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Cytomegalievirus (CMV) ist bei immunsupprimierten Patienten nach Organ- oder Stammzelltransplantation sowie bei Patienten mit chronisch entzündlichen Darmerkrankungen und nicht immunsupprimierten kritisch kranken Patienten ein ernstzunehmender Risikofaktor für eine manifeste CMV-Infektion. Diese ist durch eine hohe Morbidität und Letalität gekennzeichnet. Daher ist eine zeitnahe und zuverlässige Diagnosestellung für die Einleitung einer adäquaten Therapie und damit für das klinische Ergebnis der Patienten von entscheidender Bedeutung. Ziel dieser retrospektiven Arbeit war es, die diagnostischen Verfahren der endoskopischen, pathologischen und virologischen Untersuchung bezüglich ihrer Treffsicherheit bei der gastrointestinalen CMV-Infektion zu untersuchen. Dafür wurde eine quantitative molekularvirologische Nachweismethode für CMV aus formalinfixiertem, in Paraffin eingebettetem Gewebe etabliert. Des Weiteren wurde das Procedere der Entnahme und der Verteilung der Biopsien an die Institute für Virologie und Pathologie evaluiert und die Ergebnisse von endoskopischer und molekularvirologischer Untersuchung in Blut- und Gewebeproben miteinander verglichen. In einem weiteren Schritt konnte die Korrelation der molekularvirologischen mit den immunhistochemischen Ergebnissen untersucht werden. Für die genannten Fragestellungen wurde CMV spezifisches Genom aus Blutproben und Gewebeproben des Gastrointestinaltraktes von 164 Patienten im Zeitraum von Oktober 2008 bis September 2010 quantitativ ausgewertet. Insgesamt wurden 860 Gewebeproben und 2550 Plasma- und Serumproben untersucht. Basierend auf den Ergebnissen der Datenerhebung zeigt die vorliegende Arbeit, dass ohne eine Anpassung der Vorgehensweise einer von vier Fällen mit gastrointestinaler CMV-Infektion nicht diagnostiziert werden würde und es wird macht einen Vorschlag zur weiteren Optimierung des diagnostischen Procedere.

Orientadores: Claudio Saddy Rodrigues Coy, Licio Augusto Velloso / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-12T15:28:55Z (GMT). No. of bitstreams: 1 Leal_RaquelFranco_D.pdf: 2568047 bytes, checksum: 4350cbde82eea7d21d3dd58ccd0a5ad3 (MD5) Previous issue date: 2009 / Resumo: A retocolectomia total com anastomose do reservatório ileal ao canal anal é a cirurgia de escolha para doentes com retocolite ulcerativa inespecífica (RCUI) refratária ao tratamento clínico e para polipose adenomatosa familiar (PAF), com pólipos retais. A ileíte do reservatório é uma das complicações mais comuns, sendo freqüente nos doentes com RCUI, porém rara na PAF. Objetivo: Avaliar a atividade inflamatória e apoptótica em mucosa de reservatórios ileais endoscopicamente normais pela expressão de IFN-?, STAT-1, IL-10, SOCS-3, Bax, Bcl-2, FADD/Caspase-8 e Apaf-1/Caspase-9 em RCUI e PAF operados. Casuística e Métodos: Estudou-se 18 doentes submetidos à cirurgia com reservatório ileal (RI) em "J", sendo nove doentes com RCUI e nove com PAF. O grupo controle foi constituído por nove doentes com íleo-colonoscopia normal. As biópsias foram congeladas em nitrogênio líquido e as expressões de IFN-?, STAT-1, IL-10, SOCS-3, Bax e Bcl-2 foram avaliadas por meio de imunoblot de extrato protéico total. As expressões de FADD/Caspase-8 e Apaf-1/Caspase-9 foram determinadas por meio de ensaio de imunoprecipitação e imunoblot. Utilizou-se imunoistoquímica para Bax e Bcl-2 e imunofluorescência com Anexina V. Resultados: Expressão de STAT-1 foi maior em RCUI, quando comparada com PAF e controles (p<0.05). A expressão de IFN-? foi maior em RCUI quando comparada aos controles (p<0.05). Expressões de IL-10, SOCS-3 e Bcl-2 foram semelhantes em todos os grupos (p>0.05). Expressão de Apaf-1/Caspase-9 foi maior em RCUI comparada à PAF (p<0.05), entretanto FADD/Caspase-8 foi similar entre os grupos (p>0.05). Conclusão: Os doentes com RCUI apresentaram maiores níveis das citocinas pró-inflamatórias na mucosa do RI, sendo estas semelhantes àquelas presentes em mucosa colorretal de RCUI ativa, mesmo na ausência de sinais clínicos e endoscópicos de ileíte do reservatório. Além disso, houve expressão aumentada de proteínas pró-apoptóticas no Grupo RCUI, podendo justificar a maior susceptibilidade dos doentes operados por RCUI a esta complicação. Demonstrou-se também, alteração dos mecanismos de apoptose em PAF, que poderia explicar a diminuição da renovação celular e presuntivamente, o aparecimento de adenomas nesta síndrome. / Abstract: Ileal pouch-anal anastomosis is the surgical procedure of choice for patients with refractory ulcerative colitis (UC) and for familial adenomatous polyposis (FAP) with rectal polyps. Pouchitis is the most common complication in UC, while it is quite rare in FAP. Objective: Evaluate the inflammatory and apoptotic activity in endoscopically normal ileal pouch mucosa, by determining the expressions of IFN-?, STAT-1, IL-10, SOCS-3, Bax, Bcl-2, FADD/Caspase-8 and Apaf-1/Caspase-9 in operated patients with UC and FAP. Patients and Methods: Eighteen patients submitted to total retocolectomy and J pouch were evaluated; nine were patients with UC and nine with FAP. The control group consisted of nine individuals with normal ileo-colonoscopy examination. The collected specimens were snap-frozen in liquid nitrogen and expressions of IFN-?, STAT-1, IL-10, SOCS-3, Bax and Bcl-2 were determined by immunoblot of total protein extracts. FADD/Caspase-8 and Apaf-1/Caspase-9 were evaluated by immunoprecipitation and immunoblot. Immunohistochemistry analysis for Bax and Bcl-2, and immunofluorescence with Annexin V assays were applied in all biopsies. Results: STAT-1 expression was increased in patients with UC, when compared with FAP and controls (p<0.05). IFN-? expression was increased in UC when compared with controls (p<0.05). IL-10, SOCS-3 and Bcl-2 were similar among the groups (p>0.05). Apaf-1/Caspase-9 expression was increased in UC when compared with FAP (p<0.05); however FADD/Caspase-8 was similar in the groups (p>0.05). Conclusion: Patients with UC had increased pro-inflammatory cytokines levels, even without clinical and endoscopic evidence of pouchitis; these alterations were similar to those of UC disease. Indeed, there was increased pro-apoptotic protein expression in UC. These findings may suggest a higher susceptibility to this complication in operated patients with UC, when it was compared to PAF. In addition, a down-regulation of apoptosis in FAP was observed, possibly explaining the decreased cell turn over and presence of adenomas in this syndrome. / Doutorado / Cirurgia / Doutor em Cirurgia

Cytomegalievirus (CMV) ist bei immunsupprimierten Patienten nach Organ- oder Stammzelltransplantation sowie bei Patienten mit chronisch entzündlichen Darmerkrankungen und nicht immunsupprimierten kritisch kranken Patienten ein ernstzunehmender Risikofaktor für eine manifeste CMV-Infektion. Diese ist durch eine hohe Morbidität und Letalität gekennzeichnet. Daher ist eine zeitnahe und zuverlässige Diagnosestellung für die Einleitung einer adäquaten Therapie und damit für das klinische Ergebnis der Patienten von entscheidender Bedeutung. Ziel dieser retrospektiven Arbeit war es, die diagnostischen Verfahren der endoskopischen, pathologischen und virologischen Untersuchung bezüglich ihrer Treffsicherheit bei der gastrointestinalen CMV-Infektion zu untersuchen. Dafür wurde eine quantitative molekularvirologische Nachweismethode für CMV aus formalinfixiertem, in Paraffin eingebettetem Gewebe etabliert. Des Weiteren wurde das Procedere der Entnahme und der Verteilung der Biopsien an die Institute für Virologie und Pathologie evaluiert und die Ergebnisse von endoskopischer und molekularvirologischer Untersuchung in Blut- und Gewebeproben miteinander verglichen. In einem weiteren Schritt konnte die Korrelation der molekularvirologischen mit den immunhistochemischen Ergebnissen untersucht werden. Für die genannten Fragestellungen wurde CMV spezifisches Genom aus Blutproben und Gewebeproben des Gastrointestinaltraktes von 164 Patienten im Zeitraum von Oktober 2008 bis September 2010 quantitativ ausgewertet. Insgesamt wurden 860 Gewebeproben und 2550 Plasma- und Serumproben untersucht. Basierend auf den Ergebnissen der Datenerhebung zeigt die vorliegende Arbeit, dass ohne eine Anpassung der Vorgehensweise einer von vier Fällen mit gastrointestinaler CMV-Infektion nicht diagnostiziert werden würde und es wird macht einen Vorschlag zur weiteren Optimierung des diagnostischen Procedere.

No / Methionine dependence is unique to cancer cells and defined as the inability to grow in a methionine-deprived environment even if supplemented with the metabolic precursor homocysteine. Cobalamin-dependent methionine synthase (MS) catalyses the formation of methionine and tetrahydrofolate from homocysteine and methyltetrahydrofolate, thus linking the methionine and folate pathways. The apparent altered methionine metabolism in methionine-dependent cancer cells suggests a role for MS, although results to date are conflicting. We have analysed key metabolites of the MS-associated transmethylation, transsulphuration and folate pathways of the methionine-dependent MAC15A tumour model as a function of tumour progression over a 10-day period. MS activity increased 2-fold from day I to day 10. Cysteine, homocysteine, S-adenosylmethionine and S-adenosylhomocysteine levels in tumour cytosolic fractions decreased as a function of tumour progression. Plasma cysteine levels also decreased, whilst the distribution of folates in erythrocytes was altered, with a maximum increase in methyltetrahydrofolate observed by day 5. The increasing MS activity and decreasing cysteine levels suggest an increasing methionine requirement by the tumour, whilst the induction of enzyme activity indicates that MS is not defective in the methionine-dependent MAC15A tumour. The decrease in tumour S-adenosylmethionine and S-adenosylhomocysteine levels suggests that methionine is required for some function other than cellular methylation, e.g., incorporation into protein. Overall, the results support a theory of methionine conservation in response to tumour growth, where the methionine-dependent MAC15A tumour has a higher than normal methionine requirement.

Case reports describe significant norovirus gastroenteritis morbidity in immunocompromised patients. We evaluated norovirus pathogenesis in prospectively enrolled solid organ (SOT) and hematopoietic stem cell transplant (HSCT) patients with diarrhea who presented to Texas Children's Hospital and submitted stool for enteric testing. Noroviruses were detected by real-time reverse transcription polymerase chain reaction. Clinical outcomes of norovirus diarrhea and non-norovirus diarrhea patients, matched by transplanted organ type, were compared. Norovirus infection was identified in 25 (22%) of 116 patients, more frequently than other enteropathogens. Fifty percent of norovirus patients experienced diarrhea lasting ≥14 days, with median duration of 12.5 days (range 1–324 days); 29% developed diarrhea recurrence. Fifty-five percent of norovirus patients were hospitalized for diarrhea, with 27% requiring intensive care unit (ICU) admission. One HSCT recipient developed pneumatosis intestinalis. Three HSCT patients expired ≤6 months of norovirus diarrhea onset. Compared to non-norovirus diarrhea patients, norovirus patients experienced significantly more frequent ICU admission (27% vs. 0%, p = 0.02), greater serum creatinine rise (median 0.3 vs. 0.2 mg/dL, p = 0.01), and more weight loss (median 1.6 vs. 0.6 kg, p < 0.01). Noroviruses are an important cause of diarrhea in pediatric transplant patients and are associated with significant clinical complications.

The thesis deals with the lifestyle of patients with chronic intestinal disease. The theoretical part contains topics of theoretical knowledge essential to the orientation in the issue. It describes the principles of a healthy lifestyle, the issue of chronic intestinal disease, especially Crohn's disease and ulcerative colitis as a disease of clinical manifestations, from diagnosis to treatment. An important chapter of the theoretical part of the work are the impacts of IBD on lifestyle at chronically ill patients. The empirical part deals with the qualitative research. For datas collecting was chosen and used the method of questioning with narrative interview technique. Methodology of narrative interview was expanded to include specific methods of collection datas, the life curve method. The content of each interpretation is the final report that summarizes the observed facts associated with answers to research questions. Significant elements of the interviews are recorded in tables. The aim of the thesis was to find out in what areas and how the selected people with chronic intestinal diseases have changed their lifestyle. To provide information to the public about the limitations of patients with chronic intestinal diseases that directly affect their everyday lives. Finally to assist society tolerance to constraints of patients with chronic intestinal disease.

One of the aims included in the United Nations Millennium Development Goals is to decrease the number of the world’s population without access to sanitation and water that is safe, by half by the year 2015. The use of water that is not safe for consumption leads to water–related diseases. For the purpose of this study gastro–intestinal disease was redefined as diseases of the gastro–intestinal tract caused by pathogens that spread via contaminated drinking water, poor sanitation and inadequate hygiene. Information obtained regarding the use of gastro–intestinal disease medication, may provide information about the prevalence of gastro–intestinal disease in South Africa. The general objective of this study was to determine the prescribing patterns of gastro–intestinal medication in different geographical areas in the private health care sector of South Africa. A retrospective drug utilisation review was conducted on data obtained from a medicine claims database of a pharmacy benefit management company for 2007 and 2008. A pharmacoepidemiological approach was followed in order to determine the prevalence of gastro–intestinal disease as well as the use of gastro–intestinal medication in South Africa as well as the different provinces of South Africa. The impact of water quality and sanitation on the prevalence of gastro–intestinal disease was also investigated. Gastro–intestinal medication (used in the treatment of gastro–intestinal disease) included the following pharmacological groups according to the MIMS®–classification: antivertigo and anti–emetic agents (group 1.8), antispasmodics (group 12.3), antidiarrhoeals (group 12.7), minerals and electrolytes (group 20.4, selected according to specified NAPPI–codes) and antimicrobials (group 18). Antimicrobials had to be prescribed in combination with one of the specified gastro–intestinal medication groups in order to be classified as a gastro–intestinal medication. In 2007 and 2008 respectively, 428864 and 340921 gastro–intestinal medication items were prescribed. The most frequently prescribed gastro–intestinal medication pharmacological groups in 2007 and 2008 were beta–lactam antimicrobials (with proportion percentages of 22.77% and 20.85% in 2007 and 2008 respectively), antivertigo and anti–emetic agents, antispasmodics, antidiarrhoeals and quinolone antimicrobials. Minerals and electrolytes represented only a small proportion (2.99% and 2.56% in 2007 and 2008 respectively) of the prescribed gastro–intestinal medication in South Africa. In the Free State and Western Cape antivertigo and anti–emetic agents were the most frequently prescribed gastro–intestinal medication items, while in other provinces beta–lactam antimicrobials ranked the highest. In all provinces except the Western Cape and the Northern Cape, amoxicillin/clavulanic acid was the most frequently prescribed gastro–intestinal medication active ingredient. In the Western Cape loperamide was the most frequently prescribed active ingredient, while ciprofloxacin ranked highest as active ingredient in the Northern Cape in 2008. Based on the prescribing patterns of gastro–intestinal disease medications the treatment of gastro–intestinal disease in this section of the private health care sector of South Africa, does not fully comply with the Standard Treatment Guidelines with regard to the use of antimicrobials and electrolyte replacement therapy. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.