Browsing by Subject "PLASMA-LEVELS"

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  • Luoto, Teemu M.; Raj, Rahul; Posti, Jussi P.; Gardner, Andrew J.; Panenka, William J.; Iverson, Grant L. (2017)
    Background: The extensive use of computed tomography (CT) after acute head injury is costly and carries potential iatrogenic risk. This systematic review examined the usefulness of blood-based glial fibrillary acidic protein (GFAP) for predicting acute trauma-related CT-positive intracranial lesions following head trauma. The main objective was to summarize the current evidence on blood-based GFAP as a potential screening test for acute CT-positive intracranial lesions following head trauma. Methods: We screened MEDLINE, EMBASE, Psychlnfo, CINAHL, Web of Science, the Cochrane Database, Scopus, Clinical Trials, OpenGrey, ResearchGate, and the reference lists of eligible publications for original contributions published between January 1980 and January 2017. Eligibility criteria included: (i) population: human head and brain injuries of all severities and ages; (ii) intervention: blood -based GFAP measurement Results: The initial search identified 4,706 articles, with 51 eligible for subsequent full-text assessment. Twenty-seven articles were ultimately included. Twenty-four (89%) studies reported a positive association between GFAP level and acute trauma-related intracranial lesions on head CT. The area under the receiver operating characteristic curve for GFAP prediction of intracranial pathology ranged from 0.74 to 0.98 indicating good to excellent discrimination. GFAP seemed to discriminate mass lesions and diffuse injury, with mass lesions having significantly higher GFAP levels. There was considerable variability between the measured GFAP averages between studies and assays. No well-designed diagnostic studies with specific GFAP cutoff values predictive of acute traumatic intracranial lesions have been published. Conclusion: Intracranial CT-positive trauma lesions were associated with elevated GFAP levels in the majority of studies. Methodological heterogeneity in GFAP assessments and the lack of well-designed diagnostic studies with commercially validated GFAP platforms hinder the level of evidence, and variability in levels of GFAP with no clearly established cutoff for abnormality limit the clinical usefulness of the biomarker. However, blood based GFAP holds promise as a means of screening for acute traumatic CT-positive lesion following head trauma.
  • Posti, Jussi P.; Takala, Riikka S. K.; Raj, Rahul; Luoto, Teemu M.; Azurmendi, Leire; Lagerstedt, Linnea; Mohammadian, Mehrbod; Hossain, Iftakher; Gill, Jessica; Frantzen, Janek; van Gils, Mark; Hutchinson, Peter J.; Katila, Ari J.; Koivikko, Pia; Maanpää, Henna-Riikka; Menon, David K.; Newcombe, Virginia F.; Tallus, Jussi; Blennow, Kaj; Tenovuo, Olli; Zetterberg, Henrik; Sanchez, Jean-Charles (2020)
    Background: Blood biomarkers may enhance outcome prediction performance of head computed tomography scores in traumatic brain injury (TBI). Objective: To investigate whether admission levels of eight different protein biomarkers can improve the outcome prediction performance of the Helsinki computed tomography score (HCTS) without clinical covariates in TBI. Materials and methods: Eighty-two patients with computed tomography positive TBIs were included in this study. Plasma levels of beta-amyloid isoforms 1-40 (A beta 40) and 1-42 (A beta 42), glial fibrillary acidic protein, heart fatty acid-binding protein, interleukin 10 (IL-10), neurofilament light, S100 calcium-binding protein B, and total tau were measured within 24 h from admission. The patients were divided into favorable (Glasgow Outcome Scale-Extended 5-8, n = 49) and unfavorable (Glasgow Outcome Scale-Extended 1-4, n = 33) groups. The outcome was assessed 6-12 months after injury. An optimal predictive panel was investigated with the sensitivity set at 90-100%. Results: The HCTS alone yielded a sensitivity of 97.0% (95% CI: 90.9-100) and specificity of 22.4% (95% CI: 10.2-32.7) and partial area under the curve of the receiver operating characteristic of 2.5% (95% CI: 1.1-4.7), in discriminating patients with favorable and unfavorable outcomes. The threshold to detect a patient with unfavorable outcome was an HCTS > 1. The three best individually performing biomarkers in outcome prediction were A beta 40, A beta 42, and neurofilament light. The optimal panel included IL-10, A beta 40, and the HCTS reaching a partial area under the curve of the receiver operating characteristic of 3.4% (95% CI: 1.7-6.2) with a sensitivity of 90.9% (95% CI: 81.8-100) and specificity of 59.2% (95% CI: 40.8-69.4). Conclusion: Admission plasma levels of IL-10 and A beta 40 significantly improve the prognostication ability of the HCTS after TBI.
  • Hänninen, Mikko; Jäntti, Toni; Tolppanen, Heli; Segersvärd, Heli; Tarvasmäki, Tuukka; Lassus, Johan; Vausort, Melanie; Devaux, Yvan; Sionis, Alessandro; Tikkanen, Ilkka; Harjola, Veli-Pekka; Lakkisto, Päivi (2020)
    Cardiogenic shock (CS) is a life-threatening emergency. New biomarkers are needed in order to detect patients at greater risk of adverse outcome. Our aim was to assess the characteristics of miR-21-5p, miR-122-5p, and miR-320a-3p in CS and evaluate the value of their expression levels in risk prediction. Circulating levels of miR-21-5p, miR-122-5p, and miR-320a-3p were measured from serial plasma samples of 179 patients during the first 5-10 days after detection of CS, derived from the CardShock study. Acute coronary syndrome was the most common cause (80%) of CS. Baseline (0 h) levels of miR-21-5p, miR-122-5p, and miR-320a-3p were all significantly elevated in nonsurvivors compared to survivors (p <0.05 for all). Above median levels at 0h of each miRNA were each significantly associated with higher lactate and alanine aminotransferase levels and decreased glomerular filtration rates. After adjusting the multivariate regression analysis with established CS risk factors, miR-21-5p and miR-320a-3p levels above median at 0 h were independently associated with 90-day all-cause mortality (adjusted hazard ratio 1.8 (95% confidence interval 1.1-3.0), p = 0.018; adjusted hazard ratio 1.9 (95% confidence interval 1.2-3.2), p = 0.009, respectively). In conclusion, circulating plasma levels of miR-21-5p, miR-122-5p, and miR-320a-3p at baseline were all elevated in nonsurvivors of CS and associated with markers of hypoperfusion. Above median levels of miR-21-5p and miR-320a-3p at baseline appear to independently predict 90-day all-cause mortality. This indicates the potential of miRNAs as biomarkers for risk assessment in cardiogenic shock.
  • Vilander, Laura M.; Vaara, Suvi T.; Kaunisto, Mari A.; Pettilä, Ville; FINNAKI Study Grp; Laru-Sompa, Raili; Pulkkinen, Anni; Saarelainen, Minna; Reilama, Mikko; Tolmunen, Sinikka; Rantalainen, Ulla; Miettinen, Marja; Suvela, Markku; Pesola, Katrine; Saastamoinen, Pekka; Kauppinen, Sirpa; Kaukonen, Kirsi-Maija; Korhonen, Anna-Maija; Nisula, Sara; Vaara, Suvi; Suojaranta-Ylinen, Raili; Mildh, Leena; Haapio, Mikko; Nurminen, Laura; Sutinen, Sari; Pettilä, Leena; Laitinen, Helinä; Syrja, Heidi; Henttonen, Kirsi; Lappi, Elina; Boman, Hillevi; Varpula, Tero; Porkka, Päivi; Sivula, Mirka; Rahkonen, Mira; Tsurkka, Anne; Prittinen, Niina; Alaspaa, Ari; Salanto, Ville; Juntunen, Hanna; Sanisalo, Teija; Parviainen, Ilkka; Uusaro, Ari; Ruokonen, Esko; Bendel, Stepani; Rissanen, Niina; Lång, Maarit; Rahikainen, Sari; Rissanen, Saija; Ahonen, Merja; Halonen, Elina; Vaskelainen, Eija; Poukkanen, Meri; Lintula, Esa; Suominen, Sirpa; Heikkinen, Jorma; Lavander, Timo; Heinonen, Kirsi; Juopperi, Anne-Mari; Kaminski, Tadeusz; Gäddnäs, Fiia; Kuusela, Tuija; Roiko, Jane; Karlsson, Sari; Reinikainen, Matti; Surakka, Tero; Jyrkönen, Helena; Eiserbeck, Tanja; Kallinen, Jaana; Lund, Vesa; Tuominen, Päivi; Perkola, Pauliina; Tuominen, Riikka; Hietaranta, Marika; Johansson, Satu; Hovilehto, Seppo; Kirsi, Anne; Tiainen, Pekka; Myllärinen, Tuija; Leino, Pirjo; Toropainen, Anne; Kuitunen, Anne; Leppänen, Ilona; Levoranta, Markus; Hoppu, Sanna; Sauranen, Jukka; Tenhunen, Jyrki; Kukkurainen, Atte; Kortelainen, Samuli; Varila, Simo; Inkinen, Outi; Koivuviita, Niina; Kotamäki, Jutta; Laine, Anu; Ala-Kokko, Tero; Laurila, Jouko J.; Sälkiö, Sinikka; Koivisto, Simo-Pekka; Hautamäki, Raku; Skinnar, Maria (2019)
    Acute kidney injury (AKI) is a syndrome with high incidence among the critically ill. Because the clinical variables and currently used biomarkers have failed to predict the individual susceptibility to AKI, candidate gene variants for the trait have been studied. Studies about genetic predisposition to AKI have been mainly underpowered and of moderate quality. We report the association study of 27 genetic variants in a cohort of Finnish critically ill patients, focusing on the replication of associations detected with variants in genes related to inflammation, cell survival, or circulation. In this prospective, observational Finnish Acute Kidney Injury (FINNAKI) study, 2647 patients without chronic kidney disease were genotyped. We defined AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We compared severe AKI (Stages 2 and 3, n = 625) to controls (Stage 0, n = 1582). For genotyping we used iPLEX(TM) Assay (Agena Bioscience). We performed the association analyses with PLINK software, using an additive genetic model in logistic regression. Despite the numerous, although contradictory, studies about association between polymorphisms rs1800629 in TNFA and rs1800896 in IL10 and AKI, we found no association (odds ratios 1.06 (95% CI 0.89-1.28, p = 0.51) and 0.92 (95% CI 0.80-1.05, p = 0.20), respectively). Adjusting for confounders did not change the results. To conclude, we could not confirm the associations reported in previous studies in a cohort of critically ill patients.
  • Haapakoski, Rita; Mathieu, Julia; Ebmeier, Klaus P.; Alenius, Harri; Kivimaki, Mika (2015)
    Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and Psychlnfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d = 0.54, p <0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d = 0.47, p <0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-alpha levels and major depression (d = 0.40, p = 0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1 beta levels and major depression (d = -0.05, p = 0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-alpha, interleukin-1 beta and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression. (C) 2015 The Authors. Published by Elsevier Inc.
  • Pesonen, Eero; Passov, Arie; Andersson, Sture; Suojaranta, Raili; Niemi, Tomi; Raivio, Peter; Salmenperä, Markku; Schramko, Alexey (2019)
    Objective: Experimental inflammation induces degradation of glycocalyx. The authors hypothesized that inflammation is an important determinant of glycocalyx degradation in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Design: A prospective observational study. Setting: Operation theater and intensive care unit of a university hospital. Participants: Two separate prospective patient cohorts. Interventions: Blood samples were collected at 5 perioperative time points in the trial cohort (30 patients) and only preoperatively in the preoperative cohort (35 patients). Plasma syndecan-1 (biomarker of glycocalyx degradation), interleukin-6 (IL-6), IL-8, and IL-10 were measured. Measurements and Main Results: In the trial cohort, preoperative ranges were as follows: 0.8-198 ng/mL for syndecan-1; 0-902 pg/mL for IL-6; 0-314.9 pg/mL for IL-8, and 0-2,909 pg/mL for IL-10. Seven out of 30 patients were outliers in terms of plasma concentrations of syndecan-1 and all cytokines preoperatively. The increase of syndecan-1 was 2.7-fold, and those of IL-6 and IL-8 were both 2.5-fold. The increase of IL-10 was modest. Plasma syndecan-1 correlated with all cytokines preoperatively (IL-6: R = 0.66, p <0.001; IL-8: R = 0.67, p = 0.001; IL-10: R = 0.73, p <0.001) as well as at 6 hours postoperatively (IL-6: R = 0.49, p = 0.006; IL-8: R = 0.43, p = 0.02; IL-10: R = 0.41, p = 0.03) and on the postoperative morning (IL-6: R = 0.57, p = 0.001; IL-8: R = 0.37, p = 0.06; IL-10: R = 0.51, p = 0.005) but not intraoperatively. The preoperative findings of the trial cohort could be confirmed in the preoperative cohort. Conclusions: In patients undergoing cardiac surgery with CPB, inflammation in terms of proinflammatory cytokines IL-6 and IL-8 and anti-inflammatory cytokine IL-10 is associated with glycocalyx degradation measured as plasma syndecan-1 concentrations. (C) 2018 Elsevier Inc. All rights reserved.
  • Nguyen, SD; Korhonen, EA; Lorey, MB; Hakanpaa, L; Mayranpaa, MI; Kovanen, PT; Saharinen, P; Alitalo, K; Oorni, K (2021)
    Background and aims: Secretory phospholipase A(2) (PLA(2)) hydrolyzes LDL phospholipids generating modified LDL particles (PLA(2)-LDL) with increased atherogenic properties. Exocytosis of Weibel-Palade bodies (WPB) releases angiopoietin 2 (Ang2) and externalizes P-selectin, which both play important roles in vascular inflammation. Here, we investigated the effects of PLA(2)-LDL on exocytosis of WPBs. Methods: Human coronary artery endothelial cells (HCAECs) were stimulated with PLA(2)-LDL, and its uptake and effect on Ang2 release, leukocyte adhesion, and intracellular calcium levels were measured. The effects of PLA(2)-LDL on Ang2 release and WPB exocytosis were measured in and ex vivo in mice. Results: Exposure of HCAECs to PLA(2)-LDL triggered Ang2 secretion and promoted leukocyte-HCAEC interaction. Lysophosphatidylcholine was identified as a critical component of PLA(2)-LDL regulating the WPB exocytosis, which was mediated by cell-surface proteoglycans, phospholipase C, intracellular calcium, and cytoskeletal remodeling. PLA(2)-LDL also induced murine endothelial WPB exocytosis in blood vessels in and ex vivo, as evidenced by secretion of Ang2 in vivo, P-selectin translocation to plasma membrane in intact endothelial cells in thoracic artery and tracheal vessels, and reduced Ang2 staining in tracheal endothelial cells. Finally, in contrast to normal human coronary arteries, in which Ang2 was present only in the endothelial layer, at sites of advanced atherosclerotic lesions, Ang2 was detected also in the intima, media, and adventitia. Conclusions: Our studies reveal PLA(2)-LDL as a potent agonist of endothelial WPB exocytosis, resulting in increased secretion of Ang2 and translocation of P-selectin. The results provide mechanistic insight into PLA(2)-LDL-dependent promotion of vascular inflammation and atherosclerosis.
  • Kormi, Immi; Nieminen, Mikko T.; Havulinna, Aki S.; Zeller, Tanja; Blankenberg, Stefan; Tervahartiala, Taina; Sorsa, Timo; Salomaa, Veikko; Pussinen, Pirkko J. (2017)
    Background Extracellular matrix degrading proteases and their regulators play an important role in atherogenesis and subsequent plaque rupture leading to acute cardiovascular manifestations. Design and methods In this prospective cohort study, we investigated the prognostic value of circulating matrix metalloproteinase-8, tissue inhibitor of matrix metalloproteinase-1 concentrations, the ratio of matrix metalloproteinase-8/ tissue inhibitor of matrix metalloproteinase-1 and, for comparison, myeloperoxidase and C-reactive protein concentrations for incident cardiovascular disease endpoints. The population-based FINRISK97 cohort comprised 7928 persons without cardiovascular disease at baseline. The baseline survey included a clinical examination and blood sampling. During a 13-year follow-up the endpoints were ascertained through national healthcare registers. The associations of measured biomarkers with the endpoints, including cardiovascular disease event, coronary artery disease, acute myocardial infarction, stroke and all-cause death, were analysed using Cox regression models. Discrimination and reclassification models were used to evaluate the clinical implications of the biomarkers. Results Serum tissue inhibitor of matrix metalloproteinase-1 and C-reactive protein concentrations were associated significantly with increased risk for all studied endpoints. Additionally, matrix metalloproteinase-8 concentration was associated with the risk for a coronary artery disease event, myocardial infarction and death, and myeloperoxidase concentration with the risk for cardiovascular disease events, stroke and death. The only significant association for the matrix metalloproteinase-8/ tissue inhibitor of matrix metalloproteinase-1 ratio was observed with the risk for myocardial infarction. Adding tissue inhibitor of matrix metalloproteinase-1 to the established risk profile improved risk discrimination of myocardial infarction (p=0.039) and death (0.001). Both matrix metalloproteinase-8 (5.2%, p <0.001) and tissue inhibitor of matrix metalloproteinase-1 (12.9%, p <0.001) provided significant clinical net reclassification improvement for death. Conclusions Serum matrix metalloproteinase-8 and tissue inhibitor of matrix metalloproteinase-1 can be considered as biomarkers of incident cardiovascular disease events and death.
  • Lähteenmäki, Jaakko; Vuorinen, Anna-Leena; Pajula, Juha; Harno, Kari; Lehto, Mika; Niemi, Mikko; Gils, Mark van (2021)
    This study aimed to analyze associations between genetic variants and the occurrence of clinical outcomes in dabigatran, apixaban, and rivaroxaban users. This was a retrospective real-world study linking genotype data of three Finnish biobanks with national register data on drug dispensations and healthcare encounters. We investigated several single-nucleotide variants (SNVs) in the ABCG2, ABCB1, CES1, and CYP3A5 genes potentially associated with bleeding or thromboembolic events in direct oral anticoagulant (DOAC) users based on earlier research. We used Cox regression models to compare the incidence of clinical outcomes between carriers and noncarriers of the SNVs or haplotypes. In total, 1,806 patients on apixaban, dabigatran, or rivaroxaban were studied. The ABCB1 c.3435C>T (p.Ile1145=, rs1045642) SNV (hazard ratio (HR) 0.42, 95% confidence interval (CI), 0.18-0.98, P = 0.044) and 1236T-2677T-3435T (rs1128503-rs2032582-rs1045642) haplotype (HR 0.44, 95% CI, 0.20-0.95, P = 0.036) were associated with a reduced risk for thromboembolic outcomes, and the 1236C-2677G-3435C (HR 2.55, 95% CI, 1.03-6.36, P = 0.044) and 1236T-2677G-3435C (HR 5.88, 95% CI, 2.35-14.72, P < 0.001) haplotypes with an increased risk for thromboembolic outcomes in rivaroxaban users. The ABCB1 c.2482-2236G>A (rs4148738) SNV associated with a lower risk for bleeding events (HR 0.37, 95% CI, 0.16-0.89, P = 0.025) in apixaban users. ABCB1 variants are potential factors affecting thromboembolic events in rivaroxaban users and bleeding events in apixaban users. Studies with larger numbers of patients are warranted for comprehensive assessment of the pharmacogenetic associations of DOACs and their relevance for clinical practice.
  • Baker, Jason V.; Sharma, Shweta; Grund, Birgit; Rupert, Adam; Metcalf, Julia A.; Schechter, Mauro; Munderi, Paula; Aho, Inka; Emery, Sean; Babiker, Abdel; Phillips, Andrew; Lundgren, Jens D.; Neaton, James D.; Lane, H. Clifford; INSIGHT START Strategic Timing (2017)
    Background. The Strategic Timing of AntiRetroviral Treatment (START) trial demonstrated that immediate (at CD4+ > 500 cells/mu L) vs deferred (to CD4+ Methods. Biomarkers were measured from stored plasma prior to randomization and at month 8. Associations of baseline biomarkers with event risk were estimated with Cox regression, pooled across groups, adjusted for age, gender, and treatment group, and stratified by region. Mean changes over 8 months were estimated and compared between the immediate and deferred ART arms using analysis of covariance models, adjusted for levels at entry. Results. Baseline biomarker levels were available for 4299 START participants (92%). Mean follow-up was 3.2 years. Higher levels of IL-6 and D-dimer were the only biomarkers associated with risk for AIDS, SNA or death, as well as the individual components of SNA and AIDS events (HRs ranged 1.37-1.41 per 2-fold higher level), even after adjustment for baseline CD4+ count, HIV RNA level, and other biomarkers. At month 8, biomarker levels were lower in the immediate arm by 12%-21%. Conclusions. These data, combined with evidence from prior biomarker studies, demonstrate that IL-6 and D-dimer consistently predict clinical risk across a broad spectrum of CD4 counts for those both ART-naive and treated. Research is needed to identify disease-modifying treatments that target inflammation beyond the effects of ART.
  • Hemilä, Harri; Chalker, Elizabeth; de Man, Angelique M. E. (2022)
    Background: Vitamin C deprivation can lead to fatigue, dyspnea, oedema and chest pain, which are also symptoms of heart failure (HF). In animal studies vitamin C has improved contractility and mechanical efficiency of the heart. Compared with healthy people, patients with HF have lower vitamin C levels, which are not explained by differences in dietary intake levels, and more severe HF seems to be associated with lower plasma vitamin C levels. This meta-analysis looks at the effect of vitamin C on left ventricular ejection fraction (LVEF).Methods: We searched for trials reporting the effects of vitamin C on LVEF. We assessed the quality of the trials, and pooled selected trials using the inverse variance, fixed effect options. We used meta-regression to examine the association between the effect of vitamin C on LVEF level and the baseline LVEF level.Results: We identified 15 trials, three of which were excluded from our meta-analysis. In six cardiac trials with 246 patients, vitamin C increased LVEF on average by 12.0% (95% CI 8.1-15.9%; P < 0.001). In six non-cardiac trials including 177 participants, vitamin C increased LVEF on average by 5.3% (95% CI 2.0-8.5%; P = 0.001). In meta-regression analysis we found that the effect of vitamin C was larger in trials with the lowest baseline LVEF levels with P = 0.001 for the test of slope. The meta-regression line crossed the null effect level at a baseline LVEF level close to 70%, with progressively greater benefit from vitamin C with lower LVEF levels. Some of the included trials had methodological limitations. In a sensitivity analysis including only the four most methodologically sound cardiac trials, the effect of vitamin C was not substantially changed.Conclusions: In this meta-analysis, vitamin C increased LVEF in both cardiac and non-cardiac patients, with a strong negative association between the size of the vitamin C effect and the baseline LVEF. Further research on vitamin C and HF should be carried out, particularly in patients who have low LVEF together with low vitamin C intake or low plasma levels. Different dosages and different routes of administration should be compared.