| 1. |
- Ragnarsdottir, Bryndis, et al.
(författare)
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TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections.
- 2008
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38 Suppl 2, s. 12-20
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Forskningsöversikt (refereegranskat)abstract
- The susceptibility to urinary tract infection (UTI) is controlled by the innate immune response and Toll like receptors (TLRs) are the sentinels of this response. If productive, TLR4 signalling may initiate the symptomatic disease process. In the absence of TLR4 signalling the infected host instead develops an asymptomatic carrier state. The activation of mucosal TLR4 is also influenced by the properties of the infecting strain, and pathogens use their virulence factors to trigger 'pathogen-specific' TLR4 responses in the urinary tract but do not respond to the asymptomatic carrier strains in patients with asymptomatic bacteriuria (ABU). The TLR4 dependence has been demonstrated in mice and the relevance of low TLR4 function for protection for human disease was recently confirmed in children with asymptomatic bacteriuria, who expressed less TLR4 than age matched controls. Functional chemokines and functional chemokine receptors are crucial for neutrophil recruitment, and for the neutrophil dependent bacterial clearance. Interleukin (IL)-8 receptor deficient mice develop acute septic infections and chronic tissue damage, due to aberrant neutrophil function. This mechanism is relevant for human UTI as pyelonephritis prone children express low levels of the human CXCL8 (Il-8) receptor, CXC chemokine receptor 1 (CXCR1) and often have heterozygous CXCR1 polymorphisms. This review illustrates how intimately the innate response and the susceptibility to UTI are linked and sophisticated recognition mechanisms that rely on microbial virulence and on host TLR4 and CXCR1 signalling.
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| 2. |
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| 3. |
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| 4. |
- Wagenlehner, Florian, et al.
(författare)
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The Global Prevalence of Infections in Urology (GPUI) Study : A Worldwide Surveillance Study in Urology Patients
- 2016
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Ingår i: European Urology Focus. - : Elsevier BV. - 2405-4569. ; 2:4, s. 345-347
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Tidskriftsartikel (refereegranskat)abstract
- The GPIU study is currently the only study registering health care–associated urogenital tract infections, especially in urology patients, in an ongoing surveillance protocol that can help to deliver data on adequate empirical antibiotic therapy in hospitalised urology patients according to guideline recommendations. The annual GPIU study will continue to be performed in November of each year under the URL http://gpiu.esiu.org/.
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| 5. |
- Ambite, Ines, et al.
(författare)
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Molecular Basis of Acute Cystitis Reveals Susceptibility Genes and Immunotherapeutic Targets
- 2016
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Tissue damage is usually regarded as a necessary price to pay for successful elimination of pathogens by the innate immune defense. Yet, it is possible to distinguish protective from destructive effects of innate immune activation and selectively attenuate molecular nodes that create pathology. Here, we identify acute cystitis as an Interleukin-1 beta (IL-1β)-driven, hyper-inflammatory condition of the infected urinary bladder and IL-1 receptor blockade as a novel therapeutic strategy. Disease severity was controlled by the mechanism of IL-1β processing and mice with intact inflammasome function developed a moderate, self-limiting form of cystitis. The most severe form of acute cystitis was detected in mice lacking the inflammasome constituents ASC or NLRP-3. IL-1β processing was hyperactive in these mice, due to a new, non-canonical mechanism involving the matrix metalloproteinase 7- (MMP-7). ASC and NLRP-3 served as transcriptional repressors of MMP7 and as a result, Mmp7 was markedly overexpressed in the bladder epithelium of Asc-/- and Nlrp3-/- mice. The resulting IL-1β hyper-activation loop included a large number of IL-1β-dependent pro-inflammatory genes and the IL-1 receptor antagonist Anakinra inhibited their expression and rescued susceptible Asc-/- mice from bladder pathology. An MMP inhibitor had a similar therapeutic effect. Finally, elevated levels of IL-1β and MMP-7 were detected in patients with acute cystitis, suggesting a potential role as biomarkers and immunotherapeutic targets. The results reproduce important aspects of human acute cystitis in the murine model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common infections in man. Trial Registration: The clinical studies were approved by the Human Ethics Committee at Lund University (approval numbers LU106-02, LU236-99 and Clinical Trial Registration RTP-A2003, International Committee of Medical Journal Editors, www.clinicaltrials.gov).
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| 6. |
- Forsberg, Annika Mandahl, et al.
(författare)
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Open partial nephrectomy for renal cell cancer in a medium patient volume centre: Is high quality possible?
- 2010
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 1651-2065 .- 0036-5599. ; 44, s. 204-211
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Objective. To describe the surgical complication rate of open partial nephrectomy (OPN) in patients with renal tumours, and to report the oncological long-term outcome in unilateral renal cell cancer patients subjected to this procedure, from a medium patient volume urological centre. Material and methods. Data from all patients (n = 89) subjected to OPN for proven or suspected renal cell cancer during the period 1965-2007 were registered in a specifically designed database system. Tumour stage and size, surgical margin, histology, perioperative and postoperative complications were analysed in all patients. In addition, long-term follow-up outcomes in malignant unilateral tumours (n = 51) were analysed. Results. Seventy-four of the resected tumours were malignant. Six of these had a positive surgical margin; five from patients with multifocal or bilateral tumours and one from a patient with a solitary malignant cyst. Perioperative complications were registered in only one case (1%). Postoperative complications (within 30 days postoperatively) reached 18%. The long-term follow-up (mean 79 months, median 49 months, range 14 months to 26 years) in patients with unilateral malignant tumours, all staged T1-T2, revealed two systemic recurrences, both in patients with poor prognostic markers at the time of surgery, but no local recurrence. Conclusions. OPN has complication rates similar to open radical nephrectomy. Long-term tumour control in unilateral cases and with organ confined disease is excellent. The results demonstrate that carefully performed OPN at a medium-volume centre can achieve equal results to high-volume centres.
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| 9. |
- Grönberg Hernandez, Jenny, et al.
(författare)
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Genetic control of the variable innate immune response to asymptomatic bacteriuria.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:11
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Tidskriftsartikel (refereegranskat)abstract
- The severity of urinary tract infection (UTI) reflects the quality and magnitude of the host response. While strong local and systemic innate immune activation occurs in patients with acute pyelonephritis, the response to asymptomatic bacteriuria (ABU) is low. The immune response repertoire in ABU has not been characterized, due to the inherent problem to distinguish bacterial differences from host-determined variation. In this study, we investigated the host response to ABU and genetic variants affecting innate immune signaling and UTI susceptibility. Patients were subjected to therapeutic urinary tract inoculation with E. coli 83972 to ensure that they were exposed to the same E. coli strain. The innate immune response repertoire was characterized in urine samples, collected from each patient before and after inoculation with bacteria or PBS, if during the placebo arm of the study. Long-term E. coli 83972 ABU was established in 23 participants, who were followed for up to twelve months and the innate immune response was quantified in 233 urine samples. Neutrophil numbers increased in all but two patients and in an extended urine cytokine/chemokine analysis (31 proteins), the chemoattractants IL-8 and GRO-α, RANTES, Eotaxin-1 and MCP-1, the T cell chemoattractant and antibacterial peptide IP-10, inflammatory regulators IL-1-α and sIL-1RA and the T lymphocyte/dendritic cell product sIL-2Rα were detected and variably increased, compared to sterile samples. IL-6, which is associated with symptomatic UTI, remained low and numerous specific immune mediators were not detected. The patients were also genotyped for UTI-associated IRF3 and TLR4 promoter polymorphisms. Patients with ABU associated TLR4 polymorphisms had low neutrophil numbers, IL-6, IP-10, MCP-1 and sIL-2Rα concentrations. Patients with the ABU-associated IRF3 genotype had lower neutrophils, IL-6 and MCP-1 responses than the remaining group. The results suggest that the host-specific, low immune response to ABU mainly includes innate immune mediators and that host genetics directly influence the magnitude of this response.
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| 10. |
- Hallgren, Oskar, et al.
(författare)
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Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).
- 2008
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer New York. - 0065-2598. ; 606, s. 217-240
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Forskningsöversikt (refereegranskat)abstract
- HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.
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