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  • FINNAKI Study Grp (2019)
    Background Injury to endothelium and glycocalyx predisposes to vascular leak, which may subsequently lead to increased fluid requirements and worse outcomes. In this post hoc study of the prospective multicenter observational Finnish Acute Kidney Injury (FINNAKI) cohort study conducted in 17 Finnish intensive care units, we studied the association of Syndecan-1 (SDC-1), Angiopoetin-2 (Ang-2), soluble thrombomodulin (sTM), vascular adhesion protein-1 (VAP-1) and interleukin-6 (IL-6) with fluid administration and balance among septic critical care patients and their association with development of acute kidney injury (AKI) and 90-day mortality. Results SDC-1, Ang-2, sTM, VAP-1 and IL-6 levels were measured at ICU admission from 619 patients with sepsis. VAP-1 decreased (p <0.001) and IL-6 increased (p <0.001) with increasing amounts of administered fluid, but other biomarkers did not show differences according to fluid administration. In linear regression models adjusted for IL-6, only VAP-1 was significantly associated with fluid administration on day 1 (p <0.001) and the cumulative fluid balance on day 5/ICU discharge (p = 0.001). Of 415 patients admitted without AKI, altogether 112 patients (27.0%) developed AKI > 12 h from ICU admission (AKI(>12 h)). They had higher sTM levels than patients without AKI, and after multivariable adjustment log, sTM level was associated with AKI(>12 h) with OR (95% CI) of 12.71 (2.96-54.67), p = 0.001). Ninety-day non-survivors (n = 180; 29.1%) had higher SDC-1 and sTM levels compared to survivors. After adjustment for known confounders, log SDC-1 (OR [95% CI] 2.13 [1.31-3.49], p = 0.002), log sTM (OR [95% CI] 7.35 [2.29-23.57], p <0.001), and log Ang-2 (OR [95% CI] 2.47 [1.44-4.14], p = 0.001) associated with an increased risk for 90-day mortality. Finally, patients who had high levels of all three markers, namely, SDC-1, Ang-2 and sTM, had an adjusted OR of 5.61 (95% CI 2.67-11.79; p <0.001) for 90-day mortality. Conclusions VAP-1 and IL-6 associated with fluid administration on the first ICU day. After adjusting for confounders, sTM was associated with development of AKI after 12 h from ICU admission. SDC-1, Ang-2 and sTM were independently associated with an increased risk for 90-day mortality.
  • Virtanen, Helena; Silvola, Johanna M. U.; Autio, Anu; Li, Xiang-Guo; Liljenback, Heidi; Hellberg, Sanna; Siitonen, Riikka; Ståhle, Mia; Käkelä, Meeri; Airaksinen, Anu J.; Helariutta, Kerttuli; Tolvanen, Tuula; Veres, Tibor Z.; Saraste, Antti; Knuuti, Juhani; Jalkanen, Sirpa; Roivainen, Anne (2017)
    Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a ligand of inflammation-inducible vascular adhesion protein-1 (VAP1). We compared Ga-68-DOTA-and F-18-fluorodeoxyribose-(FDR) labeled Siglec-9motif peptides for PET imaging of inflammation. Methods. Firstly, we examined Ga-68-DOTA-Siglec-9 and F-18-FDR-Siglec-9 in rats with skin/muscle inflammation. We then studied F-18-FDR-Siglec-9 for the detection of inflamed atherosclerotic plaques in mice and compared it with previous Ga-68-DOTA-Siglec-9 results. Lastly, we estimated human radiation dosimetry fromthe rat data. Results. In rats, Ga-68-DOTA-Siglec-9 (SUV, 0.88 +/- 0.087) and F-18-FDR-Siglec-9 (SUV, 0.77 +/- 0.22) showed comparable (P = 0.29) imaging of inflammation. In atherosclerotic mice, 18 FFDR- Siglec-9 detected inflamed plaques with a target-to-background ratio (1.6 1/8 0.078) similar to previously tested Ga-68-DOTASiglec- 9 (P = 0.35). Humaneffectivedose estimates for Ga-68-DOTA-Siglec-9 and (18) F-FDR-Siglec-9were 0.024 and 0.022 mSv/MBq, respectively. Conclusion. Both tracers are suitable for PET imaging of inflammation. The easier production and lower cost of (68)GaDOTA-Siglec-9 present advantages over F-18-FDR-Siglec-9, indicating it as a primary choice for clinical studies.
  • Elovaara, Heli; Huusko, Teija; Maksimow, Mikael; Elima, Kati; Yegutkin, Gennady G.; Skurnik, Mikael; Dobrindt, Ulrich; Siitonen, Anja; McPherson, Michael J.; Salmi, Marko; Jalkanen, Sirpa (2015)
    Escherichia coli amine oxidase (ECAO), encoded by the tynA gene, catalyzes the oxidative deamination of aromatic amines into aldehydes through a well-established mechanism, but its exact biological role is unknown. We investigated the role of ECAO by screening environmental and human isolates for tynA and characterizing a tynA-deletion strain using microarray analysis and biochemical studies. The presence of tynA did not correlate with pathogenicity. In tynA+ Escherichia coli strains, ECAO enabled bacterial growth in phenylethylamine, and the resultant H2O2 was released into the growth medium. Some aminoglycoside antibiotics inhibited the enzymatic activity of ECAO, which could affect the growth of tynA+ bacteria. Our results suggest that tynA is a reserve gene used under stringent environmental conditions in which ECAO may, due to its production of H2O2, provide a growth advantage over other bacteria that are unable to manage high levels of this oxidant. In addition, ECAO, which resembles the human homolog hAOC3, is able to process an unknown substrate on human leukocytes.
  • Ollila, Aino; Vikatmaa, Leena; Virolainen, Juha; Nisula, Sara; Lakkisto, Paivi; Vikatmaa, Pirkka; Tikkanen, Ilkka; Venermo, Maarit; Pettila, Ville (2019)
    Background Major surgery predisposes to endothelial glycocalyx injury. Endothelial glycocalyx injury associates with cardiac morbidity, including spontaneous myocardial infarction. However, the relation between endothelial glycocalyx injury and the development of perioperative myocardial infarction remains unknown. Methods Fifteen perioperative myocardial infarction patients and 60 propensity-matched controls were investigated in this prospective study. The diagnosis of perioperative myocardial infarction was based on repeated cardiac troponin T measurements, electrocardiographs and recordings of ischaemic signs and symptoms. We measured endothelial glycocalyx markers - soluble thrombomodulin, syndecan-1 and vascular adhesion protein 1 - and an inflammatory marker, namely interleukin-6, preoperatively and 6 h and 24 h postoperatively. We calculated the areas under the receiver operating characteristics curves (AUCs) to compare the performances of the different markers in predicting perioperative myocardial infarction. The highest value of each marker was used in the analysis. Results The interleukin-6 concentrations of perioperative myocardial infarction patients were significantly higher preoperatively and 6 and 24 h postoperatively (P = 0.002, P = 0.002 and P = 0.001, respectively). The AUCs (95% confidence intervals) for the detection of perioperative myocardial infarction were 0.51 (0.34-0.69) for soluble thrombomodulin, 0.63 (0.47-0.79) for syndecan-1, 0.54 (0.37-0.70) for vascular adhesion protein 1 and 0.69 (0.54-0.85) for interleukin-6. Conclusions Systemic inflammation, reflected by interleukin-6, associates with cardiac troponin T release and perioperative myocardial infarction. Circulating interleukin-6 demonstrated some potential to predict perioperative myocardial infarction, whereas endothelial glycocalyx markers did not.