Our goal was to develop a mucoadhesive, oral vaccination delivery platform designed to target Peyer’s patches at ileum. In order to achieve this, we prepared poly(methyl methacrylate) (PMMA) particles of various sizes using W/O/W emulsification solvent evaporation and surface polymerization methods. We then coated and employed mucoadhesive polymers into the carrier system to enhance the residence time in the targeted site. Also we developed our own in vitro mucoadhesion testing ramp as an evaluation tool. Finally, nano- and micro-structured particles were manufactured as two different oral vaccine delivery systems (Solid Lipid Nanoparticles, SLNs; and Protein Coated Microcrystals, PCMC). After the model antigen, bovine serum albumin (BSA) was loaded into the SLNs or PCMC; mucoadhesive polymers were then incorporated and formulated the mixture into pellets. The pellets were then layered with an enteric coating, which was composed of a mixture of Eudragit® FS 30 D/Eudragit® L 30 D-55 for ileum targeted delivery. The in vitro mucoadhesion test ramp was capable of investigating the mucoadhesive properties of tablets and pellets, providing a rank order for study. Most important of all, it was anticipated that this might reduce the burden of testing animals for future proposed mucoadhesive studies. Microcapsules/beads of specific size were manufactured reproducibly by solvent evaporation and surface polymerization. Although we could not specify the cut-off size at the pyloric sphincter in mice, we concluded that the cut-off size at the pyloric sphincter in rats was approximately 2.5-3 mm, which was supported by both the biodistribution data and the direct image results from scintigraphy scanning. Moreover, we found that the particle size significantly alters the gastric emptying time in both rodent models. The small microcapsules/beads were hindered in the folds of the stomach (size 50-100μm for mice and size 0.5-1 mm for rats) and emptied the slowest, followed by the large particles, then the medium particles. Finally, PCMC and SLNs we manufactured were suitable carriers for protein API, such as BSA. These particles were of fitting size for M cell uptake, which would possibly induce mucosal immune responses. Therefore, an antigen containing PCMC and SLNs might be suitable platforms for oral vaccination. / text

Gastric bypass achieves weight loss in the morbidly obese. Preoperative weight loss is used to reduce the enlarged fatty liver that otherwise reduces visibility during surgery. The purpose of gastric bypass is to provide patients with long-term weight loss. The aim of this thesis was to investigate the result of preoperative low calorie diet on liver volume and to evaluate the long-term result of gastric bypass. Paper I showed that four weeks of low calorie diet reduces intrahepatic fat by 40% and facilitates surgery mainly through improved visualisation. Paper II demonstrated that all of the reduction of liver volume occurs during the first two weeks of treatment with low calorie diet.  In paper I liver volume was reduced by 12% and in paper II by 18%. Paper III focused on long-term results and showed that gastric bypass achieves a mean 63% excess body mass index loss in obese patients after 11 years. However, of these 40% undergo abdominoplasty and 2% require additional bariatric surgery. Only 24% adhere to the lifelong recommendation on multivitamins and 72% to Vitamin B12 recommendations. Paper IV evaluated gastric bypass as a revisional procedure after earlier restrictive surgery had failed. Similar weight results as after primary gastric bypass are attained. No patient taking vitamin B12 supplementation was deficient at follow-up, regardless of whether the vitamin was taken as a pill or as intramuscular injections.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

<p>Background: Bariatric surgery produces marked weight loss and improvement in comorbid health conditions among individuals with Class II or Class III obesity (Class I = 30.0 &le; BMI &le; 34.9kg/m2; Class II = 35.0 &le; BMI &ge; 39.9kg/m2; Class III = BMI &ge; 40 kg/m2). However, suboptimal weight outcomes occur in a significant minority of patients. Evidence suggests that psychological and behavioral factors might affect weight loss, but most of the literature has focused on preoperative factors, with mixed results. The current study tested the hypothesis that postoperative depressive symptoms, eating behaviors, and lower levels of physical activity would be associated with poorer weight loss outcomes. Method: Preoperative data were obtained from an extant clinical database, and postoperative data were collected via a mail or online questionnaire in a sample of 141 female Roux-en-y gastric bypass (RYGB) patients at an average of 16.80 (SD=2.20) months post-surgery. Self-report measures assessed cognitive-affective and somatic symptoms of depression; binge eating, grazing, night eating, distress about overeating or loss of control over eating; and physical activity. Results: Weight outcome measures were defined as percentage of excess BMI loss (%EBMIL) and successful weight loss (&ge; 50% EBMIL). Higher distress was associated with poorer %EBMIL, and higher level of physical activity was associated with greater %EBMIL. Decreased cognitive-affective symptoms and increased somatic symptoms of depression were associated with a higher probability of successful weight loss. Increased somatic complaints predicted greater %EBMIL unless those symptoms were associated with higher sedentary behavior. Conclusions: Consistent with hypotheses, preoperative depressive symptoms and binge eating disorder did not predict weight loss. Aspects of all three postoperative domains were associated with weight outcomes. Future research should explore the relations among these psychological and behavioral factors and weight loss over a longer follow-up period.</p> / Dissertation

Background: Gastric cancer is often diagnosed in the metastatic stage, and only 10% of patients survive for as long as 2 years. Current chemotherapy regimens show significant treatment-related toxicities. It is crucial to identify the patients that will benefit most from certain chemotherapy regimens in order to avoid unnecessary side effects. Patients and Methods: 2 patients with advanced gastric cancer repeatedly received 5-FU/cisplatin combination chemotherapy. Genomic DNA was extracted from tumor tissue and mononuclear blood cells. Genotype analysis of genes of metabolizing and DNA repair enzymes was carried out using a PCR-RFLP technique. Direct sequencing was used to identify mutations of the gene dihydropyrimidine dehydrogenase (DPD). Results: Prolonged survival of 51 and 29 months, respectively were observed in our 2 patients. Both patients were positive for genotypes of thymidylate synthase - the target enzyme of 5-FU - that are associated with improved drug response. DPD variants connected with increased toxicity were not observed. However, both patients also showed genotypes in cisplatin metabolizing enzymes which enhance the effect of the drug. Conclusion: Genotype analysis in drug metabolizing enzymes of 5-FU and cisplatin provide a possible explanation for extraordinary therapy effects observed in 2 patients with advanced gastric cancer. / Hintergrund: Das Magenkarzinom wird häufig im fortgeschrittenen Stadium diagnostiziert, und nur etwa 10% der Patienten überleben 2 Jahre. Aktuelle Chemotherapien zeigen eine hohe therapiebedingte Toxizität. Es ist daher von großer Bedeutung, diejenigen Patienten zu identifizieren, die von einer bestimmten Therapie profitieren, um anderen Patienten die Nebenwirkungen einer solchen Therapie zu ersparen. Patienten und Methoden: 2 Patienten mit fortgeschrittenem Magenkarzinom erhielten wiederholt eine Kombinationschemotherapie aus 5-FU/Cisplatin. Genomische DNS wurde aus Tumorgewebe und Leukozyten isoliert. Genotypanalysen von Genen, die am Metabolismus der Substanzen und am DNS-Reparaturprozess beteiligt sind, wurden mithilfe einer PCRRFLP-Methode durchgeführt. Das Gen der Dihydropyrimidindehydrogenase (DPD) wurde direkt sequenziert. Ergebnisse: Beide Patienten zeigten ein deutlich verlängertes Überleben von 51 bzw. 29 Monaten. Genotypen des 5-FU-Zielenzyms Thymidylatsynthase, die mit einem verbesserten Ansprechen assoziiert sind, konnten in beiden Patienten nachgewiesen werden. DPD-Varianten, die mit einer erhöhten Toxizität verbunden sind, wurden nicht beobachtet. Zusätzlich konnten bei beiden Patienten Genotypen in Cisplatin metabolisierenden Genen gefunden werden, die eine prolongierte Wirkung der Substanz bedingen. Schlussfolgerungen: Durch Genotypanalysen in Genen des 5-FU- und Cisplatin-Metabolismus konnte ein spezifisches pharmakogenetisches Profil identifiziert werden, das möglicherweise die Ursache eines außergewöhnlich guten Therapieeffektes in 2 Patienten mit fortgeschrittenem Magenkarzinom ist. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

DNR pažaidų atitaisymas ir apoptozė - dvi pagrindinės grandys, palaikančios žmogaus genomo vientisumą. Sutrikus šiems procesams, ląstelė išgyvena, nepaisant susikaupusių DNR pažaidų ir sudaromas pagrindas tolesnei transformacijai. Tyrimu įvertinome DNR pažaidų atitaisymo funkcijoje dalyvaujančių (hMLH1, MGMT) ir su apoptoze susijusių (DAPK-1, CASP8) genų epigenetinio reguliavimo - metilinimo aspektus pakopiniame skrandžio onkogenezės procese. Šio mokslinio tyrimo metu pirmą kartą buvo nustatytas skirtingas hMLH1 geno metilinimo dažnis atskirose skrandžio anatominėse dalyse atrofiniu pangastritu sergančiųjų audinyje. Įvertinta, kad hMLH1 geno metilinimas sergančiųjų skrandžio vėžiu aplinkiniame nenavikiniame audinyje sietinas su pacientų amžiumi. Išgyvenamumo analizės rezultatai parodė, kad MGMT geno metilinimas agresyvios skrandžio vėžio histologinės formos atveju yra geresnės prognozės rodiklis. Tyrimo metu nustatėme mokslinėje periodikoje neaprašytų tirtųjų genų metilinimo derinių sąsajų su klinikiniais, morfologiniais ir prognoziniais onkologinės ligos ypatumais. / DNA repair and apoptosis are two main pathways supporting the integrity of human genome. After the disturbance of these processes the cell survives, despite the accumulation of DNA lesions, and in this way a basis for a subsequent transformation is formed. In our research we evaluated the epigenetic regulation - methylation - aspects of genes participating in DNA repair function (hMLH1 and MGMT) and also of apoptosis-related genes (DAPK-1, CASP8) in relation to a stepwise gastric oncogenesis process. During this investigation a different hMLH1 gene methylation observation frequency in tissues obtained from separate anatomical parts of the stomach in atrophic pangastritis patients was determined for the first time. It was estimated, that hMLH1 gene methylation in tumor-surrounding non-cancerous tissue in gastric cancer patients could be associated with patient age. Results of survival analysis indicated that MGMT gene methylation is an indicator of better prognosis in case of diffuse form of gastric cancer. During the study we determined some additional associations (not described in previous publications) between methylation combinations of analyzed genes and clinical, morphological and prognostic features of oncological illness.

Delayed gastric emptying, that manifests clinically as intolerance to enteral feeding, occurs in over 50% of critically ill patients and has a major impact on patient morbidity and mortality. Despite the recognition that the proximal stomach has a major role in gastric emptying of liquids, only the motor activity of the antro-pyloro-duodenal region has been evaluated in detail. In addition, many of the proposed risk factors for the gastric dysmotility, particularly a prior history of diabetes mellitus, have not been evaluated formally but have been extrapolated from data from non-critically ill patients. The currently available prokinetic drugs, erythromycin and metoclopramide, are considered to be the first line treatment for feed intolerance. However, neither data comparing the effectiveness of these agents nor the data on the effects of combination of therapy in the treatment of feed intolerance are available. The aims of this thesis were, therefore, to examine: (i) proximal gastric motor activity and the association between proximal and distal motility; (ii) the relationship between entero-gastric humoral responses to nutrients, gastric emptying and feed intolerance; (iii) the impact of admission diagnoses, choice of sedations, timing of initiation of feeding, and pre-existing history of diabetes mellitus on gastric emptying and feed intolerance; and (iv) the efficacy of erythromycin, metoclopramide and combination of these drugs in treatment of feed intolerance in critically ill patients. The current thesis indicates that motor activity is impaired in multiple regions of the stomach in the critically ill. When compared to healthy humans, proximal gastric relaxation was prolonged and fundic wave activity was educed during small intestinal nutrient infusion in critically ill patients. In addition, simultaneous assessment of proximal and distal gastric motility demonstrated a possible disruption of the motor integration between the proximal and distal stomach. In light of the recent data that suggested a significantly greater proportion of meal distributed proximally in critically ill patients with delayed gastric emptying (Nguyen, et al. 2006), the disruption of the gastric motor integration and the prolonged gastric relaxation in response to duodenal nutrients may play a significant role in the pathogenesis of slow gastric emptying during critical illness, especially as liquid formulae. The entero-gastric hormonal feedback responses were also disturbed during critical illness. Both fasting and duodenal nutrient-stimulated plasma CCK and PYY concentrations were significantly higher in critically ill patients, particularly those who did not tolerated gastric feeds. The rate of gastric emptying of a liquid meal was inversely related to both fasting and postprandial plasma CCK and PYY concentrations, supporting the potential role of plasma CCK and PYY in the pathogenesis of gastric dysmotility in critically ill patients. Admission diagnosis, choice of sedative drug and blood glucose control but not the timing of enteral feeds were important factors for delayed gastric emptying and feed intolerance in these patients. In particular, delaying enteral feeding by 4 days had no impact on the rate of gastric emptying, intra-gastric meal distribution, or plasma CCK and PYY concentrations. Contrary to traditional belief, critically ill patients with a pre-existing diagnosis of type 2 DM have only a minor disturbance to the proximal stomach, a relatively normal gastric emptying and are at no higher risk of feed intolerance than those without DM, suggesting the presence of pre-existing DM 2 in critically ill patients should not influence the standard practice of gastric feeding. Therapeutically, short-term treatment with low dose erythromycin was more effective than metoclopramide, but the effectiveness decreased rapidly overtime at similar rate as observed with metoclopramide. In patients who failed to response to either agent, treatment with both agents was highly effective in re-establishing feeding success. The use of combination therapy as the initial treatment for feed intolerance was also more effective than erythromycin alone and had less tachyphylaxis. Treatment with erythromycin and metoclopramide, either as a single agent or in combination did not associated with major cardiovascular adverse side effects. Although diarrhoea was a common side effect and was highest with combination therapy, it was not associated with Clostridium difficile infection and settled quickly after the cessation of the prokinetic therapy. In summary, the work performed in the current thesis has provided substantial insights into the understanding of the nature, risk factors, pathogenesis and treatment of disturbed gastric motor function in critically ill patients. Not only do these findings stimulate further research into the mechanisms responsible for gastric dysmotility in critical illness, they also lead to the development of new strategies for optimizing the management of feed intolerance. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1320667 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.