forty eight patients completed at least three days on enteral feeding and thereby became eligible for analysis. In 10/48 patients (21%) diarrhoea was present before enteral feeding began. Four of these 1 O patients continued to pass loose stools when enteral feeding was started while the remaining 6 settled. Diarrhoea developed in a further 10 patients (21%) after enteral feeding began. The overall incidence of diarrhoea in the group of critically ill patients studied was therefore 42% (20/48). However, of the fourteen patients who experienced diarrhoea during enteral feeding four had diarrhoea before feeding began. Therefore, the true incidence of diarrhoea related to enteral feeding was only 10/38 (26%). Furthermore, in 7 of these 10 patients, another possible cause of diarrhoea was present. There was no significant association between diarrhoea and nutritional status, hypoalbuminaemia, sepsis, length of bowel rest, sucralfate and antibiotic therapy other than amikacin. Twenty one patients received Ensure and 27 received Casilan Oil. Despite the differences in the composition of the feeds, the incidence of diarrhoea was similar on the Ensure and the Casilan Oil. No particular factor pertaining to the composition of the feeds was associated with diarrhoea. Significant contamination of feeds was universal but there was no constant relationship between bacterial counts, or types, and the occurrence of diarrhoea. Certain other factors were found to be significantly associated with diarrhoea. Abdominal injury was positively associated with the occurrence of diarrhoea (p<0.05). Diarrhoea could have been attributed to the underlying disease state in 7 of the patients. All three patients who were receiving lactulose as treatment for liver failure developed diarrhoea. While no association was noted between diarrhoea and antibiotic therapy in general, treatment with the antibiotic, amikacin, correlated significantly, albeit marginally, with the occurrence of diarrhoea (p<0.05). Twenty six patients were tested for small intestinal bacterial overgrowth. Only one patient, with an elevated excretion of ¹⁴CO₂, indicative of small intestinal bacterial overgrowth, developed diarrhoea. There was, however, a positive association between diarrhoea and decreased excretion of ¹⁴CO₂. It would appear that the bacterial flora was suppressed in patients with diarrhoea. Amikacin therapy was also associated with decreased excretion of ¹⁴CO₂. This may suggest that amikacin could have altered the bowel flora with resultant development of diarrhoea. While abdominal injury and disease were associated with the development of diarrhoea and amikacin was a possible factor associated with diarrhoea, the results of the present study indicate that enteral tube feeding with either the commercial feed, Ensure or the home-made feed, Casilan Oil was not a cause of diarrhoea in the majority of critically ill patients assessed. Furthermore, in most patients who commenced the trial with diarrhoea, improvement was noted on enteral feeding.

Objective: Paraquat is a commonly used herbicide worldwide and is a well-documented cause of pulmonary fibrosis in studies of laboratory animals and in humans following high dose exposure (usually accidental or as parasuicide). The respiratory effects of long-term, low dose paraquat exposure have not been fully evaluated. We set out to evaluate the possible effects of paraquat spraying among deciduous fruit farm workers in the Western Cape, South Africa. Methods: A cross-sectional study of 126 workers was performed. Administered questionnaires generated information on exposure, respiratory symptoms and confounding variables. Spirometry and gas transfer were measured and chest radiographs performed. Oxygen desaturation on exercise testing was by oximetry during a modified stage one exercise test. Results: No association was found between long-term paraquat exposure and reported symptoms, spirometry (FVC, FEVl, FEVl/FVC) and gas transfer (TLco and Kco) or chest radiography. Multivariate analysis showed a significant relationship between measures of long-term paraquat exposure and arterial oxygen desaturation during exercise (p < 0.05). Conclusion: Previous studies have also not shown a significant relationship between measures of paraquat exposure and standard tests of lung function. Arterial oxygen desaturation during exercise represents a more sensitive test. Our findings indicate that working with paraquat under usual field conditions for a long period is associated with abnormal exercise physiology in a dose dependant fashion.