| 1. |
- 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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| 2. |
- Ambite, Ines, et al.
(författare)
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Susceptibility to urinary tract infection : Benefits and hazards of the antibacterial host response
- 2016
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Ingår i: Microbiology spectrum. - Washington, DC, USA : ASM Press. - 2165-0497. ; 4:3
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Forskningsöversikt (refereegranskat)abstract
- A paradigm shift is needed to improve and personalize the diagnosis of infectious disease and to select appropriate therapies. For many years, only the most severe and complicated bacterial infections received more detailed diagnostic and therapeutic attention as the efficiency of antibiotic therapy has guaranteed efficient treatment of patients suffering from the most common infections. Indeed, treatability almost became a rationale not to analyze bacterial and host parameters in these larger patient groups. Due to the rapid spread of antibiotic resistance, common infections like respiratory tract- or urinary-tract infections (UTIs) now pose new and significant therapeutic challenges. It is fortunate and timely that infectious disease research can offer such a wealth of new molecular information that is ready to use for the identification of susceptible patients and design of new suitable therapies. Paradoxically, the threat of antibiotic resistance may become a window of opportunity, by encouraging the implementation of new diagnostic and therapeutic approaches. The frequency of antibiotic resistance is rising rapidly in uropathogenic organisms and the molecular and genetic understanding of UTI susceptibility is quite advanced. More bold translation of the new molecular diagnostic and therapeutic tools would not just be possible but of great potential benefit in this patient group. This chapter reviews the molecular basis for susceptibility to UTI, including recent advances in genetics, and discusses the consequences for diagnosis and therapy. By dissecting the increasingly well-defined molecular interactions between bacteria and host and the molecular features of excessive bacterial virulence or host-response malfunction, it is becoming possible to isolate the defensive from the damaging aspects of the host response. Distinguishing "good" from "bad" inflammation has been a long-term quest of biomedical science and in UTI, patients need the "good" aspects of the inflammatory response to resist infection while avoiding the "bad" aspects, causing chronicity and tissue damage.
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| 3. |
- Butler, Daniel S.C., et al.
(författare)
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Neuroepithelial control of mucosal inflammation in acute cystitis
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- The nervous system is engaged by infection, indirectly through inflammatory cascades or directly, by bacterial attack on nerve cells. Here we identify a neuro-epithelial activation loop that participates in the control of mucosal inflammation and pain in acute cystitis. We show that infection activates Neurokinin-1 receptor (NK1R) and Substance P (SP) expression in nerve cells and bladder epithelial cells in vitro and in vivo in the urinary bladder mucosa. Specific innate immune response genes regulated this mucosal response, and single gene deletions resulted either in protection (Tlr4−/− and Il1b−/− mice) or in accentuated bladder pathology (Asc−/− and Nlrp3−/− mice), compared to controls. NK1R/SP expression was lower in Tlr4−/− and Il1b−/− mice than in C56BL/6WT controls but in Asc−/− and Nlrp3−/− mice, NK1R over-activation accompanied the exaggerated disease phenotype, due, in part to transcriptional de-repression of Tacr1. Pharmacologic NK1R inhibitors attenuated acute cystitis in susceptible mice, supporting a role in disease pathogenesis. Clinical relevance was suggested by elevated urine SP levels in patients with acute cystitis, compared to patients with asymptomatic bacteriuria identifying NK1R/SP as potential therapeutic targets. We propose that NK1R and SP influence the severity of acute cystitis through a neuro-epithelial activation loop that controls pain and mucosal inflammation.
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| 4. |
- Godaly, Gabriela, et al.
(författare)
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Urinary Tract Infection Molecular Mechanisms and Clinical Translation.
- 2016
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Ingår i: Pathogens. - : MDPI AG. - 2076-0817. ; 5:1
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Forskningsöversikt (refereegranskat)abstract
- Rapid developments in infection biology create new and exciting options for individualized diagnostics and therapy. Such new practices are needed to improve patient survival and reduce morbidity. Molecular determinants of host resistance to infection are being characterized, making it possible to identify susceptible individuals and to predict their risk for future morbidity. Immunotherapy is emerging as a new strategy to treat infections worldwide and controlled boosting of the host immune defense represents an important therapeutic alternative to antibiotics. In proof of concept studies, we have demonstrated that this approach is feasible. The long-term goal is not just to remove the pathogens but to also develop technologies that restore resistance to infection in disease-prone patients and devise personalized therapeutic interventions. Here, we discuss some approaches to reaching these goals, in patients with urinary tract infection (UTI). We describe critical host signaling pathways that define symptoms and pathology and the genetic control of innate immune responses that balance protection against tissue damage. For some of these genes, human relevance has been documented in clinical studies, identifying them as potential targets for immune-modulatory therapies, as a complement to antibiotics.
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| 5. |
- Morrison, Catriona A., et al.
(författare)
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Covariation in population trends and demography reveals targets for conservation action
- 2021
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Ingår i: Royal Society of London. Proceedings B. Biological Sciences. - : The Royal Society. - 1471-2954. ; 288:1946, s. 20202955-20202955
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Tidskriftsartikel (refereegranskat)abstract
- Wildlife conservation policies directed at common and widespread, but declining, species are difficult to design and implement effectively, as multiple environmental changes are likely to contribute to population declines. Conservation actions ultimately aim to influence demographic rates, but targeting actions towards feasible improvements in these is challenging in widespread species with ranges that encompass a wide range of environmental conditions. Across Europe, sharp declines in the abundance of migratory landbirds have driven international calls for action, but actions that could feasibly contribute to population recovery have yet to be identified. Targeted actions to improve conditions on poor-quality sites could be an effective approach, but only if local conditions consistently influence local demography and hence population trends. Using long-term measures of abundance and demography of breeding birds at survey sites across Europe, we show that co-occurring species with differing migration behaviours have similar directions of local population trends and magnitudes of productivity, but not survival rates. Targeted actions to boost local productivity within Europe, alongside large-scale (non-targeted) environmental protection across non-breeding ranges, could therefore help address the urgent need to halt migrant landbird declines. Such demographic routes to recovery are likely to be increasingly needed to address global wildlife declines.
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| 6. |
- Nagy, Károly, et al.
(författare)
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Approximation by Walsh-Marcinkiewicz means on the Hardy space H-2/3
- 2014
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Ingår i: Kyoto Journal of Mathematics. - : Duke University Press. - 2156-2261 .- 2154-3321. ; 54:3, s. 641-652
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Tidskriftsartikel (refereegranskat)abstract
- The main aim of this paper is to find necessary and sufficient conditions for the convergence of Walsh-Marcinkiewicz means in terms of the modulus of continuity on the Hardy space H-2/3.
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| 7. |
- Nagy, Károly, et al.
(författare)
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Strong convergence theorem for Walsh-Marcinkiewicz means
- 2016
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Ingår i: Mathematical Inequalities & Applications. - : Element d.o.o.. - 1331-4343 .- 1848-9966. ; 19:1, s. 185-195
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Tidskriftsartikel (refereegranskat)abstract
- It is known that the maximal operator ofWalsh-Marcinkiewicz means is bounded from the dyadic martingale Hardy space Hp to the space Lp for p > 2/3 and the condition p > 2/3 is essential. In the case p = 2/3 the boundedness of the maximal operator does not hold. This means that the investigation of the maximal operator at the endpoint case p = 2/3 plays an important role. The main aim of this paper is to prove a strong convergence theorem for the Walsh-Marcinkiewicz means on the Hardy space H2/3.
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| 8. |
- Nagy, Károly, et al.
(författare)
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The Walsh–Kaczmarz–Marcinkiewicz means and Hardy spaces
- 2016
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Ingår i: Acta Mathematica Hungarica. - : Springer Science and Business Media LLC. - 0236-5294 .- 1588-2632. ; 149:2, s. 346-374
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Tidskriftsartikel (refereegranskat)abstract
- It is known that the maximal operator σ κ,∗ (f):=sup n∈P |σ κ n (f)| σκ,∗(f):=supn∈P|σnκ(f)| is bounded from the dyadic Hardy space H p Hp into the space L p Lp for p>2/3 p>2/3 [6]. Moreover, Goginava and Nagy showed that σ κ,∗ σκ,∗ is not bounded from the Hardy space H 2/3 H2/3 to the space L 2/3 L2/3 [9]. The main aim of this paper is to investigate the case 0
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| 9. |
- Nagy, Károly, et al.
(författare)
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Walsh-Marcinkiewicz means and Hardy spaces
- 2014
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Ingår i: Central European Journal of Mathematics. - : Walter de Gruyter GmbH. - 1895-1074 .- 1644-3616. ; 12:8, s. 1214-1228
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Tidskriftsartikel (refereegranskat)abstract
- The main aim of this paper is to investigate the Walsh-Marcinkiewicz means on the Hardy space Hp, when 0 < p < 2/3. We define a weighted maximal operator of Walsh-Marcinkiewicz means and establish some of its properties. With its aid we provide a necessary and sufficient condition for convergence of the Walsh-Marcinkiewicz means in terms of modulus of continuity on the Hardy space Hp, and prove a strong convergence theorem for the Walsh-Marcinkiewicz means
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| 10. |
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