The Influence of Tacrolimus Exposure and Metabolism on the Outcomes of Kidney Transplants.

Tacrolimus (TAC) has a narrow therapeutic window and patient-specific pharmacokinetic variability. In our study, we analyzed the association between TAC exposure, metabolism, and kidney graft outcomes (function, rejection, and histological lesions). TAC trough (C0), coefficient of variation (TAC CV), concentration/dose ratio (C/D), and biomarkers related to kidney injury molecule-1 (KIM-1) and neutrophil gelatinase lipocalin (NGAL) were analyzed. We examined 174 patients who were subjected to a triple immunosuppressive regimen and underwent kidney transplantation between 2017 and 2022. Surveillance biopsies were performed at the time of kidney implantation and at three and twelve months after transplantation. We classified patients based on their Tac C/D ratios, classifying them as fast (C/D ratio < 1.05 ng/mL × 1/mg) or slow (C/D ratio ≥ 1.05 ng/mL × 1/mg) metabolizers. TAC exposure/metabolism did not significantly correlate with interstitial fibrosis/tubular atrophy (IF/TA) progression during the first year after kidney transplantation. TAC CV third tertile was associated with a higher chronicity score at one-year biopsy. TAC C/D ratio at three months and Tac C0 at six months were associated with rejection during the first year after transplantation. A fast TAC metabolism at six months was associated with reduced kidney graft function one year (OR: 2.141, 95% CI: 1.044-4.389, p = 0.038) and two years after transplantation (OR: 4.654, 95% CI: 1.197-18.097, p = 0.026), and TAC CV was associated with reduced eGFR at three years. uNGAL correlated with IF/TA and chronicity scores at three months and negatively correlated with TAC C0 and C/D at three months and one year. Conclusion: Calculating the C/D ratio at three and six months after transplantation may help to identify patients at risk of suffering acute rejection and deterioration of graft function.

Deceased Kidney Donor Biomarkers: Relationship between Delayed Kidney Function and Graft Function Three Years after Transplantation.

With an increasing number of marginal donors, additional methods for the evaluation of cadaveric kidney quality are required. This study aimed to evaluate pretransplant deceased donor serum (s) and urine (u) biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18, and C-X-C motif chemokine 10 (CXCL10) for predicting early and late graft function. In total, 43 deceased kidney donors and 76 corresponding recipients were enrolled. Delayed graft function (DGF) occurred in 27.6% of cases. sIL-18, sKIM-1, uNGAL, and uKIM-1 were predictors of DGF. A model incorporating sIL-18, uKIM-1, and clinical factors was developed to predict DGF (AUROC 0.863). Univariate analysis showed a negative association between uKIM and graft eGFR at 6, 12, 24, and 36 months, but this was not confirmed in the multivariate analysis. In conclusion, we report a superior performance of donor biomarkers for predicting DGF and later graft function over serum creatinine. Higher levels of donor sIL-18 and uKIM in conjunction with expanded-criteria donors and longer cold ischemia times predicted DGF. With no renal tubular damage in zero-time donor biopsies, higher pretransplant urine and serum NGAL levels were associated with better allograft function one year after transplantation, and sNGAL with graft function three years after transplantation.

Circulating Levels of IL-8 and MCP-1 in Healthy Adults: Changes after an Acute Aerobic Exercise and Association with Body Composition and Energy Metabolism.

The most recent WHO recommendations about physical activity emphasise the importance of total exercise volume above the significance of the duration of each bout. This study examined whether acute aerobic exercise changes circulating levels of IL-8 and MCP-1 and if these changes are associated with body composition and energy metabolism. Healthy adult volunteers completed a 10 min walking-running exercise on a treadmill. Indirect calorimetry was used to determine their resting metabolic rate (RMR) and energy expenditure (EE) during the exercise. Pre-exercise levels of IL-8 and MCP-1 were similar in both sexes. There were positive correlations of pre-exercise IL-8 with body mass, waist circumference, and lean body mass in men and pre-exercise MCP-1 with RMR in women. The exercise led to an increase in IL-8 of 68% and a decrease in MCP-1 of 74% of participants. An increase in post-exercise IL-8 in men was associated with greater walking EE and a greater increase in walking EE. The increase in post-exercise MCP-1 was associated with a lower RMR and running EE in women. There are both sex and individual variations in changes in chemokine secretion in response to the same exercise situation and their associations with values of metabolic parameters.

Cytokine Response Following SARS-CoV-2 Antigen Stimulation in Patients with Predominantly Antibody Deficiencies.

Predominantly antibody deficiencies (PADs) are inborn disorders characterized by immune dysregulation and increased susceptibility to infections. Response to vaccination, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may be impaired in these patients, and studies on responsiveness correlates, including cytokine signatures to antigen stimulation, are sparse. In this study, we aimed to describe the spike-specific cytokine response following whole-blood stimulation with SARS-CoV-2 spike peptides in patients with PAD (n = 16 with common variable immunodeficiency and n = 15 with selective IgA deficiency) and its relationship with the occurrence of coronavirus disease 2019 (COVID-19) during up to 10-month follow-up period. Spike-induced antibody and cytokine production was measured using ELISA (anti-spike IgG, IFN-γ) and xMAP technology (interleukin-1ß (IL-1ß), IL-4, IL-6, IL-10, IL-15, IL-17A, IL-21, TNF-α, TGF-ß1). No difference was found in the production of cytokines between patients with PAD and controls. Anti-spike IgG and cytokine levels did not predict contraction of COVID-19. The only cytokine that distinguished between vaccinated and naturally infected unvaccinated PAD patients was IFN-γ (median 0.64 (IQR = 1.08) in vaccinated vs. 0.10 (IQR = 0.28) in unvaccinated). This study describes the spike-specific cytokine response to SARS-CoV-2 antigens, which is not predictive of contracting COVID-19 during the follow-up.

Association of Body Mass Index, Blood Pressure, and Interictal Serum Levels of Cytokines in Migraine with and without Aura.

The aim of the study was to clarify correlations between body mass index (BMI), blood pressure (BP), and serum levels of cytokines in female migraine patients. A total of 14 migraineurs with aura, and 12 without aura during their interictal period were compared with 25 controls. Interleukin-8 (IL-8), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), matrix metalloproteinase-9 (MMP-9), interferon gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor alpha (TGF-α), and plasminogen activator inhibitor-1 (PAI-1) were measured. Migraineurs have elevated levels of IL-8, but decreased serum levels of PAI-1 and sICAM-1 during the interictal period, regardless of aura. BMI correlates with BP, and also with IFN-γ and MMP-9 only in patients with aura. There are three correlations in migraine patients with aura that are absent in patients without aura: between IL-8 and PAI-1; MMP-9 and IL-8; and IL-8 and sICAM-1. Migraineurs without aura, on the other hand, have correlations that patients with aura do not have (between PAI-1 and MCP-1, sICAM-1; between MMP-9 and sICAM-1, MCP-1; between TGF-α and PAI-1, MMP-9, sICAM-1; between sICAM-1 and MMP-9, PAI-1, MCP-1; as well as between sVCAM-1 and MCP-1). PAI-1, TGF, and MMP-9 could be used as biomarkers to distinguish migraineurs from healthy individuals.

Biomarker combinations in predicting sepsis in hospitalized children with fever.

Sepsis is among the leading causes of critical illness worldwide. It includes physiologic, pathologic, and biochemical abnormalities, induced by infection. Novel methods for recognizing a dysregulated inflammatory response and predicting associated mortality must be developed. Our aim was to investigate biomarkers that characterize a pro-inflammatory and anti-inflammatory response in patients with fever by comparing predictive validity for sepsis. 165 patients with fever were enrolled in this study, 55 of them had sepsis according to pSOFA criteria. All patients had blood samples drawn at the time of inclusion and after 24 h. CRP, PCT and also IL-6, IL-8 and sFAS levels were significantly higher in patients with sepsis. The AUC of CRP to predict sepsis was 0.799, all the other biomarkers had AUC's lower than that. Cytokines, when used as a single marker, did not show a significant diagnostic performance We analyzed various models of biomarker combinations. CRP combined with sFAS showed increase in sensitivity in predicting sepsis (88% vs. 83%). The highest AUC was achieved, when CRP, IL-6, sFAS and sVCAM-1 markers were combined 0.830 (95% CI 0.762-0.884) with a sensitivity of 70% and specificity of 84%. vs. 0.799 for CRP alone.

Thioredoxin-1 and Correlations of the Plasma Cytokines Regarding Aortic Valve Stenosis Severity.

Aortic valve stenosis (AS) develops not only with a pronounced local inflammatory response, but also oxidative stress is involved. The aim of this study was to evaluate the plasma levels of thioredoxin-1 (TRX1), myeloperoxidase (MPO), chemerin, growth differentiation factor 15 (GDF-15), angiopoietin-2 (Ang-2), vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2), fibroblast growth factor 21 (FGF-21), and metalloproteinase (MMP)-1, -3, and -9 in acquired AS patients as well as to clarify the correlations of TXR1 and the plasma inflammatory biomarkers regarding AS severity. AS patients were classified into three groups: 16 patients with mild AS stenosis, 19 with moderate and 11 with severe AS, and 30 subjects without AS were selected as a control group. AS patients had significantly higher plasma levels of TRX1 compared to controls, but the highest difference was found in mild AS patients compared to the controls. We conclude that AS is associated with significantly increased plasma TRX1 levels, and TRX1 might serve as a specific and sensitive biomarker of AS. TRX1 and also chemerin, GDF-15, VEGF-A, FGF-2 and FGF-21 significantly correlate with AS severity degrees. TRX1 also showed positive association with FGF-2, VEGF-A, and MMP-3 in all AS patients.

Prognostic Utility of Circulating Growth Factors in Aortic Valve Stenosis: A Pilot Study.

Background and Objectives: Aortic valve stenosis (AS) develops with a pronounced local inflammatory response, where a variety of growth factors are involved in the process, and may have a pro-inflammatory and anti-inflammatory effect. The aim of our study was to elucidate whether circulating growth factors: growth differentiation factor 15 (GDF-15), angiopoietin-2 (Ang-2), vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2), and fibroblast growth factor 21 (FGF-21) could be proposed as clinically relevant biomarkers to improve risk stratification in AS patients. Materials and Methods: AS patients were classified into three groups: 16 patients with mild AS stenosis; 19 with moderate and 11 with severe AS, and 30 subjects without AS (echocardiographically approved) were selected as a control group. GDF-15, Ang-2, VEGF-A, FGF-2, and FGF-21 were measured in plasma by the ELISA method. Results: GDF-15 levels differed significantly not only when comparing AS patients with control groups (p < 0.0001), but also a statistically significant difference was achieved when comparing AS patients at a mild degree stage with control individuals. We found a strong relationship of GDF-15 levels regarding AS severity degree (p < 0.0001). VEGF-A, FGF-2 and FGF-21 levels were significantly higher in AS patients than in controls, but relationships regarding the AS severity degree were weaker (p < 0.02). ROC analysis of the study growth factors showed that GDF-15 might serve as a specific and sensitive biomarker of AS stenosis (AUC = 0.75, p = 0.0002). FGF-21 correlated with GDF-15, Ang-2, and FGF-2, but it did not reach the level to serve as a clinically relevant biomarker of AS stenosis. Conclusions: AS is associated with significantly increased GDF-15, VEGF-A, FGF-2, and FGF-21 levels in plasma, but only GDF-15 shows a pronounced relationship regarding AS severity degree, and GDF-15 might serve as a specific and sensitive biomarker of AS stenosis.

Circulating Irisin in Healthy Adults: Changes after Acute Exercise, Correlation with Body Composition, and Energy Expenditure Parameters in Cross-Sectional Study.

Background and Objectives: Skeletal muscles are considered to be the main source of circulating irisin, both at rest and during physical activity. The aim of this study was to investigate the connection between irisin, body composition, and energy metabolism in humans. Materials and Methods: Serum irisin concentrations before and after acute aerobic exercise on a treadmill in 84 healthy adults were measured and their association with body composition and energy expenditure (EE) (obtained from indirect calorimetry) was determined. Results: The total pre-exercise irisin concentrations in males and females were similar, but higher in females when expressed per body mass kg (p < 0.001). There was an association between pre-exercise irisin per body mass kg, visceral fat rating (rho = -0.52, p = 0.001), and lean tissue % (rho = 0.41, p < 0.05) in males and lean body mass index (LBMI) (rho = -0.59, p < 0.001) in females. The pre-exercise irisin concentration correlated with the resting metabolic rate (RMR) in both sexes (rho = 0.44 in males, rho = 0.36 in females; p < 0.05), but with walking, running, and the EE difference from RMR in running (Δ running EE) in males only (rho = 0.32 to 0.37, p < 0.05). There was no significant change in irisin concentration after exercise in 58% of participants, while it decreased in 23%, and increased in 19%. In male subjects with no change in irisin concentration after exercise, running (p < 0.05) and Δ running EE per body mass kg (p < 0.05) were higher than in those with decreased irisin concentration. Conclusions: These findings indicate that the association of irisin concentration with body composition and EE parameters has sex-dependent differences, and acute exercise can lead to various changes in post-exercise irisin levels.

Angiopoietin 2 and Neuropeptide Y are Associated with Diabetic Kidney Disease in Type 1 Diabetes Mellitus.

BACKGROUND: Serum angiopoietin 2 levels have been associated with endothelial dysfunction and diabetic kidney disease. Derangements in autonomous nervous system lead to increased production of vasoconstrictory and angiogenic mediators such as norepinephrine and neuropeptide Y and are associated with increased risk of microvascular complications. AIM: To investigate associations between angiopoietin 2, neuropeptide Y and diabetic kidney disease in patients with type 1 diabetes mellitus. METHODS: 289 patients with type 1 diabetes mellitus duration > 1 year were included. Patients were stratified according to presence of diabetic nephropathy (macroalbuminuria, estimated glomerular filtration rate<60 ml/min/1.73 m2 or end-stage renal disease). Angiopoietin 2 was measured by Luminex technology. Neuropeptide Y was measured by ELISA. RESULTS: Patients with diabetic nephropathy had significantly increased levels of angiopoietin 2 (4020.5 (2172.4-5778.1) pg/ml vs. 2001.0 (1326.7-2862.7) pg/ml) and neuropeptide Y (18.22 (14.85-21.85) ng/ml vs. 12.91 (9.96-17.07) ng/ml). Higher levels of angiopoietin 2 and neuropeptide Y were observed also in patients with arterial hypertension. Angiopoietin 2 and neuropeptide Y correlated significantly (ρ=0.245, p<0.001). Both biomarkers were significant predictors of estimated glomerular filtration rate and diabetic nephropathy in univariate regression models. In the fully adjusted regression models and after application of a stepwise selection regression method, angiopoietin 2 demonstrated a stronger predictive power for diabetic nephropathy compared to neuropeptide Y. CONCLUSION: Diabetic nephropathy is associated with increased serum concentrations of angiopoietin 2 (marker of endothelial dysfunction) and neuropeptide Y (marker of sympathetic activity) in type 1 diabetes. Angiopoietin 2 is a more potent predictor of diabetic nephropathy compared to neuropeptide Y.

HDL-C Role in Acquired Aortic Valve Stenosis Patients and Its Relationship with Oxidative Stress.

Background and objectives: Mechanical stress is currently considered as the main factor promoting calcific aortic valve stenosis (AS) onset. It causes endothelial damage and dysfunction. The chronic inflammatory process causes oxidative stress. Oxidative stress-induced high-density lipoprotein cholesterol (HDL-C) dysfunction is an important component of the development of AS. The aim of the study was to evaluate the role of HDL-C in AS patients in three severity grades and in relation to the biomarkers of oxidative stress, thioredoxin reductase 1 (TrxR1) and myeloperoxidase (MPO). Materials and Methods: 18 patients with mild, 19 with moderate. and 15 with severe AS were included in the study, and 50 individuals were enrolled in the control group. Stenosis severity was determined by echocardiography. The TrxR1 and MPO were analyzed by ELISA, and HDL-C by commercially available tests. Data were analyzed using GraphPad Prism 8. Results: HDL-C in AS patients vs. control substantially decreases and this decline was observed in all three AS severity groups: mild (p = 0.018), moderate (p = 0.0002), and severe (p = 0.004). In both the control and the stenosis group, the HDL-C was higher in women than in men. In comparison to control, the HDL-C level was lower in the AS group, and more pronounced in women (p = 0.0001) than in men (p = 0.049). A higher TrxR1 level was observed in patients with mild (p = 0.0001) and severe AS (p = 0.047). However, a clear correlation between TrxR1 and HDL-C was not obtained. Analysis of MPO showed differences in all severity grades vs. control (p = 0.024 mild stenosis; p = 0.002 moderate stenosis; p = 0.0015 severe stenosis). A negative correlation (p = 0.047; rp = -0.28) was found between MPO and HDL-C, which confirms the adverse effects of MPO resulting in HDL-C dysfunction. Conclusions: In this study, we justified HDL-C level association with AS development process. The results unequivocally substantiated the association between HDL-C and AS in all severity grades in women, but only in moderate AS for men, which we explained by the small number of men in the groups. The obtained correlation between the HDL-C and MPO levels, as well as the concurrent decrease in the HDL-C level and increase in the TrxR1 level, indicate in general an HDL-C association with oxidative stress in AS patients.

Assessment of ADAMTS-13 Level in Hospitalized Children with Serious Bacterial Infections as a Possible Prognostic Marker.

Background and objectives: In children, acute infection is the most common cause of visits in the primary care or emergency department. In 2002, criteria for diagnostics of pediatric sepsis were published, and then revised in 2016 as "life-threatening organ dysfunction due to a dysregulated host response to infection". In the pathophysiology of sepsis endothelial dysfunction plays a very important role. Deficient proteolysis of von Willebrand factor, due to reduced ADAMTS-13 activity, results in disseminated platelet-rich thrombi in the microcirculation. ADAMTS-13 deficiency has been detected in systemic inflammation. The clinical relevance of ADAMTS-13 during sepsis is still unclear. We aimed to investigate the possible use of ADAMTS-13 as a prognostic marker in children with serious bacterial infection (SBI). Materials and Methods: Inclusion criteria were hospitalized children with SBI, aged from 1 month to 17 years. SBI was defined based on available clinical, imaging, and later also on microbiological data. Sepsis was diagnosed using criteria by The International Consensus Conference. In all the patients, the levels of ADAMTS-13 were measured at the time of inclusion. Results: Data from 71 patients were analyzed. A total of 47.9% (34) had sepsis, 21.1% (15) were admitted to the ICU, 8.5% (6) had mechanical ventilator support, and 4.2% (3) patients had a positive blood culture. The median level of ADAMTS-13 in this study population was 689.43 ng/mL. Patients with sepsis, patients admitted to the Intensive Care Unit, and patients in need of mechanical ventilator support had significantly lower levels of ADAMTS-13. None of the patients had ADAMTS-13 deficiency. In patients with SBI, the area under the curve (AUC) to predict sepsis was 0.67. A cut-off ADAMTS-13 level of ≤730.49 had 82% sensitivity and 60% specificity for sepsis in patients with SBI. Conclusions: ADATMS-13 levels were lower in patients with SBI and sepsis, but AUC and sensitivity were too low to accept it as a prognostic marker.

Impact of several proinflammatory and cell degradation factors in patients with aortic valve stenosis.

Aortic valve (AoV) stenosis is the third most common cardiovascular disease. The pathogenesis of AoV stenosis is associated with an inflammatory process where MMPs serve important roles. The aim of the present study was to determine the association between matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and inflammatory factors, and AoV stenosis at various degrees of severity compared with the control. A total of 18 patients with mild, 19 with moderate and 15 with severe AoV stenosis were included in the present stud, and 50 individuals were enrolled in the control group. The severity of stenosis was determined by echocardiography. The expression levels of chemerin, fibroblast growth factor 21, MMP-1, -3, and -9, and TIMP-1 and -3 were analyzed by ELISA. Data were analyzed using GraphPad Prism7 software. The expression levels of MMP-1 was increased in patients with stenosis compared with the control group (P=0.0043). Distribution of the trimodal MMP-1 values was obtained in the stenosis group and monomodal in the control group. A total of 80% of patients in the stenosis group presented significantly increased expression levels of MMP-1 compared with the control group (P=0.0002). Expression of MMP-1 was significantly higher in all stenosis groups compared with the control. The highest expression level of MMP-1 appeared in patients with moderate stenosis (P<0.0001). There was no significant difference in the expression of MMP-3, MMP-9 and TIMP-1 in the aortic stenosis group, compared with the control group. A positive correlation between MMP-1 and MMP-9 expression levels was identified (r=0.37; P=0.017). The increase of MMP-1 was correlated with the increase of MMP-9, but not with the level of MMP-3. The expression levels of chemerin was significantly elevated in patients with stenosis compared with healthy patients. The highest expression levels of chemerin were determined in patients with mild (P=0.0001) and moderate (P=0.0007) stenosis and decreased with the grade of severity compared with the control group. The expression of FGF-21 was significantly different between the control and mild (P=0.013), moderate (P=0.015) and severe stenosis (P=0.003) groups. The expression levels of FGF-21 increased with the increase in severity grade, reaching the maximum for severe stenosis. The results of the present study indicated that the inflammatory process is predominantly occurring at the early, mild stage of stenosis and the most prominent extracellular matrix remodeling occurs in moderate stenosis (demonstrated by MMP-1 levels). In patients with severe stenosis, the levels of MMP-1 and chemerin (which are lower than in a case of mild or moderate stenosis) could indicate the development of calcinosis and the reduction in activity or inactivation of the inflammatory process.

Inflammatory Cytokine and Chemokine Patterns in Paediatric Patients with Suspected Serious Bacterial Infection.

Background and objectives: In children, acute infection is the most common cause of visits to the emergency department. Although most of them are self-limiting, mortality due to severe bacterial infections (SBI) in developed countries is still high. When the risk of serious bacterial infection is too high to ignore, yet too low to justify admission and hospital observation, clinicians try to improve diagnostic accuracy by performing various laboratory tests. The aim of the study was to investigate whether an early inflammatory cytokine and chemokine panel can add information in diagnostics of SBI and assessment of efficacy of early therapies in hospitalized children with fever. Methods: This study included 51 children with febrile infections that were admitted to the emergency department (ED). Clinical examination and microbiological and radiological tests were used as reference standards for the definition of SBI. Study population was categorized into two groups: (1) patients with SBI (n = 21); (2) patients without SBI (n = 30). Inflammatory cytokine and chemokine panels were analyzed from the first routine blood samples at hospital admission and after 24 h. Results: Out of 12 cytokines and chemokines, only Eotaxin and granulocyte colony-stimulating factor (G-CSF) had statistically significant differences between groups at the time of inclusion. Receiver operator characteristic analysis to predict SBI showed an area under the curve (AUC) of 0.679 for G-CSF. Conclusions: Analysis of inflammatory cytokine profiles may provide additional information in early diagnostics of SBI.

Increased serum chemerin level to predict early onset of aortic valve stenosis.

Inflammation appears to be the cause of aortic valve (AoV) stenosis and identification of predictive biomarkers is therefore imperative. The aim of the current study was to evaluate the potential role of serum chemerin and fibroblast growth factor-21 (FGF-21) in the pathogenesis of the disease. A total of 102 patients were selected based on certain criteria and divided into an aortic stenosis group and a control group. Patients with AoV stenosis were subdivided into three groups depending on the severity according to the echocardiography criteria: Aortic jet velocity, Vmax (m/sec); mean pressure gradient, PG (mmHg); aortic valve area (AVA), cm2; and indexed AVA, cm2/m2. Patients were graded as: Severe: Vmax >4 m/sec, PG >40 mmHg, AVA <1.0 cm2, indexed AVA <0.6; moderate: Vmax 3.0-4.0 m/sec, PG 20-40 mmHg, AVA 1.0-1.5 cm2, indexed AVA 0.60-0.85; mild: Vmax 2.5-2.9 m/sec, PG <20 mmHg, AVA >1.5 cm2, indexed AVA >0.85. ELISA was used for the detection of chemerin and FGF-21. Post-hoc analysis with Tukey's correction was performed. The highest chemerin levels were found in mild and moderate AoV stenosis and decreased along with the grade of severity, compared with the control group. The FGF-21 level was increased in all the stenosis groups, reaching the highest level at severe stenosis. Receiver-operating characteristic analysis of chemerin in all the AoV stenosis groups without grading the severity included, area under the curve (AUC)=0.76; 0.70-0.80= fair; P<0.001 and for mild AoV stenosis was AUC=0.82; 0.80-0.90= good; P<0.001. In conclusion, chemerin is a good diagnostic biomarker for mild AoV stenosis, while FGF-21 is a moderate diagnostic marker.

Ectopic Adipose Tissue Storage in the Left and the Right Renal Sinus is Asymmetric and Associated With Serum Kidney Injury Molecule-1 and Fibroblast Growth Factor-21 Levels Increase.

OBJECTIVE: A potential mechanism by which obesity could promote hypertension and kidney diseases is through accumulation of adipose tissue in the renal sinus (RS). The aim of the study was to quantify RS and abdominal adipose tissue volumes and to evaluate serum kidney injury molecule (sKIM)-1 and fibroblast growth factor (FGF)-21 association with different adipose tissue compartments. METHODS: The cross-sectional study included 280 and follow-up study-40 asymptomatic participants; aged 38.30±4.10. For all study participants computed tomography examination was performed, sKIM-1 and FGF-21 levels were measured. RESULTS: The results indicated asymmetrical deposition of adipose tissue into the RS even after corresponding kidney volume adjustment. The cross-sectional and the follow-up studies showed that sKIM-1 level was positively associated with RS adipose tissue volume increase for both genders. FGF-21 was positively associated with RS and retroperitoneal adipose tissue amount. CONCLUSIONS: Regardless of gender adipose tissue in RS accumulates asymmetrically-the left RS accumulates a significantly higher amount of adipose tissue. Thus, primarily RS adipose tissue effects should be assessed on the left kidney. Accumulation of adipose tissue in the RS is related with the visceral adipose amount, KIM-1 and FGF-21 concentration increase in the blood serum.

Role of serum cytokines in acute appendicitis and acute mesenteric lymphadenitis among children.

BACKGROUND AND OBJECTIVE: The diagnostic role of serum cytokines depends on the etiology and pathogenesis of acute appendicitis (AA) and acute mesenteric lymphadenitis (AML). The aim of this study was to evaluate differences in cytokine levels between AA and AML. MATERIALS AND METHODS: Data of 7- to 18-year-old children were collected prospectively from October 2010 to October 2013. There were 31 patients with AA (AA group), 26 with AML (AML group), and 17 with elective non-inflammatory surgical disease (control group). Serum levels of IL-10, IL-12(p70), IL-1ß, IL-4, IL-6, IL-8, IL-17, MCP-1, EGF, TNF-α and white blood count (WBC) were measured three times consecutively in each group. RESULTS: The level of IL-6 and IL-10 was significantly higher in the AA group than the AML group at the first measurement (8pg/mL vs. 3.2pg/mL, P=0.000; 6.1pg/mL vs. 3.2pg/mL, P=0.005, respectively). There was a significant difference observed in time dynamics of concentration of IL-6 and MCP-1 for AA and AML. The area under the curve (AUC) was 0.77 (95% CI 0.64-0.89; P=0.001) for IL-6 with a cut-off value of 4.3pg/mL (67.7% sensitivity and 76.9% specificity) for AA 1h before surgery. The AUC for WBC was 0.72 (95% CI 0.58.4-0.85; P=0.005) with a cut-off value of 10.7×103/µL (sensitivity 71.0% and specificity 46.2%). CONCLUSIONS: Serum IL-6 with a cut-off value of 4.3pg/mL and WBC with a cut-off value of 10.7×103/µL assessed together will yield more sensitivity for AA.

Increase in IL-6, TNF-α, and MMP-9, but not sICAM-1, concentrations depends on exercise duration.

It has been suggested that exercise intensity is of importance in the regulation of increase in pro-inflammatory molecules, but there is still a debate about the effect of duration on these molecules. Therefore, the effect of exercise duration on the serum concentrations of interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), soluble form of intercellular adhesion molecule-1 (sICAM-1), and matrix metalloproteinase-9 (MMP-9) was studied in 22 half-marathon (HM) and 18 marathon (M) male amateur runners who completed their exercise task in 1.8 ± 0.2 (mean ± standard deviation) and 3.6 ± 0.4 h, respectively (thus, average speed was 11.7 ± 1.5 and 11.9 ± 1.8 km h(-1), respectively). Blood was sampled 2 days before, 15 min after, and 28 h after the race. IL-6, TNF-α, and MMP-9 always increased immediately after exercise, but the increase was larger (P < 0.05) in M versus HM (∆IL-6: 31 ± 24 vs. 5 ± 4 pg ml(-1); ∆TNF-α: 1.7 ± 1.9 vs. 0.5 ± 0.8 pg ml(-1); MMP-9: 288 ± 216 vs. 145 ± 128 ng ml(-1), respectively). sICAM-1 also increased with exercise, but similarly in M and HM (20 ± 40 vs. 23 ± 32 ng ml(-1), respectively). Only sICAM-1 remained elevated 28 h post-exercise in both HM and M, while IL-6, TNF-α, and MMP-9 returned to pre-exercise levels. Competitive HM and M races induce significant increases in IL-6, TNF-α, sICAM-1, and MMP-9 concentrations. As HM and M runners performed the competition with similar absolute intensity, the difference in response between the groups suggests that exercise duration is of importance in the regulation of IL-6, TNF-α, and MMP-9, but not sICAM-1 concentrations in response to prolonged running.

Circulating adhesion molecules, matrix metalloproteinase-9, plasminogen activator inhibitor-1, and myeloperoxidase in coronary artery disease patients with stable and unstable angina.

BACKGROUND: There are many pathophysiological mechanisms underlying reciprocal relationships between changes in cytokines and insulin resistance in metabolic and cardiovascular disorders. The aim of this study was to evaluate alterations in soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), matrix metalloproteinase-9 (MMP-9), plasminogen activator inhibitor-1 (PAI-1), and myeloperoxidase (MPO) levels, and their relation to insulin resistance in coronary artery disease (CAD) patients with stable and unstable angina (SAP, UAP). METHODS: Non-diabetic CAD patients were classified into two groups: 22 patients with SAP and 22 patients with UAP. 22 healthy subjects were selected as controls. The study groups were matched for age and sex. Insulin resistance was evaluated by HOMA-IR method. Serum levels of sICAM-1, sVCAM-1, sE-selectin PAI-1(total), MPO and MMP-9 were quantified by xMAP technology (Luminex-200 analyzer). RESULTS: Both patient groups demonstrated significantly elevated serum levels of sICAM-1, sE-selectin, PAI-1(total), MPO and MMP-9 (p<0.05) as well as higher IR-HOMA values (p<0.05) than those of healthy controls. The elevation was more pronounced in the UAP group (p<0.01). HOMA-IR was correlated with sICAM-1, PAI-1(total), and MMP-9 (p<0.01). CONCLUSION: Our findings show that CAD patients have elevated HOMA-IR values. Furthermore, CAD patients with UAP have higher levels of sICAM-1, sVCAM-1, sE-selectin, MMP-9, PAI-1(total), and MPO than patients with SAP, and there are relationships between three of the above biomarkers: sICAM-1, PAI-1(total), MMP-9 and HOMA-IR.

Relation of inflammatory chemokines to insulin resistance and hypoadiponectinemia in coronary artery disease patients.

BACKGROUND: Although many studies have shown that the metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) both are associated with chronic inflammatory state and are risk factors for coronary artery disease (CAD), it is still unclear which condition is a more important contributor to the increased production of inflammatory chemokines. The purpose of this study was to assess monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) levels and their association with insulin resistance and adiponectin concentrations in CAD patients, who were categorized as having T2DM, MS, or neither. METHODS: CAD male patients were categorized into three groups: 24 non-obese patients with T2DM (D), 24 obese patients with MS (M) and 24 patients without T2DM or MS (W). 20 healthy subjects were selected as controls (C). Insulin resistance was assessed by the HOMA-IR method, but serum MCP-1, IL-8, and adiponectin levels were measured by xMAP technology. RESULTS: Serum levels of MCP-1 and IL-8 in D and M groups were increased in comparison with W and C groups (p<0.001, p<0.01), but the increase in the M group was significantly higher than that in the D group (p<0.05, p<0,001), besides MCP-1 and IL-8 concentrations were correlated with HOMA-IR indexes (r=0.52; r=0.49, p<0.0001) and adiponectin levels (r=-0.59, p<0.0001). The M group demonstrated a diminution in the adiponectin level (p<0.01) and pronounced increase of HOMA-IR in comparison with the other three groups (p<0.01). CONCLUSION: Obese CAD patients with MS have a more pronounced increase of MCP-1, IL-8 and HOMA-IR and more decreased adiponectin levels than non-obese CAD patients without MS.