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- Dlugosz, Aldona
(författare)
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Towards a bacterial origin of irritable bowel syndrome
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The irritable bowel syndrome (IBS) is one of the most prevalent disorders and affects about 15% of the Swedish population. Patients with IBS suffer from abdominal pain and disturbed bowel function. Despite being so common, little is known about causality in IBS. Patients with IBS have been found to exhibit low-grade inflammation of nerve plexuses in the gut. The driving force for observed immune activation is yet unknown. Aim of the thesis: To assess if bacteria may have a role in the pathogenesis of IBS. This was addressed using different models. The first was to investigate if Chlamydia antigens were present in the small bowel of patients with severe IBS. Then the interaction between Chlamydia and enteroendocrine cells (EEC) in vitro using enteroendocrine cell lines was studied and finally the composition of small bowel mucosa-associated microbiota was explored in patients with IBS and healthy controls using pyrotag sequencing. Material and methods: In Study I full-thickness jejunum biopsies and mucosa biopsies from the duodenum and the jejunum from patients with severe IBS and healthy controls were investigated with immunofluorescence for chlamydial antigens. In studies II and III two different human enteroendocrine cell lines were studied: LCC-18 from a neuroendocrine colonic tumour and CNDT-2 from a small intestinal carcinoid. Cell lines were infected with C. trachomatis serovar LGV II strain 434. Penicillin G was used for inducing persistent infection. The ultrastructure of infected cells was studied using transmission electron microscopy and immunofluorescence and we used RT-PCR analysis and microarray analysis (Affymetrix GeneChip®) for studying changes in gene expression at different stages of infection. In Study IV capsule biopsies from the jejunum of patients with IBS and healthy volunteers were studied using barcoded 454-pyrosequencing to determine the composition of microbial communities in the upper small bowel. Results: Chlamydia LPS was detected in enteroendocrine cells of the mucosa or subepithelial macrophages in 89% of patients with IBS, but in only 14% of healthy controls (p < 0.001) and 79% of LPS-positive biopsies were also positive for C. trachomatis major outer membrane protein. The cell line experiments showed that both cell lines could be infected with C. trachomatis yielding productive infection and persistence could be induced using penicillin G. The cellular distribution of serotonin and chromogranin A was altered by infection from a cytoplasmatic distribution to a location mostly in chlamydial inclusions. Significant differences in the gene transcription levels between persistently infected and non-infected cells were found in 10 genes coding for different solute carrier transporters (SLC) and 5 genes related to endocrine function (GABARAPL1, GRIP1, DRD2, SYT5 and SYT7). Study IV showed no major difference in small bowel mucosa-associated microbiota between patients with IBS and healthy controls. Conclusions: Study I introduced the novel concept that infection with C. trachomatis might be involved in the pathogenesis of IBS. In vitro studies confirmed that such an infection affects enteroendocrine cell function. The luminal flora of the small bowel was not identified as a host factor for developing IBS.
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| 2. |
- Remberger, Mats, et al.
(författare)
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Improved survival after allogeneic hematopoietic stem cell transplantation in recent years : A single-center study
- 2011
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 17:11, s. 1688-1697
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.
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