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Mårtensson, Ellinor. "Foaming in Apple Wine". Thesis, Linnaeus University, School of Natural Sciences, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-8354.
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At Kiviks Musteri AB, situated in the southeast part of Scania, a wide variety of products based on fruits and berries, are produced. One of these products is base apple wine, which is used for the production of cider and mulled wine and also is sold to other producers of cider. A foaming problem has occurred at some customers when the cider is bottled, and this problem has been traced to the base wine. The aim of this paper is to investigate what causes the foaming and how the foaming is affected by the clarifying agents used during the production of the wine. An investigation whether silica based antifoaming agents might be a solution of the problem will be performed. During the work fermentations, clarification and foaming tests will be performed in laboratory scale in Kivik. Tests with four different silica based antifoaming compounds are carried out and on these samples the surface tension and viscosity are measured to see how these factors correlate with the foaming when antifoaming agents are added to the wine. What is more, fermentations with a new yeast type and fermentations with less fruit are made to investigate if this could give better foaming properties in the wine.
The tests showed that it is probably proteins that are the main cause of the foaming, but an increase of the amount of bentonite, the clarifying agent reducing protein content in the wine, is not possible since this causes too much sediment. Antifoaming agents gave reduced foaming times, which were at an acceptable level, but when the wine was mixed to cider base and filtered the effect was lost. No significant differences were observed between the four antifoaming compounds. The test with the new yeast type gave no positive results when it came to foaming. The test with less fruit showed a decrease in foaming but not sufficient enough.
2
Lamont, Kim. "Delineation of the Cardioprotective Agents found in red wine". Master's thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3415.
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Secondary leach concentrate (SLC) is an important bleed stream for minor elements from Anglo Platinum's Base Metal Refinery (BMR) which produces copper nickel and cobalt sulphate. It contains mainly sulphur, iron jarosites, unleached base metals and platinum group metals (PGMs), which makes the treatment of SLC necessary. The SLC is currently toll-refined at Umicore's Hoboken smelter and refinery to recover revenue from entrapped valuable metals. This method of treatment results in excessively high costs due to high transport and toll refining expenses as well as penalties. Thus, an in-house method of treatment by Anglo Platinum itself would prove beneficial in that it would eliminate these excessive costs and also provide a method of treatment in the event of residues exporting becoming banned or strongly penalised in future. Therefore, a method for treating SLC in-house is investigated. The first stage of the proposed treatment method involves a pyrometallurgical process where the removal of amphoterics by oxidative fuming, followed by reduction to recover base metals from the slag takes place. The PGMs are reported mainly to the metal alloy phase along with the base metals during this process. The project discussed in this report deals with the treatment of this furnace alloy which is referred to as Cu alloy. The Cu alloy is used to produce anodes to be applied to an electrorefining application for the recovery of Cu as a Cu cathode and PGMs in the form of anode slimes. Spent electrolyte from the BMR copper electrowinning section adjusted to specific pH and Cu concentration is used as electrolyte to which dissolvable metals (such as Ni and Fe) are recovered. The purpose of the process is to recover PGMs to anode slimes with a composition suitable to be blended with the final concentrate that is sent to the Precious Metals Refinery (PMR). The performance of this process on the Cu alloy provided is investigated and the anode slimes produced are characterised in order to propose further methods of purification before blending with PMR feed. The typical energy consumption, cathodic current efficiency, anodic copper dissolution rate and deportment of elements (especially PGMs) are determined. The effects of various operating parameters on the performance are also investigated in order to propose operating conditions. The operating parameters that are investigated are current density, Cu and H2SO4 concentrations in electrolyte and the use of an additive. A preliminary process design based on knowledge and experience gained during the literature review and test work is given. -PAGE 3 OF 181 The major technical factors in electrorefining are the cathode purity, the production rate and the specific energy consumption. These factors are influenced primarily by anode quality, electrolyte conditions and cathode current density. Design considerations and typical design parameters for other industrial Cu electrorefining applications are studied as well as possible further treatment of anode slimes for the concentration of PGMs. A total of eleven experiments were performed with a variety combinations of Cu concentration (30, 40 and 50 g/l), H2SO4 concentration (110, 130, 160 and 190 g/l) and current density (100, 125, 150, 250, 300 A/m2). In each experiment only one parameter was changed while all others were kept constant at the base-case setting of 40 g/l Cu, 160 g/l H2SO4, and 125 A/m2. The testwork showed that electrolytic refining of the Cu alloy, produced by a two stage pyrometallurgical treatment of current SLC, produces a highly concentrated PGM residue at an overall SLC mass reduction of 99.3%, with excellent PGM recovery to the anode slimes material. The different operating parameters that were tested successfully, all showed very good repeatability and greater than 99% PGM recovery from the Cu alloy, which would result in an overall recovery of 98% from SLC. Very little or none of the base metals that were supplied by the anode or the electrolyte feed reported to the anode slimes. The typical operating conditions (cell potential, current efficiency, anodic Cu dissolution and element deportment) that were observed correlated well with literature and the theoretically calculated values. The characteristics of the anode slimes produced stayed relatively similar throughout the different operating parameters and strong confidence can be placed in the production thereof and the recovery of the PGMs. The characteristics of the spent electrolyte and the Cu cathodes were also found to be suitable for integration in the BMR circuit. The anode slimes composition was 20 to 30% PGMs, 20 to 30% base metals, 15 to 20% Ag, As, Te, Se, Pb and 2 to 5% Al, Si, Sb, Bi, Zn and Sn. The blending of these slimes with typical PMR feed will result in a new PMR feed where the Pt grade of the feed to PMR is reduced by 4 to 5.5%, the Cu grade increased by 2 to 4% and the Ni content reduced by +-4%. Other concerns are the increase of As, Te, and Pb by between 0.5 and 1%. -PAGE 4 OF 181 The PGM-rich (<60%) phase in the anode slimes is a mostly amorphous matrix phase containing mostly palladium and other PGMs, arsenic and tellurium [Pd73As6Te21] with small amounts of Cu. Anode slimes produced from electrorefining can either be subjected to an additional process step to remove Ag, Pb and base metals before it is blended with the final concentrate (FICO) as feed for PMR, or it can be sent to the metallics section in PMR which includes a roast and a leach stage. The treatment of the anode slimes depends on the nature of the slimes. A preliminary process design was performed with proposed design parameters of electrolyte concentrations of 40 g/l Cu and 160 g/l H2SO4 at 65 deg C and a current density of 200 A/m2. The process consists out of seven cells in series with 55 anode cathode pairs in parallel per cell. The process has a maximum capacity of 127 t/m of anode material which allows 56 days of downtime per year if the current SLC produced (6600 t/a) is treated. The maximum capacity for Cu production is 1349 t/a and anode slimes 50.3 t/m. The power consumption per kg of anode dissolved will be 0.175 kWh/kg.
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Blackhurst, Diane Mary. "Potential health benefits of antioxidant effects of wine on lipids". Doctoral thesis, University of Cape Town, 2005. http://hdl.handle.net/11427/3363.
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Includes bibliographical references.The consumption of wine dates back to the Stone Age, but its potential health benefits only really began to make an impact after the French Paradox was postulated by Renaud and de Lorgeril in the 1990s. Their observations indicated that moderate consumption of red wine may have health benefits. Research since then has shown that wine, in particular red wine, is a source of a large number of different polyphenolic compounds that have antioxidant activity. The finding that the consumption of red wine might have a beneficial health effect was very appealing, resulting in a large number of epidemiological and experimental studies. To date, controversy still surrounds wine and its health effects. Several pertinent questions are still to be answered: What in vitro methods can be used to determine the antioxidant effects of wine? What are some of the in vivo effects of wine? Can wine be used directly as an antioxidant in cooking of the food that would ordinarily be exposed to conditions that may induce peroxidation of lipids? What effects does wine have at the cellular level?
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Burns, Jennifer. "Phenolic antioxidants in red wine : content and activity". Thesis, University of Glasgow, 2000. http://theses.gla.ac.uk/3534/.
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Sensitive and selective methods were applied to the analysis of two batches of bottled wines. The relationship between the antioxidant activity, based on the reduction in Fremy's radical, vasodilation activity (batch 1 only), and phenolic content was investigated. Wines were selected to provide a range of origins, grape varieties and vinification methods. Batch 1 wines were sourced mainly from the Old World, while those in batch II were predominantly from the New World. The total phenolic content was determined by the Folin-Ciocalteu colorimetric assay and by the cumulative measurements obtained by HPLC. Total anthocyanins were determined using a spectral assay. While the wines exhibited a wide range in values in all parameters, with both batches the total phenol content, determined by both the Folin-Ciocalteu assay and HPLC, was very closely correlated with the ESR-derived antioxidant activity. Likewise a strong correlation was noted between the phenolic content and the vasodilation activity of Batch I wines. The antioxidant activity of Batch I wines was significantly correlated with the gallic acid, total stilbene and total flavin-3-ol content. Similarly with Batch II wines, gallic acid and total flavan-3-ols, along with polymeric pigments were significantly correlated with the ESR-derived antioxidant activity. Batch I and II had significantly different phenolic profiles though in both cases the flavin-3-ols and anthocyanins were quantitatively the major skin-derived phenolics present. However, in thirteen of the sixteen Batch I wines the major phenolics present were the flavin-3-ols compared with only five of the twenty-two Batch II wines. This discrepancy may be attributed to the viticultural practices of the Southern Hemisphere where many of these wines originated.
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Norrie, Philip Anthony, University of Western Sydney, College of Health and Science i School of Medicine. "Wine and health through the ages with special reference to Australia". THESIS_CHS_MED_Norrie_P.xml, 2005. http://handle.uws.edu.au:8081/1959.7/709.
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The use of wine as a medicine is not a new idea, but one that has been rediscovered and given credibility due to current research findings. This research examines the use of wine as a medicine in the past and currently. The whole question of wine and health is put into a more balanced and proper perspective, instead of the ill-informed, negative anti-alcohol view. The aim of the thesis is to document the history of the uses of wine as a medicine, particularly in Australia. The author uses a social ecology framework,which is concerned with the interrelationships between the domains of the personal, social and environmental, with a critical, holistic transdisciplinary understanding approach. One aim of the research is to change the perception of wine from one of a drink for special occasions to one of a daily health drink taken in moderation with a mealDoctor of Philosophy (PhD)
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Benhameid, Osama Saleh. "Myocardial revascularization using Omentum graft "Old wine in a new bottle"". Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=81267.
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Background. Therapeutic angiogenesis in cardiovascular disease aims at improving myocardial function by increasing blood flow to ischemic myocardium that is not amenable to traditional forms of revascularization. This study hypothesizes that using the Omental graft to wrap the ischemic heart will lead to formation of multiple collateral anastomoses between surrounding systemic arteries and the coronary arteriolar system of right and left coronary arteries.Results. Left ventricular end diastolic pressure was reduced in the group treated with revascularized Omental graft compared to vehicle group. Ejection fraction was also improved in revascularized group then infarcted group. Measurements of the myocardial infarction area showed more reduction in the MI area of the revascularized group than in the vehicle group, however this difference did not reach statistical significances. In comparison between free and pedicle Omental grafts, the free Omentum was shown to be superior over the pedicle in terms of cardiac function EF% (41.3 +/- 0.75 Vs. 35.6 +/- 0.75, P = 0.01), and infarction size (36.2 +/- 6.6 Vs. 39.5 +/- 13, P = NS). All different Omental grafts showed the ability to form a neovascularization between the ischemic myocardium and the surrounding structures.
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Diaba-Nuhoho, Patrick. "Potential cardioprotective effect of chronic, moderate consumption of reduced-alcohol wine in a rat model of pulmonary hypertension". Master's thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/29320.
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Background: Pulmonary arterial hypertension (PAH) is a severe disease which leads to right ventricular (RV) dysfunction and possibly death. The pathophysiological process of PAH remains unclear but oxidative stress is thought to contribute to arterial and ventricular dysfunction. Red wine has powerful antioxidant properties and is cardioprotective. However, side effects of alcohol may limit the use of wine as a therapeutic agent. The aim of this study was to test whether reduced-alcohol red wine (RARW) or regular red wine (RW) consumption would limit monocrotaline (MCT)-induced PAH in rats.
Methods: Long Evans male rats (150-175g) were randomly assigned into 6 groups: (1) Control: no subcutaneous injection of MCT; (2) MCT; (3) RARW; (4) MCT-Treated with RARW: 5.5% alcohol red wine (5) RW and (6) MCT-Treated with RW: 15% alcohol red wine. The wines were diluted with water (1:7), to supply an equivalent of 2-3 glasses daily consumed in humans ad libitum for 7 days before MCT treatment and for 28 days after MCT treatment with 80mg/kg. The stability of the wine was determined for 4 weeks by analysing ORAC values, total phenolic concentration, anthocyanin and catechin concentrations. Prior to randomisation, and at day 28, echocardiography (VEVO 2100, Visualsonics Inc.) was performed to evaluate pulmonary artery acceleration time (PAAT), an accurate estimate of pulmonary artery pressure, PAAT/Ejection fraction and RV thickness as a marker of RV hypertrophy. Oxidative stress was evaluated by measuring lipid peroxidation markers (conjugated dienes (CD), thiobarbituric acid reactive substances (TBARS)) and antioxidant measures of oxygen radical absorbance capacity (ORAC), superoxide dismutase (SOD) and catalase (CAT) activities in blood plasma were analysed.
Results: Baseline echocardiography showed similar cardiac function amongst all groups. MCT injection induced right ventricular hypertrophy compared to controls (1.22 ± 0.01 mm and 0.52 ± 0.04 mm; p< 0.0001). A decrease in PAAT was observed in the MCT group compared to controls (13.95 ± 0.95 vs 23.43 ± 1.64 ms, p< 0.001). However, MCT treatment with RARW ameliorated the trend in the MCT group (18.93 ± 1.80 vs 13.95 ± 0.95 ms, p=0.02). Similarly, PAAT/Ejection fraction in the MCT group was reduced compared to the control group (0.18 ± 0.02 ms and 0.32 ± 0.18 ms; p< 0.001). Chronic moderate treatment with RARW in PAH animals improved hypertrophy and PAAT/Ejection fraction (0.85 ± 0.07 mm; P< 0.001and 0.25 ± 0.30 ms, respectively; p=0.02 versus the MCT group). Oxidative stress markers showed an increase in CD amongst animals with MCT compared to controls (671.60 ± 42.53 nmol/L and 453.10 ± 34.76 nmol/L; p=0.004). Chronic moderate treatment with RARW reduced lipid peroxidation (CD: 471.60 ± 27.45 nmol/L; p=0.004 versus the MCT group). Plasma TBARS, ORAC, SOD and CAT were not significantly affected by the condition or the treatment. The RARW had a consistently higher antioxidant status than the RW for the duration of the study. The mean concentration of RARW to the RW after 4 weeks in the total phenol was (291.90 ± 10.42 vs 235.80 ± 9.22 mg/L, p=0.006), that of the anthocyanins was (190.00 ± 3.53 vs 172.20 ± 5.13 mg/L M-3-G, p=0.0008), that of catechin was (12.06 ± 0.31 vs 10.26 ± 0.19 mg/L, p=0.157), and that of ORAC was (32.55 ± 2.75 vs 26.55 ± 2.37 nmol/L trolox equivalents, p=0.983).
Conclusion: This study suggests that a moderate and chronic treatment with RARW but not RW attenuates MCT-induced PAH in rats, an effect which may be mediated, at least in part, by reduction of lipid peroxidation. The use of RARW could be tested in a randomised controlled trial and may be more beneficial than RW. This simple, inexpensive treatment might represent a new therapeutic option for PAH
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Norrie, Philip Anthony. "Wine and health through the ages with special reference to Australia". Thesis, View thesis, 2005. http://handle.uws.edu.au:8081/1959.7/709.
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The use of wine as a medicine is not a new idea, but one that has been rediscovered and given credibility due to current research findings. This research examines the use of wine as a medicine in the past and currently. The whole question of wine and health is put into a more balanced and proper perspective, instead of the ill-informed, negative anti-alcohol view. The aim of the thesis is to document the history of the uses of wine as a medicine, particularly in Australia. The author uses a social ecology framework,which is concerned with the interrelationships between the domains of the personal, social and environmental, with a critical, holistic transdisciplinary understanding approach. One aim of the research is to change the perception of wine from one of a drink for special occasions to one of a daily health drink taken in moderation with a meal
9
Dlamini, Lindizwe. "Exploring the cardioprotective effect of synthetic wine in Long Evans rats". Master's thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/15763.
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[No copyright notice] Background: Moderate and chronic consumption of red wine protects against cardiovascular disease. Wine is a complex matrix containing multiple molecules whose concentrations can vary from one bottle to another. Therefore, the delineation of the putative cardioprotective components in wine such as alcohol, resveratrol and melatonin is very challenging when using commercially available red wine. Aim: We aimed to use synthetic wine, whose composition is well characterized, to explore whether the presence of alcohol, resveratrol and melatonin (as found in commercial wines) contributes to the cardioprotective effect of chronic and moderate consumption of red wine (equivalent to 2 glasses of wine/day) in an animal model. Additionally, we hypothesized that synthetic wine enriched with resveratrol and melatonin confers cardioprotection via improvement of overall antioxidant profile.
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Partington, Lee Ian. "Molecular wire based bio-electrochemical sensing systems". Thesis, University of Hull, 2016. http://hydra.hull.ac.uk/resources/hull:15133.
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This thesis aims to develop rapid, quantitative point of care sensing systems that exploit molecular wire platforms to enable the electrochemical detection of multiple target biomarkers, thereby empowering new technologies for the diagnosis of various medical conditions. Accordingly, the first chapter provides an overview of clinically important biomarkers for pregnancy and cardiovascular disease. The second chapter of this thesis details the electrochemical concepts underpinning subsequent chapters, with the third chapter providing an experimental overview. The first two research chapters develop a nano-structured, molecular wire platform based on diazonium salt electrochemistry coupled with immobilisation of antibodies conjugated to a suitable electroactive label. Here, the abundance of amine functionalities present at the antibody paratope enable the statistically large number of redox tags to be present at the antibody-antigen binding site, empowering the exquisitely selective and strong affinity of the antibody for a suitable antigen to be monitored quantitatively, through assessing the extent with which the redox labels are partially blocked in the presence of the antigen. In Chapter 4, experiments are contrasted with bespoke theory developed in order to unravel the thermodynamic and kinetic factors that empower this methodology to be singularly sensitive for the pregnancy biomarker human chorionic gonadotropin (hCG). It is demonstrated that quantitative analysis of hCG detection in artificial urine does not suffer interference. Chapter 5 adapts this approach to survey other biomarkers including β-hCG and brain natriuretic peptide. Combinatorial immunoassays are also investigated through the use of two types of antibodies, each tagged with a different redox label. Chapter 6 exploits the electroactive spin-trapping molecule TEMPO for the detection of biomolecules that have been damaged through oxidative stress. Last, Chapter 7 presents an overall conclusion to the work presented in this thesis.
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Ayati, Marzieh. "Algorithms to Integrate Omics Data for Personalized Medicine". Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1527679638507616.
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Yeoh, Chit Cheng. "Molecular gene expression and genome wide profiling in tamoxifen-resistant breast cancer". Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/370.
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Oestrogen receptor positive (ER+) breast cancers (BC) are heterogeneous in both their clinical behaviour and response to therapy. The ER and Progesterone (PgR) are currently the best predictors of response to the anti-oestrogen tamoxifen, yet up to 40% of ER+ breast cancer will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance (TR) are required. There has been an explosion of greater understanding since the arrival of cutting-edge gene and genomic profiling technology. The two major aims of this research are to develop stable gene signatures that are effective at distinguishing „prognostic‟ groups and, when tested directly for response to tamoxifen, a set of „predictive‟ markers. In order to establish cellular pathways responsible for TR, tissue at relapse while on tamoxifen is preferred. However, in practice, this is difficult to obtain. Hence, in this study, I have established TR derivatives of breast cancer cell lines, T47D and ZR75-1, and analysed their gene-expression by microarray. MAGEA2 and EGLN3 were 4.0 and 3.8 fold upregulated respectively in TR cell lines. For MAGEA2- and EGLN3-overexpressing lines, the proliferation and growth rates in tamoxifen-containing media were significantly higher (p-value <0.001 and p<0.05, respectively) than for control cells. I have investigated possible downstream targets for each protein which may contribute to the mechanism of resistance. Immunohistochemistry validation was performed on a cohort of 196 tamoxifen-treated primary breast tumour tissues: MAGEA2 and EGLN3 were found to be valuable predictive (Positive predictive value of 89%, and 85%, with high sensitivity 38% and 42% respectively) biomarkers for TR in primary breast tumours. In the human breast tumour arm of this study, 25 frozen samples with known response to tamoxifen were analysed on both SNP6.0 and expression EXON arrays. The integrated analysis suggested that 5 genes (OPCML, OR10G7, SNF1LK2, PALM and ZBTB-16) are good predictors of TR, with high negative predictor values (68%, 71%, 59% and 73% respectively for the last 4 genes). Significant regions of copy number variation (CNV) were identified at chromosomes 8q24, 17q21-22 and 11q23-25. The application of this high-resolution approach should lead to a better understanding of the roles of complex genetic alterations in TR.
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Raghavan, Manoj. "High-resolution genome-wide single nucleotide polymorphism mapping in acute myeloid leukaemia". Thesis, Queen Mary, University of London, 2008. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1884.
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Investigation of the genetics of acute myeloid leukaemia (AML) has revealed the underlying basis of the disease and led to targets for therapy. High-resolution single nucleotide polymorphism (SNP) arrays detected regions of loss of heterozygosity and DNA copy number changes, augmenting the results of conventional cytogenetic analysis in AML. Fifteen out of 72 (20%) primary AML samples exhibited large regions of homozygosity that could not be accounted for by visible chromosomal abnormalities in the karyotype. Further analysis confirmed that these patterns were due to partial uniparental disomy (UPD). Remission marrow was available from five patients showing UPD in their leukemias, and in all cases the homozygosity was found to be restricted to the diagnostic leukemic clone. These cryptic nonrandom chromosomal abnormalities are characteristic of mitotic recombination. In 7 of 13 cases with UPD, concurrent homozygous mutations were identified at four distinct loci (WTI, FLT3, CEBPA, and RUNXI). This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele. Clonal evolution from heterozygous to homozygous mutations by mitotic recombination would provide a mechanism for relapse of AML. Analysis of 27 paired diagnostic and relapsed AML samples demonstrated newly acquired segmental UPDs at relapse in 11 AML samples (40%). Six were segmental UPDs of chromosome 13q, which led to a change from heterozygosity to homozygosity for internal tandem duplication of FLT3. Three further AML samples had evidence of acquired segmental UPD of 13q in a subclone of the relapsed leukemia. One patient acquired segmental UPD of 19q which led to homozygosity for a CEBPA mutation 207 C-'T. Finally, a single AML patient acquired segmental UPD of chromosome 4q, for which the candidate gene is unknown. In conclusion, the acquisition of segmental UPD and the resulting homozygous mutation is a common event associated with relapse of AML.
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Heap, Graham Alastair Richard. "Assigning function to genome wide association study variants associated with complex gastrointestinal disease". Thesis, Queen Mary, University of London, 2009. http://qmro.qmul.ac.uk/xmlui/handle/123456789/535.
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The genome‐wide association study era has identified numerous loci associated with many common polygenic diseases. The next challenge is to identify the functional consequences of these variants and elicit how they impact on disease risk. Using a combination of protein based assays, large scale microarrays and high‐throughput generation sequencing platforms this thesis aims to identify the functional effects of disease loci, with particular focus on Crohn’s disease and coeliac disease, two common complex gastrointestinal diseases. Variants located within the Interleukin 23 receptor are associated with both susceptibility and protection from Crohn’s disease, a debilitating chronic inflammatory disease of the bowel. A study was undertaken to investigate the effect of these variants, at the mRNA as well as the protein level, on both cytokine and receptor levels. Coeliac disease is a dietary intolerance to the gluten component of wheat, barley and rye and has an estimated prevalence of approximately 1%. Genome‐wide association studies have identified eight genomic different loci as associated with coeliac disease but none have been functionally characterised. To investigate the effect that genotype has on gene transcript levels, a genetical genomics study was undertaken in patients with coeliac disease generating results with relevance to a range of autoimmune disorders. Before disease based effects can be identified, it is first important to fully characterise the normal human transcriptome and methylome. To this end CD4 + T cells were studied using novel high‐throughput sequencing techniques, with the aim of providing some insight into novel genomic properties that may illuminate current and future disease associated loci. Given the base pair resolution approach of high‐throughput sequencing, a novel method of assaying for SNP effects on gene expression was developed. This allele specific method, using whole transcriptome sequencing, is capable of identifying alterations in transcript expression on a genome‐wide scale.
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Knight, Dave. "Variation in silicosis prevalence in South African gold miners : an industry-wide study". Master's thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/12412.
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Includes bibliographical references (leaves 55-65).Includes abstract.
This study investigates the prevalence of silicosis in the South African gold mining industry. Gold mining is an important industry in South Africa, yet has been blighted by silicosis and tuberculosis in miners since its inception in 1887. There have been two previous studies conducted in black in-service miners using modern epidemiologic methods that found high prevalences of silicosis .The objectives of our study were three-fold. Firstly, to determine silicosis prevalence stratified by certain variables. Secondly, to compare silicosis prevalences to these two previous studies conducted in order to determine whether any secular trends are present. Thirdly, to report on any variation in silicosis between mining shaft, mining company or mining region, and to generate hypotheses for any variation found.
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Waldron, Joseph Alexander. "The role of the exoribonuclease Pacman/Xrn1 in wing development in Drosophila". Thesis, University of Brighton, 2014. https://research.brighton.ac.uk/en/studentTheses/6bd7b8c8-9448-4af2-b99f-aadf2e60c91b.
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RNA stability plays a critical role in the control of gene regulation by determining the levels of mRNA that can be translated into protein. The aim of this thesis is to investigate the role of the exoribonuclease Pacman in regulating gene expression during wing development in Drosophila melanogaster. Pacman is the only known cytoplasmic exoribonuclease which degrades RNA in a 5’‐3’ direction and is highly conserved across all eukaryotes.
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Welton, William E. "The impact of differences in market structure on community-wide Medicare expenditures". Ann Arbor, Mich. : University of Michigan, 1999. http://books.google.com/books?id=YC9YAAAAMAAJ.
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Patel, Riyaz. "Beyond genome wide discovery : an exploration of novel genetic variants for coronary heart disease". Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/38470/.
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Recent developments spurred on by the Human Genome Project have for the first time permitted genome wide association studies leading to identification of multiple novel variants for complex diseases. This thesis consists of a series of studies exploring recent genetic findings for coronary heart disease (CHD) within the broader context of the promises of the genomic era that new findings would ultimately lead to 1) Identification of new disease mechanisms 2) Permit genotype based risk prediction and 3) Promote development of novel and targeted therapies based on genotype. We sought to address these questions, using the Emory Genebank, a collection of angiographically phenotyped subjects with stored blood samples and long-term follow up. We first refined the phenotype for CHD to help understand underlying mechanism and demonstrated differential associations between 8 novel risk variants including 9p21, and sub-phenotypes of CHD and thereby proposed differing mechanisms of risk for these loci. With two non-CHD cohorts we then demonstrated further association between one particular risk variant at 6p24 and the intermediate phenotype of arterial elasticity and related this to a potential novel mechanism of risk. Despite significant association with first events in population cohorts, we showed that these risk variants including 9p21 have limited value in secondary risk prediction, failing to demonstrate any association with prospective events in our cohort as single markers or when combined into a cumulative genetic risk score. Finally in subjects carrying leukotriene pathway CHD risk variants, we administered an oral leukotriene synthesis inhibitor and after just 4 week of therapy observed significant improvement in their endothelial function. In summary, these studies demonstrate the value of refining the phenotype to understand potential mechanisms, the complexities of genetic risk prediction and the feasibility and benefit of targeting therapy based on risk genotype.
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Duong, Cuong V. "Investigation of the pituitary epigenome : a genome-wide analysis of changes associated with sporadic tumours". Thesis, Keele University, 2014. http://eprints.keele.ac.uk/625/.
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Pituitary tumours harbour epigenetic aberrations; however, characterisation of these aberrations, on a genome-wide basis, is hampered by their infrequent occurrence and their small size. To overcome the constraint of limited tissue, whole genome amplification of sodium bisulphite converted DNA was employed and provided a consistent 25-fold amplification from individual samples. This material was used in a genome-wide analysis the DNA methylation of 27,578 CpG sites for each of the major adenoma subtypes. In a discovery cohort, on the basis of stringent criteria, pyrosequencing validated 12 of 16 hypermethylated genes. Overall, the criteria identified 40 genes in non-functional, 21 in growth hormone, six in prolactin and two in corticotrophinoma. In an independent cohort, different frequencies of hypermethylation were apparent for each of these genes; however, association between methylation and reduced transcript expression was infrequent. For the EFEMP1 gene, following its initial identification, studies of an independent cohort of tumours showed frequent reduced EFEMP1 expression, irrespective of adenoma subtype. However, reduced expression was not invariantly associated CpG island methylation. Conversely, chromatin immunoprecipitation assays (ChIP) showed histone modifications that were consonant with expression status. The causal relationship between gene silencing and epigenetic change was established by observing that epidrug challenges induced re-expression of EFEMP1 in pituitary cells that was concomitant with histone modification associated with expressed genes. Enforced expression of EFEMP1 was without effect on cell proliferation or apoptotic end-points but was responsible for decreased expression of the MMP2 transcript. This association was not apparent in primary adenomas, however, MMP7, showed a positive correlation with EFEMP1 and this may reflect cell or species specific differences, suggesting that the relationship between EFEMP1 and MMP7 requires more detailed investigation. This study is the first whole genome identification of a potential biomarker signature and their functional characterisation will provide insight of tumour aetiology and identification of new therapeutic targets.
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Martínez, García Fernando. "Elucidating the genetic susceptibility of hypertension associated microalbuminuria: genome wide scan". Doctoral thesis, Universitat de València, 2010. http://hdl.handle.net/10803/39085.
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Objective: To identify genetic susceptibility variants for hypertension associated microalbuminuria.
Methods: The study design was a nested case-control genetic association study. Three hundred and three patients were selected from one prospective cohort recruited in the hypertension clinic of two different hospitals with the objective of identify clinical factors associated with microalbuminuria. All the patients were less than 50y, hypertensive grade I and naïve regarding to the treatment at the time of the recruitment. Cases were those who developed microalbuminuria (UAE>=30 mg/day) during the follow up and controls were those who remained with an UAE less than 30 mg/day. UAE was assessed in 24 hour urinary and in two or three samples. The Nsp array of the Affymetrix Gene-Chip Human Mapping 500K was used for genotyping, BRLMM algorithm for inferring the genotypes and PLINK software for performing the association analysis after quality control procedures.
Results: The final sample size compromised of 201 controls and 102 cases with genotypes for 250000 SNPs. A few polymorphisms and haplotypes resulted in an association with the presence of an increment in UAE expressed as a qualitative or as a quantitative trait.
The significantly associated loci were 8p22 for UAE as a qualitative trait and 8q12.1, 2p11.2, 9p22.2 and 18q23 for the quantitative trait. Some possible candidate genes within the significantly associated loci are: MSR1 for the qualitative trait and IMPAD1, REEP1, BNC2, and CNDP1 for the quantitative trait.
There was another group of SNPs which did not reach the statistical significance but they seemed to stand out from the rest of SNPs. Within those regions there were also some possible candidate genes such as ELMO, LOX1, NRP1 or PEBP1 among others.
Conclusions: GWAS strategy has enabled the identification of some genomic areas with potential influence on UAE in hypertensive patients. We were able to replicate some of the previously reported linked or associated loci with renal damage.Objetivo: Identificar variantes genéticas de susceptibilidad al desarrollo de microalbuminuria en la hipertensión arterial esencial Métodos: Se trata de un estudio de asociación genética tipo caso-control anidado. Trescientos tres pacientes fueron seleccionados en las unidades de hipertensión de dos hospitales dentro un estudio de cohortes encaminado al estudio de aquellos factores clínicos que influyen en el desarrollo de microalbuminuria. Los pacientes seleccionados eran menores de 50 años con niveles de presión arterial en rango normal-alto o hipertensión grado 1 al inicio del periodo de seguimiento. Los casos fueron aquellos pacientes que desarrollaron microalbuminuria (EUA >=30 mg/día) durante el seguimiento y los controles aquellos que permanecieron normoalbuminuricos (EUA menor de 30 mg/día). EUA se determinó en orina de 24 horas y en dos o tres muestras consecutivas. Como plataforma de genotipado se utilizó el array Nsp del Gene-Chip Human Mapping 500K de Affymetrix. El algoritmo BRLMM se utilizó para inferir los genotipos y el software PLINK para realizar el estudio de asociación una vez realizados todos los controles de calidad oportunos característicos de este tipo de estudios. Resultados: La muestra final incluyó 201 controles y 102 casos con genotipos para mas de 250000 SNPs. Unos pocos polimorfismos y haplotipos resultaron asociados con el incremento de los niveles de EUA expresados como variable cualitativa o cuantitativa. Los loci que presentaron asociación significativa fueron: 8p22 para la EUA expresada como variable cualitativa y 8q12.1, 2p11.2, 9p22.2 y 18q23 fpara la asociación con la variable cuantitativa. Algunos de los posibles genes candidatos en la zonas de asociación geneética fueron:: MSR1 para la variable qualitativa y IMPAD1, REEP1, BNC2, y CNDP1 para la EUA expresada de forma cuantitativa. Otro grupo de marcadores no alcanzó la significación estadística a nivel de genoma completo pero aparecieron claramente destacados del resto. Dentro de esas regiones algunos posibles genes candidatos fueron : ELMO, LOX1, NRP1 o PEBP1 entre otros. Conclusiones: La estrategia de estudio genómico completo ha permitido la identificación de regiones cromosómicas con influencia potencial sobre la EUA en hipertensos. Algunas de las regiones cromosómicas previamente asociadas en estudios de asociación o de ligamiento han podido ser replicadas.
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Alsanosi, Safaa Mohammed M. "Blood pressure-lowering agents response : a systematic review and genome wide study". Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8100/.
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In spite of the vast amount of evidence on the benefits of blood pressure (BP) lowering that has accumulated to date, hypertension (HTN) remains the leading risk factor for disease and disability worldwide. Since the first BP-lowering agents became available in the 1950s, their effects have been tested thoroughly by means of the best evidence-providing approach, namely, large randomised controlled trials (RCTs). In the same way, the pharmacogenomics of HTN have the potential to identify genetic biomarkers that predict the response of BP-lowering agents through genome-wide association studies (GWAS), which analyse quantitative traits at millions of markers across the genome to identify genetic variations that could contribute to HTN. For the most part, computational approaches and software tools have played a significant role in translating RCTs and GWAS findings. This thesis aims first to systematically review the BP responses of main BP-lowering agents, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), diuretics (DIs) and beta-blockers (BBs) in RCTs, and second to identify the single nucleotide polymorphisms (SNPs) associated with the BP-lowering responses of CCBs and BBs on Nordic Diltiazem (NORDIL) subjects using GWAS. Description of the research results: Following the Population Intervention Comparison Outcome Study (PICOS) design framework, a literature search of multiple sources resulted in the identification of 10,577 publications, with 5,568 unique records identified after duplicates were excluded. In total, 184 studies were identified as potentially eligible, of which 82 RCTs with a total of 197,684 participants were selected for quantitative synthesis. With regard to BP-lowering strategies, 13 studies with 41,886 participants focused on lowering BP intentionally, while the remaining 69 studies (155,798 participants) were classified as unintentional BP-lowering studies. Risk of bias in included studies: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, all included studies were described as RCTs; however, most studies did not address how treatment randomization occurred or how allocation of treatment was concealed. All included studies also stated that they were double-blind studies, but again, most did not describe how the double blinding was ensured throughout the studies. The risk of attrition bias was avoided as all randomized participants were included in the analysis. All of the studies had a low risk for reporting bias. BP-lowering agents were added to randomly allocated treatment to control high BP; consequently, one potentially unclear source of bias was present in 13 of the 82 studies. The overall quality was rated to be acceptable to high. In all, 48 studies were rated to be high-quality studies, and 34 studies were rated as acceptable quality. Effect of intervention: After a systematic search and selection process, 56 studies were included in the analysis of delta BP response, 37 studies were included in the analysis of single-measure BP response and 20 studies were included in the analysis of repeated measures. A number of BP-lowering agents showed a significantly (P<0.05) superior BP response in comparison with other agents included in the review; however, the level of BP response was still small. CCBs were superior to ACEIs in lowering both systolic BP (SBP) and diastolic BP (DBP). DIs were superior to ACEIs and CCBs in lowering SBP. ARBs were superior to BBs in lowering SBP. CCBs and DIs were significantly superior to placebos in lowering both SBP and DBP. Genome-wide study: Following NORDIL quality control standards, a final set of 3,850 samples and 500,905 SNPs was available for analysis. In total, 51 SNPs showed a significant (P<1X10-5) association with BP response. The top discordant signals identified in NORDIL included five SNPs for SBP on BB arm, seven SNPs for DBP on BB arm, 12 SNPs for SBP on CCB arm and nine SNPs for DBP on CCB arm. Discordant SNPs from the NORDIL were replicated, based on the interests of five collaborative RCTs; including 11 SNPs for SBP on BB arm, 22 SNPs for DBP on BB arm, 23 SNPs for SBP on CCB arm and 18 SNPs for DBP on CCB arm. However, no SNP achieved a genome-wide significance of (P<5x10-8). Future recommendations: Further systematic reviews of RCTs comparing different BP-lowering agents are required to provide evidence of the options for BP-lowering medication. Specifically, there is a need to study BP response as an outcome by itself, taking into account different BP-lowering agent combinations,including classes and sub-classes, along with co-morbidities such as type 2 diabetes mellitus, coronary heart disease and chronic renal failure. Regarding the genome-wide study, further studies are needed to clarify the potential contribution of plausible SNPs in relation to CCB and BB response in HTN. These studies should include comprehensive sequencing of the candidate interval, genotyping of variants in many population samples, testing for association, functional studies and investigation of interactions with other genes or environmental factors. Furthermore, genome-wide studies need to identify directionally discordant signals between SNP and BP response for BB and CCB and confirm the validity of a SNP BP response by analysing the SNP effect on mortality.
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Sandling, Johanna K. "Genetic Analyses of Multiple Sclerosis and Systemic Lupus Erythematosus : From Single Markers to Genome-Wide Data". Doctoral thesis, Uppsala universitet, Molekylär medicin, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-117776.
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In autoimmune diseases an individual’s immune system becomes targeted at the body’s own healthy cells. The aim of this thesis was to identify genetic risk factors for the two autoimmune diseases multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In Study I, we found that genetic variation in the interferon regulatory factor 5 gene (IRF5), previously shown to be associated with SLE, rheumatoid arthritis and inflammatory bowel diseases, was associated also with MS. An insertion/deletion polymorphism in the first intron of IRF5 is as a good functional candidate for this association. IRF5, together with the signal transducer and activator of transcription 4 gene (STAT4), are the most important genetic risk factors for SLE, outside the HLA region. In Study II we showed using a family-based study design that genetic variation in STAT4 is associated with SLE also in the Finnish population. In Study III, we investigated a STAT4 risk allele for SLE for its association with cardiovascular disease in SLE patients. The risk allele of STAT4 proved to be strongly associated with ischemic cerebrovascular disease and anti-phospholipid antibodies in SLE patients. A possible mechanism for this association is that the risk allele leads to increased production of pro-thrombotic anti-phospholipid antibodies, which in turn increases the risk for stroke. Both IRF5 and STAT4 are involved in signalling of the type I interferon system. In Study IV, we investigated 78 additional genes in this system for their association with SLE in a Swedish cohort. The most promising results were followed up in additional patients and controls from Sweden and the US. Two novel SLE genes were identified. In Study V a large follow-up of a genome-wide association study was performed. Five new SLE loci were identified: TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10. A number of genes previously shown to be associated with other autoimmune diseases were also tested for association with SLE. This analysis identified the type I interferon system gene IFIH1 as a novel SLE risk locus. These studies confirms the central role of the type I interferon system in SLE and further suggests common genetic risk factors in autoimmunity.
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Jetha, Arif. "Genome wide analysis of the response of human beta-cells to islet isolation and «in vitro» culture". Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=97157.
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The biggest challenge to islet transplantation is preserving cell mass and function. It is known that the stresses encountered during islet isolation have deleterious effects on beta-cell physiology. The nature of these effects, however, are incompletely known, partly due to the heterogeneity of islet preparations. Using a combination of laser capture microdissection and microarray technology, we therefore sought to determine the beta-cell specific events that occur as a result of islet isolation and in vitro culture. Our data shows that islet isolation and in vitro culture induce a large inflammatory response that is NF-kB dependent and involves the upregulation of several pro-inflammatory cytokines such as IL-8, IL-1 and MCP-1. Furthermore, several transcription factors involved in ß-cell differentiation, such as NeuroD1, NKX2.2, and MafA were decreased, providing insight into mechanisms of beta-cell dedifferentiation. Therefore, therapies aimed at targeting NF-kB and re-expressing transcription factors necessary to beta-cell function should be explored further.Le stress subi durant l'isolation des îlots de Langerhans a des effets négatifs sur la physiologie des cellules bêta. Nous avons tenté de déterminer les événements survenant suite à une isolation d'îlots et de leur culture in vitro grâce à la capture et découpage laser et la puce à gènes. Nos résultats démontrent que l'isolation d'îlots et leur culture in vitro produisent une importante réponse inflammatoire. Cette réponse dépend de la protéine NF-kB et implique une augmentation de plusieurs cytokines pro-inflammatoires, incluant IL-8, IL-1, et MCP-1. Aussi, plusieurs facteurs de transcription essentiels dans la différenciation des cellules bêta comme NeuroD1, NKX2.2, et MafA ont diminué, suggérant que les cellules bêta se dédifférencient après leur isolation et culture in vitro. Par conséquent, les thérapies visant NF-kB et la réexpression des facteurs de transcription nécessaires à la fonction des cellules bêta devraient être explorées plus en détails.
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Fleming, Michael. "Using Scotland-wide record linkage to investigate the educational and health outcomes of children treated for chronic conditions". Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8594/.
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Objectives: This study linked Scottish education data to a number of administrative health datasets to explore associations between childhood chronic ill health and subsequent educational and health outcomes. Chronic conditions investigated were diabetes, asthma, epilepsy, attention deficit hyperactivity disorder (ADHD) and depression. Educational outcomes were number of days absent from school, number of school exclusions, special educational need (SEN), academic attainment and unemployment. Health outcomes were all-cause and cause-specific hospital admission, total number of hospital admissions, total length of hospital admission and all-cause mortality. Approach: Pupil census data and associated education records for all children attending primary and secondary schools in Scotland between 2009 and 2013 were linked to national prescribing data, hospital admissions, death records and retrospective maternity records enabling outcomes to be studied whilst controlling for socioeconomic, demographic and obstetric factors including birth outcomes and maternal antecedents. Specific medications are prescribed for some particular chronic conditions; therefore, children identified as receiving these medications whilst at school were assumed to have these conditions. Results: Children treated for each of the five conditions had more frequent absenteeism from school and were more likely than their peers to have SEN. However, only children treated for depression, epilepsy or ADHD experienced poorer academic attainment and increased odds of unemployment. Furthermore, children treated for depression or ADHD were significantly more likely to be excluded from school. Children treated for asthma experienced poorer academic attainment but no increased odds of unemployment and the association with attainment disappeared after adjusting for their increased absenteeism. Children treated for each of the five conditions had an increased risk of hospital admission and children treated for depression or epilepsy also had an increased risk of recurrent hospitalisation and longer stays in hospital. All of the chronic conditions, with the exception of ADHD, were associated with increased mortality. Conclusion: All five of the chronic conditions investigated in this thesis were associated with adverse educational and health outcomes. The number of outcomes affected varied by condition. Treated depression, epilepsy and ADHD were associated with the most wide-ranging impacts. Children treated for depression fared worse than their peers across all nine outcomes, and children treated for epilepsy and ADHD across eight and six respectively. In contrast, children treated for asthma and diabetes fared worse than their peers in respect of around half the outcomes investigated. Children with these chronic conditions at school appear to experience significant educational and health disadvantage; therefore further work is required to understand the underlying mechanisms and to develop effective interventions to reduce their risk.
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Tahrani, Ahmad [Verfasser], i Michael [Akademischer Betreuer] Wink. "Mass Spectrometric Approaches in Profiling and Monitoring Bioreactivity of Polyphenols in Medicinal Plants / Ahmad Tahrani ; Betreuer: Michael Wink". Heidelberg : Universitätsbibliothek Heidelberg, 2011. http://d-nb.info/1179783018/34.
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Gentles, Jeremy A. "Reducing Injuries is NOT Enough – It Also Helps to Win". Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/etsu-works/3983.
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Hillman, Timothy R. "Microstructural information beyond the resolution limit : studies in two coherent, wide-field biomedical imaging systems". University of Western Australia. School of Electrical, Electronic and Computer Engineering, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0085.
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Pira, Rahim S. "Supporting asynchronous telemedicine : electronic mail vs. the world wide web vs. replicated databases /". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0007/MQ42422.pdf.
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Veronin, Michael A. "The Validity of Health Claims on the World Wide Web: A Case Study of the Herbal Remedy Opuntia". Thesis, University of North Texas, 2000. https://digital.library.unt.edu/ark:/67531/metadc2441/.
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The World Wide Web has become a significant source of medical information for the public, but there is concern that much of the information is inaccurate, misleading, and unsupported by scientific evidence. This study analyzes the validity of health claims on the World Wide Web for the herbal Opuntia using an evidence-based approach, and supports the observation that individuals must critically assess health information in this relatively new medium of communication.
A systematic search by means of nine search engines and online resources of Web sites relating to herbal remedies was conducted and specific sites providing information on the cactus herbal remedy from the genus Opuntia were retrieved. Validity of therapeutic health claims on the Web sites was checked by comparison with reports in the scientific literature subjected to two established quality assessment rating instruments. 184 Web sites from a variety of sources were retrieved and evaluated, and 98 distinct health claims were identified. 53 scientific reports were retrieved to validate claims. 25 involved human subjects, and 28 involved animal or laboratory models. Only 33 (34%) of the claims were addressed in the scientific literature. For 3% of the claims, evidence from the scientific reports was conflicting or contradictory. Of the scientific reports involving human subjects, none met the predefined criteria for high quality as determined by quality assessment rating instruments. Two-thirds of the claims were unsupported by scientific evidence and were based on folklore, or indirect evidence from related sources.
Information on herbal remedies such as Opuntia is well represented on the World Wide Web. Health claims on Web sites were numerous and varied widely in subject matter. The determination of the validity of information about claims made for herbals on the Web would help individuals assess their value in medical treatment. However, the Web is conducive to dubious health information and individuals should exercise caution in accepting health claims unsupported by scientific evidence.
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Wallerman, Ola. "Genome-Wide Studies of Transcriptional Regulation in Mammalian Cells". Doctoral thesis, Uppsala universitet, Medicinsk genetik, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-132882.
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The key to the complexity of higher organisms lies not in the number of protein coding genes they carry, but rather in the intrinsic complexity of the gene regulatory networks. The major effectors of transcriptional regulation are proteins called transcription factors, and in this thesis four papers describing genome-wide studies of seven such factors are presented, together with studies on components of the chromatin and transcriptome. In Paper I, we optimized a large-scale in vivo method, ChIP-chip, to study protein – DNA interactions using microarrays. The metabolic-disease related transcription factors USF1, HNF4a and FOXA2 were studied in 1 % of the genome, and a surprising number of binding sites were found, mostly far from annotated genes. In Paper II, a novel sequencing based method, ChIP-seq, was applied to FOXA2, HNF4a and GABPa, allowing a true genome-wide view of binding sites. A large overlap between the datasets were seen, and molecular interactions were verified in vivo. Using a ChIP-seq specific motif discovery method, we identified both the expected motifs and several for co-localized transcription factors. In Paper III, we identified and studied a novel transcription factor, ZBED6, using the ChIP-seq method. Here, we went from one known binding site to several hundred sites throughout the mouse genome. Finally, in Paper IV, we studied the chromatin landscape by deep sequencing of nucleosomal DNA, and further used RNA-sequencing to quantify expression levels, and extended the knowledge about the binding profiles for the transcription factors NFY and TCF7L2.
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Choudhry, Hani. "Genome-wide analysis of the hypoxic breast cancer transcriptome using next generation sequencing". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:9a66b553-a66c-4164-a854-5881be65ca45.
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Hypoxia pathways are associated with the pathogenesis of both ischaemic and neoplastic diseases. In response to hypoxia the transcription factor hypoxia‐inducible factor (HIF) induces the expression of hundreds of genes with diverse functions. These enable cells to adapt to low oxygen availability. To date, pan-genomic analyses of these transcriptional responses have focussed on protein-coding genes and microRNAs. However, the role of other classes of non-coding RNAs, in particular lncRNAs, in the hypoxia response is largely uncharacterised. My thesis aimed at improving understanding of the transcriptional regulation of the non-coding transcriptome in hypoxia. I performed an integrated genomic analysis of both non-coding and coding transcripts by massively parallel sequencing. This was interfaced with pan-genomic analyses of DNAse hypersensitivity and HIF, H3k4me3 and RNApol2 binding in hypoxic cells. These analyses have revealed that hypoxia profoundly regulated all RNA classes. snRNAs and tRNAs are globally downregulated in hypoxia, whilst miRNAs, mRNAs and lncRNAs are both up- and downregulated with an overall trend towards slight upregulation. In addition, a significant number of previously non-annotated (and largely hypoxia upregulated) transcripts were identified, including novel intergenic transcripts and natural antisense transcripts. HIF bound close to genes for mRNAs, miRNAs and lncRNAs that were upregulated by hypoxia, but was excluded from binding at genes for RNA classes that showed global downregulation. This suggests that HIF acts as a transcriptional activator (but not repressor), of lncRNAs as well as mRNAs and miRNAs. Consistent with direct regulation by HIF, many of these hypoxia-inducible, HIF-binding lncRNAs were downregulated following HIF knockdown. Analysis of RNApol2 binding and DNAse HSS signals at HIF transcriptional target genes indicated that HIF-dependent transcriptional activation occurs through release of RNApol2 that is pre-bound to open promoters of lncRNAs as well as mRNAs. In these datasets, NEAT1 was the most hypoxia-upregulated, HIF-targeted lncRNA in MCF-7 cells and, despite binding of both HIF-1 and HIF-2 isoforms at its promoter, was selectively regulated by HIF-2 alone. Furthermore, NEAT1 was induced by hypoxia in a wide range of breast cancer cell lines and in hypoxic xenograft models. Functionally, NEAT1 is required for the assembly of nuclear paraspeckle structures. Increased nuclear paraspeckle formation was observed in hypoxia and was dependent on both NEAT1 and HIF-2. Knockdown of hypoxia-induced NEAT1 significantly reduced cell proliferation and survival and induced apoptosis. Finally, high expression of NEAT1 correlated with poor clinical outcome in a large cohort of breast cancer patients. These findings extend the role of the hypoxic transcriptional response in cancer into the spectrum of non-coding transcripts and provide new insights into molecular roles of hypoxia-regulated lncRNAs, which may provide the basis for novel therapeutic targets in the future.
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Diehl, K., T. Görig, Joel J. Hillhouse, J. L. Stapleton, R. Greinert i S. S. Schneider. "Wie Plausibel Ist Die Erfassung Von Bräunungssucht? – Ein Multimethodischer Ansatz Zur Evaluation Eines Neuen Instruments". Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/2782.
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Einleitung: Ultraviolette (UV) Strahlung – sei sie natürlich oder künstlich – kann zu Hautkrebs führen. In Verbindung mit Solarien, einer Hauptquelle künstlicher UV-Strahlung, wird häufig auf die Möglichkeit der Entstehung einer Bräunungssucht (oft auch „Tanorexie“) hingewiesen. Bisherige Instrumente zum Screening auf eine solche Bräunungssucht ergaben sich jedoch als nicht valide. Aus diesem Grund war es unser Ziel, ein in den USA neu entwickeltes Instrument, den Behavioral Addiction Indoor Tanning Screener (BAITS), auf Validität und Reliabilität zu testen.
Methodik: Der BAITS ist ein kurzes Screeninginstrument, welches aus sieben Items (Antwortkategorien: ja/nein) besteht. Die englischsprachige Itembatterie wurde in einer fünfstufigen Prozedur ([1] Übersetzung ins Deutsche, [2] Expert Panel, [3] Rückübersetzung ins Englische, [4] kognitive Interviews, [5] Erstellung der finalen Version) übersetzt. Zur Überprüfung der Validität und Reliabilität zogen wir die Daten der ersten Welle des Nationalen Krebshilfe Monitorings zur Solariennutzung (NCAM) bestehend aus einem kognitiven Pretest (n = 15) und einer bundesweiten Repräsentativbefragung (n = 3.000) heran.
Ergebnisse: Der kognitive Pretest ergab eine leichte Veränderung in der Formulierung eines Items. Insgesamt wurden in der bundesweiten Befragung 19,7% der aktuellen und 1,8% der ehemaligen Nutzer von Solarien positiv auf Symptome einer möglichen Bräunungssucht gescreent. Es fanden sich signifikante Zusammenhänge zwischen Solariennutzungsparametern und dem BAITS (Kriteriumsvalidität). Die interne Konsistenz (Reliabilität) ergab sich ebenfalls als gut (Kuder-Richardson-20 = 0,854) und der BAITS erwies sich als homogenes Konstrukt (Konstruktvalidität).
Schlussfolgerungen: Verglichen mit anderen Kurzinstrumenten zur Messung von Symptomen einer möglichen Bräunungssucht ergab sich der BAITS als valideres und reliableres Tool. Aufgrund seiner Kürze und der binären Items ist er auch in großen Surveys einfach einzusetzen.
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Cardona-Morrell, Magnolia. "Evaluation of a Community-wide Diabetes Prevention Program". Phd thesis, University of Sydney, 2011. http://hdl.handle.net/2123/8349.
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This thesis is an evaluation of the effectiveness of a community-wide diabetes prevention program conducted in three Divisions of General Practice in Sydney, Australia. The aims were to assess whether translation of diabetes prevention programs was feasible in real-life settings and whether results achieved were comparable with those of randomised trials on which this intervention was based. Its primary goals were to assess whether the lifestyle intervention could increase participation in moderate-to-vigorous physical activity to 210 minutes per week, reduce total fat and saturated fat consumption to 30% and 10% of total daily energy intake, increase fibre consumption to 15 g/1,000 kcal/day, and lead to 5% weight loss over one year. The background section covers the physiopathology of type 2 diabetes, its risk factors, and the available population screening tools to identify people at risk. The growing morbidity and mortality burden, the economic implications of this public health problem, and the importance and feasibility of preventing or delaying the onset by intervening in the precursor stages are then summarised. Evidence for preventability is examined through a literature review of lifestyle interventions in research settings comprising highly structured and closely monitored physical activity and dietary programs under controlled conditions. Examples of the effectiveness of translation of randomised controlled trials (RCTs) into less stringent programs in community settings such as workplaces, churches, indigenous communities and whole-of-country initiatives are presented. A systematic review and meta-analysis of effectiveness of the lifestyle approaches in routine clinical practice supplements the evidence for application of prevention principles in real-life settings. The main chapters of the thesis centre on process and impact evaluation of the semi-structured Sydney-based intervention, which recruited 1,250 participants from the mainstream Australian 29 public using general practitioner services in the study area, who were followed for 12 months. The intervention’s goals aligned with those of the Finnish Diabetes Prevention Program but with less stringent entry criteria and less intensive intervention components delivered by purpose-trained lifestyle officers. The Program included an initial individual assessment and coaching session, three subsequent group sessions in the following three months, then three follow-up coaching calls at three, six and nine months. A final assessment at one year, using the same objective and self-reported measures as in the initial assessment, captured changes in body weight, physical activity and dietary habits. The process evaluation showed that it is feasible and effective to use targeted screening to identify and recruit high-risk individuals into a free-of-charge program in the general practice setting, however a quarter of participants were lost to follow-up by one year. While minor variations in aspects of the Program were required to meet local need, Program fidelity in delivering components, and self-reported adherence to diet and physical activity was high. Using a before-after study design, the impact evaluation measured 1-year changes in key Program parameters in relation to baseline. These comprised: measured weight, waist circumference, BMI, and glycaemia measurements; and self-reported dietary intake and structured physical activity, using a 3-day food record and the Physical Activity Scale for the Elderly (PASE) questionnaire, respectively. The main findings at 12 months for the 586 completers as at December 2010 were: a mean weight loss of 2.1 kg; waist circumference reduction of 2.5 cm; no significant change in glycaemia; 3% reduction of fat and saturated fat intake; 16% increase in fibre intake; and mean increase in moderate-to-vigorous physical activity of 13.7 minutes/week. All these changes were smaller than those achieved by the RCTs in research settings, most likely due to the lower intensity and monitoring of the Sydney intervention. Weight loss and waist circumference reductions were similar for participants in 30 group session and those who received telephone-only coaching. Diabetes incidence was 1% at the end of the first year. An economic appraisal of the Program implementation completes the evaluation. A cost of A$400 per kg lost among people achieving the weight goal was estimated on Program completion, but the cost was double for the overall group that included non weight losers. The cost of achieving the physical activity goal and the dietary goals was not feasible or sustainable with resources available in routine clinical settings. The costs per outcome were similar for participants not attending group sessions, who received only telephone coaching. Hence it is worth exploring this less labour-intensive modality if a general practice based Program were to be delivered as routine preventive care. In sum, the evaluation of this community-wide diabetes prevention program showed that translation of diabetes prevention programs into routine practice, while feasible at less intensive levels than in RCTs, has a somewhat lower effect on diabetes risk reduction and it can still be a financial burden in clinical settings. However, given the potential for population-wide benefit, the effectiveness of alternative delivery modes, number and duration of program components and more targeted patient sub-groups should be investigated.The Sydney Diabetes Prevention Program was funded by New South Wales Health as part of the Australian Better Health Initiative. Financial contribution and other in-kind support were provided by the Sydney South West Area Health Service and the Australian Diabetes Council -NSW.
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Aragam, Nagesh Ramarao. "Genome-Wide Association Analysis of Major Depressive Disorder and Its Related Phenotypes". Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etd/1368.
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Major Depressive Disorder (MDD) is a complex and chronic disease that ranks fourth as cause of disability worldwide. Thirteen to 14 million adults in the U.S. are believed to have MDD and an estimated 75% attempt suicide making MDD a major public health problem. Recently several genome-wide association (GWA) studies of MDD have been reported; however, few GWA studies focus on the analysis for MDD related phenotypes such as neuroticism and age at onset of MDD. The purpose of this study is to determine risk factors for MDD, identify genome-wide genetic variants affecting neuroticism and age at onset as quantitative traits, and detect gender differences influencing neuroticism.
Bivariate and multiple logistic regression analyses were performed on 1,738 MDD cases and 1,618 non-MDD controls to determine phenotypic risk factors for MDD. Multiple linear regression analyses in PLINK software were used for GWA analyses for neuroticism and age at onset of MDD with 437,547 Single Nucleotide Polymorphisms (SNPs).
Gender (OR: 1.43; 95% CI: 1.24 - 1.64) and a family history (OR: 2.88; 95% CI: 2.48 - 3.35) were significantly associated with an increased risk of MDD, which supports the findings of prior studies. Through GWA analysis 34 SNPs were identified to be associated with neuroticism (p < 10-4). The best SNP was rs4806846 within the TMPRSS9 gene (p = 7.79 x10-6). Furthermore, 46 SNPs were found showing significant gene x gender interactions for neuroticism with p<10-4. The best SNP showing gene x gender interaction was rs2430132 (p = 5.37x10-6) in HMCN1 gene. In addition, GWA analysis showed that several SNPs within 4 genes (GPR143, ASS1P4, MXRA5 and MAGEC1/2) were significantly associated with age at onset of MDD (p < 5x10-7).
This study confirmed previous findings that MDD is associated with an increased prevalence in women (about 43% more compared to men) and is highly heritable among first degree relatives. Several novel genetic loci were identified to be associated with neuroticism and age at onset. Gender differences were found in genetic influence of neuroticism. These findings offer the potential for new insights into the pathogenesis of MDD.
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Janes, Jennifer Gail. "THE ROLES OF ORTHOPAEDIC PATHOLOGY AND GENETIC DETERMINANTS IN EQUINE CERVICAL STENOTIC MYELOPATHY". UKnowledge, 2014. http://uknowledge.uky.edu/gluck_etds/16.
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Cervical stenotic myelopathy (CSM) is an important musculoskeletal and neurologic disease of the horse. Clinical disease occurs due to malformations of the vertebrae in the neck causing stenosis of the cervical vertebral canal and subsequent spinal cord compression. The disease is multifactorial in nature, therefore a clearer understanding of the etiology and pathogenesis of CSM will allow for improved management and therapeutic practices. This thesis examines issues of equine CSM diagnosis, skeletal tissue pathology, and inherited genetic determinants utilizing advances in biomedical imaging technologies and equine genomics. Magnetic resonance imaging (MRI) data provided a more complete assessment of the cervical column through image acquisition in multiple planes. First, MRI was compared to standing cervical radiographs for detection of stenosis. Using canal area or the cord canal area ratio, MRI more accurately predicted sites of compression in CSM cases. Secondly, articular process skeletal pathology localized on MRI was found to be more frequent and severe in CSM horses compared to controls. In addition, lesions were generalized throughout the cervical column and not limited to the spinal cord compression sites. A subset of lesions identified on MRI was evaluated using micro-CT and histopathology. Osteochondrosis, osseous cyst-like structures, fibrous tissue replacement of bone, and osteosclerosis were observed. These lesions support likely developmental aberrations of vertebral bone and cartilage maturation with secondary biomechanical influences. Bone cyst-like structures are a novel finding in this disease. Finally, the long-standing question of the contribution of genetic determinants to CSM was investigated using a genome wide association study (GWAS). Multiple significant loci were identified supporting the influence of a complex genetic trait in clinical disease. A simple Mendelian trait controlled by one gene is unlikely given the detection of variants across multiple chromosomes. Major contributions from this research include documentation of articular process bone and cartilage pathology in horses with CSM, support for abnormal cervical vertebrae development being an important contributing factor in the etiology and/or pathogenesis of equine CSM, and evidence that multiple genetic loci contribute to the CSM disease phenotype.
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Tsuchiya, Mio. "Attitudes toward and current status of disclosure of secondary findings from next-generation sequencing: a nation-wide survey of clinical genetics professionals in Japan". Kyoto University, 2021. http://hdl.handle.net/2433/261616.
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Gaubatz, Breanna M. "EQUINE PROTOZOAL MYELOENCEPHALITIS: INVESTIGATION OF GENETIC SUSCEPTIBILITY AND ASSESSMENT OF AN EQUINE INFECTION METHOD". UKnowledge, 2013. http://uknowledge.uky.edu/gluck_etds/8.
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Equine protozoal myeloencephalitis (EPM) is a progressive neurological disease of horses caused by Sarcocystis neurona. Two projects were conducted to identify factors involved in the development of EPM. The first study explored a possible genetic susceptibility to EPM by attempting a genome-wide association study (GWAS) on formalin-fixed, paraffin-embedded (FFPE) tissue from 24 definitively-positive EPM horses. DNA extracted from tissues older than 14 months was inadequate for SNP analysis on the Illumina Equine SNP50 BeadChip probably due to degradation and formalin cross-linking. Results were inconclusive as analysis was not possible with the small sample set. The second study evaluated an artificial infection method in creating a reliable equine EPM model. Five horses were injected intravenously at 4 time points with autologous blood incubated with 1,000,000S. neurona merozoites. Challenged horses progressively developed mild to moderate clinical signs and had detectable S. neurona serum antibodies on day 42 post challenge. Horses appeared to have produced a Th1 immune response and cleared the infection by the conclusion of the study on day 89. No histopathological evidence of S. neurona infection was found within central nervous system tissue. This artificial infection method was not effective in replicating the severe clinical EPM seen in natural infections.
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Godeiro, José Renato Gurgel. "Reação tecidual induzida pelos fios de quitosana e náilon em ratas (Rattus norvegicus)". Universidade Federal Rural do Semi-Árido, 2013. http://bdtd.ufersa.edu.br:80/tede/handle/tede/339.
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Previous issue date: 2013-11-18Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Chitosan is a natural biopolymer that has large portfolio of structural applications with potential mechanical modifications to generate new properties, functions and specially applications in the biomedical field. This work evaluates the induced tissue reaction between chitosan and nylon sutures used on the skin and subcutaneously, after the 7th, 14th and 28th post-operative day. It was also observed the ability to remove the suture by degradation after application of the suture removal spray QiGel®. Thirty five rats were distributed in 2 groups, namely G1 (chitosan), with 20 rats, and G2 (nylon), with 15 ratsin 3 periods of observation. The G1 group had 5 extra rats for the removal test with the spray. The following evaluations were performed: clinical, macroscopic, tension force and histology. The results led us to conclude that the chitosan based sutures showed qualities contribute concerning removal with the Suture Removal QiGel® when compared with manual removal. The tension force evaluation showed that nylon is stronger than chitosan; however there was no difference on the sutured skin in the observed periods. The skin histology showed no difference on the quantification of fibroblast and collagen in both groups in the different observation periods
A quitosana é um biopolímero natural que possuidiversasaplicações estruturais que possibilitam modificações mecânicas para gerar novas propriedades, funções e aplicaçõesespecialmente na área biomédica.O presente estudo objetivou avaliar a reação tecidual induzida pelos fios de quitosana e de náilon suturados na pele e implantados no tecido subcutâneo, após o 7º, 14º e 28º dia pós-operatório, e observar a capacidade de remoção do fio pela degradação após aplicação do spray Suture RemovalQiGel®. Foram utilizadas 35 ratas distribuídas em dois grupos sendo G1 (quitosana), com 20 animais, e G2 (náilon), com 15 animais, em três períodos de observação. Os cinco animais a mais do G1 foram utilizados para comparar a retirada dos fios. Foram realizadas avaliações clínica, macroscópica, tensiométrica e histológica. Os resultados mostraram que o spray (Suture RemovalQiGel®) apresentou qualidades que contribuem com a retirada dos fios, quando comparado a retirada manual. Na avaliação tensiométrica dos fios, o náilon foi mais resistente, enquanto que na tensão da pele não houve diferença nos períodos de observação analisados.Na avaliação histológica da pele, não houve diferença na quantificação de fibroblastos e colágeno em ambos os grupos e períodos analisados
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Costa, Claudio Giulliano Alves da. "Desenvolvimento e avaliação tecnologica de um sistema de prontuario eletronico do paciente, baseado nos paradigmas da World Wide Web e da engenharia de software". [s.n.], 2001. http://repositorio.unicamp.br/jspui/handle/REPOSIP/260174.
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Orientadores : Renato Marcos Endrizzi Sabbatini, Antonio Augusto Fasolo QuevedoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Eletrica e de Computação
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Mestrado
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Motallebipour, Mehdi. "Genetic and Genomic Analysis of Transcriptional Regulation in Human Cells". Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9407.
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There are around 20.000 genes in the human genome all of which could potentially be expressed. However, it is obvious that not all of them can be active at the same time. Thus, there is a need for coordination achieved through the regulation of transcription. Transcriptional regulation is a crucial multi-component process involving genetic and epigenetic factors, which determine when and how genes are expressed. The aim of this thesis was to study two of these components, the transcription factors and the DNA sequence elements with which they interact. In papers I and II, we tried to characterize the regulatory role of repeated elements in the regulatory sequences of nitric oxide synthase 2 gene. We found that this type of repeat is able to adopt non B-DNA conformations in vitro and that it binds nuclear factors, in addition to RNA polymerase II. Therefore it is probable that these types of repeats can participate in the regulation of genes. In papers III-V, we intended to analyze the genome-wide binding sites for six transcription factors involved in fatty acid and cholesterol metabolism and the sites of an epigenetic mark in a human liver cell line. For this, we applied the chromatin immunoprecipitation (ChIP) method together with detection on microarrays (ChIP-chip) or by detection with the new generation massively parallel sequencers (ChIP-seq). We found that all of these transcription factors are involved in other liver-specific processes than metabolism, for example cell proliferation. We were also able to define two sets of transcription factors depending on the position of their binding relative to gene promoters. Finally, we demonstrated that the patterns of the epigenetic mark reflect the structure and transcriptional activity of the promoters. In conclusion, this thesis presents experiments, which moves our view from genetics to genomics, from in vitro to in vivo, and from low resolution to high resolution analysis of transcriptional regulation.
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Padilla, Carmenita C. "High school counselor knowledge of NCAA regulations for prospective student-athlete transition to college". Scholarly Commons, 2015. https://scholarlycommons.pacific.edu/uop_etds/308.
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This descriptive study examines whether high school counselors are equipped to advise potential recruits on new NCAA academic eligibility regulations. It highlights the NCAA’s new Division I academic eligibility regulations in effect for current seniors in high school (entering collegiate class of 2016) and gives an overview of academic rule changes within the national governing body. The enhanced academic eligibility rules increase minimum GPA and test score as well as mandates strict core course requirements, prioritizing the role of a high school counselor in the entire process. The study will seek to examine the knowledge of high school counselors on new NCAA academic eligibility rules, the resources available to them and those needed to better assist potential recruits from underserved backgrounds. This study will focus on high school counselors employed in California at underserved schools characterized by those receiving Title I wide funding from the federal government. The majority of students at Title I wide institutions are minorities and first generation students and these populations rely heavily on their high school counselors for college knowledge. In many cases, athletic scholarships are these student’s only means of obtaining a collegiate degree; highlighting the need to examine the knowledge and resources high school counselors have and need to properly advise potential NCAA student-athletes. High school counselors need information and resources specific to NCAA academic eligibility regulations to help student-athletes from underserved backgrounds keep their collegiate dreams alive.
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Bazzocco, Sarah. "Identification of novel therapeutic targets and tumor suppressor genes in colon cancer using genome-wide high‐throughput approaches". Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/350805.
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Colorectal cancer is a disease caused by genetic and epigenetic changes. Inactivation of tumor suppressor genes and activation of oncogenes are key landmarks in tumor progression. However, the list of tumor suppressor genes and oncogenes is far from complete, even in the case of the tumor types that are best characterized, such as colorectal cancer. Colorectal cancer is the second most frequent cause of cancer-related death in the Western world and is a serious health issue for the European Union. Patients having stage III or IV cancer undergo surgery followed by chemotherapy. However, the clinical management of these patients is far from optimal, and only about 30 % of the patients show an objective response to even the best chemotherapeutic agents available. In this study genome-wide high throughput assays were used to better characterize important aspects of the oncogenic progression such as deregulation of proliferation and aberrant expression caused by epigenetic mechanisms.
Because rapid tumor proliferation is associated with poor patient prognosis, here we characterized the transcriptional signature of rapidly proliferating colorectal cancer cells in an attempt to identify genes important to sustain tumor growth and that could be used as novel therapeutic targets. The proliferation rate of 52 colorectal cancer cell lines was determined and genome-wide expression profiling of a subset of these lines was assessed by microarray analysis. The expression of 1,290 genes was significantly correlated with the growth rates of colorectal cancer cells. These included genes involved in cell cycle, RNA processing/splicing and protein transport. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and protoporphyrinogen oxidase (PPDX) were shown to have higher expression in faster growing cancer cells. Importantly, pharmacological and genetic inhibition of GAPDH or PPDX reduced the growth of colon cancer cells in vitro and in vivo.
To better understand the mechanisms underlying the profound transcriptional reprogramming observed in cancer cells, we investigated the association between the levels of DNA methylation in the promoters of >14,000 genes and the levels of expression of these genes in a panel of 45 colorectal cancer cell lines. A group of cell lines with significantly higher methylation levels was observed, supporting the notion that there is a group of colorectal tumors with a CpG methylator phenotype (CIMP+). A significant negative regulation between methylation and expression levels was observed for 1,409 genes, suggesting that these genes are silenced during the tumorigenic process through this epigenetic mechanism. A significant number of these genes were zinc finger proteins, suggesting an important role of these DNA-binding proteins on the tumorigenic process. Strikingly, approximately one fourth of these genes are not associated with CpG islands, indicating that DNA methylation outside these CpG rich regions is an important mechanism regulating gene expression and significantly contribute to tumor progression. In addition, we postulate that at least some of those genes have tumor suppressor activity. As a proof-of-concept, we show that restoration of the expression of ZNF238, a gene showing a significant methylation/expression correlation, resulted in reduced growth of colon cancer cells in vitro and in vivo.
In conclusion, in this study we shed new light on the mechanisms underlying the uncontrolled proliferation of colon cancer cells and the expression reprograming imposed in these cells through CpG methylation. The results of this study may contribute to the identification of novel chemotherapeutic targets for patients with colorectal cancer, and the characterization of novel genes/pathways with tumor suppressor activity, that are epigenetically silenced.El càncer colorectal és una malaltia causada per canvis genètics i epigenètics. La inactivació de gens supressors de tumors i l'activació d'oncogens són fites clau en la progressió tumoral. Els pacients amb càncer en estadi III o IV són sotmesos a cirurgia seguida de quimioteràpia. No obstant això, només el 30% dels pacients mostren una resposta objectiva fins i tot als millors agents quimioterapèutics disponibles. En aquest estudi es van utilitzar assajos d'alt rendiment de tot el genoma per caracteritzar millor els aspectes importants de la progressió oncogènica, com la desregulació de la proliferació i l'expressió aberrant causada per mecanismes epigenètics. La ràpida proliferació tumoral s'associa al pitjor pronòstic del pacient, aquí hem caracteritzat la signatura transcripcional de les cèl.lules de càncer colorectal amb ràpida proliferació de cèl.lules en un intent d'identificar els gens importants per sostenir el creixement tumoral i que podrien ser utilitzats com a dianes terapèutiques. Per comprendre millor els mecanismes subjacents a la profunda reprogramació transcripcional observada en les cèl.lules canceroses, es va investigar l'associació entre els nivells de metilació de l'ADN en els promotors i els nivells d'expressió d'aquests gens en línies cel.lulars de càncer colorectal. Els resultats d'aquest estudi poden contribuir a la identificació de noves dianes quimioterapèutics per a pacients amb càncer colorectal, i la caracterització de nous gens / vies amb activitat supressora de tumors, que són silenciats epigeneticament.
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Vieira, Anderson Roberto Assunção. "Distúrbios de comportamento, desgaste anormal dos dentes incisivos e cólica em eqüinos estabulados no 1º regimento de cavalaria de guardas, Exército Brasileiro, Brasília- DF". Universidade Federal de Viçosa, 2006. http://locus.ufv.br/handle/123456789/5111.
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Previous issue date: 2006-09-25There is much debate over the possible causes of the behavioral problems of horses; stable stress is among the most significant. Nevertheless, given the large number of variables related to these abnormal behaviors, all conclusions reached until today remain questionable. Furthermore, it is also possible that the real determining factor of these behavioral problems is simply the incapacity of horses to adapt to the environment to which they are submitted today. The unceasing search for the etiology of these disorders aims to prevent and treat diseases that are possibly related to these behavioral problems, such as tympanic colic, compaction colic, dental wear and decreased performance; in addition to addressing problems related to aesthetical and economical factors. The present experiment aims to show the correlation between behavioral problems and prevalence of colic; between wear of incisive teeth and colic. Furthermore, it analyses other variables such as age, stable, weight, body condition, heart frequency and incisive teeth size. 407 horses were examined, of various breeds, with ages between 2 and 25 years, of both sexes. All animals were kept in stalls, with standardized feeding for each group, at the Regimento de Cavalaria de Guarda (RCG), located in Brasília, Federal District, Brazil. The total incidence of behavioral problem found in this group of animals was of 28.9%, divided among the following stereotypy: cribbiting, wind sucking, crib-biting with the neck, gnawing wood, bear syndrome, aggression, stable walking and kicking. On studying crib-biting, a significant incidence of colic was found between the years 2000 and 2005. During that period, 900 colic episodes were observed, and most of them due to spasmodic colics, compaction and overfeeding, as registered by the RCG veterinary hospital. Wear of incisive teeth in those horses was 14.5%. Fisher's exact test and the regression test were used for the different correlations investigated, using a reference of p< 0.05.
Há grande discussão em torno das possíveis causas dos distúrbios de comportamento apresentados pelos eqüinos; o estresse de baia é tido como a principal delas. No entanto, o grande número de variáveis que existe acerca desses comportamentos considerados anormais faz com que todas as conclusões a que se tem chegado até hoje sejam questionáveis. Existe ainda a possibilidade de que o real fator determinante de todos estes transtornos comportamentais seja simplesmente a incapacidade do eqüino adaptar-se ao meio a que é submetido na vida moderna. A inesgotável busca da etiologia desses distúrbios visa, além de preservar fatores estéticos e econômicos, prevenir e tratar algumas doenças às quais os distúrbios estejam possivelmente relacionados tais como cólicas gasosas, cólicas por compactação, desgaste dentário e diminuição de rendimento. Este experimento tem como objetivo mostrar que há correlação entre distúrbio de comportamento e a prevalência de cólica; entre desgaste dos dentes incisivos e a cólica. Além disso, o experimento analisa outras variáveis como idade, baia, peso, escore, freqüência cardíaca e tamanho dos incisivos. Foram examinados 407 eqüinos, sem raça definida, com idade variando entre 2 e 25 anos, de ambos os sexos, todos em sistema intensivo de baia, com alimentação padronizada por cada grupo, no Regimento de Cavalaria do Exército (RCG), Brasília, Distrito Federal. A incidência de distúrbio de comportamento total encontrada nestes animais foi de 28,9%, distribuídos entre as seguintes estereotipias: aerofagia com apoio, aerofagia sem apoio, aerofagia com pescoço, roer madeira, síndrome de urso, agressividade, andar na baia e coices. Quando analisada a aerofagia com apoio houve significância quanto à incidência de cólica nos anos de 2000 a 2005. Nesse período foram identificados 900 episódios de cólica, esses em sua maioria compostos por cólicas espasmódicas, compactação e sobrecarga alimentar, conforme registrado no hospital veterinário do RCG. O desgaste dos dentes incisivos destes eqüinos foi de 14,5%. O teste exato de Fisher e de regressão foi utilizado para diferentes correlações analisadas, tomando como referência: p< 0,05.
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Meyers, Jacquelyn. "Elucidating Genetic and Environmental Influences on Alcohol-Related Phenotypes". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2830.
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Decades of work has led researchers to believe that risk for complex behavioral phenotypes, such as alcohol use disorders, is likely influenced by multiple genes of small effect acting in conjunction with each other and the environment. Currently, the field of psychiatric genetics is developing methodologies for the identification of genetic risk variants that predispose individuals to the development of complex behavioral disorders. Several challenges related to the complex and polygenic nature of these phenotypes, must be considered. This dissertation study attempts to address these important challenges in the context of alcohol use disorders and related phenotypes. A rich twin and family study literature has indicated that 40-70% of the variance in alcohol use disorders (AUDs) is influenced by genetics. Recent attempts to identify specific x genetic risk variants associated with AUDs have been met with limited success. Meanwhile, evidence of the moderating effects of the environment on AUDs has been mounting, providing a strong rationale for examining gene-environment interaction. In the following chapters several studies will be described that integrate established twin methodologies into gene identification projects in an effort to reduce heterogeneity (both phenotypic and genotypic), elucidate environmental constructs that moderate genetic influences, and to enhance statistical power to detect the subtle genetic influences on alcohol related phenotypes.
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Magalhães, Lucas Vilas Bôas 1979. "Aplicação do método Crônica Médica e Oficina Diagnóstica para educação médica via web". [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312814.
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Orientador: Li Li MinTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A educação médica via web (EMVW) em Ambientes Virtuais de Aprendizagem (AVA) vem crescendo muito, e apresenta potenciais vantagens. Os desenhos bem estruturados e comprovadamente eficazes para uso em AVA são pouco utilizados, pois, em geral, verifica-se apenas a "digitalização" da sala de aula, ou o AVA serve apenas como depósito de textos. O uso isolado de tecnologias também não garante resultados. Necessitam-se métodos com características pedagógicas positivas, capazes de guiar a aprendizagem, enfocando o método clínico e objetivando melhora da capacidade diagnóstica, considerada frequentemente inadequada, nas avaliações de profissionais. Assim, esta pesquisa propôs a utilização do método Crônica Médica/Oficina Diagnóstica (CM/OD), que procura reunir as características pedagógicas que favorecem o aprendizado em AVA e visa, fundamentalmente, melhorar a habilidade diagnóstica do graduando em Medicina. Há uma leitura inicial motivadora (CM) e um programa estruturado de construção do conhecimento, feito a partir de casos, quase sempre reais, acoplados aos recursos audiovisuais (OD). Foram elaborados dois conjuntos CM/OD, sobre Acidente Vascular Encefálico (AVE) e Crises Epilépticas/Epilepsias. Ambos foram inseridos em um AVA. Essa pesquisa objetivou fundamentar teoricamente a proposta CM/OD para EMVW em AVA e apresentá-la por meio de material suplementar sobre Crises Epilépticas/Epilepsias. Além disto, inferir opiniões dos estudantes expostos e verificar a eficácia do método para melhorar a capacidade diagnóstica dos graduandos em Medicina, em longo prazo, por meio de um estudo longitudinal, cuja coleta de dados foi feita utilizando um questionário de opiniões e questionários de conhecimentos e habilidades diagnósticas (CHD). O método CM/OD permite o aprendizado ativo, inicialmente individual, com autoavaliação, reflexão e interatividade, usando várias estratégias de ensino com exemplos práticos e reais, proporcionando um bom tempo de exposição, de forma repetida, e com gabarito baseado em evidências. O material suplementar permite a sua replicação em um módulo ou disciplina de qualquer curso médico. As opiniões dos expostos mostram que o método estimula a leitura pré e a pós-atividade; que a CM motiva; que o gabarito da oficina sana dúvidas; e que as principais sugestões foram o uso de redes sociais e uma discussão coletiva final. Os questionários CHD1, CHD2 e CHD3 foram respondidos por 81 alunos. A média geral do CHD1 foi de 1,59, desvio-padrão de 0,71. Durante o seguimento, 66 estudantes acessaram o AVA, denotando uma alta taxa de participação, e apresentaram significativa melhora das notas em longo prazo, pois tiveram maiores notas no CHD 2 (t = 8,88, p-valor < 0,05) e também no CHD 3 (t = 8,39, p-valor <0,05). Os resultados foram atribuídos às características pedagógicas positivas do método, já que o tempo de exposição à aula teve pouca influência nas notas finais. Concluiu-se que o método CM/OD para AVA reúne características pedagógicas positivas; pode ser adaptado e replicado em um AVA básico; foi bem aceito pelos estudantes; e apresentou eficácia satisfatória na melhora da capacidade diagnóstica dos graduandos em Medicina, mesmo em longo prazo
Abstract: Web-Based Medical Education (WBME) in Virtual Learning Environments (VLE) has become increasingly available and presents potential advantages. Well-structured and effective VLE designs are scarce and little used since, in general, only classroom digitalization is observed, or the VLE is used only for text storage. The isolated use of technologies does not guarantee results, either. Methods with positive pedagogical characteristics are needed to guide students¿ learning, focusing on the clinical method and improved diagnostic skills, which are frequently considered inadequate in professional evaluations. Thus, we have proposed the method Medical Chronicle/ Diagnostic Workshop (MC/DW), that aims to combine teaching characteristics favoring VLE learning, and, mainly, to improve the diagnostic skills of undergraduate medical students. The students were initially exposed to a motivating reading (MC) and a structured program of knowledge construction, based on real cases plus audiovisual aids (DW). Two sets were elaborated (MC/DW) on Stroke and Epileptic Seizures/Epilepsies, both part of a VLE. This work aimed to provide a theoretical basis of the MC/ DW proposal for WBME in VLE, through supplementary material on Epileptic Seizures / Epilepsies. It also aimed to infer the students¿ opinions and verify the effectiveness of the method in improving the diagnostic skills of undergraduate medical students in the long term, by applying a longitudinal intervention study consisting of an opinion survey and a Knowledge and Diagnostic Skills questionnaire (KDS) to collect data. The MC/DW method allowed an active, initially individual learning experience, combined with self-evaluation, critical thinking and interactivity, using several teaching strategies, real cases, long term exposure, repetition, and evidence-based feedback. The supplementary material allows replicating the method as a module or discipline in any medical course. The students¿ comments revealed that the method stimulates pre- and post-reading, and that the MC is highly motivating; the DW¿s answer key sheet removes doubts, offering suggestions to use social networks and a final collective reflection on the topic. The questionnaires KDS 1, 2, and 3 were answered by 81 students. The KDS1¿s general mean was 1.59, and the standard deviation was 0.71. A total of 66 students used VLE, showing a high rate of participation and a significant grade improvement in the long term, with higher means in KDS 2 (t = 8,88, p-value < 0,05) and KDS 3 (t = 8,39, p-value <0,05). These results were attributed to the positive pedagogical characteristics of the method, since time of class exposure had little influence on the final grades. It was concluded that the MC/DW method in VLE presented positive teaching characteristics, and may be adapted and replicated to a basic VLE; it was well-accepted by the students and satisfactorily effective in improving the diagnostic capacity of undergraduate medical students, in the long run
Doutorado
Neurologia
Doutor em Ciências Médicas
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Martínez, Marigorta Urko 1983. "Genetic architecture of complex disease in humans :a cross-population exploration". Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/96909.
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The aetiology of common diseases is shaped by the effects of genetic and environmental factors. Big efforts have been devoted to unravel the genetic basis of disease with the hope that it will help to develop new therapeutic treatments and to achieve personalized medicine. With the development of high-throughput genotyping technologies, hundreds of association studies have described many loci associated to disease. However, the depiction of disease architecture remains incomplete. The aim of this work is to perform exhaustive comparisons across human populations to evaluate pressing questions. Our results provide new insights in the allele frequency of risk variants, their sharing across populations and the likely architecture of diseaseLa etiología de las enfermedades comunes está formada por factores genéticos y ambientales. Se ha puesto mucho empeño en describir sus bases genéticas. Este conocimiento será útil para desarrollar nuevas terapias y la medicina personalizada. Gracias a las técnicas de genotipado masivo, centenares de estudios de asociación han descrito una infinidad de genes asociados a enfermedad. Pese a ello, la arquitectura genética de las enfermedades no ha sido totalmente descrita. Esta tesis pretende llevar a cabo exhaustivas comparaciones entre poblaciones para responder diversas preguntas candentes. Nuestros resultados dan pistas sobre la frecuencia de los alelos de riesgo, su presencia entre poblaciones y la probable arquitectura de las enfermedades.
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Biasci, Daniele. "Predicting prognosis in Crohn's disease". Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/270034.
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Carrera, Salazar David. "Utilidad de la técnica ROLL (radioguided ocult lesion localization) en la exéresis de lesiones no palpables de mama". Doctoral thesis, Universitat Rovira i Virgili, 2016. http://hdl.handle.net/10803/364780.
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Avaluar l'eficàcia de la localització radioguiada (ROLL) de lesions ocultes de mama (LNPM)respecte a la tècnica estàndard, l'ham quirúrgic.
MÈTODE: S'han estudiat 161 dones amb LNPM, 80 marcades amb ham quirúrgic el mateix dia de la intervenció i 81 marcades amb la injecció intratumoral de 3 mCi de Tc99m Nanocoloide el dia previ a la cirurgia. Les lesions es van localitzar per ecografia o estereotàxia. Les tumorectomies es van fer , en el primer grup seguint la direcció de l'ham des de l'entrada fins la punta, i en el segon grup amb l'ajuda d'una sonda gammadetectora que indicava el lloc de màxima concentració de radioactivitat, on es trobava el tumor. Posteriorment es comprovaven els marges quirúrgics al servei d'anatomia patològica, determinant la necessitat d'ampliació si el marge es trobava a menys de 5 mm de la vora tumoral en l'estudi intraoperatori i a menys de 2 mm en l'estudi diferit.
Es van recollir dades de percentatge de detecció, afectació de marges quirúrgics, número d'ampliacions, presència de tumor residual a l'ampliació, reintervencions, volum de la tumorectomia i volum total extret, ratio volum/tumor, complicacions i influència del metge nuclear.
RESULTATS: Es van observar resultats sense diferencies significatives entre els dos grups en percentatge de detecció, afectació de marges, número d'ampliacions, presència de tumor residual a l'ampliació, reintervencions, volum de la tumorectomia , volum total extret, ratio volum/tumor i complicacions. L'anàlisi multivariant mostra que els factors condicionants del volum extret son la tècnica de marcatge radiològic, el cirurgià i el metge nuclear.
CONCLUSIONS: La tècnica ROLL permet la detecció i exeresis de les LNPM amb la mateixa eficàcia que l'ham i afegeix la possibilitat de detecció del gangli sentinella en un mateix acte.OBJETIVO: Evaluar la eficacia de la localización radioguiada (ROLL) de lesiones ocultas de mama (LNPM) respecto a la técnica estándar, el arpón quirúrgico. MÉTODO: Se han estudiado 161 mujeres con LNPM, 80 marcadas con arpón el mismo día de la intervención y 81 marcadas con inyección intratumoral de 3 mCi de Tc99m Nanocoloide el día previo a la cirugía. Las lesiones se localizaron por ecografía o estereotaxia. Las tumorectomías se realizaron , en el primer grupo siguiendo la dirección del arpón desde su entrada hasta la punta, y en el segundo grupo con la ayuda de una sonda gammadetectora que indicaba el punto de máxima concentración de radioactividad, donde se encontraba el tumor. Posteriormente se comprobaron los márgenes quirúrgicos en el servicio de anatomía patológica, determinando la necesidad de ampliación si el margen era menor a 5 mm del borde tumoral en el estudio intraoperatorio y menor a 2 mm en el estudio diferido. Se recogieron datos de porcentaje de detección, afectación de márgenes quirúrgicos, número de ampliaciones, presencia de tumor residual en la ampliación, reintervenciones, volumen de la tumorectomía y volumen total extraído, ratio volumen/tumor, complicaciones e influencia del médico nuclear. RESULTADOS: Se observaron resultados sin diferencias significativas entre ambos grupos en porcentaje de detección, afectación de márgenes, número de ampliaciones, presencia de tumor residual en la ampliación, reintervenciones, volumen de la tumorectomía , volumen total extraído, ratio volumen/tumor y complicaciones. El análisis multivariante mostró que los factores condicionantes del volumen extraído son la técnica de marcaje radiológico, el cirujano y el médico nuclear. CONCLUSIONES: La técnica ROLL permite la detección i exeresis de las LNPM con la misma eficacia que el arpón y añade la posibilidad de detección simultánea del ganglio centinela.
PURPOSE: Evaluate the efficiency of radioguided occult lesion localization (ROLL) in non palpable breast lesions (NPBL) regard to the gold standard technique, the surgical wire. METHOD: Has been studied 161 women with NPBL, 80 marked with wire the same day of the surgery, and 81 marked with the intratumoral injection of 3 mCi of Tc99m-Nanocoloide the previous day to the surgery. The NPBL were located by ultrasound or stereotactic guidance. The lumpectomies were made , in the first group following the wire direction since its entry to the tip, and in the second group with the help of a gammaprobe that indicated the place of maximum radioactivity concentration, where tumor was located. Surgical margins were checked by pathology service, determining the need of extension if the margin were less than 5 mm of the tumoral edge in the intrasurgical study and to less than 2 mm in the differed study. Data were collected about detection average, surgical margins, number of extensions, presence of residual tumor on the extension, second surgeries, lumpectomy volume and total resected volume, volume/tumor ratio, complications and influence of the nuclear doctor. RESULTS: Not significant differences were observed between the two groups in detection average, surgical margins, number of extensions, presence of residual tumor on the extension, second surgeries, lumpectomy volume and total resected volume, volume/tumor ratio and complications. The multivariate analysis showed the factors that condition the resected volume were the radiological guidance technique, the surgeon and the nuclear doctor. CONCLUSIONS: ROLL allows the detection and resection of the NPBL with the same efficiency than the wire and adds the possibility of the sentinel node detection in a same act.
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Peterson, Roseann. "On the genetic and environmental associations between body composition, depression symptoms and smoking behavior". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2889.
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Obesity is a serious public health crisis and recent estimates of its incidence are the highest in United States history, with 35% and 17% of American adults and children affected, respectively. The clinical definition of adult obesity is operationalized as a body mass index (BMI) greater than 30 kg/m2. Although the prevalence of common obesity has increased dramatically over the past 30 years–largely thought to be due to changes in the environment, such as high calorie diets and sedentary lifestyles—twin and family studies have shown consistently that relative body weight is under considerable genetic influence in both children and adults, with heritability estimates ranging from 40% to 90%. Elucidating the genetic and environmental liability to relative body weight is an important public health endeavor. To further our understanding of the genetics of BMI and common complex obesity, several studies are described that integrate clinical, twin, and genome-wide association (GWAS) methodology in the context of genetic risk scores, clinical risk prediction, development across adolescence into adulthood, and comorbidity with depression symptoms and smoking behavior. First, in two cross-sectional genetic association studies, the utility of genetic risk sum scores (GRSS) were assessed, which summarize the total number of risk alleles, as an alternative form of replication and for potential clinical utility for obesity risk prediction. Next, since there has been only limited research on when during development BMI-associated variants begin influencing BMI, a longitudinal twin study was utilized to assess the effects of adult-validated BMI-SNPs across adolescence into adulthood. In addition, obesity is comorbid with numerous medical conditions including cardiovascular disease, insulin-resistance and some forms of cancer, as well as, various psychiatric disorders including eating disorders, mood disorders, and substance use. The next series of studies aimed to understand phenotypic and genetic associations between BMI/obesity and binge eating disorder (BED), depression symptoms and smoking behavior. Using a clinical sample of overweight and obese women with and without BED, the relationship of BED, food intake and internalizing symptoms of depression and anxiety was examined. Next, twin study methodology was used to investigate if shared genetic and/or environmental liability was responsible for phenotypic associations found between BMI, depression symptoms, and impulsivity. Finally, a genetic association study aimed at investigating whether genetic variants were associated with multiple behaviors, body composition and smoking behavior, or were trait-specific is presented. By utilizing several samples and methodologies and by pursuing methods development, a comprehensive approach is presented that is hoped to represent a more powerful evidence-based strategy to understanding the genetic and environmental determinants of BMI and common complex obesity, along with associated depression symptoms and smoking behavior.
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Janunger, Tomas. "The genetic contribution to stroke in northern Sweden". Doctoral thesis, Umeå : Umeå university, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-31929.
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