Background: Cardiovascular disease (CVD) is the leading global cause of death. CVD risk factors are considered intermediaries for the association between dietary fatty acids and CVD. Raised plasma total cholesterol, low density lipoprotein (LDL) cholesterol, raised triglycerides and decreased levels of high density lipoprotein (HDL) cholesterol, as well as reduced fibrinolytic potential (measured as increased clot lysis time) are known risk factors for CVD. Plasminogen activator inhibitor-1 (PAI-1) is a major inhibitor of the fibrinolytic process and an elevated PAI-1 level is therefore considered to be a potential risk factor for CVD. The growing number of controversies around the role that fat intake (more specifically the type of dietary fat) plays in CVD risk, is making it increasingly difficult for consumers and practitioners alike to form conclusions, and make recommendations and decisions regarding fat intake. Knowledge of the intake of individual fatty acids, fatty acid status (as opposed to subgroups of fat such as polyunsaturated fatty acids) and their associations with blood lipids, PAI-1act and fibrinolytic potential is lacking in black South Africans and other populations. Therefore we aimed to investigate dietary fatty acid intake, as well as plasma phospholipid fatty acid status and their associations with blood lipids, PAI-1act and clot lysis time, as a marker for fibrinolytic potential. Methods: Cross-sectional data analysis within the Prospective Rural Urban Epidemiology (PURE) baseline study of apparently healthy black South African men and women (n=1950, 35– 70 years) from rural and urban areas in the North West Province, from whom dietary data were collected. Blood lipid analyses, as well as laboratory analyses of fibrinolysis markers such as PAI-1act and clot lysis time were also performed. Plasma phospholipid fatty acid extraction and isolation were performed on a random subsample (n = 716). Results: The intake of individual fatty acids was significantly higher in urban than rural dwellers. However, the intake of omega-3 polyunsaturated fatty acids was below recommendations in all groups (rural and urban males, and rural and urban females). Total cholesterol and LDL cholesterol were higher in females than in males, with no rural‒urban differences. Intake of alpha-linolenic acid was positively associated with total cholesterol (β=0.143) and triglycerides (β=0.256) in males. The risk of having elevated LDL cholesterol also increased with increased intake of alpha-linolenic acid (OR 1.49, 95% CI 1.04, 2.14). In females, dietary arachidonic acid and eicosapentaenoic acid (EPA) were positively associated with total cholesterol and LDL cholesterol, whereas docosahexaenoic acid (DHA) was negatively associated with total cholesterol and LDL cholesterol. Dietary alpha-linolenic acid was positively correlated with plasma EPA (males r = 0.19, p = 0.002, females r = 0.25, p < 0.001) and DHA (males r = 0.33, p < 0.001, females r = 0.30, p < 0.001). Plasma DHA was positively associated with triglycerides in males (β = 0.410, p< 0.001) and in females (β = 0.379, p< 0.001). PAI-1act was positively associated with clot lysis time, and plasma myristic acid and DHA were positively associated with PAI-1act in females. However, these fatty acids were not associated with clot lysis time. Different types of plasma fatty acids were associated with PAI-1act than with clot lysis time. Plasma alpha-linolenic acid (β = 0.123, P = 0.037), mead acid (β = 0.176, P = 0.019), arachidonic acid (β = 0.253, 0.025) and omega-3 docosapentaenoic acid (omega-3 DPA) (β = 0.224, P = 0.002) were positively associated with clot lysis time, while both myristic acid (β = - 0.130, P = 0.016) and EPA (β = -0.131, P = 0.021) were negatively associated with clot lysis time in male subjects. Plasma oleic acid (C18:1n9) (β = -0.411, P = 0.001) and omega-6 DPA (C22:5n6) (β = -0.285, P = 0.001) were negatively associated with clot lysis time, while dihomogamma- liolenic acid (DGLA) (C20:3n6) were positively associated (β = 0.178, P = 0.001) with clot lysis time in females. Conclusions: These results suggest that specific individual dietary fatty acids might be associated with blood lipids in males differently than in females, irrespective of rural or urban dwelling. It is not known however, if associations would still be present under conditions of greater intake of alpha-linolenic acid. Our results further suggest that a higher percentage of alpha-linolenic acid might be converted to DHA in this population with low intake of essential and long-chain polyunsaturated fatty acids compared to populations with a high intake of these fatty acids. These results suggest that plasma phospholipid fatty acids should not be used in isolation as biomarkers for intake of fat, without taking dietary intake data into consideration also. Associations between fatty acids and clot lysis time might be independent from PAI-1act. The association between mead acid and clot lysis time indicates that clot lysis time might increase with an essential fatty acid deficiency. This may be of particular concern in this population with a documented lower fat intake. Because the study design of this study is crosssectional, it is not able to determine cause-and-effect, and results should therefore be verified with a randomised controlled trial. / PhD (Nutrition), North-West University, Potchefstroom Campus, 2015

Adipositas und die damit verbundenen Folgeerkrankungen sind eine der zentralen Gesund-heitsherausforderungen unserer Zeit. Dauerhafte Adipositas führt zu einer Dysregulation fettgewebseigener Peptidhormone. Diese sogenannten Adipokine stellen ein Verbindungsglied zwischen Fettgewebsakkumulation und den vielfältigen Adipositaskomplikationen des gesamten Organismus dar. Adipocyte fatty acid binding protein (AFABP) wurde in den letzten Jahren als zirkulierendes Adipokin mit diabetogenen, proinflammatorischen und proateriosklerotischen Effekten etabliert. Zu Beginn der Dissertation lagen unzureichende Erkenntnisse über die Elimination von AFABP sowie die Regulation des Adipokins bei eingeschränkter Nierenfunktion vor. Aus diesem Grund untersucht die vorliegende Arbeit die AFABP-Regulation in Abhängigkeit von der Nierenfunktion in 532 Patienten mit chronischer Niereninsuffizienz (Studienpopulation 1) und 32 Patienten mit akuter Nierenfunktionsverminderung nach Nephrektomie (Studienpopulation 2). In beiden Kohorten stiegen die medianen AFABP-Serumkonzentrationen mit abfallender Nierenfunktion an. Zudem waren Marker der Nierenfunktion in beiden Studienpopulationen die stärksten unabhängigen Prädiktoren für zirkulierendes AFABP. Untersuchungen aus der Arbeitsgruppe zur AFABP-Regulation in einem Rattenmodell der akuten Niereninsuffizienz unterstützen die klinischen Studienergebnisse. Zusammenfassend zeigen diese Ergebnisse zum ersten Mal signifikant steigende AFABP-Serumspiegel bei chronischer und akuter Nierenfunktionsstörung, sowie bei akutem Abfall der Nierenfunktion. Diese Befunde stützen die Hypothese, dass AFABP renal eliminiert wird. Inwiefern AFABP darüber hinaus in die Pathogenese der chronischen Niereninsuffizienz eingreift, muss in weiterführenden Studien beleuchtet werden.

Polyunsaturated fatty acids are major structural components of plant chloroplast and endoplasmic reticulum membranes. Two fatty acid desaturases (designated FAD2 and FAD3) desaturate 75% of the fatty acids in the endoplasmic reticulum. The w -6 fatty acid desaturase (FAD2) may be responsible for cold acclimation response, since polyunsaturated phospholipids are important in helping maintain plant viability at lowered temperatures. To study regulation of FAD2 gene expression in cotton, a FAD2 gene was isolated from two genomic libraries using an Arabidopsis FAD2 hybridization probe and a cotton FAD2 5¢ -flanking region gene-specific probe, respectively. A cotton FAD2 gene was found to be in two overlapping genomic clones by physical mapping and DNA sequencing. The cloned DNA fragments are identical in size to cotton FAD2 genomic DNA fragments shown by genomic blot hybridization. The cotton FAD2 coding region has 1,155 bp with no introns and would encode a putative polypeptide of 384 amino acids. The cotton FAD2 enzyme has a high identity of 75% with other plant FAD2 enzymes. The enzyme has three histidine-rich motifs that are conserved in all plant membrane desaturases. These histidine boxes may be the iron-binding domains for reduction of oxygen during desaturation. To confirm that this FAD2 enzyme is functional, a plasmid construct containing the cotton FAD2 coding region was transformed into Saccharomyces cerevisiae. The transformed yeast cells were able to catalyze the conversion of oleic acid (C18:1) into linoleic acid (C18:2). The FAD2 gene contains an intron of 2,967 bp in its 5¢ -flanking region, 11 bp upstream from the initiation codon. The intron could be essential for transcriptional regulation of FAD2 gene expression. Several putative promoter elements occur in the 5¢ -flanking region of this gene. A potential TATA basal promoter element occurs at 41 bp upstream from the cap site. Two presumptive helix-loop-helix (bHLH) motifs that may be seed-specific promoter elements are located at 109 bp and 135 bp upstream from the potential cap site.

Thirty-five volunteers were randomized and twenty-nine completed the study. Mean plasma and red blood cell (RBC) total DHA concentrations, which were analyzed among all participants as a measure of adherence, increased significantly in the DHA-enriched treatment compared to control oil-control flour. The plasma and RBC n-6: n-3 ratio was reduced after consumption of HOCODHA-control flour compared to control oil- control flour. The present study failed to see differences in body composition with the HOCODHA-barley flour treatment versus control oil-control flour treatment. In conclusion, significant increases in plasma EPA and DHA levels, as well as the omega-3 index, provide evidence supporting the cardioprotective effects of HOCODHA. The present study demonstrated that in the context of current Western macronutrient intakes, altering the dietary fatty acid composition and adding β-glucan had no major effect on body composition during the 28 days controlled dietary intervention. / February 2017

Tuberculosis emerged from its grave to be one of the deadliest diseases of the present time after recently developing a synergy with AIDS. A fatty acid condensing enzyme-mtFabH has been proposed to connect the key processes involved in biosynthesis of mycolic acids, an important component of mycobacterial cell wall. It condenses long acyl Coenzymes A (CoA; up to C20CoA) with malonyl Acyl Carrier Protein (ACP) to form the elongated β-ketoacyl-ACP which further undergoes rounds of elongation to form mero-mycolate branch of mature mycolic acids. Owing to its proposed central position in mycolic acid synthesis, mtFabH has attracted considerable attention as a good anti-mycobacterial target.In this study, we utilized important biochemical tools such as site directed mutagenesis, mass spectrometry and X-ray crystallography to address some of the key unanswered questions regarding the intricate workings of mtFabH. We solved the first co-crystal structure of substrate C12CoA with mtFabH and further analyzed the substrate specificity of this acylation step. This structure depicts the mode of acyl-CoA binding in mtFabH channels; and its comparison with the parallel E.Coli-acetyl CoA structure provides important similarities and differences in substrate binding in these two FabH enzymes. It also posed an important question about the trajectory of long acyl chain CoA into the deep and "seemingly closed" substrate binding pocket of mtFabH. By utilizing disulfide-based inhibitors, we showed that large conformational changes are necessary to facilitate ligand trafficking in mtFabH while the high catalytic turnover rate of the enzyme is maintained. We also proposed the most likely location of the involved loop.A much faster and less cumbersome assay for mtFabH was also developed and it was utilized to characterize a series of inhibitors. This assay utilizes the commercially available radioactive malonyl-CoA in lieu of malonyl-ACP, the physiological substrate, and thus can serve as ACP independent assay for mtFabH.These studies further our understanding of the biochemistry of mtFabH, which along with the faster assay could be helpful in designing potent mtFabH inhibitors as anti-tubercular agents in the future.

Master of Science / Grain Science and Industry / Greg Aldrich / Processing pet food can be beneficial, but can also have adverse effects on shelf-life and nutrient survival. Most affected are supplemental vitamins and essential fatty acids (EFA). Pet food complicates this relative to human foods by combining all elements into the product before processing and requiring an extensive shelf-life (up to 2 years). The objective of this research was to determine the effects of processing, diet, and storage conditions on vitamin (vitamin A, vitamin D₃, vitamin E, folic acid and thiamine) and omega-3 fatty acid (with an emphasis on eicosapentaenoic acid; EPA 20:5n3, and docosahexaenoic acid; DHA; 22:6n3) retention. The research was conducted in two separate experiments. Each experimental diet was produced on a single-screw extruder and triple-pass dryer. Target nutrients were evaluated in premixes in tandem to extruded diets. The vitamin study was conducted as a 3 X 2 X 2 factorial arrangement of treatments with 3 levels of dietary crude protein (CP), 2 screw speeds in the extruder, and 2 levels of time X temperature combinations in the dryer. Vitamins were added at 10 times normal levels to aid in analysis. The EFA study was conducted as a 3 X 3 factorial arrangement of treatments with 3 levels of dietary protein and 3 different omega-3 sources: fish oil, fish meal, or purpose-grown algae rich in DHA. In the vitamin premix study, the quantity of vitamins declined by approximately 50% over 6 months storage in ambient conditions (AMB; 20C, 50%RH), and all except folic acid were lost to some degree in stressed shelf life testing (SSLT; 50C, 70% RH) over 6 weeks. In all cases, the concentration of vitamins in food exiting the extruder and dryer were lower than target levels. As CP increased, the retention was higher (P ≤ 0.05) for vitamins A, E, and folic acid off the extruder (e.g. 225,352 vs. 219,184 and 206,249 IU/kg of vitamin A for high vs. medium and low CP, respectively), and vitamin D₃, E, and folic acid off the dryer (e.g. 9,047 vs. 7,473 and 6,945 IU/kg of vitamin D₃ for high vs. medium and low CP, respectively). During storage of finished pet food in AMB, vitamins A and D₃ were lost (P < 0.05) to the greatest degree (49 and 22%, respectively). The total retention following both processing and AMB storage was 27, 68, 78% for vitamins A, D₃, and E, respectively, while folic acid and thiamine were relatively stable. In SSLT storage, all vitamins except vitamin E were depleted more than 60% (P < 0.05) by 24 weeks, whereas total retention following both processing and SSLT storage was 3, 59, 43, 33, and 7% for vitamins A, D₃, and E, folic acid, and thiamine, respectively. This would suggest that beyond processing losses, the vitamins are relatively stable in premixes and foods if stored in AMB conditions. In the study to evaluate fatty acid stability within a vitamin premix, EPA, DHA, and total omega-3 fatty acids were relatively stable during storage over 6 weeks with losses no greater than 12% in stressed shelf life testing (SSLT; 40C, 70% RH). While in ambient conditions (23C, 50% RH) over 3 months, there was a total loss of EPA, DHA and total fatty acids by 17, 9, and 11%, respectively. Exiting the extruder and dryer, EPA and DHA were not affected by CP level or Omega-3 source. As SSLT storage of finished pet food increased through 24 weeks, EPA, DHA, and total fatty acids declined slightly (P < 0.05; 125, 82 mg/kg for EPA and 77, 60 mg/kg for DHA, and 418, 476 mg/kg for total fatty acids at 0 vs. 24 wk. As time in ambient storage reached 24 months, EPA, DHA, and total fatty acids declined slightly (P < 0.05; 125 vs. 78 mg/kg for EPA and 77 vs. 50 mg/kg for DHA, and 387 vs. 373 for total fatty acids at 0 vs. 24 mo.) Algal-DHA appears to be a stable source of DHA when compared to fish oil and fishmeal. During processing retention of fat soluble vitamins was less than water soluble vitamins, and the omega-3 fatty acids were relatively unaffected. Whereas, vitamins appeared to be more sensitive to temperature during storage and the omega 3 fatty acids more affected by time.

研究背景及實驗目的: 非酒精性脂肪性肝炎(NASH)使得肥胖和2 型糖尿病變得複雜，肝臟炎症的持續產生是其主要的發病機理。CXCL10 是一種促進炎症的細胞因數，其在肥胖和2 型糖尿病中的表達顯著升高。CXCL10 以及其受體CXCR3 是否在NASH 的發生發展中起作用尚不清楚。在本研究中，我們探索了CXCL10 以及其受體CXCR3 在脂肪性肝炎中的功能， 並評估了CXCL10 在NASH 中的臨床價值。 / 實驗方法：CXCL10 基因敲除鼠，CXCR3 敲除鼠以及野生型C57BL/6 小鼠給予蛋氨酸膽鹼缺乏食(MCD)4 周或者8 周。CXCL10 的信號通路以及下游靶點通過細胞因數分析，cDNA array, 蛋白DNA 結合實驗，自噬溶酶體系統分析進行檢測。為了闡明CXCL10 抑制對NASH 的預防治療作用，我們給MCD 餵養的小鼠注射抗CXCL10 抗體。用不同濃度的CXCL10 抗體以及CXCR3 抑制劑NIBR2130 幹預MCD 培養的肝細胞株AML-12。臨床研究中，我們收集了147個非酒精性脂肪肝患者以及73 個健康對照的血清，用酶聯免疫吸附試驗檢測血清中CXCL10 的水準。 / 結果：野生型小鼠給予MCD 餵養後，CXCL10 以及CXCR3 的表達升高，並出現脂肪性肝炎的表現。然而，MCD 飼養的CXCL10 以及CXCR3 基因敲除鼠中，脂肪性肝炎明顯減輕。CXCL10 通過促炎細胞因數的產生以及NK-κB 信號通路促進MCD 飼養的小鼠NASH 的發生。CXCL10 通過促進脂質合成的基因SREBP-1c, ChREBP 和 SCD-1 引起脂肪變性，並通過CYP2E1 以及 C/EBPβ 的上調引起氧化應激。值得注意的是，自噬的損傷在CXCL10 以及CXCR3 導致的脂肪性肝炎的進展中起重要作用。 MCD 飼養的野生型小鼠中p62 以及LC3-II 表達明顯高於CXCL10 以及CXCR3 基因敲除鼠。通過抗CXCL10 抗體中和CXCL10 可以減輕MCD 食引起的小鼠脂肪性肝炎以及MCD 培養液引起的AML-12 細胞損傷。高選擇性的CXCR3 抑制劑NIBR2130 也可以抑制MCD 引起的肝細胞損傷。我們進一步研究了CXCL10 的臨床應用價值，發現NASH 患者血清以及肝臟中CXCL10 的水準明顯升高。更重要的是，血液中CXCL10 的水準與肝小葉炎症程度有關，是NASH 的獨立危險因素。 / 結論：我們的研究首次發現CXCL10 以及其受體CXCR3 通過促進炎症，脂質聚集，氧化應激以及自噬缺乏在NASH 的發病中起重要作用。抑制CXCL10 或者CXCR3 為NASH 患者的治療提供了新的方法。CXCL10 可作為NASH 患者非侵入性診斷的標誌物。 / Background and aims: Non-alcoholic steatoheaptitis (NASH) complicates obesity and type 2 diabetes, while recruitment and perpetuation of liver inflammation is central to its pathogenesis. Expression of C-X-C motif chemokine 10 (CXCL10), a proinflammatory cytokine, correlates positively with obesity and type 2 diabetes. Whether CXCL10 and its receptor CXCR3 play a role in NASH is unknown. In this study, we investigated the functional significance of CXCL10 and its receptor CXCR3 in steatoheaptitis. Moreover, the clinical impact of CXCL10 in NASH was examined. / Methods: Gene-deleted CXCL10 (CXCL10-/-), CXCL10 receptor CXCR3 (CXCR3-/-) and C57BL/6 wildtype (WT) mice were fed methionine and choline-deficient (MCD) diet for 4 or 8 weeks. Cytokine profiling assay, cDNA array, protein-DNA binding activity assay and autophagosome-lysosome system analysis of CXCL10 signaling and downstream targets were performed. In other experiments, we injected neutralizing anti-CXCL10 monoclonal antibodies (mAb) into MCD diet-fed WT mice, while AML-12 cells were cultured in MCD medium in the presence of anti-CXCL10 mAb or CXCR3 inhibitor (NIBR2130) for 24 hours. Human serum was obtained from 147 patients with biopsy-proven non-alcoholic fatty liver disease and 73 controls. Circulating CXCL10 levels were determined by enzyme-linked immunosorbent assay. / Results: MCD-fed WT mice developed steatohepatitis with higher hepatic CXCL10 and CXCR3 expression. CXCL10-/- and CXCR3-/- mice were refractory to MCDinduced steatohepatitis. In WT mice with steatohepatitis, but not in CXCL10-/- mice, CXCL10 was associated with the induction of pro-inflammatory chemokines and cytokines, as well as activation of nuclear factor-κB (NF-κB) signaling. CXCL10 expression was linked to steatosis through lipogenic factors, including liver X receptors and its downstream targets (SREBP-1c, ChREBP and SCD-1), and also to oxidative stress (up-regulation of CYP2E1 and C/EBPβ). In particular, autophagy deficiency was involved in CXCL10- and CXCR3-induced steatohepatitis as indicated by p62 and LC3-I/II protein accumulation in MCD-fed WT mice than in CXCL10-/- and CXCR3-/- mice. Moreover, the impaired autophagic function was related to the reduction of lysosomal function in CXCL10- or CXCR3-induced NASH. Blockade of CXCL10 by anti-CXCL10 mAb protected against MCD-induced steatohepatitis in vivo and against MCD-mediated injury to AML-12 cells in vitro. The highly selective CXCR3 antagonist NIBR2130 also inhibited MCD-induced injury in AML-12 hepatocytes. We further investigated the clinical impact of CXCL10 and found circulating and hepatic CXCL10 levels were significantly higher in human NASH. Importantly, circulating CXCL10 level was correlated with the degree of lobular inflammation and was an independent risk factor for NASH patients. / Conclusions: We demonstrate for the first time that CXCL10 and its receptor CXCR3 plays a pivotal role in the pathogenesis of NASH by promoting inflammation, fatty acid accumulation, oxidative stress and autophagy deficiency. Blockade of CXCL10 or CXCR3 is a potential novel approach for NASH intervention. CXCL10 is a noninvasive biomarker for NASH patients. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Zhang, Xiang. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 145-167). / Abstracts also in Chinese.

Immortalized normal hepatocytes AML-12 or primary hepatocytes were cultured in control, and the methionine and choline deficient (MCD) culture medium in the presence or absence of Phyllanthus urinaria for 24 hours. Hepatocyte triglyceride contents, release of alanine aminotransferase, lipoperoxides and reactive oxygen species production were determined in the cell culture study. Age-matched wild-type C57BL/6 and diabetes db/db mice were fed control or MCD diet for 10 days with or without Phyllanthus urinaria. The levels of Hepatic steatosis, necroinflammation, triglycerides and oxidative stress were investigated. Hepatic expression of inflammatory factors and lipid regulatory mediators were assayed. The results demonstrated that Phyllanthus urinaria reduced steatosis and alanine aminotransferase (ALT) levels in culture of hepatocytes in a dose-dependent manner. Phyllanthus urinaria protected the livers against MCD-induced hepatic fat accumulation and steatohepatitis in mice. This effect was associated with repressed levels of hepatic lipid peroxides, reduced expression of cytochrome P450 (CYP) 2e1, pro-inflammatory tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), dampened activation of inflammatory C-jun N-teuninal kinase (JNK) and nuclear factor kappaB (NF-kappaB), increased expression of lipolytic Cyp4a10 and suppressed transcriptional activity of lipogenic CCAAT/enhancer binding protein beta (C/EBPbeta). Hepatic acyl co-enzyme A oxidase (ACO) that regulated hepatic beta-oxidation of fatty acid and other lipid regulators were not affected by Phyllanthus urinaria. / Non-alcoholic steatohepatitis (NASH) results from excessive accumulation of hepatic fat (steatosis) and oxidative stress. Therefore, inhibition of fatty acid cytotoxicity and liver inflammtary change is an important goal in the treatment of NASH. Phyllanthus urinaria, a herbal medicine, has been reported to have potential anti-oxidant property. We tested the effects of Phyllanthus urinaria on nutritional steatohepatitis both in vitro and in vivo, and determined the mechanism of its action. / Our study indicated that Phyllanthus urinaria effectively prevented MCD-induced steatohepatitis. This effect were probably mediated through dampening oxidative stress, ameliorating inflammation and decreasing lipid accumulation. Phyllanthus urinaria deserves further evaluation for its potential therapeutic effect on NASH in humans. / Shen, Bo. / Adviser: Henry Ly Chan. / Source: Dissertation Abstracts International, Volume: 70-09, Section: B, page: . / Thesis submitted in: November 2008. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 128-142). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Submitted by Natalia Vieira (natalia.vieira@famerp.br) on 2016-05-20T17:39:42Z No. of bitstreams: 1 giovannazanellisilva_dissert.pdf: 2457622 bytes, checksum: 3faf263a6839bd66d93d3bcefc887385 (MD5) / Made available in DSpace on 2016-05-20T17:39:42Z (GMT). No. of bitstreams: 1 giovannazanellisilva_dissert.pdf: 2457622 bytes, checksum: 3faf263a6839bd66d93d3bcefc887385 (MD5) Previous issue date: 2015-11-27 / Introduction: Nonalcoholic Fatty Liver Disease (NAFLD) is characterized by an increase in intracellular content of triglycerides; its prevalence worldwidely is nearly 20-30% of the population. This disease has spectral nature that includes steatosis and nonalcoholic steatohepatitis (NASH) in the absence of significant alcohol consumption. Although NAFLD may remain as a stable disease for longer periods, this condition may progress to advanced stages of cirrhosis and liver cancer. Diabetes Mellitus Type 2, insulin resistance and obesity are important risk factors, among others, for development of NAFLD, and are directly related to sedentary lifestyle and inappropriate eating habits. Thus, alteration in lifestyle, changes in eating habits and regular physical activity play a fundamental role in treating this disease. Aim: To evaluate the effectiveness of hypocaloric diet for the treatment of NASH as well as adherence to treatment. Methods: This is a prospective longitudinal open cohort study, in which 26 NASH patients were divided into 2 group: 15 patients in the control group and 11 patients in the treatment group which were followed up for 6 months. Both groups were diagnosed by liver biopsy. The treatment group was a given lifestyle change program with supervised low-calorie diet (20-25 kcal / kg actual weight / day), monitored exercise, standard treatment of metabolic syndrome and drug maintenance treatment with metformin and N- acetylcysteine. The control group received general guidelines on diet and weight loss, encouragement to practice physical exercise, standard treatment of metabolic syndrome and maintenance of drug treatment with metformin. Criteria for inclusion: patients with at least one of the component of metabolic syndrome; BMI ≥ 25 and ≤ 40 kg /m² and sedentary for at least three months. Criteria for exclusion: other concomitant liver diseases, alcohol intake greater than or equal to 21 drinks / week, or 140 g / day for men and 14 drinks / week or 70g / day for women, medication known to be associated with NAFLD, untreated hypothyroidism or hyperthyroidism, previous bariatric surgery, or uncontrolled psychiatric disorder. Diagnostic criteria: the diagnosis of NASH was done by liver biopsy in patients with steatosis on ultrasound or MRI and at least one risk factor for advanced fibrosis into the period up to one year before entering the study. The lifestyle change program in the treatment group had a weight loss goal of 5% or more of their initial weight within six months. Evaluation criteria: a monthly basis applied the clinical evaluation protocol and on a quarterly basis the laboratorial, according to the following variables: weight, height, body mass index, waist circumference, hip circumference, aminotransferase levels, gamma GT, total cholesterol and fractions, triglycerides. Statistical analysis: the descriptive variables were expressed as frequency, mean or median, standard deviation and variation as applicable. The Student t test and Mann-Whitney test were used for comparative analysis. It was admitted confidence interval of 95% and a significance level of P <0.05. Results: Of the 15 patients enrolled with a diagnosis of NASH who were submitted to nutritional treatment, 12 patients completed the six month follow-up of the study. The average age was 51.42 years ± 8.50, being 08 (66%) women and 04 (33%) men. Of this total, only one patient refused to carry out physical activity. Two (17%) among the 12 participants who completed the six month follow-up reached the percentage of expected weight loss. The average percentage of adaptation to the proposed diet was 82.93% ± 13.51%. Conclusion: The lifestyle change program tested for six months associated with NASH treatment, was not effective for clinical and biochemical improvement even with satisfactory adherence by most patients. Our data point out to the potential role of more restrictive diets and intensive supervision in this context combined with multidisciplinary team for the treatment of NASH. This real-life study produced crucial information for readjustment of the multidisciplinary treatment protocol for patients followed up in the service. / Introducao: A doenca hepatica gordurosa nao alcoolica (DHGNA) e caracterizada pelo aumento do conteudo intracelular de triglicerideos, com prevalencia mundial de aproximadamente 20 a 30% da populacao. Esta doenca tem natureza espectral que engloba esteatose e esteatohepatite nao-alcoolica (NASH), na ausencia de consumo significante de alcool. Embora DHGNA possa permanecer como uma doenca estavel por longos periodos, esta condicao pode progredir para estagios avancados de cirrose e cancer de figado. O Diabetes Mellitus Tipo 2, resistencia a insulina e obesidade sao importantes fatores de risco, dentre outros, para desenvolvimento da DHGNA, e estao diretamente relacionadas ao estilo de vida sedentario e habitos alimentares inapropriados. Dessa forma, alteracao no estilo de vida, mudancas nos habitos alimentares e atividade fisica regular tem papel fundamental no tratamento desta doenca. Objetivo: Avaliar a eficacia da dieta hipocalorica durante o tratamento do NASH, assim como, a adesao ao tratamento instituido. Metodo e Casuistica: Trata-se de um estudo de coorte aberto prospectivo, longitudinal, no qual foram incluidos consecutivamente 26 pacientes, divididos em dois grupos: 15 pacientes no grupo tratamento e 11 pacientes no grupo controle acompanhados durante 6 meses. Ambos tinham diagnostico de NASH por biopsia. O grupo tratamento recebeu programa de mudanca no estilo de vida com dieta hipocalorica supervisionada (20 - 25 kcal/kg de peso atual/dia), exercicio fisico supervisionado, tratamento padrao dos componentes da sindrome metabolica e manutencao de tratamento medicamentoso com metformina e N-acetilcisteina. O grupo controle recebeu orientacoes gerais de dieta e perda de peso, estimulo a pratica de exercicio fisico, tratamento padrao dos componentes da sindrome metabolica e manutencao do tratamento medicamentoso com metformina. Criterios de inclusao: portadores de pelo menos uma caracteristica de sindrome metabolica, IMC . 25 e . 40kg/m2, e sedentarios por no minimo tres meses. Criterios de exclusao: outras doencas hepaticas concomitantes, ingestao alcoolica igual ou superior a 21 doses/semana ou 140g/dia para homens e 14 doses/semana ou 70g/dia para mulheres, medicacao conhecidamente relacionada com DHGNA, hipotireoidismo ou hipertireoidismo nao tratados, pos operatorio de cirurgia bariatrica, compulsao alimentar ou outro disturbio psiquiatrico nao controlado. Criterios diagnosticos: o diagnostico de NASH foi feito por biopsia de figado em pacientes portadores de esteatose ao ultrassom ou ressonancia magnetica e pelo menos um fator de risco para fibrose avancada, no periodo de ate 1 ano antes da entrada no estudo. Programa de mudanca no estilo de vida no grupo tratado teve como meta a reducao minima ou superior a 5% de seu peso inicial no periodo de seis meses. Criterios de avaliacao: aplicado mensalmente o protocolo de avaliacao clinica e trimestralmente o laboratorial, de acordo com as seguintes variaveis: peso, altura, indice de massa corporal, circunferencia abdominal, circunferencia do quadril, niveis de aminotransferases, gama GT, colesterol total e fracoes, triglicerideos. Analise estatistica: as variaveis descritivas foram expressas em frequencia, media ou mediana, desvio padrao e variacao conforme aplicaveis. Foram utilizados os testes t de Student e teste de Mann-Whitney para analises comparativas. Foi admitido intervalo de confianca de 95% e nivel de significancia para P<0,05. Resultados: Dos 15 pacientes incluidos com diagnostico de NASH que foram submetidos ao programa de mudanca no estilo de vida, 12 pacientes concluiram o acompanhamento de 6 meses do estudo. A idade média foi de 51,42 anos ± 8,50, sendo 08 (66%) pessoas do gênero feminino e 04(33%) do gênero masculino. Deste total, apenas um paciente negou a realização de atividade física. Dois (17%) participantes dentre os 12 que concluíram os seis meses de acompanhamento atingiram a porcentagem de perda de peso esperada. A média da porcentagem de adequação à dieta proposta dos participantes do estudo encontrada foi de 82,93% ± 13,51%. Conclusão: O programa de mudança no estilo de vida testado durante seis meses associado ao tratamento do NASH, não foi eficaz para a melhora clínica e bioquímica mesmo com adesão satisfatória pela maioria dos pacientes. Este estudo de vida real produziu informações de fundamental importância para readequação do protocolo de atendimento multidisciplinar dos pacientes em acompanhamento no serviço.

Submitted by Fabíola Silva (fabiola.silva@famerp.br) on 2018-01-08T16:01:25Z No. of bitstreams: 1 viniciusdelimafreitas_tese.pdf: 8494219 bytes, checksum: 35b61ce25b380b2ebf2433cf44ff18e5 (MD5) / Made available in DSpace on 2018-01-08T16:01:25Z (GMT). No. of bitstreams: 1 viniciusdelimafreitas_tese.pdf: 8494219 bytes, checksum: 35b61ce25b380b2ebf2433cf44ff18e5 (MD5) Previous issue date: 2017-05-05 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Introduction: The prevalence of hepatic steatosis and non-alcoholic fatty liver disease (NAFLD) in the Brazilian population is not known, and there are few studies about this disease in the country. Lifestyle modification, including physical activity and exercise are first line recommendation for the tratment of patients with NAFLD. Aim: To evaluate the efficacy of the Supervised physical activity and exercise program on-site and distance-supervised with duration of 12-month for patients with non-alcoholic steatohepatitis (NASH). Methods: This is a prospective, longitudinal, open cohort study including consecutive patients who had a histological diagnosis of NASH in the last 12 months and who were followed up at the outpatient NAFLD clinic. Exclusion criteria were: patients with concomitant liver diseases who could lead to steatosis; history or active significant alcohol intake such as equal or greater than 210g / week for men and 140g / week for women; drugs known to be related to NAFLD; untreated hypo or hyperthyroidism; pevious bariatric surgery; obesity equal or greater than grade III; binge eating or other uncontrolled psychiatric disorder. The patients were studied withing a pre-stated protocol study including clinical and laboratory evaluation, as well as the Baecke questionnaire and the six minute walk test (6MWT), before and after participation in the physical conditioning program. Descriptive statistics, Student's tes and the Mann-Whitney test, were performed for parametric and non-parametric variables as apropriated. The significance level adopted was p-value >0.05. Results: From the 15 included patients, three of them did not complete the multidisciplinary program during the 12-month study period. Thus, the total sample analyzed was 11 patients, that is, 73.33% of included patients. The 5% goal for body weight loss was not reached, however low density lipoprotein (LDL) presented significant reduction at the end of the study (p = 0.0130). The distance-supervised program was chosen by all patients and walking was the main physical activity (66.67%), followed by soccer. The 6-min walk distance (6MWD) was sgnificantly higher at trhee and six month when compared with basal distance at the entry of the study. Conclusion: The distancesupervised physical activity and exercise program had high adherence and was effective in improving the functional capacity for patitients with NASH. On the other hand, there was partial improvement for biochemical and antropometric variables. Aditionally, this is a distance-supervised life-style modification program with low cost and high potential cost-benefit for patients with DHGNA and NASH attended on the National Health System. / Introdução: A prevalência da Esteatose Hepática (EH) e da Doença Hepática Gordurosa Não Alcoólica (DHGNA) na população brasileira não é conhecida, e são poucos os estudos sobre esta doença no país. A mudança no estilo de vida representa a principal recomendação para o tratamento da DHGNA, assim, a atividade física e o exercício físico são ferramentas eficientes no combate à dislipidemia e acúmulo de gordura no fígado. Objetivo: Avaliar os efeitos do programa de condicionamento físico supervisionado in loco e supervisionado à distância com duração de 12 meses em pacientes com Esteatohepatite não alcoólica (NASH). Casuística e Método: Trata-se de um estudo de coorte aberto prospectivo, longitudinal, no qual foram estudados, pacientes em acompanhamento nos ambulatórios de DHGNA do Hospital de Base de São José do Rio Preto, que tiveram o diagnóstico histológico de NASH nos últimos 12 meses. Os critérios de exclusão apresentados foram: pacientes com outras doenças hepáticas concomitantes que possam cursar com esteatose; história prévia de ingestão alcoólica igual ou superior a 210g/semana para homens e 140g/semana para mulheres; medicação conhecidamente relacionada com a etiologia de DHGNA; hipotireoidismo ou hipertireoidismo não tratado; pós-operatório de cirurgia bariátrica; obesidade maior ou igual ao grau III; compulsão alimentar ou outro distúrbio psiquiátrico não controlado. Os pacientes foram analisados em protocolo de avaliação clínica e laboratorial, como o questionário de Baecke e o Teste de Caminhada de 6 minutos (TC6), antes e após a participação no programa de condicionamento físico em estudo. A estatística descritiva foi composta pelas variáveis paramétricas e não paramétricas (média, desvio padrão). As comparações entre os valores basais e, após a intervenção do programa de condicionamento físico foram efetuadas pelo teste t de Student (dados pareados) e teste não paramétrico de Mann-Whitney, com nível de significância (valores de p) inferior a 0,05. Resultados: Dos 15 pacientes incluídos no estudo, três pacientes não concluíram o programa multidisciplinar no período de 12 meses. Assim, a amostra total analisada foi de 11 pacientes, isto é, 73,33% dos incluídos no estudo. O programa supervisionado a distância foi escolhido por todos os pacientes avaliados tendo a caminhada como atividade física mais praticada (66,67%), seguido do futebol. A meta de perda de 5% do peso corporal não foi atingida ao final do estudo, e a lipoproteína plasmática de baixa densidade (LDL) apresentou redução significante (Tempo 4, p=0,0130) durante o estudo. A Distância Percorrida no Teste (DTC6) foi maior nos Tempos 1 e 2 quando comparado ao Tempo 0, com diferença significante (p < 0,05). Conclusão: O programa de condicionamento físico supervisionado à distância teve alta adesão e foi eficaz para a melhora da capacidade funcional de pacientes com NASH. A melhora foi parcial para os parâmetros bioquímicos e antropométricos. Adicionalmente, este programa de condicionamento físico, monitorado à distância, tem baixo custo e é de facil implantação no Sistema Único de Saúde, com alto potencial de custo-benefício para pacientes com DHGNA e NASH, que poderão ser maiores a longo prazo.