| 1. |
- Karpman, D, et al.
(författare)
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Platelet activation in hemolytic uremic syndrome
- 2006
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Ingår i: Seminars in Thrombosis and Hemostasis. - : Georg Thieme Verlag. - 0094-6176 .- 1098-9064. ; 32:2, s. 128-145
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Tidskriftsartikel (refereegranskat)abstract
- Platelet consumption in platelet-fibrin aggregates leading to thrombocytopenia and small vessel obstruction are major features of the hemolytic uremic syndrome (HUS). Although thrombocytopenia has been correlated to poor prognosis, the mechanisms by which thrombocytopenia develops in HUS have not been completely elucidated. However, plausible explanations have been platelet contact with thrombogenic surfaces and/or direct contact with an aggregating agent. This article summarizes several mechanisms of platelet activation, interactions with leukocytes, chemokine release, complement activation, and antimicrobial defense. Specific mechanisms are outlined by which platelets may be activated, leading to thrombocytopenia during HUS. In diarrhea-associated HUS Shiga toxin has been shown to injure the endothelium, thus exposing the subendothelium, releasing tissue factor, and rendering the vessel wall prothrombotic. Shiga toxin also binds to and activates platelets. The toxin may activate endothelial cells and platelets simultaneously. In atypical HUS the alternative complement pathway is activated because of mutations in complement regulatory proteins. Mutated factor H does not bind to endothelium and platelets efficiently, enabling complement activation on these cells. In thrombotic thrombocytopenic purpura, intravascular platelet clotting Occurs due to dysfunction of the von Willebrand factor (VWF)-cleaving protease ADAMTS13. Thrombi are formed by binding of platelets to ultralarge VWF multimers.
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| 2. |
- Vaziri-Sani, Fariba, et al.
(författare)
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Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome
- 2006
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Ingår i: Kidney International. - : Nature Publishing Group. - 0085-2538 .- 1523-1755. ; 69:6, s. 981-988
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the phenotypic expression of factor H mutations in two patients with atypical hemolytic uremic syndrome (HUS). Factor H in serum was assayed by rocket immunoelectrophoresis, immunoblotting, and double immunodiffusion and in tissue by immunohistochemistry. Functional activity was analyzed by hemolysis of sheep erythrocytes and binding to endothelial cells. A homozygous mutation in complement control protein (CCP) domain 10 of factor H was identified in an adult man who first developed membranoproliferative glomerulonephritis and later HUS. C3 levels were very low. The patient had undetectable factor H levels in serum and a weak factor H 150 kDa band. Double immunodiffusion showed partial antigenic identity with factor H in normal serum owing to the presence of factor H-like protein 1. Strong specific labeling for factor H was detected in glomerular endothelium, mesangium and in glomerular and tubular epithelium as well as in bone marrow cells. A heterozygous mutation in CCP 20 of factor H was found in a girl with HUS. C3 levels were moderately decreased at onset. Factor H levels were normal and a normal 150 kDa band was present. Double immunodiffusion showed antigenic identity with normal factor H. Factor H labeling was minimal in the renal cortex. Factor H dysfunction was demonstrated by increased sheep erythrocyte hemolysis and decreased binding to endothelial cells. In summary, two different factor H mutations associated with HUS were examined: in one, factor H accumulated in cells, and in the other, membrane binding was reduced.
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| 3. |
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| 4. |
- Aradottir, Sigridur Sunna, et al.
(författare)
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Complement dysregulation associated with a genetic variant in factor H-related protein 5 in atypical hemolytic uremic syndrome
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Ingår i: Pediatric Nephrology. - 1432-198X.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) can be associated with mutations, deletions, or hybrid genes in factor H-related (FHR) proteins.METHODS: A child with aHUS was investigated. Genetics was assessed by Sanger and next generation sequencing. Serum FHR5 was evaluated by immunoblotting, ELISA, and by induction of rabbit red blood cell hemolysis in the presence/absence of recombinant human rFHR5. Mutagenesis was performed in HEK cells.RESULTS: A heterozygous genetic variant in factor H-related protein 5 (CFHR5), M514R, was found in the child, who also had a homozygous deletion of CFHR3/CFHR1, and antibodies to factor H, as well as low levels of C3. Patient serum exhibited low levels of FHR5. In the presence of rabbit red blood cells, patient serum induced hemolysis which decreased when rFHR5 was added at physiological concentrations. Similar results were obtained using serum from the father, bearing the CFHR5 variant without factor H antibodies. Patient FHR5 formed normal dimers. The CFHR5 M514R variant was expressed in HEK cells and minimal secretion was detected whereas the protein level was elevated in cell lysates.CONCLUSIONS: Decreased secretion of the product of the mutant allele could explain the low FHR5 levels in patient serum. Reduced hemolysis when rFHR5 was added to serum suggests a regulatory role regarding complement activation on red blood cells. As such, low levels of FHR5, as demonstrated in the patient, may contribute to complement activation. A higher resolution version of the Graphical abstract is available as Supplementary information.
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| 5. |
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| 6. |
- Aradottir, Sigridur Sunna, et al.
(författare)
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Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Complement factor B (FB) mutant variants are associated with excessive complement activation in kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy and membranoproliferative glomerulonephritis (MPGN). Patients with aHUS are currently treated with eculizumab while there is no specific treatment for other complement-mediated renal diseases. In this study the phenotype of three FB missense variants, detected in patients with aHUS (D371G and E601K) and MPGN (I242L), was investigated. Patient sera with the D371G and I242L mutations induced hemolysis of sheep erythrocytes. Mutagenesis was performed to study the effect of factor D (FD) inhibition on C3 convertase-induced FB cleavage, complement-mediated hemolysis, and the release of soluble C5b-9 from glomerular endothelial cells. The FD inhibitor danicopan abrogated C3 convertase-associated FB cleavage to the Bb fragment in patient serum, and of the FB constructs, D371G, E601K, I242L, the gain-of-function mutation D279G, and the wild-type construct, in FB-depleted serum. Furthermore, the FD-inhibitor blocked hemolysis induced by the D371G and D279G gain-of-function mutants. In FB-depleted serum the D371G and D279G mutants induced release of C5b-9 from glomerular endothelial cells that was reduced by the FD-inhibitor. These results suggest that FD inhibition can effectively block complement overactivation induced by FB gain-of-function mutations.
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| 7. |
- Ariceta, Gema, et al.
(författare)
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Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome
- 2009
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Ingår i: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 1432-198X .- 0931-041X. ; 24:4, s. 687-696
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- This guideline for the investigation and initial treatment of atypical hemolytic uremic syndrome (HUS) is intended to offer an approach based on opinion, as evidence is lacking. It builds on the current ability to identify the etiology of specific diagnostic sub-groups of HUS. HUS in children is mostly due to infection, enterohemorrhagic Escherichia coli (EHEC), Shigella dysenteriae type 1 in some geographic regions, and invasive Streptococcus pneumoniae. These sub-groups are relatively straightforward to diagnose. Their management, which is outside the remit of this guideline, is related to control of infection where that is necessary and supportive measures for the anemia and acute renal failure. A thorough investigation of the remainder of childhood HUS cases, commonly referred to as "atypical" HUS, will reveal a risk factor for the syndrome in approximately 60% of cases. Disorders of complement regulation are, numerically, the most important. The outcome for children with atypical HUS is poor, and, because of the rarity of these disorders, clinical experience is scanty. Some cases of complement dysfunction appear to respond to plasma therapy. The therapeutic part of this guideline is the consensus of the contributing authors and is based on limited information from uncontrolled studies. The guideline proposes urgent and empirical plasmapheresis replacement with whole plasma fraction for the first month after diagnosis. This should only be undertaken in specialized pediatric nephrology centers where appropriate medical and nursing skills are available. The guideline includes defined terminology and audit points so that the early clinical effectiveness of the strategy can be evaluated.
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| 8. |
- Arvidsson, Ida, et al.
(författare)
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Apyrase decreases phage induction and Shiga toxin release from E. coli O157:H7 and has a protective effect during infection
- 2022
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Ingår i: Gut microbes. - : Informa UK Limited. - 1949-0976 .- 1949-0984. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC) cause gastrointestinal infection and, in severe cases, hemolytic uremic syndrome which may lead to death. There is, to-date, no therapy for this infection. Stx induces ATP release from host cells and ATP signaling mediates its cytotoxic effects. Apyrase cleaves and neutralizes ATP and its effect on Stx and EHEC infection was therefore investigated. Apyrase decreased bacterial RecA and dose-dependently decreased toxin release from E. coli O157:H7 in vitro, demonstrated by reduced phage DNA and protein levels. The effect was investigated in a mouse model of E. coli O157:H7 infection. BALB/c mice infected with Stx2-producing E. coli O157:H7 were treated with apyrase intraperitoneally, on days 0 and 2 post-infection, and monitored for 11 days. Apyrase-treated mice developed disease two days later than untreated mice. Untreated infected mice lost significantly more weight than those treated with apyrase. Apyrase-treated mice exhibited less colonic goblet cell depletion and apoptotic cells, as well as lower fecal ATP and Stx2, compared to untreated mice. Apyrase also decreased platelet aggregation induced by co-incubation of human platelet-rich-plasma with Stx2 and E. coli O157 lipopolysaccharide in the presence of collagen. Thus, apyrase had multiple protective effects, reducing RecA levels, stx2 and toxin release from EHEC, reducing fecal Stx2 and protecting mouse intestinal cells, as well as decreasing platelet activation, and could thereby delay the development of disease.
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| 9. |
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| 10. |
- 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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| 11. |
- Arvidsson, Ida, et al.
(författare)
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Shiga toxin-induced complement-mediated hemolysis and release of complement-coated red blood cell-derived microvesicles in hemolytic uremic syndrome.
- 2015
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 194:5, s. 2309-2318
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Tidskriftsartikel (refereegranskat)abstract
- Shiga toxin (Stx)-producing Escherichia coli (STEC) cause hemolytic uremic syndrome (HUS). This study investigated whether Stx2 induces hemolysis and whether complement is involved in the hemolytic process. RBCs and/or RBC-derived microvesicles from patients with STEC-HUS (n = 25) were investigated for the presence of C3 and C9 by flow cytometry. Patients exhibited increased C3 deposition on RBCs compared with controls (p < 0.001), as well as high levels of C3- and C9-bearing RBC-derived microvesicles during the acute phase, which decreased after recovery. Stx2 bound to P1 (k) and P2 (k) phenotype RBCs, expressing high levels of the P(k) Ag (globotriaosylceramide), the known Stx receptor. Stx2 induced the release of hemoglobin and lactate dehydrogenase in whole blood, indicating hemolysis. Stx2-induced hemolysis was not demonstrated in the absence of plasma and was inhibited by heat inactivation, as well as by the terminal complement pathway Ab eculizumab, the purinergic P2 receptor antagonist suramin, and EDTA. In the presence of whole blood or plasma/serum, Stx2 induced the release of RBC-derived microvesicles coated with C5b-9, a process that was inhibited by EDTA, in the absence of factor B, and by purinergic P2 receptor antagonists. Thus, complement-coated RBC-derived microvesicles are elevated in HUS patients and induced in vitro by incubation of RBCs with Stx2, which also induced hemolysis. The role of complement in Stx2-mediated hemolysis was demonstrated by its occurrence only in the presence of plasma and its abrogation by heat inactivation, EDTA, and eculizumab. Complement activation on RBCs could play a role in the hemolytic process occurring during STEC-HUS.
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| 12. |
- Assink, Karin, et al.
(författare)
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Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency.
- 2003
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Ingår i: Kidney International. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 63:6, s. 1995-1999
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Tidskriftsartikel (refereegranskat)abstract
- Background. The pentad of thrombocytopenia, hemolytic anemia, mild renal dysfunction, neurologic signs, and fever, classically characterizes the syndrome of thrombotic thrombocytopenic purpura (TTP). TTP usually occurs in adults as an acquired form but a congenital form in children has also been described. In the latter case, the initial presentation is often with neonatal jaundice and thrombocytopenia. The disorder may subsequently take a relapsing course. Deficiency of a recently identified novel metalloprotease, the von Willebrand factor (vWF)-cleaving protease, originating from mutations in the ADAMTS13 gene plays a major role in the development of TTP. Methods. Blood for DNA analysis was collected from six unrelated TTP families, consisting of nine patients from four different countries, and was screened for mutations in the ADAMTS 13 gene. This gene spans 29 exons encompassing ~37 kb. Conventional techniques of DNA extraction, polymerase chain reaction (PCR), and direct cycle sequencing were used. Results. Eight novel ADAMTS 13 mutations are presented. Half of the total number of mutant ADAMTS13 alleles are amino acid substitutions. The disease-causing mutations are spread over the gene. The pathogenicity of the individual mutations is based upon their predicted effect on the ADAMTS13 protein and segregation in family members. Although most of the patients (seven out of nine) had symptoms during the neonatal period, they were in a remarkably good condition. Only one of the nine patients had a decreased glomerular filtration rate (GFR) with proteinuria and hematuria. Another patient had epileptic seizures. Conclusion. We confirm that deficiency of ADAMTS13 is a molecular mechanism responsible for familial TTP. An early diagnosis allows prophylactic treatment with fresh plasma infusions.
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| 13. |
- Bekassy, Zivile, et al.
(författare)
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Crosstalk between the renin–angiotensin, complement and kallikrein–kinin systems in inflammation
- 2022
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Ingår i: Nature Reviews Immunology. - : Springer Science and Business Media LLC. - 1474-1733 .- 1474-1741. ; 22:7, s. 411-428
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Forskningsöversikt (refereegranskat)abstract
- During severe inflammatory and infectious diseases, various mediators modulate the equilibrium of vascular tone, inflammation, coagulation and thrombosis. This Review describes the interactive roles of the renin–angiotensin system, the complement system, and the closely linked kallikrein–kinin and contact systems in cell biological functions such as vascular tone and leakage, inflammation, chemotaxis, thrombosis and cell proliferation. Specific attention is given to the role of these systems in systemic inflammation in the vasculature and tissues during hereditary angioedema, cardiovascular and renal glomerular disease, vasculitides and COVID-19. Moreover, we discuss the therapeutic implications of these complex interactions, given that modulation of one system may affect the other systems, with beneficial or deleterious consequences.
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| 14. |
- Békássy, Zivile D., et al.
(författare)
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Aliskiren inhibits renin-mediated complement activation
- 2018
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538. ; 94:4, s. 689-700
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Tidskriftsartikel (refereegranskat)abstract
- Certain kidney diseases are associated with complement activation although a renal triggering factor has not been identified. Here we demonstrated that renin, a kidney-specific enzyme, cleaves C3 into C3b and C3a, in a manner identical to the C3 convertase. Cleavage was specifically blocked by the renin inhibitor aliskiren. Renin-mediated C3 cleavage and its inhibition by aliskiren also occurred in serum. Generation of C3 cleavage products was demonstrated by immunoblotting, detecting the cleavage product C3b, by N-terminal sequencing of the cleavage product, and by ELISA for C3a release. Functional assays showed mast cell chemotaxis towards the cleavage product C3a and release of factor Ba when the cleavage product C3b was combined with factor B and factor D. The renin-mediated C3 cleavage product bound to factor B. In the presence of aliskiren this did not occur, and less C3 deposited on renin-producing cells. The effect of aliskiren was studied in three patients with dense deposit disease and this demonstrated decreased systemic and renal complement activation (increased C3, decreased C3a and C5a, decreased renal C3 and C5b-9 deposition and/or decreased glomerular basement membrane thickness) over a follow-up period of four to seven years. Thus, renin can trigger complement activation, an effect inhibited by aliskiren. Since renin concentrations are higher in renal tissue than systemically, this may explain the renal propensity of complement-mediated disease in the presence of complement mutations or auto-antibodies.
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| 15. |
- Békassy, Zivile, et al.
(författare)
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Eculizumab in an anephric patient with atypical haemolytic uraemic syndrome and advanced vascular lesions.
- 2013
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Ingår i: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 28:11, s. 2899-2907
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Tidskriftsartikel (refereegranskat)abstract
- Atypical haemolytic uraemic syndrome (aHUS) is associated with dysfunction of the alternative pathway of complement. Disease activity subsides as renal failure progresses but recurs upon renal transplantation, indicating that viable renal tissue contributes to disease activity. We present evidence of cerebrovascular occlusive disease indicating that vascular injury may occur in the absence of kidneys.
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| 16. |
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| 17. |
- Békassy, Zivile, et al.
(författare)
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Intestinal damage in enterohemorrhagic Escherichia coli infection.
- 2011
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Ingår i: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 1432-198X .- 0931-041X. ; oct, s. 2059-2071
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Tidskriftsartikel (refereegranskat)abstract
- Enterohemorrhagic Escherichia coli (EHEC) infection leads to marked intestinal injury. Sigmoid colon obtained from two children during EHEC infection exhibited abundant TUNEL-positive cells. To define which bacterial virulence factors contribute to intestinal injury the presence of Shiga toxin-2 (Stx2), intimin and the type III secretion system were correlated with symptoms and intestinal damage. C3H/HeN mice were inoculated with Stx2-producing (86-24) and non-producing (87-23) E. coli O157:H7 strains and 86-24 mutants lacking eae, encoding intimin (strain UMD619) or escN regulating the expression of type III secretion effectors (strain CVD451). Severe symptoms developed in mice inoculated with 86-24 and 87-23. Few mice inoculated with the mutant strains developed severe symptoms. Strain 86-24 exhibited higher fecal bacterial counts, followed by 87-23, whereas strains UMD619 and CVD451 showed minimal fecal counts. More TUNEL-positive cells were found in proximal and distal colons of mice inoculated with strain 86-24 compared with strains 87-23 and CVD451 (p
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| 18. |
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| 19. |
- Besbas, N., et al.
(författare)
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A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders
- 2006
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Ingår i: Kidney International. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 70:3, s. 423-431
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Forskningsöversikt (refereegranskat)abstract
- The diagnostic terms hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are based on historical and overlapping clinical descriptions. Advances in understanding some of the causes of the syndrome now permit many patients to be classified according to etiology. The increased precision of a diagnosis based on causation is important for considering logical approaches to treatment and prognosis. It is also essential for research. We propose a classification that accommodates both a current understanding of causation (level 1) and clinical association in cases for whom cause of disease is unclear (level 2). We tested the classification in a pediatric disease registry of HUS. The revised classification is a stimulus to comprehensive investigation of all cases of HUS and TTP and is expected to increase the proportion of cases in whom a level 1 etiological diagnosis is confirmed.
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| 20. |
- Besbas, Nesrin, et al.
(författare)
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Neonatal onset atypical hemolytic uremic syndrome successfully treated with eculizumab
- 2013
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Ingår i: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 1432-198X .- 0931-041X. ; 28:1, s. 155-158
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Tidskriftsartikel (refereegranskat)abstract
- Atypical hemolytic uremic syndrome (aHUS) is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Neonatal cases are extremely uncommon. Plasma therapy is the first choice therapy in patients with aHUS based on the belief of an underlying complement dysregulation. Alternatively, eculizumab, which targets complement 5, is used to block complement activation. Sudden onset macroscopic hematuria, hypertension, and bruises over the entire body were noted in a 5 day-old newborn. Investigations revealed hemolytic anemia, thrombocytopenia, renal impairment, and a low serum C3, leading to the diagnosis of aHUS. Fresh frozen plasma (FFP) infusions and peritoneal dialysis for acute kidney injury were initiated. This approach yielded full renal and hematological remission. The patient was discharged with FFP infusions, but subsequently developed three life-threatening disease recurrences at 1, 3, and 6 months of age. The last relapse presented with uncontrolled hypertension and impaired renal function while the patient was receiving FFP infusions. After the first dose of eculizumab, his renal and hematological parameters returned to normal and his blood pressure normalized. Genetic screening of the CFH gene revealed a novel homozygous p. Tyr1177Cys mutation. Eculizumab can be considered as an alternative to plasma therapy in the treatment of specific patients with aHUS, even in infants.
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| 21. |
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| 22. |
- Brackman, Damien, et al.
(författare)
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Thrombotic microangiopathy mimicking membranoproliferative glomerulonephritis
- 2011
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Ingår i: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 26:10, s. 3399-3403
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Tidskriftsartikel (refereegranskat)abstract
- A 4-year-old boy presented with proteinuria and developed progressive renal failure over 6 years. In the patient's family, five individuals were affected with atypical haemolytic uraemic syndrome (aHUS) but not the patient. Renal biopsies (n = 3) showed glomerular basement membrane thickening with double contours, endothelial swelling and deposits of C3 and C1q. Electron microscopy revealed mesangial and subendothelial electron-dense deposits. Complement mutations in membrane cofactor protein (Y155D) and C3 (R713W and G1094R) were detected in all affected family members. The patient also had transient autoantibodies to factor H. The findings suggest that aHUS and glomerulopathy resembling membranoproliferative glomerulonephritis may have a common molecular background.
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| 23. |
- Burlaka, Ievgeniia, et al.
(författare)
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Ouabain Protects against Shiga Toxin-Triggered Apoptosis by Reversing the Imbalance between Bax and Bcl-xL
- 2013
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Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 24:9, s. 1413-1423
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Tidskriftsartikel (refereegranskat)abstract
- Hemolytic uremic syndrome, a life-threatening disease often accompanied by acute renal failure, usually occurs after gastrointestinal infection with Shiga toxin 2 (Stx2)-producing Escherichia coli. Stx2 binds to the glycosphingolipid globotriaosylceramide receptor, expressed by renal epithelial cells, and triggers apoptosis by activating the apoptotic factor Bax. Signaling via the ouabain/Na,K-ATPase/IP3R/NF-B pathway increases expression of Bcl-xL, an inhibitor of Bax, suggesting that ouabain might protect renal cells from Stx2-triggered apoptosis. Here, exposing rat proximal tubular cells to Stx2 in vitro resulted in massive apoptosis, upregulation of the apoptotic factor Bax, increased cleaved caspase-3, and downregulation of the survival factor Bcl-xL; co-incubation with ouabain prevented all of these effects. Ouabain activated the NF-B antiapoptotic subunit p65, and the inhibition of p65 DNA binding abolished the antiapoptotic effect of ouabain in Stx2-exposed tubular cells. Furthermore, in vivo, administration of ouabain reversed the imbalance between Bax and Bcl-xL in Stx2-treated mice. Taken together, these results suggest that ouabain can protect the kidney from the apoptotic effects of Stx2.
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| 24. |
- Calderon Toledo, Carla, et al.
(författare)
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Cross-Reactive Protection against Enterohemorrhagic Escherichia coli Infection by Enteropathogenic Escherichia coli in a Mouse Model.
- 2011
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Ingår i: Infection and Immunity. - 1098-5522. ; 79:6, s. 2224-2233
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Tidskriftsartikel (refereegranskat)abstract
- Enteropathogenic (EPEC) and enterohemorrhagic (EHEC) Escherichia coli are related attaching and effacing (A/E) pathogens. The genes responsible for the A/E pathology are encoded in a chromosomal pathogenicity island termed the locus of enterocyte effacement (LEE). Both pathogens share a high degree of homology in the LEE and additional 'O' islands. EHEC prevalence is much lower in EPEC endemic areas. This may be due to the development of antibodies against common EPEC and EHEC antigens. This study investigated the hypothesis that EPEC infections may protect against EHEC infections. We used a mouse model to inoculate BALB/c mice intragastrically, first with EPEC, followed by EHEC (E. coli O157:H7). Four control groups received either a non-pathogenic E. coli (NPEC) strain followed by EHEC (NPEC/EHEC), alternatively PBS/EHEC, EPEC/PBS or PBS/PBS. Mice were monitored for weight loss and symptoms. EPEC colonized the intestine after challenge and mice developed serum antibodies to intimin and E. coli secreted protein B (encoded in the LEE). Prechallenge with an EPEC strain had a protective effect after EHEC infection as few mice developed mild symptoms, from which they recovered. These mice had an increase in body weight similar to control animals and tissue morphology exhibited mild intestinal changes and normal renal histology. All mice that were not pre-challenged with the EPEC strain developed mild to severe symptoms after EHEC infection, weight loss as well as intestinal and renal histopathological changes. These data suggest that EPEC may protect against EHEC infection in this mouse model.
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| 25. |
- Calderon Toledo, Carla, et al.
(författare)
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Shiga toxin-mediated disease in MyD88-deficient mice infected with Escherichia coli O157:H7.
- 2008
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 173:5, s. 1428-1439
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Tidskriftsartikel (refereegranskat)abstract
- Toll-like receptors (TLRs) are key factors of innate immunity that detect pathogen invasion and trigger a host response. TLR4 can mediate a response through adaptor molecules, MyD88 or TRIF. In the present study, streptomycin-treated MyD88(-/-), Tlr4(-/-), Trif (Lps2/Lps2), and C57BL/6 wild-type (WT) mice were infected with either Shiga toxin (Stx)-producing or non-producing Escherichia coli O157:H7. Moderate to severe clinical signs of disease developed in MyD88(-/-) (n = 21/21), Tlr4(-/-) (n = 12/16), Trif (Lps2/Lps2) (n = 7/15) and WT mice (n = 6/20) infected with Stx-producing E. coli O157:H7 but not in mice inoculated with the Stx non-producing strain (n = 0/54, P < 0.001). MyD88(-/-) mice infected with Stx-producing E. coli O157:H7 developed the most severe disease and had the highest bacterial burden. Hematological analysis of sick MyD88(-/-) mice showed reduced red blood cell counts and reticulocytosis, suggesting hemolysis. Thrombocytopenia developed in MyD88(-/-), Trif (Lps2/Lps2), and WT mice, and creatinine levels were elevated in both MyD88(-/-) and WT mice infected with the Stx-producing strain. Renal histopathology showed evidence of glomerular capillary congestion, tubular desquamation, and fibrinogen deposition, and intestinal histopathology showed mucosal injury, edema, and inflammation in sick mice. Administration of purified Stx2 to MyD88(-/-) and WT mice led to severe disease in both groups, suggesting that MyD88(-/-) mice are not more sensitive to Stx than WT mice. As MyD88(-/-) mice developed the most severe disease hematological and pathological changes, the results suggest that dysfunctional innate immune responses via MyD88 enhanced Stx-induced disease.
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| 26. |
- 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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| 27. |
- Fischer, Hans, et al.
(författare)
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Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.
- 2010
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Ingår i: PLoS pathogens. - : Public Library of Science (PLoS). - 1553-7374 .- 1553-7366. ; 6:9
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Tidskriftsartikel (refereegranskat)abstract
- The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution of human genetic variation in disease susceptibility. We describe here a new, IRF3-dependent signaling pathway that is critical for distinguishing pathogens from normal flora at the mucosal barrier. Following uropathogenic E. coli infection, Irf3(-/-) mice showed a pathogen-specific increase in acute mortality, bacterial burden, abscess formation and renal damage compared to wild type mice. TLR4 signaling was initiated after ceramide release from glycosphingolipid receptors, through TRAM, CREB, Fos and Jun phosphorylation and p38 MAPK-dependent mechanisms, resulting in nuclear translocation of IRF3 and activation of IRF3/IFNβ-dependent antibacterial effector mechanisms. This TLR4/IRF3 pathway of pathogen discrimination was activated by ceramide and by P-fimbriated E. coli, which use ceramide-anchored glycosphingolipid receptors. Relevance of this pathway for human disease was supported by polymorphic IRF3 promoter sequences, differing between children with severe, symptomatic kidney infection and children who were asymptomatic bacterial carriers. IRF3 promoter activity was reduced by the disease-associated genotype, consistent with the pathology in Irf3(-/-) mice. Host susceptibility to common infections like UTI may thus be strongly influenced by single gene modifications affecting the innate immune response.
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| 28. |
- Frendeus, Björn, et al.
(författare)
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Interleukin 8 receptor deficiency confers susceptibility to acute experimental pyelonephritis and may have a human counterpart
- 2000
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Ingår i: Journal of Experimental Medicine. - 1540-9538. ; 192:6, s. 881-890
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils migrate to infected mucosal sites that they protect against invading pathogens. Their interaction with the epithelial barrier is controlled by CXC chemokines and by their receptors. This study examined the change in susceptibility to urinary tract infection (UTI) after deletion of the murine interleukin 8 receptor homologue (mIL-8Rh). Experimental UTIs in control mice stimulated an epithelial chemokine response and increased chemokine receptor expression. Neutrophils migrated through the tissues to the epithelial barrier that they crossed into the lumen, and the mice developed pyuria. In mIL-8Rh knockout (KO) mice, the chemokine response was intact, but the epithelial cells failed to express IL-8R, and neutrophils accumulated in the tissues. The KO mice were unable to clear bacteria from kidneys and bladders and developed bacteremia and symptoms of systemic disease, but control mice were fully resistant to infection. The experimental UTI model demonstrated that IL-8R-dependent mechanisms control the urinary tract defense, and that neutrophils are essential host effector cells. Patients prone to acute pyelonephritis also showed low CXC chemokine receptor 1 expression compared with age-matched controls, suggesting that chemokine receptor expression may also influence the susceptibility to UTIs in humans. The results provide a first molecular clue to disease susceptibility of patients prone to acute pyelonephritis.
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| 29. |
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| 30. |
- Friberg Hed, Niklas, et al.
(författare)
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Arginase release in hemolytic uremic syndrome affects the vasculature
- 2023
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Hemolysis is a cardinal feature of hemolytic uremic syndrome (HUS) and during hemolysis excess arginase 1 is released from erythrocytes. Increased arginase activity leads to reduced arginine, as it is converted to urea and ornithine, and thereby reduced nitric oxide bioavailability, with secondary vascular injury. In this study we investigated arginase release in HUS patients and laboratory models. Two separate cohorts of patients (n=47 in total) with HUS associated with Shiga toxin-producing enterohemorrhagic E. coli (EHEC) and pediatric controls (n=35) were investigated. HUS patients had excessively high arginase 1 levels and activity (conversion to urea and ornithine) in plasma/serum during the acute phase, compared to remission and controls. Arginase 1 levels correlated with lactate dehydrogenase activity, indicating hemolysis, as well as the need for dialysis treatment. Patients also exhibited high levels of plasma alpha-1-microglobulin, a heme scavenger. Two mouse models were used, mice were challenged intragastrically with E. coli O157:H7 or injected intraperitoneally with Shiga toxin 2. Both models exhibited significantly elevated plasma arginase 1 levels and activity. Arginase 1 levels correlated with lactate dehydrogenase activity and alpha-1-microglobulin in the plasma of EHEC-infected mice. In vitro perfusion of Shiga toxin 2- and E. coli O157-lipopolysaccharide-stimulated human blood cells combined with ADAMTS13-deficient plasma over glomerular endothelial cells induced hemolysis and the release of bioactive arginase 1. The high levels of arginase released during HUS could thereby contribute to microvascular injury during HUS.
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| 31. |
- Friberg, Niklas, et al.
(författare)
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Red blood cell-derived arginase release in hemolytic uremic syndrome
- 2024
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Ingår i: Journal of Translational Medicine. - 1479-5876. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundHemolysis is a cardinal feature of hemolytic uremic syndrome (HUS) and during hemolysis excess arginase 1 is released from red blood cells. Increased arginase activity leads to reduced L-arginine, as it is converted to urea and L-ornithine, and thereby reduced nitric oxide bioavailability, with secondary vascular injury. The objective of this study was to investigate arginase release in HUS patients and laboratory models and correlate arginase levels to hemolysis and kidney injury.MethodsTwo separate cohorts of patients (n = 47 in total) with HUS associated with Shiga toxin-producing enterohemorrhagic E. coli (EHEC) and pediatric controls (n = 35) were investigated. Two mouse models were used, in which mice were either challenged intragastrically with E. coli O157:H7 or injected intraperitoneally with Shiga toxin 2. An in vitro model of thrombotic microangiopathy was developed in which Shiga toxin 2- and E. coli O157 lipopolysaccharide-stimulated human blood cells combined with ADAMTS13-deficient plasma were perfused over glomerular endothelial cells. Two group statistical comparisons were performed using the Mann–Whitney test, multiple groups were compared using the Kruskal–Wallis test followed by Dunn’s procedure, the Wilcoxon signed rank test was used for paired data, or linear regression for continuous variables.ResultsHUS patients had excessively high plasma arginase 1 levels and activity (conversion of L-arginine to urea and L-ornithine) during the acute phase, compared to remission and controls. Arginase 1 levels correlated with lactate dehydrogenase activity, indicating hemolysis, as well as the need for dialysis treatment. Patients also exhibited high levels of plasma alpha-1-microglobulin, a heme scavenger. Both mouse models exhibited significantly elevated plasma arginase 1 levels and activity. Plasma arginase 1 levels correlated with lactate dehydrogenase activity, alpha-1-microglobulin and urea levels, the latter indicative of kidney dysfunction. In the in vitro model of thrombotic microangiopathy, bioactive arginase 1 was released and levels correlated to the degree of hemolysis.ConclusionsElevated red blood cell-derived arginase was demonstrated in HUS patients and in relevant in vivo and in vitro models. The excessively high arginase levels correlated to the degree of hemolysis and kidney dysfunction. Thus, arginase inhibition should be investigated in HUS.
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| 32. |
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| 33. |
- Gustafsson, Helena, et al.
(författare)
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Kongenital trombotisk trombocytopen purpura - Ett fall med atypisk bild upptäckt i vuxen ålder
- 2019
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Ingår i: Läkartidningen. - 0023-7205. ; 116:7
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Tidskriftsartikel (refereegranskat)abstract
- Congenital thrombocytopenic purpura (TTP) is a rare but serious condition. We present a case of a 29-year-old woman, diagnosed with this disease in adulthood. The episode that led to diagnosis was triggered by quetiapine. She presented with neurological symptoms and laboratory findings including low platelets and elevated creatinine. Interestingly, the signs of hemolysis were very subtle. Her symptoms were relieved by withdrawal of the medicine. The diagnosis was confirmed by very low ADAMTS13 activity, lack of antibodies against ADAMTS13 and the presence of a compound heterozygous ADAMTS13 mutation. Despite prophylactic plasma infusions, the patient developed a second episode of microangiopathy, leading to an extensive cerebral infarction. It is possible that even the latter episode was triggered by drugs. We suggest that the diagnosis of TTP should be considered in patients with neurological symptoms and unexplained thrombocytopenia.
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| 34. |
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| 35. |
- Hjorth, Lars, et al.
(författare)
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Correct evaluation of renal glomerular filtration rate requires clearance assays.
- 2002
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Ingår i: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 1432-198X .- 0931-041X. ; 17:10, s. 847-851
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Tidskriftsartikel (refereegranskat)abstract
- Iohexol clearance is an accepted, but time-consuming assay for the measurement of glomerular filtration rate (GFR). We investigated if simpler methods could predict GFR. Sixty-nine children with hematological-oncological disorders participated. A linear relationship was established by regression analysis between iohexol clearance ( n=734) and 1/s-creatinine ( r=0.45, n=727), s-cystatin C ( r=0.41, n=518), and the Schwartz ( r=0.45, n=723), Counahan-Barratt ( r=0.48, n=723), and modified Counahan-Barratt formulae ( r=0.48, n=723). These correlations improved when one GFR measurement per individual was compared with each of the five parameters. We further investigated if iohexol clearance could accurately be replaced. The degree of variation in predicting GFR was estimated by the standard deviation of the residuals (S(res)). For 1/s-creatinine and s-cystatin C, S(res) was 39 and 38 ml/min per 1.73 m(2). For the formulae of Schwartz, Counahan-Barratt, and modified Counahan-Barratt, the S(res) was 43, 40, and 40 ml/min per 1.73 m(2), respectively. The wide variations of the S(res) were not reduced when one GFR measurement per child was compared with the five parameters. Due to the large deviation in predicting GFR, we conclude that the five alternative methods studied cannot replace iohexol clearance for measurement of GFR.
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| 36. |
- Hjorth, Lars, et al.
(författare)
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Hyperfiltration evaluated by glomerular filtration rate at diagnosis in children with cancer.
- 2011
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5017 .- 1545-5009. ; 56:5, s. 762-766
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Renal glomerular filtration rate (GFR) of pediatric cancer patients at diagnosis has previously been investigated in a limited number of studies. PROCEDURE: GFR, measured by iohexol clearance, was prospectively investigated in 55 children over the age of 1 year with malignancies, (group A). Elevated GFR (>175 ml/min/1.73 m(2)) at diagnosis was found. To investigate if this finding was consistent, a second group of 76 children with malignancies was studied, (group B). As a method control for GFR obtained by iohexol clearance, group A and B together were compared to 298 pediatric patients without cancer, group C. RESULTS: GFR was elevated in 40/131 (31%) in Group A + B but only in 17/298 (6%) in Group C. GFR was significantly higher in children aged 1-5 in group A + B (47%) compared to group C (3%). Bone marrow involvement was significantly associated with higher GFR. Children without bone marrow involvement also hyperfiltrated more often than controls, but less often. Urea in urine was used as a marker of renal protein clearance in 14 patients in group A. A significant correlation between u-urea (mmol/L)/u-creatinine (mmol/L) and GFR was noted. CONCLUSIONS: Hyperfiltration is sometimes present in children with cancer at diagnosis. This may be related to increased amino acid turn over in patients with a large tumor burden. An elevated initial GFR in a child with cancer, which normalizes after chemotherapy may indicate chemotherapy-induced decreased renal function, but can be due to normalization of an initially high GFR. Pediatr Blood Cancer © 2011 Wiley-Liss, Inc.
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| 37. |
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| 38. |
- 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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| 39. |
- Johansson, Karl, et al.
(författare)
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Shiga Toxin-Bearing Microvesicles Exert a Cytotoxic Effect on Recipient Cells Only When the Cells Express the Toxin Receptor
- 2020
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Ingår i: Frontiers in cellular and infection microbiology. - : Frontiers Media SA. - 2235-2988. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Shiga toxin is the main virulence factor of non-invasive enterohemorrhagic Escherichia coli strains capable of causing hemolytic uremic syndrome. Our group has previously shown that the toxin can reach the kidney within microvesicles where it is taken up by renal cells and the vesicles release their cargo intracellularly, leading to toxin-mediated inhibition of protein synthesis and cell death. The aim of this study was to examine if recipient cells must express the globotriaosylceramide (Gb3) toxin receptor for this to occur, or if Gb3-negative cells are also susceptible after uptake of Gb3-positive and toxin-positive microvesicles. To this end we generated Gb3-positive A4GALT–transfected CHO cells, and a vector control lacking Gb3 (CHO-control cells), and decreased Gb3 synthesis in native HeLa cells by exposing them to the glycosylceramide synthase inhibitor PPMP. We used these cells, and human intestinal DLD-1 cells lacking Gb3, and exposed them to Shiga toxin 2-bearing Gb3-positive microvesicles derived from human blood cells. Results showed that only recipient cells that possessed endogenous Gb3 (CHO-Gb3 transfected and native HeLa cells) exhibited cellular injury, reduced cell metabolism and protein synthesis, after uptake of toxin-positive microvesicles. In Gb3-positive cells the toxin introduced via vesicles followed the retrograde pathway and was inhibited by the retrograde transport blocker Retro-2.1. CHO-control cells, HeLa cells treated with PPMP and DLD-1 cells remained unaffected by toxin-positive microvesicles. We conclude that Shiga toxin-containing microvesicles can be taken up by Gb3-negative cells but the recipient cell must express endogenous Gb3 for the cell to be susceptible to the toxin.
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| 40. |
- Johnson, Sally, et al.
(författare)
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An audit analysis of a guideline for the investigation and initial therapy of diarrhea negative (atypical) hemolytic uremic syndrome
- 2014
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Ingår i: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 1432-198X .- 0931-041X. ; 29:10, s. 1967-1978
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Tidskriftsartikel (refereegranskat)abstract
- In 2009, the European Paediatric Study Group for Haemolytic Uraemic Syndrome (HUS) published a clinical practice guideline for the investigation and initial therapy of diarrhea-negative HUS (now more widely referred to as atypical HUS, aHUS). The therapeutic component of the guideline (comprising early, high-volume plasmapheresis) was derived from anecdotal evidence and expert consensus, and the authors committed to auditing outcome. Questionnaires were distributed to pediatric nephrologists across Europe, North America, and the Middle East, who were asked to complete one questionnaire per patient episode of aHUS between July 1, 2009 and December 31, 2010. Comprehensive, anonymous demographic and clinical data were collected. Seventy-one children were reported with an episode of aHUS during the audit period. Six cases occurred on a background of influenza A H1N1 infection. Of 71 patients, 59 (83 %) received plasma therapy within the first 33 days, of whom ten received plasma infusion only. Complications of central venous catheters occurred in 16 out of 51 patients with a catheter in-situ (31 %). Median time to enter hematological remission was 11.5 days, and eight of 71 (11 %) patients did not enter hematological remission by day 33. Twelve patients (17 %) remained dialysis dependent at day 33. This audit provides a snapshot of the early outcome of a group of children with aHUS in the months prior to more widespread use of eculizumab.
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| 41. |
- Kahn, Robin, et al.
(författare)
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Contact-system activation in children with vasculitis.
- 2002
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Ingår i: The Lancet. - 1474-547X. ; 360:9332, s. 535-541
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The contact system triggers the kallikrein-kinin cascade, liberating bradykinin from high-molecular-weight kininogen. Effectors of the contact system have proinflammatory and vasoactive properties. Vasculitis is a condition characterised by inflammation around vessel walls, leading to secondary tissue damage for which the underlying molecular mechanisms are poorly understood. Our aim was to investigate contact-system activation in children with vasculitis. METHODS: We compared 17 children, aged 4-19 years, with vasculitis, engaging the skin, joints, intestines, or kidneys, with 21 controls, aged 2-18 years. We analysed proteolysis of high-molecular-weight kininogen by immunoblotting. Plasma bradykinin concentrations were quantified by ELISA. Kidney and skin biopsies were stained in situ for kinins. Concentrations of heparin binding protein (HBP) were quantified by ELISA. FINDINGS: We noted extensive proteolysis of high-molecular-weight kininogen in the plasma of 13 of 17 patients, but in only one of 21 controls (p<0.0001). Bradykinin concentrations were higher in the patients' plasma (median 320 ng/L, range <1-19680) than in plasma from controls (11 ng/L, <1-304; p=0.0004). Patients had local release of kinins at sites of inflammation in kidney and skin biopsies. HBP values were raised in patients (17.4 microg/L, 5.4-237.6) compared with controls (6 microg/L, 2.5-43.4; p=0.008). INTERPRETATION: Activation of the contact system could play a part in the pathogenesis of vasculitis, and explain the inflammation, pain, vasodilatation, and oedema seen in patients.
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| 42. |
- Kahn, Robin, et al.
(författare)
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Kinin System Activation in Vasculitis.
- 2011
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Ingår i: Acta paediatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 100:7, s. 950-957
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Tidskriftsartikel (refereegranskat)abstract
- Vasculitis is a systemic autoimmune inflammatory disease, characterized by inflammation in and around vessel walls leading to perturbed vessel patency and tissue damage. Many different organs may be involved. In this review pathogenetic mechanisms of vasculitis are discussed, with special reference to activation of the kinin system. Mechanisms of kinin system activation are described ultimately leading to release of kinins from high-molecular-weight-kininogen. These vasoactive peptides promote inflammation. Conclusion: Kinin system activation during vasculitis promotes inflammation.
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| 43. |
- Kahn, Robin, et al.
(författare)
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Microvesicle transfer of kinin B1-receptors is a novel inflammatory mechanism in vasculitis
- 2017
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538. ; 91:1, s. 96-105
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Tidskriftsartikel (refereegranskat)abstract
- During vasculitis, activation of the kinin system induces inflammation, whereby the kinin B1-receptor is expressed and activated after ligand binding. Additionally, activated blood cells release microvesicles into the circulation. Here we determined whether leukocyte-derived microvesicles bear B1-kinin receptors during vasculitis, and if microvesicles transfer functional B1-receptors to recipient cells, thus promoting inflammation. By flow cytometry, plasma from patients with vasculitis were found to contain high levels of leukocyte-derived microvesicles bearing B1-receptors. Importantly, renal biopsies from two patients with vasculitis showed leukocyte-derived microvesicles bearing B1-receptors docking on glomerular endothelial cells providing in vivo relevance. Microvesicles derived from B1-receptor-transfected human embryonic kidney cells transferred B1-receptors to wild-type human embryonic kidney cells, lacking the receptor, and to glomerular endothelial cells. The transferred B1-receptors induced calcium influx after B1-receptor agonist stimulation: a response abrogated by a specific B1-receptor antagonist. Microvesicles derived from neutrophils also transferred B1-receptors to wild-type human embryonic kidney cells and induced calcium influx after stimulation. Thus, we found a novel mechanism by which microvesicles transfer functional receptors and promote kinin-associated inflammation.
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| 44. |
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| 45. |
- Kahn, Robin, et al.
(författare)
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Neutrophil-derived proteinase 3 induces kallikrein-independent release of a novel vasoactive kinin.
- 2009
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Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 182:12, s. 7906-7915
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Tidskriftsartikel (refereegranskat)abstract
- The kinin-forming pathway is activated on endothelial cells and neutrophils when high-molecular weight kininogen (HK) is cleaved by plasma kallikrein liberating bradykinin, a potent mediator of inflammation. Kinins are released during inflammatory conditions such as vasculitis, associated with neutrophil influx around blood vessels. Some patients with vasculitis have elevated plasma levels of neutrophil-derived proteinase 3 (PR3) and anti-PR3 Abs. This study investigated if neutrophil-derived PR3 could induce activation of the kinin pathway. PR3 incubated with HK, or a synthetic peptide derived from HK, induced breakdown and release of a novel tridecapeptide termed PR3-kinin, NH(2)-MKRPPGFSPFRSS-COOH, consisting of bradykinin with two additional amino acids on each terminus. The reaction was specific and inhibited by anti-PR3 and alpha(1)-antitrypsin. Recombinant wild-type PR3 incubated with HK induced HK breakdown, whereas mutated PR3, lacking enzymatic activity, did not. PR3-kinin bound to and activated human kinin B(1) receptors, but did not bind to B(2) receptors, expressed by transfected HEK293 cells in vitro. In human plasma PR3-kinin was further processed to the B(2) receptor agonist bradykinin. PR3-kinin exerted a hypotensive effect in vivo through both B(1) and B(2) receptors as demonstrated using wild-type and B(1) overexpressing rats as well as wild-type and B(2) receptor knockout mice. Neutrophil extracts from vasculitis patients and healthy controls contained comparable amounts of PR3 and induced HK proteolysis, an effect that was abolished when PR3 was immunoadsorbed. Neutrophil-derived PR3 can proteolyze HK and liberate PR3-kinin, thereby initiating kallikrein-independent activation of the kinin pathway.
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| 46. |
- Karpman, Diana, et al.
(författare)
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A link between Krüppel-like factor 4, complement activation, and kidney damage
- 2022
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538. ; 102:1, s. 14-16
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Tidskriftsartikel (refereegranskat)abstract
- Krüppel-like factors (KLFs) are transcription factors with important roles in tissue homeostasis. KLF4 possesses antithrombotic and anti-inflammatory properties. In this issue, Estrada et al. show that endothelial KLF4 prevents complement deposition in glomeruli and in its absence the cell-bound complement regulator CD55 was reduced. The study included endothelial-specific KLF4 knockdown mice that mimic thrombotic microangiopathy and thrombotic microangiopathy patient biopsies showing decreased KLF4 and CD55. The results suggest that KLF4 is involved in the regulation of glomerular complement deposition.
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| 47. |
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| 48. |
- Karpman, Diana, et al.
(författare)
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Antibodies to intimin and Escherichia coli secreted proteins A and B in patients with enterohemorrhagic Escherichia coli infections
- 2002
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Ingår i: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 1432-198X .- 0931-041X. ; 17:3, s. 201-211
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Tidskriftsartikel (refereegranskat)abstract
- Enterohemorrhagic Escherichia coli produce an attaching and effacing lesion upon adhering to the intestinal epithelium. Bacterial factors involved in this histopathology include the intimin adhesin and E. coli secreted proteins (Esps) A and B. In this study we investigated the serum antibody responses to recombinant E. coli O157:H7 intimin, EspA, and EspB by immuno-blotting. Canadian patients with O157:H7 infection (n=10), Swedish patients with 0157:H7 (n=21), non-O157 (n=18), or infection from which the serotype was not available (n=3), and asymptomatic household members (n=25) were studied and compared with Canadian (n=20) and Swedish controls (n=52). In Canadian patients, IgG antibodies to intimin, EspA, and EspB were analyzed, in Swedish patients and their household members I-A, IgG, and IgM antibodies to EspA and EspB were studied. Patients and household members mounted an antibody response to the antigens. Significantly more patients developed an acute response to EspB compared with controls (P<0.01 Canadian patients, P<0.0001 Swedish patients). EspB IgA, IgG, and IgM had a specificity of 100%, 86%, and 86%, positive predictive value of 100%, 83%, and 81%, and sensitivity of 57%, 69%, and 63%, respectively, and appear to be an appropriate assay for the detection of EHEC infection. In cases of hemolytic uremic syndrome or hemorrhagic colitis this assay may be useful when a fecal strain has not been isolated, or in epidemics of non-O157 infection.
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| 49. |
- Karpman, Diana, et al.
(författare)
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Complement activation in thrombotic microangiopathy.
- 2013
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Ingår i: Hämostaseologie. - 0720-9355. ; 33:2, s. 96-104
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Forskningsöversikt (refereegranskat)abstract
- The endothelium lining the vascular lumen is continuously exposed to complement from the circulation. When erroneously activated on host cells, complement may generate a deleterious effect on the vascular wall leading to endothelial injury, exposure of the subendothelial matrix and platelet activation.In this review the contribution of complement activation to formation and maintenance of the pathological lesion termed thrombotic microangiopathy (TMA) is discussed. TMA is defined by vessel wall thickening affecting mainly arterioles and capillaries, detachment of the endothelial cell from the basement membrane and intraluminal thrombosis resulting in occlusion of the vessel lumen. The TMA lesion occurs in haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). HUS is further sub-classified as associated with Shiga toxin-producing Escherichia coli (STEC-HUS) or with complement dysregulation (atypical HUS) as well as other less common forms. The contribution of dysregulated complement activation to endothelial injury and platelet aggregation is reviewed as well as specific complement involvement in the development of HUS and TTP.
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| 50. |
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