Increased platelet content of SDF-1alpha is associated with worse prognosis in patients with pulmonary prterial hypertension.

Inflammatory processes and platelet activity play an important role in the pathophysiology of pulmonary arterial hypertension (PAH). Enhanced IL-6 signaling and higher concentration of stromal-derived factor alpha (SDF-1) have been previously shown to be linked with prognosis in PAH. We hypothesized that platelets of PAH patients have higher content of IL-6 and SDF-1 and thus are involved in disease progression. We enrolled into study 22 PAH patients and 18 healthy controls. Patients with PAH presented significantly higher plasma concentrations and platelet contents of IL-6, sIL-6R, and SDF-1 than healthy subjects (platelet content normalized to protein concentration: IL-6 (0.85*10-10 [0.29 - 1.37] vs. 0.45*10-10 [0.19-0.65], sIL-6R 1.54*10-7 [1.32-2.21] vs. 1.14*10-7 [1.01-1.28] and SDF-1 (2.72*10-7 [1.85-3.23] vs. 1.70*10-7 [1.43-2.60], all p < 0.05). Patients with disease progression (death, WHO class worsening, or therapy escalation, n = 10) had a significantly higher platelet SDF-1/total platelet protein ratio (3.68*10-7 [2.45-4.62] vs. 1.69*10-7 [1.04-2.28], p = 0.001), with no significant differences between plasma levels. Kaplan-Meier analysis revealed that patients with higher platelet SDF-1/total platelet protein ratio had more frequently deterioration of PAH in the follow-up (15.24 ± 4.26 months, log-rank test, p = 0.01). Concentrations of IL-6, sIL-6 receptor and SDF-1 in plasma and platelets are elevated in PAH patients. Higher content of SDF-1 in platelets is associated with poorer prognosis. Our study, despite of limitation due to small number of enrolled patients, suggests that activated platelets may be an important source of cytokines at the site of endothelial injury, but their exact role in the pathogenesis of PAH requires further investigation.

The significance of diminished sTWEAK and P-selectin content in platelets of patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by proliferative changes in pulmonary arteries. There is growing evidence suggesting that soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and P-selectin could be involved in PAH development and progression. Here we investigate whether circulating platelets may be a source of sTWEAK and contribute to diminished availability of sTWEAK and P-selectin in PAH patients. We have prospectively enrolled two independent study groups of stable patients with confirmed PAH and age matched controls: derivation (10 PAH; 15 controls) and validation (20 PAH; 12 controls). P-selectin and sTWEAK concentrations were measured in platelet-poor plasma and platelet lysate. To avoid procedural bias, in each group we employed different protocols for platelet isolation. Consistently, both in derivation and validation groups PAH patients presented significantly lower sTWEAK content in platelets than control group with no significant differences in plasma levels. Similarly, patients presented comparable to controls plasma P-selectin concentrations and lower concentration in platelet lysate. Kaplan-Meier analysis revealed that patients with low platelet sTWEAK/total protein concentration ratio had more frequently detoriation of PAH in the follow-up (16.51 ±â€¯3.32 months), log-rank test, p = .03. Patients diagnosed with pulmonary arterial hypertension present diminished sTWEAK and P-selectin storage capacity in platelets. Thrombocytes appear to be a major source of sTWEAK that could be released upon local injury and its decreased availability could have an impact on pathophysiology and prognosis in PAH.

Alterations of soluble TWEAK and CD163 concentrations in patients with chronic heart failure.

UNLABELLED: Inflammatory activation plays a pivotal role in chronic heart failure with reduced ejection fraction (HF-REF). A novel mediator from TNF family: soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) along its soluble decoy receptor CD163 (sCD163) recently has been investigated in other cardiovascular pathologies. We aimed to evaluate sTWEAK and sCD163 concentrations in HF-REF patients. The study enrolled 79 patients with stable HF-REF, EF < 35%. The control population without history of heart failure included two groups: 26 comorbidities matched patients and 27 healthy volunteers. sTWEAK and sCD163 serum concentrations were determined using ELISA kits. Univariate and multivariate analysis was performed to assess variables affecting concentration of sTWEAK and sCD163. HF-REF patients were characterized by higher sTWEAK (median 374 IQR: 321-429 vs 201 IQR: 145-412pg/ml, P=0.005), sCD163 (median 744 IQR: 570-1068 vs 584 IQR: 483-665pg/ml, P=0.03) concentrations and sTWEAK/sCD163 ratio (median 0.53 IQR: 0.32-0.7 vs 0.3 IQR: 0.22-0.37, P=0.001) comparing to healthy volunteers. Comparing to comorbidities matched controls, HF-REF patients had lower sTWEAK levels (median 374 IQR: 321-429 vs 524 IQR: 384-652pg/ml; P=0.002), while sCD163 and sTWEAK/sCD163 ratio didn't differ. Concentration of sTWEAK in HF-REF was affected by white blood cell count and aspirin intake, while sCD163 by exercise capacity, LV diastolic volume, CRP and presence of arterial hypertension. CONCLUSIONS: HF-REF patients present increased sTWEAK and sCD163 levels as well as sTWEAK/sCD163 ratio when compared to healthy subjects, however CHF itself appears to be associated with down-regulation of sTWEAK.

Enhanced IL-6 trans-signaling in pulmonary arterial hypertension and its potential role in disease-related systemic damage.

BACKGROUND: The role of IL-6 in pulmonary arterial hypertension (PAH) has been reported but the prevalence of soluble receptors for IL-6: sIL-6R and sgp130 and its potential role in PAH have not been studied.Our aim was to examine the IL-6 together with the soluble receptors and to assess its relationship with clinical status of PAH patients as well as to assess its potential prognostic significance. METHODS: Serum concentrations of IL-6, sIL-6R and sgp130 were quantified by ELISA in 26 patients with PAH and 27 healthy controls and related to functional and biochemical parameters and clinical outcome in PAH group. The PAH patients were followed up for 1 year, noting the end point of clinical deterioration (WHO class change, the need for escalation of therapy) or death. RESULTS: The PAH group was characterized by higher median serum IL-6 [2.38 (IQR 1.56-3.75) vs 0.87 (0.63-1.3) pg/ml, p=0.000003] and sIL-6R concentrations [69.7 (IQR 60.4-84.4 vs 45.7 (34.6-70.3) ng/ml, p=0.0036] compared to control subjects. Both groups did not differ in sgp130 concentrations. There were significant correlations in PAH group between IL-6 levels and uric acid, parameters of ventilatory efficiency in cardiopulmonary exercise testing: VE/VO2, VE/VCO2, VE/VCO2 slope and peak PetCO2. sIL-6R levels inversely correlated with LDL cholesterol. After 1 year the clinical deterioration occurred in 11 patients, 15 remained stable. Patients in whom the clinical deterioration occurred showed significantly higher baseline concentrations of IL-6 [3.25 (IQR 2.46-5.4) pg/ml vs 1.68 (1.38-2.78) pg/ml, p=0.004], but not sIL-6R. Median IL-6 ⩾ 2.3 pg/ml (91% sensitivity, 73% specificity) identified subjects with worse clinical course. In the univariate analysis, higher IL-6 level at baseline was associated with increased risk and earlier occurrence of clinical deterioration (HR 1.42, 95%CI 1.08-1.85, p=0.015). CONCLUSIONS: IL-6 trans-signaling is enhanced in PAH. Elevated concentration of sIL-6R suggests its potential unfavorable role in systemic amplification of IL-6 signaling in PAH. Levels of IL-6 are associated with clinical indicators of disease severity as well as indirectly with systemic metabolic alterations. IL-6 shows prognostic value regarding predicting clinical deterioration.

Serum levels of CD163 and TWEAK in patients with pulmonary arterial hypertension.

BACKGROUND: Inflammation may play a pivotal role in the pathogenesis of pulmonary arterial hypertension (PAH). We evaluated the concentrations of serum sTWEAK, its scavenger receptor sCD163 and sTWEAK/sCD163 ratio in patients with PAH. DESIGN: The study enrolled 26 stable patients with PAH confirmed by right heart catheterization and 24 healthy volunteers matched for age, sex and body weight. All patients underwent transthoracic echocardiography, cardiopulmonary exercise test, 6-min walk test, measurement of lung diffusing capacity for the carbon monoxide (DLCO) and venous blood tests. Concentrations of sTWEAK and sCD163 were determined using ELISA kits. RESULTS: The PAH patients were characterized by significantly higher median serum sCD163 levels (1072 vs 890ng/ml, p=0.04) together with lower serum sTWEAK concentrations (200 vs 278.1pg/ml, p=0.003) comparing to control subjects. sTWEAK/sCD163 ratio was therefore significantly lower in PAH group (0.18 vs 0.33, p=0.0005). No correlation was found between sTWEAK and sCD163 concentrations in both groups. We observed statistically significant inverse correlation between peak VO2 consumption and sCD163 concentrations (r=-0.52, p<0.05) and positive with sTWEAK/sCD163 ratio (r=0.45, p<0.05) in PAH group. Moreover, sTWEAK/sCD163 ratio positively correlated with % of predicted values of DLCO (r=0.42, p<0.05). CONCLUSIONS: Patients with PAH present altered serum sTWEAK and sCD163 levels. The sTWEAK/sCD163 ratio appears to be a better indicator of the severity of PAH as compared to sTWEAK or sCD163 alone. The exact role of sCD163 or interaction between CD163 and sTWEAK in the initiation or progression of PAH as well as their potential prognostic significance remains to be established.

Validation of Becton Dickinson Barricor™ tubes for use with Abbott Alinity™ and Siemens Atellica® highly sensitive cardiac troponin I measuring systems.

BACKGROUND: BD Barricor™ tubes have been proposed to decrease laboratory turnaround time (TAT). We analytically validated and then clinically verified these tubes for use with Abbott Alinity™ and Siemens Atellica® highly sensitive cardiac troponin I (hs-cTnI) assays. METHODS: hs-cTnI measurements were undertaken in paired Barricor™ and in-use PSTII™ tubes on both systems. 359 matched samples with hs-cTnI levels between 3 and 15,000 ng/L (Atellica® values) were used to assess the hemolysis rate and make method comparisons. 599 paired patient samples were collected on emergency department (ED) admission to compare the performance of the rapid acute myocardial infarction (AMI) rule-out strategy based on hs-cTnI concentrations lower than recommended thresholds (<4 ng/L Alinity™; <5 ng/L Atellica®) when different tubes and systems were employed. RESULTS: No between-tube differences in hemolysis rate were seen when free hemoglobin concentrations in plasma samples were ≥0.25 g/L, even if PSTII™ showed a significant increase of hemolysis rate vs. Barricor™ (31% vs. 22%, p=0.007) when a lower cut-off for hemolysis (≥0.11 g/L) was employed on the Atellica® detection system. The alternate use of these tubes did not influence the hs-cTnI results obtained from either of the two assays, which remained markedly biased (~40%) irrespective of the tube used. The expected optimal ability of very low hs-cTnI values on ED admission for ruling out AMI was confirmed by using both systems regardless of the tube type. CONCLUSIONS: Barricor™ and PSTII™ tubes can provide analytically equivalent hs-cTnI results when used on either Alinity™ or Atellica® hs-cTnI assays.

Observational analysiS of out-of-hospital Cardiac Arrest occurRence and temporal variability patterns in subpopulation of southern POLand from 2006 to 2018: OSCAR-POL registry.

BACKGROUND: Temporal variability of out-of-hospital cardiac arrest (OHCA) occurrence was presented in previous studies, however, the data regarding long-term observation is scarce. The aim of this study was to investigate the temporal variability of OHCA occurrence during a long-time period and analyze the circadian pattern within particular timeframes. METHODS: The retrospective analysis of 5058 OHCA cases was made covering the period from January 1st, 2006 to December 31st, 2018. Circadian, weekly, monthly and seasonal variabilities were investigated. The circadian variability of OHCA occurrence was assessed within particular years, seasons of the year, and days of the week. RESULTS: The highest OHCA incidence was observed between 08:00 and 08:59 and the lowest between 01:00 and 01:59 (7.1% vs. 1.6%, p < 0.001). After division into 6-h intervals, a significantly lower number of OHCA cases occurred between 00:00 and 05:59 (12.3%) in comparison to the highest number observed in between 06:00 and 11:59 (12.3% vs. 33.5%, p < 0.001). The highest OHCA occurrence was observed on Monday (14.9%), however, no weekly variability was found (p = 0.557). The highest OHCA occurrence was observed in the winter and lowest in the summer (27.4% vs. 22.8%, p < 0.001). Significant circadian variability was observed for every day of the week, every season and year during the observation period (p < 0.001). CONCLUSIONS: Circadian, monthly and seasonal variability of OHCA occurrence was confirmed in the long-term observation with no differences between particular days of the week. Significant circadian variability was observed within days of the week, seasons of the year, and particular years.

Elevated serum transaminases in patients with acute coronary syndromes: Do we need a revision of exclusion criteria for clinical trials?

BACKGROUND: Elevations of hepatic transaminase (serum alanine transaminase [ALT] and serum aspartate aminotransferase [AST]) levels in patients with acute coronary syndrome (ACS), although transient, may result in exclusions from clinical efficacy trials due to suspected liver disease. The aim of this study was to evaluate the concentrations of serum transaminases in ACS and relate these to currently accepted AST/ALT exclusion criteria from clinical trials. METHODS: One hundred consecutive patients with ACS were prospectively examined. Blood samples for AST, ALT, total bilirubin and troponin I concentration were obtained at the time of admission and after 6, 12 and 24 hours. RESULTS: Eighty percent of patients had elevated AST, and 47% ALT; 43% of patients characterized AST concentration > 3 × upper limit of normal (ULN) in at least one measurement, while 8% of patients presented ALT concentration > 3 × ULN. AST presented higher concentrations when compared to ALT, resulting in a high De-Ritis ratio at every time point. No significant or high correlations were found between the concentrations of serum transaminases, De-Ritis ratio and troponin I. Two different cut-off values of troponin I were adopted to define the amount of infarcted myocardium that distinguished 28-31% of individuals with "large infarction". Among these patients, approximately 93% presented AST concentrations > 3 × ULN. CONCLUSIONS: Hepatic transaminases are often elevated in ACS, with the majority of patients with more extensive myocardial injury presenting high concentrations of AST. In the setting of ACS, current transaminase thresholds for liver dysfunction used in clinical trials may lead to excessive and inadequate exclusions of patients with larger infarcts from such trials.

Effects of Multidisciplinary Rehabilitation Program in Patients with Long COVID-19: Post-COVID-19 Rehabilitation (PCR SIRIO 8) Study.

Up to 80% of COVID-19 survivors experience prolonged symptoms known as long COVID-19. The aim of this study was to evaluate the effects of a multidisciplinary rehabilitation program in patients with long COVID-19. The rehabilitation program was composed of physical training (aerobic, resistance, and breathing exercises), education, and group psychotherapy. After 6 weeks of rehabilitation in 97 patients with long COVID-19, body composition analysis revealed a significant decrease of abdominal fatty tissue (from 2.75 kg to 2.5 kg; p = 0.0086) with concomitant increase in skeletal muscle mass (from 23.2 kg to 24.2 kg; p = 0.0104). Almost 80% of participants reported dyspnea improvement assessed with the modified Medical Research Council scale. Patients' physical capacity assessed with the 6 Minute Walking Test increased from 320 to 382.5 m (p < 0.0001), the number of repetitions in the 30 s Chair Stand Test improved from 13 to 16 (p < 0.0001), as well as physical fitness in the Short Physical Performance Battery Test from 14 to 16 (p < 0.0001). The impact of fatigue on everyday functioning was reduced in the Modified Fatigue Impact Scale from 37 to 27 (p < 0.0001). Cardiopulmonary exercise test did not show any change. The multidisciplinary rehabilitation program has improved body composition, dyspnea, fatigue and physical capacity in long COVID-19 patients.

Clinical Characteristics and Predictors of In-Hospital Mortality of Patients Hospitalized with COVID-19 Infection.

Background: The identification of parameters that would serve as predictors of prognosis in COVID-19 patients is very important. In this study, we assessed independent factors of in-hospital mortality of COVID-19 patients during the second wave of the pandemic. Material and methods: The study group consisted of patients admitted to two hospitals and diagnosed with COVID-19 between October 2020 and May 2021. Clinical and demographic features, the presence of comorbidities, laboratory parameters, and radiological findings at admission were recorded. The relationship of these parameters with in-hospital mortality was evaluated. Results: A total of 1040 COVID-19 patients (553 men and 487 women) qualified for the study. The in-hospital mortality rate was 26% across all patients. In multiple logistic regression analysis, age ≥ 70 years with OR = 7.8 (95% CI 3.17−19.32), p < 0.001, saturation at admission without oxygen ≤ 87% with OR = 3.6 (95% CI 1.49−8.64), p = 0.004, the presence of typical COVID-19-related lung abnormalities visualized in chest computed tomography ≥40% with OR = 2.5 (95% CI 1.05−6.23), p = 0.037, and a concomitant diagnosis of coronary artery disease with OR = 3.5 (95% CI 1.38−9.10), p = 0.009 were evaluated as independent risk factors for in-hospital mortality. Conclusion: The relationship between clinical and laboratory markers, as well as the advancement of lung involvement by typical COVID-19-related abnormalities in computed tomography of the chest, and mortality is very important for the prognosis of these patients and the determination of treatment strategies during the COVID-19 pandemic.

Ion channel inhibition with amiodarone or verapamil in symptomatic hospitalized nonintensive-care COVID-19 patients: The ReCOVery-SIRIO randomized trial.

BACKGROUND: Ion channel inhibition may offer protection against coronavirus disease 2019 (COVID-19). Inflammation and reduced platelet count occur during COVID-19 but precise quantification of risk thresholds is unclear. The Recov ery-SIRIO study aimed to assess clinical effects of amiodarone and verapamil and to relate patient phenotypes to outcomes. METHODS: RECOVERY-SIRIO is a multicenter open-label 1:1:1 investigator-initiated randomized trial with blinded event adjudication. A sample of 804 symptomatic hospitalized nonintensive-care COVID-19 patients, follow-up for 28 days was initially planned. RESULTS: The trial was stopped when a total of 215 patients had been randomized to amiodarone (n = 71), verapamil (n = 72) or standard care alone (n = 72). At 15 days, the hazard ratio (hazard ratio [HR], 95% confidence interval [CI]) for clinical improvement was 0.77 (0.52-1.14) with amiodarone and 0.97 (0.81-1.17) with verapamil as compared to usual care. Clinically relevant associations were found between mortality or lack of clinical improvement and higher peak C-reactive protein (CRP) levels or nadir platelet count at 7, 10 and 15 days. Mortality rate increased by 73% every 5 mg/dL increment in peak CRP (HR 1.73, 95% CI 1.27-2.37) and was two-fold higher for every decrement of 100 units in nadir platelet count (HR 2.19, 95% CI 1.37-3.51). By cluster analysis, thresholds of 5 mg/dL for peak CRP and 187 × 103/mcL for nadir platelet count identified the phenogroup at greatest risk of dying. CONCLUSIONS: In this randomized trial, neither amiodarone nor verapamil were found to significantly accelerate short-term clinical improvement. Peak CRP and nadir platelet counts were associated with increased mortality both in isolation and by cluster analysis.

Epidemiology and chronobiology of out-of-hospital cardiac arrest in a subpopulation of southern Poland: A two-year observation.

BACKGROUND: Although recent studies indicate temporal variations in the incidence of out-of-hospital cardiac arrest (OHCA), the Polish experience in this research is scarce to date. We evaluated the epidemiology of OHCA and circadian, weekly and seasonal variations of OHCA frequency among the adult population of the Opole district, Poland. METHODS: The retrospective analysis of 815 OHCA cases with presumed cardiac etiology was made based on dispatch cards from the Emergency Medical Center in Opole registered during a 2 year period (2006-2007). RESULTS: The incidence of OHCA in the studied population was 1.56/1000 inhabitants per year. Mean age of the group was 69.2 ± 14.2 years, with the majority of men (63%), younger than women (66.1 vs. 74 years, p = 0.0001). The OHCA occurrence increased with age reaching a peak between 71 and 75 years. The incidence of OHCA stayed at stable low levels between 22:00 and 4:59 and started to increase at 5:00, with trimodal peaks: 8:00-10:59, 14:00-15:59 and 18.00-21.59. The lowest number of OHCA occurred from 00:00 to 5:59, the highest from 6:00 to 11:59 (13% vs. 32.4%, p < 0.001). The day with the lowest occurrence of OHCA was Friday, the highest Saturday (10.9% vs. 16%, p = 0.01). Summer was the season of the lowest incidence of OHCA, while winter - the highest (22.6% vs. 26%, p = 0.04). These seasons were the warmest and the coldest one, respectively (average temperature 18.5°C vs. 0°C, p < 0.001). CONCLUSIONS: Circadian and less marked, weekly variability in OHCA occurrence were confirmed. Existing seasonal differences may be affected by temperature. This is the first Polish analysis of a large subpopulation, which also includes seasonal temperature data.

The strengths and weaknesses of non-invasive parameters obtained by echocardiography and cardiopulmonary exercise testing in comparison with the hemodynamic assessment by the right heart catheterization in patients with pulmonary hypertension.

PURPOSE: Pulmonary hypertension (PH) diagnosis requires invasive assessment by right heart catheterization (RHC), but screening and monitoring are performed using non-invasive methods: echocardiography and cardiopulmonary exercise testing (CPET). The aim of the study was to assess correlations between the parameters obtained in non-invasive testing and RHC in patients with PH of different etiologies. MATERIAL/METHODS: The study included 53 medical records of PH patients (32 women) aged 29-81 years. We analyzed correlations between RHC (systolic pulmonary artery pressure (sPAP), diastolic pulmonary artery pressure (dPAP), pulmonary vascular resistance (PVR), cardiac output (CO)) and echocardiographic (tricuspid annular plane systolic excursion (TAPSE), sPAP) and CPET parameters (end-tidal oxygen and carbon dioxide pressures (PetO2, PetCO2), ventilation efficiency (VE/VCO2) slope). RESULTS: Echocardiographic estimation correlated well with RHC measurement of sPAP (r=0.65, P<0.001). TAPSE correlated with PVR assessed with thermodilution method (r=-0.5, P=0.005), dPAP (r=-0.53, P=0.002) and CO (r=0.53, P=0.002). PVR assessed with thermodilution and Fick methods showed positive correlation with PetO2 (r=0.74, P<0.001 and r=0.72, P<0.001) and negative correlation with PetCO2 (r=-0.59, P=0.004 and r=-0.64, P=0.002) at the anaerobic threshold. VE/VCO2 slope correlated with dPAP (r=0.43, P=0.04) and PVR calculated with both methods (r=0.52, P=0.01 and r=0.52, P=0.02). CONCLUSIONS: Simple cardiac function indicators obtained by commonly used non-invasive methods allow only approximate estimation of the main hemodynamic RHC-derived parameters: sPAP, CO and PVR. Obtained results suggest the relationship between RV dysfunction and ventilation abnormalities in PH patients.

[Current knowledge on aquaporin water channels: clinical implications]. / Aktualny stan wiedzy o akwaporynach: implikacje kliniczne.

The discovery of the aquaporin family of water channels has explained to a high degree the mechanism of water transport across cell membranes. The molecular structure of the first purified aquaporin shows its tetrameric organization with each subunit containing an individual aqueous pore selectively permeable for water but not for protons. At least 11 human aquaporins have been identified. Definition of sites of their expression enabled explanation of their physiological role as well as pathological importance in congenital cataract or nephrogenic diabetes insipidus.

Activity of the kynurenine pathway and its interplay with immunity in patients with pulmonary arterial hypertension.

OBJECTIVE: We evaluated blood concentrations of kynurenine pathway metabolites, natural and induced regulatory T cells (nTreg, iTreg), and Th17 cells in order to examine the activity of the kynurenine pathway and its relation to immune status in patients with pulmonary arterial hypertension (PAH). METHODS: Plasma concentrations of tryptophan, kynurenine, kynurenic acid, anthranilic acid, and 3-hydroxykynurenine were quantified in 26 patients with PAH (vs 30 healthy controls) at baseline and after 6 months, and assessed them in relation to clinical parameters, frequencies of lymphocyte subsets, and outcome. RESULTS: The PAH group presented higher concentrations of tryptophan (52.9 (IQR 46.3-57.5) vs 40.3 (35.2-46.3) µmol/L, p=0.00003), kynurenine 2.8 (2.4-3.4) vs 1.9 (1.5-2.3) µmol/L, p=0.000007), kynurenine/tryptophan ratio (0.051 (0.044-0.064) vs 0.043 (0.039-0.055), p=0.03), iTreg frequencies (10.5 (8.8-13.9)% vs 6.8 (5.2-9.5)%, p=0.002) and iTreg/Th17 (1.73 (1.2-2.8) vs 0.93 (0.61-1.27), p=0.003) together with lower ratios of kynurenic acid/kynurenine, 3-hydroxykynurenine/kynurenine, and anthranilic acid/kynurenine. Kynurenine concentrations and kynurenine/tryptophan ratio correlated positively with iTreg/Th17, and inversely with Th17 subsets, whereas kynurenic acid/kynurenine and anthranilic acid/kynurenine ratios correlated positively with Th17. Adverse outcomes occurred in 9 of 26 patients and they showed higher baseline concentrations of kynurenine (3.6 (2.8-4.3) vs 2.7 (2.1-3.2) µmol/L, p=0.033). Median kynurenine values ≥3.4 µmol/L (67% sensitivity, 94% specificity) identified patients with a worse clinical course. CONCLUSIONS: PAH is characterised by upregulated tryptophan metabolism and enhanced biosynthesis of kynurenine. Elevated kynurenine concentration is associated with an adverse clinical course. Dysregulated immunity, delineated by Treg-Th17 imbalance, is directly related to diverse activation of the kynurenine pathway, indicating the potential interplay between kynurenines and the immune system in PAH.

Circulating classical CD14++CD16- monocytes predict shorter time to initial treatment in chronic lymphocytic leukemia patients: Differential effects of immune chemotherapy on monocyte-related membrane and soluble forms of CD163.

Three main monocyte subsets: classical CD14++CD16-, intermediate CD14++CD16+ and non-classical CD14+CD16++, differentially regulate tumor growth and survival. Thereby, in the present study we aimed to determine the role of distinct monocyte subsets in the prognostication of chronic lymphocytic leukemia (CLL). Moreover, we set out to analyze the effects of standard immune chemotherapy on different monocyte subsets and levels of membrane-associated and soluble forms of CD163, a monocyte/macrophage-related immunomodulatory protein. We demonstrated that the number of peripheral blood classical CD14++CD16- monocytes assessed at the time of diagnosis was negatively correlated with lymphocytosis and was decreased in the CLL patients who required immediate treatment as opposed to patients who qualified to 'watch and wait' strategy. Notably, lower baseline levels of classical CD14++CD16- monocytes in CLL patients who were qualified for 'watch and wait' therapy were associated with shorter time to initial treatment. Notably, therapy with rituximab, cyclophosphamide and fludarabine resulted in a significant reduction in the number of non-classical CD14+CD16++ monocytes and soluble form of CD163 but upregulation of membrane-associated monocyte CD163. Our data indicate that distinct monocyte subsets and two forms of CD163 are differentially modulated by both CLL and immune chemotherapy. Moreover, we proposed that quantification of classical monocytes at the time of diagnosis contributes to better prognostication of CLL patients.

Potential pathogenic role of soluble receptor activator of nuclear factor-ĸB ligand and osteoprotegerin in patients with pulmonary arterial hypertension.

INTRODUCTION: Inflammation plays a significant role in the pathogenesis of pulmonary arterial hypertension (PAH). Soluble receptor activator of nuclear factor-ĸB ligand (sRANKL) and osteoprotegerin (OPG) are tumor necrosis factor α family members of immunomodulatory activity. OBJECTIVES: The aim of the study was to evaluate sRANKL and OPG concentrations in patients with PAH as potential factors contributing to the development of the disease. PATIENTS AND METHODS: We studied 26 patients with PAH, 31 volunteers, and 24 stable patients with chronic systolic left ventricular heart failure (LVHF) without pulmonary hypertension. The PAH group was followed up for 6 months for clinical deterioration or death. RESULTS: sRANKL levels were higher in the PAH group compared with controls and the LVHF group (5.6 [interquartile range, 3.9-7.9) vs. 2.0 [0.9-4.4] pmol/l; P = 0.0001, and 2.4 [1.3-4.2] pmol/l; P = 0.001, respectively). OPG levels were higher in PAH patients compared with controls (4.07 ±1.9 vs. 3.27 ±0.95 pmol/l; P = 0.048). We found significant correlations between sRANKL levels and parameters of ventilatory efficiency during exercise in the PAH group. OPG levels correlated with brain natriuretic peptide levels and with invasive hemodynamic parameters. Patients with clinical deterioration during 6-month follow-up (n = 9) showed higher baseline OPG levels compared with stable patients (n = 17, 5.09 ±2.6 vs. 3.52 ±1.19 pmol/l; P = 0.043). In the univariate analysis, the elevated OPG concentration at baseline was associated with an increased risk and earlier occurrence of clinical deterioration (hazard ratio, 1.43; 95% confidence interval, 1.06-1.9; P = 0.017). CONCLUSIONS: Concentrations of sRANKL and OPG are elevated in patients with PAH and are associated with indicators of disease severity and prognosis. sRANKL is a better discriminant between PAH and LVHF than OPG. The baseline OPG concentration is significantly associated with adverse outcomes in patients with PAH.