| 1. |
- Arvidsson, Ida, et al.
(författare)
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Early terminal complement blockade and C6 deficiency are protective in enterohemorrhagic Escherichia coli-infected mice
- 2016
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 197:4, s. 1276-1286
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Tidskriftsartikel (refereegranskat)abstract
- Complement activation occurs during enterohemorrhagic Escherichia coli (EHEC) infection and may exacerbate renal manifestations. In this study, we show glomerular C5b-9 deposits in the renal biopsy of a child with EHEC-associated hemolytic uremic syndrome. The role of the terminal complement complex, and its blockade as a therapeutic modality, was investigated in a mouse model of E. coli O157:H7 infection. BALB/c mice were treated with monoclonal anti-C5 i.p. on day 3 or 6 after intragastric inoculation and monitored for clinical signs of disease and weight loss for 14 d. All infected untreated mice (15 of 15) or those treated with an irrelevant Ab (8 of 8) developed severe illness. In contrast, only few infected mice treated with anti-C5 on day 3 developed symptoms (three of eight, p < 0.01 compared with mice treated with the irrelevant Ab on day 3) whereas most mice treated with anti-C5 on day 6 developed symptoms (six of eight). C6-deficient C57BL/6 mice were also inoculated with E. coli O157:H7 and only 1 of 14 developed disease, whereas 10 of 16 wild-type mice developed weight loss and severe disease (p < 0.01). Complement activation via the terminal pathway is thus involved in the development of disease in murine EHEC infection. Early blockade of the terminal complement pathway, before the development of symptoms, was largely protective, whereas late blockade was not. Likewise, lack of C6, and thereby deficient terminal complement complex, was protective in murine E. coli O157:H7 infection.
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| 2. |
- Chromek, Milan, et al.
(författare)
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Hyponatraemia despite isotonic maintenance fluid therapy : A time series intervention study
- 2021
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Ingår i: Archives of Disease in Childhood. - : BMJ. - 0003-9888 .- 1468-2044. ; 106:5, s. 195-491
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To examine the prevalence of dysnatraemias among children admitted for paediatric surgery before and after a change from hypotonic to isotonic intravenous maintenance fluid therapy. Design: Retrospective consecutive time series intervention study. Setting: Paediatric surgery ward at the Children's Hospital in Lund, during a 7-year period, 2010-2017. Patients: All children with a blood sodium concentration measurement during the study period were included. Hypotonic maintenance fluid (40 mmol/L NaCl and 20 mmol/L KCl) was used during the first 3 years of the study (646 patients), and isotonic solution (140 mmol/L NaCl and 20 mmol/L KCl) was used during the following period (807 patients). Main outcome measures: Primary outcomes were sodium concentration and occurrence of hyponatraemia (<135 mmol/L) or hypernatraemia (>145 mmol/L). Results: Overall, the change from hypotonic to isotonic intravenous maintenance fluid therapy was associated with a decreased prevalence of hyponatraemia from 29% to 22% (adjusted OR 0.65 (0.51-0.82)) without a significantly increased odds for hypernatraemia (from 3.4% to 4.3%, adjusted OR 1.2 (0.71-2.1)). Hyponatraemia <130 mmol/L decreased from 6.2% to 2.6%, and hyponatraemia <125 mmol/L decreased from 2.0% to 0.5%. Conclusions: Routine use of intravenous isotonic maintenance fluids was associated with lower prevalence of hyponatraemia, although hyponatraemia still occurred in over 20% of patients. We propose that the composition and the volume of administered fluid need to be addressed.
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| 3. |
- Chromek, Milan, et al.
(författare)
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The Antimicrobial Peptide Cathelicidin Protects Mice from Escherichia coli O157:H7-Mediated Disease.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated the role of the antimicrobial peptide cathelicidin in Escherichia coli O157:H7 infection and subsequent renal damage. Mouse and human cathelicidin, CRAMP and LL-37, respectively, killed E. coli O157:H7 in vitro. Intestines from healthy wild-type (129/SvJ) and cathelicidin-knock-out (Camp(-/-)) mice were investigated, showing that cathelicidin-deficient mice had a thinner colonic mucus layer compared with wild-type mice. Wild-type (n = 11) and cathelicidin-knock-out (n = 11) mice were inoculated with E. coli O157:H7. Cathelicidin-deficient animals exhibited higher fecal counts of E. coli O157:H7 and bacteria penetrated the mucus forming attaching-and-effacing lesions to a much higher extent than in wild-type animals. Cathelicidin knock-out mice developed symptoms (9/11) as well as anemia, thrombocytopenia and extensive renal tubular damage while all cathelicidin-producing mice remained asymptomatic with normal laboratory findings. When injected with Shiga toxin intraperitoneally, both murine strains developed the same degree of renal tubular damage and clinical disease indicating that differences in sensitivity to infection between the murine strains were related to the initial intestinal response. In conclusion, cathelicidin substantially influenced the antimicrobial barrier in the mouse colon mucosa. Cathelicidin deficiency lead to increased susceptibility to E. coli O157:H7 infection and subsequent renal damage. Administration of cathelicidin or stimulation of endogenous production may prove to be novel treatments for E. coli O157:H7-induced hemolytic uremic syndrome.
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| 4. |
- Chromek, Milan
(författare)
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Urinary tract infection and renal scarring
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Urinary tract infection (UTI) is the most common bacterial infection. Although most patients with UTI have a good prognosis, there is a risk of serious complications in a group of them. In up to 40% of the cases of infection of the upper urinary tract, pyelonephritis, renal scar develops and the scarring process may occasionally lead to chronic renal insufficiency. Moreover, UTI has a high tendency of recurrence and recurrent UTis even increase the risk of renal scarring. We have been studying several mechanisms in the pathogenesis of UTI and renal scarring. We described the production of cathelicidin, an endogenous antibiotic, in the epithelial cells of the urinary tract. Although present in low concentrations constitutively, after bacterial attachment the epithelial cells rapidly increased the cathelicidin synthesis and release. Genedeficient mice confirmed the relevance of the epithelial cathelicidin for the protection of the urinary tract against attaching bacteria. Bacteria, however, seemed to develop strategies to overcome the 'protective shield' of cathelicidin. We showed that the majority of uropathogenic E. coli are able to produce curli firnbriae and cellulose and thus form a multicellular community, biofilm. This tactic helps bacteria adhere to the epithelium without stimulation of the immune system, invade the cells, and be protected from cathelicidin. The low levels of cathelicidin, on the other hand, inhibit the formation of biofilm, and protect the urinary tract also against this form of bacterial virulence. Despite the effective antimicrobial defense of the urinary tract, bacteria sometimes win the 'first battle' against mucosal immunity and persist or invade the host. Then, more intense inflammation is needed with involvement of professional immune cells and with some inevitable degree of tissue damage. Cathelicidin is also an important player in these immune processes, in the recruitment of neutrophils and neutrophil-mediated killing of bacteria. During inflammation in the kidney, many proteases and their inhibitors, amongst them MMP-9 and TIMP-1, are produced. Our data suggested that the delicate balance between MNIP-9 and TIMP-1 determines the intensity of inflammation, degree of tissue destruction and proper healing after infection. If too high levels of TIMP-1 are produced during acute inflammation, renal scar will develop more probably. We indicated that the pro-scarring effect of TIMP-1 could be explained by its complex action during the acute inflammation. TIMP-1 prolongs the stay of granulocytes in the tissue by inhibiting their apoptosis and migration into urine. Moreover, TIMP- 1 stimulates respiratory burst of neutrophils. 'Entrapped' and activated granulocytes may extensively destroy the tissue and trigger renal scarring. Data presented in this thesis describe mechanisms in the pathogenesis of urinary tract infection and postinfective renal scarring. They also open new possibilities for treatment in order to protect the urinary tract from bacteria and the kidney from damage.
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| 5. |
- Johansson, Karl E., et al.
(författare)
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Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Shiga toxin (Stx) is the main virulence factor of enterohemorrhagic Escherichia coli (EHEC), that cause gastrointestinal infection leading to hemolytic uremic syndrome. The aim of this study was to investigate if Stx signals via ATP and if blockade of purinergic receptors could be protective. Stx induced ATP release from HeLa cells and in a mouse model. Toxin induced rapid calcium influx into HeLa cells, as well as platelets, and a P2X1 receptor antagonist, NF449, abolished this effect. Likewise, the P2X antagonist suramin blocked calcium influx in Hela cells. NF449 did not affect toxin intracellular retrograde transport, however, cells pre-treated with NF449 exhibited significantly higher viability after exposure to Stx for 24 hours, compared to untreated cells. NF449 protected HeLa cells from protein synthesis inhibition and from Stx-induced apoptosis, assayed by caspase 3/7 activity. The latter effect was confirmed by P2X1 receptor silencing. Stx induced the release of toxin-positive HeLa cell- and platelet-derived microvesicles, detected by flow cytometry, an effect significantly reduced by NF449 or suramin. Suramin decreased microvesicle levels in mice injected with Stx or inoculated with Stx-producing EHEC. Taken together, we describe a novel mechanism of Stx-mediated cellular injury associated with ATP signaling and inhibited by P2X receptor blockade.
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| 6. |
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| 7. |
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| 8. |
- Robertsson Grossmann, Katarina, et al.
(författare)
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Kidney outcomes in early adolescence following perinatal asphyxia and hypothermia-treated hypoxic-ischaemic encephalopathy
- 2023
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Ingår i: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 0931-041X .- 1432-198X. ; 38:4, s. 1205-1214
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Tidskriftsartikel (refereegranskat)abstract
- Background: Acute kidney injury (AKI) remains common among infants with hypothermia-treated hypoxic-ischaemic encephalopathy (HIE). Little is known about long-term kidney outcomes following hypothermia treatment. We recently reported that 21% of survivors of hypothermia-treated HIE had decreased estimated glomerular filtration rate (eGFR) based on plasma creatinine in early adolescence. Here, we assessed kidney functions more comprehensively in our population-based cohort of children born in Stockholm 2007–2009 with a history of hypothermia-treated HIE. Methods: At 10–12 years of age, we measured cystatin C (cyst C) to estimate GFR. Children with decreased cyst C eGFR also underwent iohexol clearance examination. We measured urine-albumin/creatinine ratio, blood pressure (BP) and kidney volume on magnetic resonance imaging. Fibroblast growth factor 23 (FGF 23) levels in plasma were assessed by enzyme-linked immunosorbent assay (ELISA). Outcomes were compared between children with and without a history of neonatal AKI. Results: Forty-seven children participated in the assessment. Two children (2/42) had decreased cyst C eGFR, for one of whom iohexol clearance confirmed mildly decreased GFR. One child (1/43) had Kidney Disease Improving Global Outcomes (KDIGO) category A2 albuminuria, and three (3/45) had elevated office BP. Subsequent ambulatory 24-h BP measurement confirmed high normal BP in one case only. No child had hypertension. Kidney volume and FGF 23 levels were normal in all children. There was no difference in any of the parameters between children with and without a history of neonatal AKI. Conclusion: Renal sequelae were rare in early adolescence following hypothermia-treated HIE regardless of presence or absence of neonatal AKI. Graphical abstract: [Figure not available: see fulltext.].
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| 9. |
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| 10. |
- Ståhl, Anne-lie, et al.
(författare)
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A Novel Mechanism of Bacterial Toxin Transfer within Host Blood Cell-Derived Microvesicles.
- 2015
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Shiga toxin (Stx) is the main virulence factor of enterohemorrhagic Escherichia coli, which are non-invasive strains that can lead to hemolytic uremic syndrome (HUS), associated with renal failure and death. Although bacteremia does not occur, bacterial virulence factors gain access to the circulation and are thereafter presumed to cause target organ damage. Stx was previously shown to circulate bound to blood cells but the mechanism by which it would potentially transfer to target organ cells has not been elucidated. Here we show that blood cell-derived microvesicles, shed during HUS, contain Stx and are found within patient renal cortical cells. The finding was reproduced in mice infected with Stx-producing Escherichia coli exhibiting Stx-containing blood cell-derived microvesicles in the circulation that reached the kidney where they were transferred into glomerular and peritubular capillary endothelial cells and further through their basement membranes followed by podocytes and tubular epithelial cells, respectively. In vitro studies demonstrated that blood cell-derived microvesicles containing Stx undergo endocytosis in glomerular endothelial cells leading to cell death secondary to inhibited protein synthesis. This study demonstrates a novel virulence mechanism whereby bacterial toxin is transferred within host blood cell-derived microvesicles in which it may evade the host immune system.
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