Orientador: Lígia Yukie sassaki / Resumo: Introdução: Com o advento da terapia biológica, o foco de resposta na Doença de Crohn (DC) ampliou-se, sendo essenciais a remissão clínica e endoscópica. Estudos prospectivos comparando os representantes dessa classe terapêutica mais utilizados, o Infliximabe (IFX) e o Adalimumabe (ADA), são escassos. O objetivo do estudo foi comparar a efetividade clínica e endoscópica do IFX versus ADA em pacientes com DC naïves terapia biológica, na semana 54 de tratamento. Metodologia: Foi realizado um estudo clínico, não-randomizado, no qual pacientes com DC que receberam IFX ou ADA, foram avaliados nas semanas 0, 14, 30 e 54 de tratamento. Utilizou-se o Índice de Atividade da Doença de Crohn (CDAI) para avaliação da atividade clínica da doença. Entre 6 e 12 meses, foi avaliada a atividade endoscópica através do Simplified Endoscopic Score for Crohn’s Disease (SES-CD). As variáveis foram resposta clínica (queda do CDAI > 70 pontos) e remissão clínica (CDAI < 150 pontos), avaliados nas semanas 14, 30 e 54, e resposta endoscópica (queda do SES-CD de pelo menos 50% em relação à pontuação inicial), remissão endoscópica (controle endoscópico com SES-CD ≤ 2 pontos), e taxas de internação, cirurgia, óbito e perda de resposta, analisados na semana 54. A análise estatística foi estatística descritiva, teste de ANOVA com medidas repetidas no tempo considerando a interação medicamento x tempo, seguida do teste de comparação múltipla de Tukey ajustado, com nível de significância de 5% ou o p-valor c... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: With the advent of biological therapy, the focus of the Crohn's Disease (CD) response has changed and clinical and endoscopic remission are essential. Prospective studies comparing the most used biological drugs, Infliximab (IFX) and Adalimumab (ADA), are scarce. Our aim was compare the clinical and endoscopic effectiveness of IFX versus ADA in CD patients naïve to biological therapy at the 54th week of treatment. Methods: An open, non-randomized, clinical study with CD patients receiving IFX or ADA was performed at treatment weeks 0, 14, 30 and 54. The Crohn's Disease Activity Index (CDAI) was used to evaluate the disease clinical activity. Between 6 and 12 months, colonoscopy was performed and the Simplified Endoscopic Score for Crohn's Disease (SES-CD) was used. Clinical response (CDAI decrease>70 points) and clinical remission (CDAI<150 points) were assessed at weeks 14, 30 and 54; endoscopic response (decrease of at least 50% in SES-CD), endoscopic remission (endoscopic control with SES-CD ≤ 2 points), and hospitalization rates, surgeries, deaths and loss of response, were analyzed at week 54. A statistical analysis was descriptive with ANOVA test with repeated measures considering drug interaction x time, followed by Tukey multiple comparison test adjusted, with a significance level of 5% or the corresponding p-value. Results: A total of 85 patients were included, 45 patients underwent treatment with ADA and 40 with IFX, with difference between groups only... (Complete abstract click electronic access below) / Doutor

Submitted by JÚLIO PINHEIRO BAIMA (jpbaima@yahoo.com.br) on 2018-04-25T20:09:46Z No. of bitstreams: 1 Tese Doutorado Julio Pinheiro Baima 25 abril 2018.pdf: 1976761 bytes, checksum: fade6f9adcb14ae4ad0854e9274f5c9d (MD5) / Approved for entry into archive by Sulamita Selma C Colnago null (sulamita@btu.unesp.br) on 2018-04-26T19:04:00Z (GMT) No. of bitstreams: 1 baima_jp_dr_bot_int.pdf: 1976761 bytes, checksum: fade6f9adcb14ae4ad0854e9274f5c9d (MD5) / Made available in DSpace on 2018-04-26T19:04:00Z (GMT). No. of bitstreams: 1 baima_jp_dr_bot_int.pdf: 1976761 bytes, checksum: fade6f9adcb14ae4ad0854e9274f5c9d (MD5) Previous issue date: 2018-02-27 / Introdução: Com o advento da terapia biológica, o foco de resposta na Doença de Crohn (DC) ampliou-se, sendo essenciais a remissão clínica e endoscópica. Estudos prospectivos comparando os representantes dessa classe terapêutica mais utilizados, o Infliximabe (IFX) e o Adalimumabe (ADA), são escassos. O objetivo do estudo foi comparar a efetividade clínica e endoscópica do IFX versus ADA em pacientes com DC naïves terapia biológica, na semana 54 de tratamento. Metodologia: Foi realizado um estudo clínico, não-randomizado, no qual pacientes com DC que receberam IFX ou ADA, foram avaliados nas semanas 0, 14, 30 e 54 de tratamento. Utilizou-se o Índice de Atividade da Doença de Crohn (CDAI) para avaliação da atividade clínica da doença. Entre 6 e 12 meses, foi avaliada a atividade endoscópica através do Simplified Endoscopic Score for Crohn’s Disease (SES-CD). As variáveis foram resposta clínica (queda do CDAI > 70 pontos) e remissão clínica (CDAI < 150 pontos), avaliados nas semanas 14, 30 e 54, e resposta endoscópica (queda do SES-CD de pelo menos 50% em relação à pontuação inicial), remissão endoscópica (controle endoscópico com SES-CD ≤ 2 pontos), e taxas de internação, cirurgia, óbito e perda de resposta, analisados na semana 54. A análise estatística foi estatística descritiva, teste de ANOVA com medidas repetidas no tempo considerando a interação medicamento x tempo, seguida do teste de comparação múltipla de Tukey ajustado, com nível de significância de 5% ou o p-valor correspondente. Resultados: Foram incluídos 85 pacientes, 45 submetidos ao tratamento com ADA e 40 com IFX. O uso concomitante de Azatioprina foi mais frequente no grupo que recebeu IFX (p=0,0001). As taxas de resposta clínica foram de 86,67% na semana 14, 82,22% na semana 30 e 82,22% na semana 54 no grupo ADA. No grupo IFX, as taxas de resposta foram 70%, 72,5% e 75%, respectivamente, sem diferença entre os tratamentos (p>0,05 em todas as semanas). As taxas de remissão clínica no grupo ADA foram de 86,67% na semana 14, 80% na semana 30 e 82,22% na Resumo 3 semana 54. No grupo IFX, 65%, 62,5% e 65% respectivamente, com diferença significativa apenas na semana 14 (p=0,02). Resposta endoscópica foi atingida em 60,61% dos pacientes do grupo ADA e 85,71% no grupo IFX (p=0,02). As taxas de remissão endoscópica foram de 45,45% e 60%, respectivamente (p=0,23). Internações, cirurgia, óbitos e perda de resposta ocorreram com frequência sem diferença significativa entre os grupos. Conclusões: Não houve diferença nas taxas de resposta clínica entre os tratamentos. Houve maiores taxas de remissão clínica na semana 14 no grupo ADA, não mantidas nas semanas seguintes. Taxas de resposta endoscópica foram melhores no grupo IFX. Não houve diferença nas taxas de remissão endoscópica. Não houve diferença nas taxas de internações, cirurgias e óbitos, assim como na perda de resposta. / Introduction: With the advent of biological therapy, the focus of the Crohn's Disease (CD) response has changed and clinical and endoscopic remission are essential. Prospective studies comparing the most used biological drugs, Infliximab (IFX) and Adalimumab (ADA), are scarce. Our aim was compare the clinical and endoscopic effectiveness of IFX versus ADA in CD patients naïve to biological therapy at the 54th week of treatment. Methods: An open, non-randomized, clinical study with CD patients receiving IFX or ADA was performed at treatment weeks 0, 14, 30 and 54. The Crohn's Disease Activity Index (CDAI) was used to evaluate the disease clinical activity. Between 6 and 12 months, colonoscopy was performed and the Simplified Endoscopic Score for Crohn's Disease (SES-CD) was used. Clinical response (CDAI decrease>70 points) and clinical remission (CDAI<150 points) were assessed at weeks 14, 30 and 54; endoscopic response (decrease of at least 50% in SES-CD), endoscopic remission (endoscopic control with SES-CD ≤ 2 points), and hospitalization rates, surgeries, deaths and loss of response, were analyzed at week 54. A statistical analysis was descriptive with ANOVA test with repeated measures considering drug interaction x time, followed by Tukey multiple comparison test adjusted, with a significance level of 5% or the corresponding p-value. Results: A total of 85 patients were included, 45 patients underwent treatment with ADA and 40 with IFX, with difference between groups only in concomitant use of azathioprine, more frequent in the IFX group (p=0.0001). Clinical response rates were 86.67% at week 14, 82.22% at week 30 and 82.22% at week 54 in ADA group. In IFX group, 70%, 72.5% and 75%, respectively (p> 0.05 on all weeks). Clinical remission rates were 86.67% at week 14, 80% at week 30 and 82.22% at week 54 in ADA group. In IFX group, 65%, 62.5% and 65%, respectively, with significate difference only at week 14 (p = 0.02). Endoscopic response rate was 60.61% in patients from ADA group and 85.71% in the IFX group (p = 0.02). Rates of Abstract 6 endoscopic remission were 45.45% and 60%, respectively (p = 0.23). Hospitalizations, surgery, deaths and loss of lost response occurred without significant difference between groups. Conclusions: There were no difference in the clinical response rates between treatments. There was higher rate of clinical remission at week 14 in the ADA group, not sustained in the subsequent weeks. Endoscopic response rate was better in the IFX group. There was no difference in endoscopic remission rate. There were no difference in hospitalization rates, surgeries and deaths, as well as loss of response.

Introduction: Crohn's disease is an illness of the digestive tract with an uncertain etiology which threatens the nutritional state of patients and in addition to other problems results in a worsening of the disease in reaction to primary treatment. The possibilities of optimizing the nutritional state are several: changing diet, enteral or parenteral nutrition or combination of both. It is necessary to arrange an entirely individual approach for ensuring the highest measure of attention and nutritional effectiveness. Methods: The influence of enteral nutrition was monitored during a course of Crohn's disease. 84 patients with malnutrition and with an active form of Crohn's disease were included in this study. They were divided into 2 groups according to the type and dosage of enteral nutrition. The first group included patients who used partial enteral nutrition in the form of sipping with an energy value of 1200 kcal daily. Patients covered the remaining energy needs with a low-residue diet enriched by soluble fiber. The second group included patients who were given exclusive oligomeric enteral nutrition with a nasojejunal tube for a period of eight weeks. The amount of enteral nutrition in both groups was individually adjusted and calculated, according to the Harris-Benedict equation. The...

Orientadores: Elizete Aparecida Lomazi da Costa Pinto, Maria Marluce dos Santos Vilela / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-17T21:25:30Z (GMT). No. of bitstreams: 1 Davanco_Taciana_D.pdf: 2427326 bytes, checksum: 95e80c1ee79f6b95668f4d4d893d1a87 (MD5) Previous issue date: 2011 / Resumo: A Doença de Crohn (DC) e uma desordem inflamatória intestinal crônica, com evidencia de inflamação transmural granulomatosa da mucosa. Ha aumento da permeabilidade intestinal, redução da atividade do sistema muco ciliar, alterações nas junções epiteliais, deficiência de oligoelementos ate desnutrição grave. A etiopatogenia permanece e desconhecida, mas ha hipóteses sobre a genética da doença e alterações da regulação da resposta imune da mucosa para a microbiota intestinal. O diagnostico e estabelecido pelos sintomas e sinais, imagens da endoscopia e radiologia, e histologia do tecido intestinal. O objetivo desta pesquisa foi investigar o efeito de um concentrado de proteínas de soro de leite bovino enriquecido com TGF-? sobre a inflamação e o estado nutricional dos pacientes com DC sob terapia com azatioprina sozinha ou combinada com anti-TNF? (infliximab). O desenho do estudo e prospectivo e de intervenção via oral por dezesseis semanas com um concentrado de proteínas do soro de leite enriquecido com TGF-?. Foram realizadas analises de composição centesimal, grau de hidrolise, solubilidade e determinação total de aminoácidos do suplemento da proteína do soro de leite bovino. A ingestão alimentar e estado nutricional foram avaliados antes e apos a intervenção. Para avaliação sensorial do suplemento foi aplicado teste de aceitação utilizando escala hedônica facial de 9 pontos. A inflamação foi avaliada antes, durante e apos a intervenção, através da medida do índice de atividade da doença e da dosagem do sistema oxidante H2O2 pelos granulócitos e antioxidante enzimatico da Glutationa eritrocitaria (GSH). O grupo total de pacientes com doença de Crohn apresentou, em sua maioria, consumo adequado de carboidratos e lipídeos, e o consumo de proteína foi superior ao recomendado em mais da metade dos pacientes. Constatou-se inadequação na ingestão de vitaminas A, C, D, E, fibras, cálcio, folato, ferro e zinco. A ingestão de proteínas do soro de leite resultou em melhora da composição corporal dos pacientes. A avaliação sensorial mostrou que cerca de 30% dos indivíduos gostaram do suplemento com relação a todos os atributos avaliados, já metade deles não gostaram e 20% o classificaram como "mais ou menos". A avaliação clinica pelo Índice de atividade da Doença de Crohn (IADC), mostrou que a suplementação nutricional no grupo de pacientes sob terapia combinada Azatioprina e Infliximab reduziu significativamente o IADC revelado pela melhora dos sintomas clínicos dos pacientes. O grupo de pacientes que apresentava a DC com sintomas mais leves estava sob terapia com AZA sozinha e mostrou produção de GSH similar ao controle saudável. No entanto, o grupo sob terapia combinada AZA + anti- TNF-? (Infliximab) apresentou valores de GSH significativamente mais elevados do que o controle saudável antes (p=0,023) e apos a suplementação (p<0,01). Do mesmo modo, valores significativamente mais altos de GSH no grupo da terapia combinada antes (p=0,048) e apos a suplementação foi observado quando comparado ao grupo AZA. Os valores mais elevados de GSH no grupo de terapia combinada podem ser interpretados como efeito dessa terapia, combinada, uma vez que não se observou diferença significativa quando se comparou os valores de GSH antes e apos receber a suplementação. " Em relação a produção basal de H2O2, o grupo de pacientes sob terapia com AZA sozinha mostrou resultados similares ao controle saudável, enquanto o grupo sob terapia combinada mostrou valores inferiores significativos (p<0,01) em relação ao controle saudável. A capacidade máxima de produção de espécies reativas de oxigênio não apresentou diferença significativa entre o controle saudável e os pacientes em uso de imunossupressores. Como também não foi observada diferença significativa entre H2O2 antes e apos a suplementação. Esses resultados demonstram, pela primeira vez, que a terapia combinada na DC reduz de modo acentuado a geração de espécies reativas do oxigênio por granulócitos e, o aumento de GSH encontrado nesses pacientes, reforça seu relevante papel no equilíbrio do balanço H2O2 (oxidante) versus GSH (antioxidante). Com resultados de H2O2 tão baixos e de GSH mais elevados no grupo de pacientes sob terapia combinada, o suplemento oferecido a esses pacientes pode ser metabolizado e aproveitado de modo a ter impacto na melhora no IADC e na composição corporal. O grupo sob terapia combinada, mas não suplementado, não apresentou melhora do IADC nem do índice de massa corporal. Esses resultados são muito relevantes uma vez que os pacientes ao iniciarem a terapia combinada apresentavam doença de moderada para grave e ao receberem o suplemento já se encontravam com o IADC ?150. Nessa fase, o suplemento teve sua contribuição porque não havia mais desequilíbrio no sistema oxidante versus antioxidante. Alem disso, o curto período de 16 semanas de suplementação com o concentrado de proteína do soro de leite enriquecido com TGF- ? foi suficiente para promover melhoras no IADC e no Índice de massa corporal. Concluímos que o suplemento tem grande potencial para ser comercializado e auxiliar na melhoria da clinica de indivíduos com doença de Crohn. Entretanto, para encorajar a suplementação com o concentrado de soro de leite enriquecido com TGF- ? de modo regular e fundamental melhorar a qualidade sensorial do produto / Abstract: Crohn's disease (AD) is a chronic inflammatory bowel disorder, with evidence of transmural granulomatous inflammation of the mucosa. There is increased intestinal permeability, reduced the activity of the ciliary mucus, changes in epithelial junctions, and trace element deficiency to severe malnutrition. The etiopathogenesis remains an enigma, but there are hypotheses about the genetics of disease and changes in regulation of the mucosal immune response to intestinal microbiota. The diagnosis is established by the symptoms and signs, endoscopy and radiology images, and histology of the intestinal tissue. The objective of this research was to investigate the role of a protein concentrate of whey enriched with TGF-? on inflammation and nutritional status of patients with Crohn's disease under treatment with azathioprine alone or combined with anti-TNF (infliximab). The study design is prospective and intervention orally for sixteen weeks with a protein concentrate of whey enriched with TGF-?. Were analyzed for chemical composition, degree of hydrolysis, solubility and total amino acid determination of protein supplementation of whey. Dietary intake and nutritional status were evaluated before and after intervention. To supplement the sensory evaluation test was applied for acceptance facial hedonic scale of 9 points. Inflammation was assessed before, during and after the intervention by measuring the index of disease activity and dosage of the oxidant system H2O2 by granulocytes and erythrocyte antioxidant enzyme glutathione (GSH). The total group of patients with Crohn's disease had, in most cases, adequate intake of carbohydrates and lipids, and protein consumption was higher than recommended in more than half of patients. It was found inadequate intake of vitamins A, C, D, E, fiber, calcium, folate, iron and zinc. Protein intake of whey resulted in improved body composition of patients. The sensory evaluation showed that about 30% of individuals liked the supplement with respect to all attributes, since half of them did not like and 20% classified it as "more or less". The clinical activity index for Crohn's disease (CDAI), showed that nutritional supplementation in patients under azathioprine and infliximab combination therapy significantly reduced the IADC revealed by the improvement of clinical symptoms of patients. The group of patients who presented with the DC milder symptoms were being treated with AZA alone and showed production of GSH similar to healthy control. However, the AZA group under combined therapy + anti-TNF-? (infliximab) had GSH values significantly higher than healthy controls before (p = 0.023) and after supplementation (p <0.01). Similarly, significantly higher values of GSH in the combined therapy group before (p = 0.048) and after supplementation was observed when compared to the AZA group. Highest levels of GSH in the combined therapy group can be interpreted as an effect of this therapy, combined, since there was no significant difference when comparing the values before and after receiving GSH supplementation. "In relation to the basal production of H2O2, the group of patients on AZA therapy alone showed similar results to healthy control, while the group under combined therapy showed significant lower values (p <0.01) compared to healthy control. The ability Maximum production of reactive oxygen species showed no significant difference between healthy control and patients using immunosuppressive drugs. Nor was no significant difference between H2O2 before and after supplementation. These results demonstrate for the first time that therapy combined in DC markedly reduces the generation of reactive oxygen species by granulocytes and the increase of GSH found in these patients, strengthen its important role in balancing the balance sheet H2O2 (oxidative) versus GSH (antioxidant). With results of H2O2 as low GSH and higher in the group of patients on combination therapy, the supplement offered to these patients could be metabolized and used in order to have an impact on improvement in CDAI and body composition. The group under combined therapy, but not supplementation, showed no improvement in the CDAI or the body mass index. These results are very relevant since patients starting combination therapy had moderate to severe disease and to receive the supplement has met with the CDAI ? 150. At this stage, the supplement had its contribution because there was an imbalance in oxidant versus antioxidant system. Moreover, the short period of 16 weeks of supplementation with protein concentrate of whey enriched with TGF-? was sufficient to promote improvements in CDAI and Score body mass. We conclude that the supplement has great potential to be commercialized and help to improve the clinic from individuals with Crohn's disease. However, to encourage supplementation with the concentrate of whey enriched with TGF-? on a regular basis is essential to improve the sensory quality of the product / Doutorado / Saude da Criança e do Adolescente / Doutor em Saude da Criança e do Adolescente

Orientador: Jose Geraldo P. Ferraz / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T17:03:45Z (GMT). No. of bitstreams: 1 Coppi_LucianeCristina_D.pdf: 5991264 bytes, checksum: bbcad7dd36b02092b27ac1c30b751988 (MD5) Previous issue date: 2004 / Resumo: Os eosinófilos estão envolvidos na patogênese de várias doenças inflamatórias crônicas? incluindo doenças inflamatórias intestinais (Dll)? como doença de Crohn (DC) e retocolite ulcerativa inespecífica (RCVI). No entanto? ainda é desconhecido como os eosinófilos contribuem para a patogênese das Dll. Portanto? o objetivo deste estudo foi avaliar a atividade dos eosinófilos isolados de sangue periférico de pacientes com Dll comparada aos voluntários sadios. Eosinófilos dos voluntários sadios (n=5)? com DC (n=5) e RCVI (n=5) foram purificados usando-se um gradiente de Percoll? seguido de separação imunomagnética. A atividade dos eosinófilos foi avaliada usando-se os ensaios de quimiotaxi~ adesão? liberação de peroxidase do eosinófilo (EPO)? citometria de fluxo? contagem histológica e análise morfométrica. A quimiotaxia dos eosinófilos induzida pelo N-formyl-metionyl-Ieucyl-fenilanina(fMLP) foi significativamente maior para as células isoladas de pacientes com DC e RCVI? quando comparada aos voluntários sadios.A adesão basal dos eosinófilos de pacientes com DC aumentou significativamente para fibronectina ou soro? quando comparada aos voluntários sadios e RCVI. A liberação basal e estimulada de EPO foi reduzida em células de pacientes com DC? quando comparada aos voluntários sadios. Entretanto? em células isoladas de pacientes com RCVI? a liberação de EPO basal foi significativamente maior quando comparada aos voluntários sadios. A expressão das moléculas de adesão macrophage-l antigen (Mac-l) e very late antigen 4 (VLA-4) não apresentou diferença em relação aos voluntários sadios. A contagem histológica dos eosinófilos em tecido intestinal e morfométrica dos grânulos destas células mostrar~ respectivamente? aumento significativo do número de eosinófilos e de seus grânulos em pacientes com DC e RCVI quando comparadas aos voluntários sadios. Nossos resultados sugerem que os eosinófilos periféricos estão pré-ativados em pacientes com Dll. A ativação dos eosinófilos periféricos? seguida da migração para o tecido intestinal deve contribuir para a patogênese das Dll / Abstract: Eosinophils are involved in the pathogenesis of several chronic inflammatory diseases, including inflammatory bowel disease (ffiD), as Crohn's disease (CD) and ulcerative colites (DC). However, how activation of intravascular eosinophils contributes to disease activity or ffiD pathogenesis is still unknown. The aim of this study was to investigate if eosinophils isolated ITomperipheral blood ITomffiD patients are activated compared to healthy volunteers. Eosinophils ITomhea1thyvolunteers (n=5), CD (n=5) and DC patients (n=5) were purified using a Percoll gradient followed by immunomagnetic cell separator. Eosinophil activity was investigated using chemotaxis, adhesion and mediator release assays (eosinophil peroxidase, EPO), flow cytometric, histologic counting and morphometric analysis. -formyl-metionyl-Ieucyl-fenilanina (fMLP) induced eosinophil chemotaxis was significandy augmented in cells isolated from CD and DC patients compared to hea1thyvolunteers. Eosinophil basal adhesion of CD significantlyincreased to fibronectin or serum if compared to DC or hea1thyvolunteers. Basal and stimulated EPO release was reduced in cells ITomCD patients compared to hea1thyvolunteers. However, basal EPO release was significantly enhanced in cells isolated from DC patients when compared to hea1thy volunteers. The expression of adhesion molecules macrophage-l antigen (Mac-l) and very late antigen 4 (VLA-4) isn't different in patients with DC and CD compared to hea1thyvolunteers. Histologic counting of eosinophils in intestinal tissue and morphometric analysis of granules of this cells showed, respectively, significant augmentation in the number of eosinophils and its granules in CD and DC patients compared to hea1thy volunteers. Our results suggest that peripheral eosinophils are preactivated in ffiD patients. Activation of peripheral eosinophils followed by migration to intestinal tissue probably contributes to ffiD pathogenesis / Doutorado / Ciencias Basicas / Doutor em Clínica Médica

Orientadores: Claudio Saddy Rodrigues Coy, Maria de Lourdes Setsuko Ayrizono / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T21:08:20Z (GMT). No. of bitstreams: 1 Giordano_LucianeCristinaRosimSundfeld_M.pdf: 1272088 bytes, checksum: a62f7566f62b1cbbda19579638b0a5d8 (MD5) Previous issue date: 2009 / Resumo: Pacientes com Doença de Crohn (DC) cursam frequentemente com diarréia e desnutrição, sendo estas de difícil manejo e influenciadas pela atividade da doença, extensão e local do acometimento intestinal. O emprego dos probióticos na doença inflamatória intestinal pode ser útil em função de seus efeitos sobre a microbiota intestinal, com potenciais ações anti-inflamatórias e imunológicas. O objetivo deste estudo foi avaliar a eficácia do uso dos probióticos Lactobacillus casei e Bifidobacterium breve (PROLB) em portadores de DC por meio da análise da freqüência de evacuações, grau de atividade da doença e variação de parâmetros nutricionais. No período compreendido entre março de 2007 a outubro de 2008, foram estudados 15 doentes portadores de DC, com freqüência de evacuações líquidas maior ou igual a três vezes ao dia. A idade média foi de 43,83 (21-56) anos, com predomínio do sexo feminino (66,67%). Os participantes fizeram uso diário de PROLB oral por três meses, utilizando o produto Regulador Intestinal Yakult LB® (Yakult Honsha Co., Ltd, Tokyo - Japan), que contém em cada envelope de um grama, duas cepas probióticas: Lactobaccillus casei (2 x 107 a 109 UFC) e Bifidobacterium breve (5 x 107 a 109 UFC). Para a avaliação do grau de atividade da doença, foi empregado o índice clínico de Harvey-Bradshaw (H-B) e dosagens de VHS e PCR e a freqüência de evacuações foi obtida a partir de diário preenchido pelos pacientes e por ocasião da primeira e última consulta. A avaliação do estado nutricional (EN) foi realizada pela dosagem sérica de albumina (ALB) e pelas seguintes medidas antropométricas: peso, índice de massa corpórea (IMC), prega cutânea do tríceps (PCT) e circunferência do braço (CB) e medidas derivadas. Para a classificação do EN, foram utilizados os critérios de Frisancho (1981,1990). O emprego do PROLB evidenciou que houve redução do grau de atividade da doença pelo índice de H-B (p<0,05) e do número de evacuações líquidas pela avaliação ambulatorial (p=0,013). Os dados antropométricos evidenciaram aumento do peso atual (p=0,043), da % de alteração do peso habitual (p=0,03), do IMC (p=0,043), da CB (p=0,016). Com relação à classificação do EN, identificou-se diferença da % de adequação da PCT (p=0,043), sem diferenças nos demais parâmetros (% de adequação da CMB e AMBc (p>0,05). As dosagens de ALB sérica, VHS e PCR não apresentaram alterações. O emprego do PROLB possibilitou melhora de parâmetros clínicos relacionados à atividade da doença, do número de evacuações líquidas e dos parâmetros antropométricos relacionados ao peso atual, IMC, CB e da classificação do EN pela PCT. / Abstract: Patients with Crohn's disease (CD) frequently present diarrhea and malnutrition, which is hard to treat and influenced by the disease activity, location and extension of intestinal involvement. The application of probiotics on intestinal inflammatory diseases can be useful because of its effects on intestinal microbiota, with potential anti-inflammatory and immunologic actions. The goal of this study is to assess the effectiveness of the usage of probiotics Lactobacillus casei and Bifidobacterium breve (PROLB) in CD carriers with relation to the evacuation frequency, degree of disease activity, and nutrition parameters variation. Between March 2007 and October 2008, fifteen patients caring CD disease were assessed with liquid evacuation frequency greater than or equal to three times a day. The average age was 43.83 (21-56 years), predominantly females (66,67%). All the participant patients used the PROLB orally for three months, daily ingesting the product Yakult LB Intestinal Regulator (Yakult Honsha Co., Ltd, Tokyo - Japan), which contains in each envelop a gram, two probiotic strains: Lactobaccillus casei (2 x 107 a 109 UFC) and Bifidobacterium breve (5 x 107 a 109 UFC). In order to asses the degree of the disease the clinic index Harvey-Bradshaw (H-B) and erythrocyte sedimentation rate (ESR) and C reative protein (CRP) sampling. The evacuation frequencies were obtained by forms fulfilled by the patients and also during the first and last appointment. The assessment of the nutritional state was performed by albumin seric sampling and through the following anthropometric measures: weight, body mass index (BMI), triceps skinfold thickness (TST), arm circumference (AC), and derived measurements. The Frisancho (1981, 1990) criteria were used to classify the nutritional status. The application of PROLB evidenced (i) the reduction of the disease activity degree by the H-B index and the number of liquid evacuations by the ambulatorial evaluation (p=0.013). The anthropometric data evidenced the increase of the current weight (p=0.043), of the change of the % of the habitual weight (p=0.03), of the BMI (p=0.043), of the AC (p=0.016). With relationship to the nutritional status (NS) classification, it has been identified differences on the suitability percentage of TST, without differences affecting to the additional parameters. The sampling of seric ALB, ESR and CRP did not present any changes. The application of PROLB allowed the improvement of clinic parameters related to the disease activity, to the number of liquid evacuations and to the anthropometric parameters related to the current weight, to the BMI, to the AC, and to the classification of NS by TST. / Mestrado / Pesquisa Experimental / Mestre em Cirurgia

Orientador: Maria Marluce dos Santos Vilela / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-15T16:38:12Z (GMT). No. of bitstreams: 1 Oya_Vanessa_M.pdf: 7331490 bytes, checksum: 529a54e17d287da53b76a70429a62b6d (MD5) Previous issue date: 2010 / Resumo: A doença de Crohn (DC) é uma doença crônica inflamatória que acomete o trato gastrointestinal (TGI) com repercussão sistêmica. Existe uma interação de agentes patogênicos, tais como a microbiota intestinal e a imunidade de mucosa em indivíduos geneticamente susceptíveis. DC é mediada por uma resposta T helper 1 (Th1). Atualmente, dietas compostas de proteínas de soro de leite bovino enriquecidas com TGF-? poderiam indicar uma alternativa para controlar a doença, já que não são uma opção invasiva, resultando em uma melhoria na qualidade de vida dos pacientes. Objetivos: Avaliar a influência da suplementação nutricional oral com proteínas de soro de leite bovino enriquecido com TGF-? durante 16 semanas, na resposta imune celular para o BCG em pacientes com DC. Métodos: Vinte e dois pacientes com DC que estavam em terapia anti-TNF-? e azatioprina participaram de um ensaio clínico, prospectivo, de intervenção nutricional com um concentrado de proteínas de soro de leite bovino enriquecido com TGF- ? durante 16 semanas. Os grupos de comparação sem suplementação nutricional foram compostos por 10 pacientes com DC sob terapia com anti-TNF-? e azatioprina, 11 pacientes em uso apenas de azatioprina e 21 indivíduos normais como controle. A imunidade celular para o BCG foi caracterizada pela proliferação linfocitária (por citometria de fluxo) em cultura de células mononucleares de sangue periférico e a produção de citocinas (IFN-?, TNF-? e IL-6, dosadas por ELISA) em sobrenadante de cultura. Foi realizada a fenotipagem de subpopulações de linfócitos T em sangue periférico e a dosagem de TGF-_ ?2 e TGF- ?3 em soro e plasma por ELISA. Resultados: Em pacientes com DC, a suplementação nutricional com um concentrado de proteínas de soro de leite bovino enriquecido com TGF-? aumentou o percentual de linfócitos T em sangue periférico e a concentração de TGF- ?2 no plasma, após as 16 semanas de intervenção. Os pacientes apresentaram proliferação de subpopulações de linfócitos T (CD4+, CD8+ e TCR ??+) e a produção de IFN-?, TNF-? e IL-6 BCG específicas, que não diferiram no início e no fim da suplementação nutricional. Com relação ao grupo controle normal, os três grupos de pacientes com DC apresentaram menor concentração de IFN-y BCG específica. Conclusão: Assim, conclui-se que, uma dieta baseada em proteínas de soro de leite bovino enriquecido com TGF- ? pode levar a uma imunomodulação sistêmica. / Abstract: Crohn's disease (CD) is a inflammatory chronic disease that affects the gastrointestinal tract with systemic repercussion. There is an interaction of pathogens such as enteric microbiota with mucosal immunity in genetically susceptible individuals. CD is mediated by a T-helper 1 (Th1) response. Currently diets containing bovine whey proteins enriched with TGF-? could indicate an alternative for controlling the disease. Objective: To investigate the influence of oral supplementation for 16 weeks with bovine whey proteins enriched with TGF-? on the BCG cellular immune response in patients with Crohn's disease. Methods: Twenty-two CD patients who were under anti-TNF-? and azathioprine therapy took part in a prospective, clinical trial of nutritional intervention with bovine whey proteins enriched with TGF- ? for 16 weeks. As comparison groups without nutritional supplementation, 10 CD patients under anti-TNF-? and azathioprine therapy, 11 CD patients under taking just azathioprine and 21 health controls were selected. The cellular immunity to BCG was evaluated by lymphoproliferation (by flow cytometry) in peripheral blood mononuclear cell cultures and cytokine production (IFN-?, TNF-? and IL-6, by ELISA) on supernatant cultures. Immunophenotyping of T cell subpopulations in peripheral blood and TGF-_ ?2 and TGF- ?3 plasma and serum levels were also evaluated in CD patients. Results: Nutritional supplementation with concentrated whey proteins enriched with TGF- ? increased T lymphocyte percentage in peripheral blood and plasma TGF- ?2 concentration after 16 weeks of intervention in DC patients. They showed BCG-specific proliferation of CD4+, CD8+ and TCRy?+ T lymphocytes and IFN-?, TNF-? and IL-6 production, which were not different between begin and end of the supplementation period. In relation to the healthy controls, all three groups of CD patients had lower BCG-specific IFN-? production. Conclusions: Thus, it is concluded that a diet based on bovine whey proteins enriched with TGF- ? can lead to a systemic immunomodulation. / Mestrado / Saude da Criança e do Adolescente / Mestre em Saude da Criança e do Adolescente

Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-07-04T14:43:46Z No. of bitstreams: 1 alinecorrearibeiro.pdf: 2333411 bytes, checksum: 7c0df6693f47a6872d99460a06bc865b (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-07-06T14:24:16Z (GMT) No. of bitstreams: 1 alinecorrearibeiro.pdf: 2333411 bytes, checksum: 7c0df6693f47a6872d99460a06bc865b (MD5) / Made available in DSpace on 2018-07-06T14:24:16Z (GMT). No. of bitstreams: 1 alinecorrearibeiro.pdf: 2333411 bytes, checksum: 7c0df6693f47a6872d99460a06bc865b (MD5) Previous issue date: 2017-08-29 / Devido à importância que o sistema imune desempenha na doença de Crohn (DC), as tiopurinas são os imunomoduladores mais indicados na terapia. Entretanto, as tiopurinas, como a Azatioprina (AZA) e seus metabólitos intraeritrocitários, levam a uma série de reações adversas ou falha terapêutica, podendo ocasionar em não adesão ou abandono da terapia. A conversão da AZA para os nucleotídeos ativos de 6-tioguanina (6-TGN) é necessária para a eficácia clínica, entretanto, outro metabólito, a 6-metilmercaptopurina (6-MMP), é formado através de uma via concorrente pela tiopurina metil transferase e está relacionado à hepatotoxicidade. Devido à ampla variabilidade interindividual da tiopurina metil transferase e a uma faixa terapêutica estreita, torna-se importante a realização do monitoramento terapêutico do metabólito ativo 6-TGN e da 6-MMP. Neste trabalho, um método cromatográfico (CLAE/HPLC-UV) foi desenvolvido e validado para a quantificação dos metabólitos nos eritrócitos, envolvendo um procedimento de tratamento simples baseado na desproteinização por ácido perclórico seguido de hidrólise ácida e aquecimento para a conversão dos metabólitos em suas respectivas bases livres. A cromatografia foi realizada em coluna C18 (250 x 4,6 mm, 5 μm). A fase móvel consistiu em mistura de solução tampão fosfato de potássio (0,02 mol/L, pH = 3), acetonitrila e metanol, eluição por gradiente, num fluxo de 1,0 mL/minuto, com detecção de UV em 291 ηm e 342 ηm. Os tempos de retenção foram de 6,2 min (6-TGN); 23,1 min (6-MMP) e 24,7 min (cafeína: padrão interno). A resposta do detector foi linear na concentração de 0,89-29,91 μmol/L (r=0,999) para 6-TGN e entre 0,90-30,08 μmol/L (r=0,999) para 6-MMP. Os limites de detecção foram de 0,29 μmol/L e 0,30 μmol/L e os limites de quantificação foram de 0,89 μmol/L e 0,90 μmol/L, para 6-TGN e 6-MMP respectivamente. As médias das recuperações de 87,9% para 6-TGN e 91,9% para 6-MMP. Os CV da repetibilidade, de 5,48 e 10,48% (intradia) e 9,23 e 10,48% (interdia), enquanto os EPR da reprodutibilidade de 11,36 e 9,85% (intradia) e 10,48 e 7,32% (interdia) para 6-TGN e 6-MMP, respectivamente. As concentrações de 6-TGN e 6-MMP foram determinadas para todos os pacientes do estudo e os resultados encontrados variaram de 4,51 a 1515,27 ρmol/8 x 10⁸ eritrócitos para a 6-TGN e de 169,98 a 53951,53 ρmol/8 x 10⁸ eritrócitos para a 6-MMP. Observou-se uma correlação entre os pacientes em terapia combinada AZA e alopurinol e a diminuição da dosagem de AZA, consequentemente a diminuição significativa dos níveis de 6-MMP (2030,71 ρmol/8 x 10⁸ eritrócitos) em comparação com o grupo de pacientes sob monoterapia (9098,43 ρmol/8 x 10⁸ eritrócitos). Um outro achado foi a diminuição estatisticamente significativa da transaminase TGO/AST (25,03 + 18,62 U/L) no grupo de pacientes que apresentavam a doença em atividade, com os níveis de 6-TGN a 540,51 ρmol/8 x 10⁸ eritrócitos e de 6-MMP a 7952,32 ρmol/8 x 10⁸ eritrócitos, semelhante a relatos anteriores da literatura. O método proposto de quantificação por CLAE-UV mostrou-se preciso, exato e reprodutível, podendo ser utilizado como uma importante ferramenta na rotina de monitorização terapêutica de pacientes com DC, permitindo a individualização da dose, o acompanhamento dos efeitos adversos relacionados com a terapia farmacológica, o monitoramento da adesão ao tratamento e a avaliação da evolução clínica do paciente. / The conversion of azathioprine (AZA) to active nucleotides of 6-thioguanine (6-TGN) is essential for clinical efficacy in Crohn's disease. However, other metabolite, 6-methylmercaptopurine (6-MMP), which is formed through a competitive pathway for thiopurine methyltransferase (TPMT), is related to hepatotoxicity of this drug. Due to the wide interindividual variability of TPMT and a narrow therapeutic range it is important to accomplish the therapeutic monitoring of active metabolite 6-TGN and 6-MMP, which is an unusual procedure in Brazil. In this study, a HPLC-UV method for simultaneous quantification of these metabolites was developed, validated and applied in 37 Crohn's disease patients. The chromatographic process was performed on C18 column (250 x 4.6 mm, 5 μm i.d.), mobile phase consisted of potassium phosphate buffer (0.02 mol/L, pH = 3), acetonitrile and methanol, flow rate at 1.0 ml/min and UV detection at 291 ηm and 342 ηm. Retention times were 6.2 min (6-TGN); 23.1 min (6-MMP) and 24.7 min (caffeine: internal standard). The detector response was linear at 0.89-29.91 μmol/L (r=0.999) for 6-TGN and 0.90-30.08 μmol/L (r=0.999) for 6-MMP. Limits of detection were 0.29 μmol/L and 0.30 μmol/L, while the quantification limits were 0.89 μmol/L and 0.90 μmol/L, for 6-TGN and 6-MMP respectively. Precision, accuracy and recovery, were according FDA and ANVISA guidelines. The concentrations of 6-TGN and 6-MMP were determined in patients’ blood and the results found ranged from 4.51 to 1515 ρmol/8 x 10⁸ erythrocytes for 6-TGN and from 169.98 to 53.951 ρmol/8 x 10⁸ erythrocytes for 6-MMP. It was observed a reduction of levels of 6-MMP in patients using AZA + allopurinol therapy (2030.7 ρmol/8 x 10⁸ erythrocytes) when compared with patients undergoing monotherapy (9098.43 ρmol/8 x 10⁸ erythrocytes). Another finding was the correlation between the decrease in GOT transaminase in the group of patients who had the active disease with the increase in the 6-TGN levels, similar to previous reports in the literature. These results indicate that the method developed was reliable, accurate and reproducible, and can be used as an important tool in the routine monitoring of patients with Crohn's disease, allowing the individualization of the dose, the monitoring of the adverse effects related to the pharmacological therapy, monitoring the adherence to the treatment and the evaluation of the clinical evolution of these patients.

Orientador: Maria Marluce dos Santos Vilela / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T14:15:40Z (GMT). No. of bitstreams: 1 Machado_JuliaFigueiredo_M.pdf: 1776163 bytes, checksum: 25832a16e6e32e0da542e7591cac5bdd (MD5) Previous issue date: 2013 / Resumo: A Doença de Crohn (DC) é caracterizada por uma inflamação crônica que pode afetar qualquer parte do trato digestivo. Na fase aguda, os sintomas gastrointestinais podem levar à desnutrição. Na remissão da doença, alguns pacientes podem apresentar sobrepeso ou obesidade, o que contribui para aumentar a produção de citocinas pró-inflamatórias pelo tecido adiposo. Com o objetivo de avaliar os efeitos de dois suplementos nutricionais sobre o estado nutricional de pacientes com DC, foi realizado um ensaio clínico, randomizado, duplo-cego, paralelo com dois braços. Os participantes receberam suplemento com proteínas do soro de leite (PSL) ou suplemento com proteínas de soja (PS), durante 16 semanas. A avaliação nutricional foi feita por meio de medidas antropométricas, bioimpedância, recordatório alimentar de 24 horas e dosagens de albumina e pré-albumina. Para a avaliação da atividade da doença foram utilizados o Índice de Atividade da Doença de Crohn (IADC) e a dosagem de proteína C reativa (PCR). Na primeira avaliação (n=68), 93% dos pacientes estavam em remissão da doença (IACD<150), 36% apresentaram sobrepeso ou obesidade e apenas 5% estavam desnutridos. Com relação à ingestão alimentar, mais de 50% dos pacientes tinha um consumo inadequado de cálcio, potássio, e vitaminas A, C e D. Pacientes que estavam sob terapia com anti-TNF-? apresentaram Índice de Massa Corporal (IMC), percentual de gordura corporal (%GC) e prega cutânea tricipital (PCT) maiores do que aqueles sob terapia com, apenas, azatioprina. As 16 semanas de suplementação foram concluídas por 19 pacientes no grupo com PSL e 22 no grupo PS. Os suplementos não tiveram efeitos no IADC e PCR, porém modificaram a composição corporal. Houve aumento da circunferência muscular do braço (CMB), área muscular do braço corrigida (AMBc) e percentual de massa magra (%MM), e redução da PCT e do %GC, nos dois grupos. O sobrepeso, a obesidade e a ingestão inadequada de micronutrientes foram alterações nutricionais observadas em alguns pacientes com DC deste estudo, e indicam a necessidade de orientações dietéticas para corrigi-las. Os suplementos nutricionais com PSL e PS, após 16 semanas de uso, reduziram a gordura corporal dos pacientes, e poderiam ser utilizados como estratégia para tratar a obesidade. Além disso, a inflamação decorrente do excesso de tecido adiposo poderia ser prevenida, contribuindo para uma melhor evolução clínica / Abstract: Crohn's Disease (CD) is characterized by a chronic inflammation that affects any part of the gastrointestinal tract. In the acute phase, gastrointestinal symptoms may lead to malnutrition. During disease remission, some patients are overweight or obese; as adipose tissue produces proinflammatory cytokines, its excess may aggravate inflammation. To evaluate the effects of two supplements on nutritional status in CD patients, we performed a prospective, randomized, double-blind, parallel-arm trial. Participants received whey protein (WP) or soy protein (SP) supplement for 16 weeks. Nutritional assessment was performed by anthropometric measurements, bioelectrical impedance, 24-hour dietary recall, serum albumin and pre-albumin. The Crohn's Disease Activity Index (CDAI) and serum C-reactive protein (CRP) were used for the assessment of the disease activity. In the first evaluation (n = 68), 93% of the patients were in clinical remission (CDAI <150), 36% were overweight or obese and only 5% were malnourished. Over 50% of the patients had an inadequate intake of calcium, potassium, and vitamins A, C and D. Patients under treatment with anti-TNF- alpha had body mass index (BMI), body fat percentage (%BF) and triciptal skin fold (TSF) greater than those undergoing azathioprine therapy. Nineteen patients in the WP group and twenty-two in the SP group completed the 16 weeks of supplementation. The supplements had no effect on CDAI and CRP, but contributed to body composition change. The TSF and %BF decreased, whereas mid-arm muscle circumference (MAMC), corrected arm muscle area (CAMA) and body lean percentage (%BL) increased, in the two groups. Some patients in this study presented overweight, obesity or low intake of micronutrients, dietary advice is needed to correct these nutritional abnormalities. The supplementation with WP and SP may contribute to the reduction of overweight and obesity through reducing body fat and thus contributing to inflammatory control, preventing disease progression / Mestrado / Saude da Criança e do Adolescente / Mestra em Saúde da Criança e do Adolescente

Magister Scientiae (Medical Bioscience) - MSc(MBS) / Background: A subtype of inflammatory bowel disease, Crohn’s disease is thought to represent a complex interaction between environmental factors, a defective immune system, the gastrointestinal microbiome and genetic susceptibility. Aim: The focus of this study was to investigate the association between environmental exposures during childhood and the subsequent development of Crohn’s disease, thus the two primary aims were to: 1) conduct a systematic review of the literature evaluating environmental risk factors during childhood, defined by studies either as, age intervals (e.g., 0-5, 6-10 and 11-18 years), or more 'broadly' as 0-18 years; and 2) investigate the association between childhood environmental exposures during three age intervals (0-5, 6-10 and 11-18 years), as well as frequency of childhood infections and the future development of Crohn's disease based on a score analysis, using a subset of previously collected data from a completed doctoral thesis involving a case control study design in study population, in the Western Cape, South Africa. The aim included a primary analysis of the latter dataset for childhood infections. Design: For the first aim of the study, a systematic search was conducted during March 2015 in electronic databases, such as EMBASE, EBSCOhost (Medline), Ovid, Scopus and World Cat, PubMed and Biomed Central, to identify epidemiological studies that examined the association between childhood environmental exposures and the subsequent development of Crohn's disease. Studies evaluating childhood exposure either by age intervals, or more broadly, from birth until 18 years were included. The environmental exposures evaluated in the review were; farm animal contact, place of upbringing, sibship size, household pets, primary water source and hot water availability. Of the 181 identified articles, 16 were included in the final systematic review. The second aim of the study involved a post hoc analysis of a subset of findings from the completed doctoral research by Abigail Basson with regard to the multiple logistic regression analysis evaluating environmental risk factor exposure during three age intervals; 0-5 years, 6-10 years and 11-18 years. In the present research, two different methodological approaches were undertaken. Briefly, exposure variables, of similar nature, were combined into subgroups and assigned weighting scores. The two 'subgroup models' were designated as: Group A and Group B. Based on these premises, a score analysis was performed, and the difference in scores, between case and control groups, was compared. In addition, multiple logistic regression models were conducted on a subset of original data from the aforementioned completed doctoral study to assess the association between the frequency of childhood infections between 0-20 years and risk of Crohn’s disease development. Following this, a score analysis was again performed. Results: Sixteen studies were included in the systematic review. Of the five studies that investigated the association between place of upbringing during the age interval 0-5 years and the subsequent development of Crohn's disease, three found no significant association; however of the three studies evaluating place of upbringing during the age intervals 6-10 and 11-18 years, only one study identified a significant association. Three studies investigated exposure to farm animals during the age interval 0-5 years, of which, two identified a significant association. Of the latter three studies, two investigated farm animal contact during the age intervals 6-10 and 11-18 years, but only one reported a significant association during these age intervals. Notably, this was the study which had failed to identify an association during the 0-5 year age interval. Both studies which broadly evaluated farm animal exposure during 'childhood' reported that not having contact with animals significantly increased the risk of developing Crohn's disease. Of the five studies that investigated exposure to pets during the age interval 0-5 years, only one identified a significant risk association, namely with exposure to cats. Of the three which investigated pet exposure during the age intervals 6-10 years and 11-18 years, one identified a significant association, for both age intervals. Five studies investigated pet exposure during 'childhood'; one found that having a pet significantly increased the risk of developing Crohn's disease, two reported that not having a pet significantly increased risk in developing Crohn's disease, whereas the remaining studies found no significant association. Only one study evaluated primary water source during the three age intervals; during the age interval 0-5 years and 11-18 years, having piped tap or bottled water was significantly associated with CD development. Of the four studies investigating primary water source during ‘childhood’, only one reported a significant association between primary water source and the development of Crohn's disease. The availability of hot water during the age interval 0-5 years was significantly associated with Crohn's disease development in one of the three relevant studies. Two studies investigated hot water availability during 6-10 and 11-18 years, however both failed to identify a significant association. When broadly evaluated, hot water availability during 'childhood' was significantly associated with Crohn's disease risk, in two of the three relevant studies. None of the studies which investigated sibship size and the risk of future Crohn's disease development during defined age intervals reported a significant association. Only two of the seven studies that evaluated sibship size during childhood reported a significant association. Results of the score analysis revealed a significant difference during all three age intervals between the case and control groups with Group A and Group B, with cases having significantly lower exposure scores (approximately 30% and 40% lower, respectively), when compared with that of controls. On multiple logistic regression analysis, subjects who never had tooth decay/cavity (OR = 1.78; 95% CI, 1.05-3.04), periodontitis (OR = 1.95; 95% CI, 1.10, 3.48), diarrhoea (OR = 2.71; 95% CI, 1.62-4.62), gastritis (OR = 2.13; 95% CI, 1.30-3.35), or mouth ulcers (OR = 2.02; 95% CI, 1.12-3.70), at least once per year or more, were at an increased risk for later development of Crohn's disease, when compared to those who were exposed to these infections at least once per year or more. There was a significant difference in exposure scores between the case and control groups (OR = 0.88; 95% CI, 0.82-0.94), thus indicating that cases had 12% less exposure to childhood infections from birth until the age of 20 years, when compared to the controls. Conclusion: The systematic review of the literature provides evidence in support of the hygiene hypothesis, in that delayed exposure to immunostimulatory microbes through the environmental exposures increases the risk for future CD development, in genetically susceptible individuals. In addition, the literature supports that the childhood environment plays an important role in the aetiology of Crohn's disease. However, the lack of consistent findings between studies, particularly those which have broadly defined ‘childhood’ implies that timing of exposure plays a crucial role in this ever evolving paradigm. Results from the score analysis provide insight into the 'compound' effects from multiple environmental exposures in the aetiology of Crohn's disease. While the present research was unable to provide any explanation for the underlying mechanism of disease pathogenesis, overall, the findings have important implications for future IBD-related studies as they demonstrate the importance of accounting for environment as a 'whole' when conducting epidemiological studies, as opposed to focusing on individual environmental factors, as well as that it is imperative to investigate environmental exposures within the context of defined age intervals.