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Interaction of neutrophil counts and folic acid treatment on new-onset proteinuria in hypertensive patients.
Zhang, Z, Liu, M, Zhang, Y, Zhou, C, He, P, Li, H, Li, J, Zhang, Y, Liang, M, Wang, B, et al
The British journal of nutrition. 2021;(7):1040-1047
Abstract
We aimed to examine whether baseline neutrophil counts affected the risk of new-onset proteinuria in hypertensive patients, and, if so, whether folic acid treatment is particularly effective in proteinuria prevention in such a setting. A total of 8208 eligible participants without proteinuria at baseline were analysed from the renal substudy of the China Stroke Primary Prevention Trial. Participants were randomised to receive a double-blind daily treatment of 10 mg of enalapril and 0·8 mg of folic acid (n 4101) or 10 mg of enalapril only (n 4107). The primary outcome was new-onset proteinuria, defined as a urine dipstick reading of ≥1+ at the exit visit. The mean age of the participants was 59·5 (sd, 7·4) years, 3088 (37·6 %) of the participants were male. The median treatment duration was 4·4 years. In the enalapril-only group, a significantly higher risk of new-onset proteinuria was found among participants with higher neutrophil counts (quintile 5; ≥4·8 × 109/l, OR 1·44; 95 % CI 1·00, 2·06), compared with those in quintiles 1-4. For those with enalapril and folic acid treatment, compared with the enalapril-only group, the new-onset proteinuria risk was reduced from 5·2 to 2·8 % (OR 0·49; 95 % CI 0·29, 0·82) among participants with higher neutrophil counts (≥4·8 × 109/l), whereas there was no significant effect among those with neutrophil counts <4·8 × 109/l. In summary, among hypertensive patients, those with higher neutrophil counts had increased risk of new-onset proteinuria, and this risk was reduced by 51 % with folic acid treatment.
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Differential effects of testosterone on circulating neutrophils, monocytes, and platelets in men: Findings from two trials.
Gagliano-Jucá, T, Pencina, KM, Guo, W, Li, Z, Huang, G, Basaria, S, Bhasin, S
Andrology. 2020;(5):1324-1331
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BACKGROUND Testosterone treatment increases erythrocytes in men, but its effects on leukocyte and platelet counts are unknown and could affect its safety. OBJECTIVE To determine whether testosterone affects circulating leukocytes and platelets in men. METHODS Secondary analyses of two randomized testosterone trials were performed: the 5α-reductase (5aR) and OPTIMEN trials. In 5aR trial, 102 healthy men, 21-50 years (mean age 38), received a long-acting GnRH agonist, and 50, 125, 300, or 600 mg/week testosterone enanthate (TE) plus placebo or 2.5 mg/ day dutasteride for 20 weeks. In OPTIMEN, 78 functionally limited men, ≥65 years (mean age 72) with protein intake ≤ 0.83 g kg-1 day-1 , were randomized to controlled diets with 0.8 g kg-1 day-1 protein or 1.3 g kg-1 day-1 protein plus placebo or TE (100 mg/week) for 6 months. Changes from baseline in total and differential leukocyte count, and platelet count were evaluated. RESULTS In 5aR, testosterone administration was associated with increases in total leukocyte (estimated change from baseline 40, 490, 1230, and 1280 cells/µL, P < .001), neutrophil (65.1, 436.1, 1177.2, and 1192.2 cells/µL, P < .001), monocyte (-20.2, 24.5, 90.6, and 143.9 cells/µL, P < .001), platelet (-7.3, 8.4, 8.7, and 8.9 × 103 cells/µL, P = .033), and erythrocyte counts. Testosterone did not affect absolute lymphocyte count. Similar increase in total leukocyte count was observed with testosterone treatment in OPTIMEN (change 0.77 × 103 cells/µL, P vs placebo = 0.004). CONCLUSIONS Testosterone administration in men differentially increases neutrophil and monocyte counts. These findings, together with its erythropoietic effects, suggest that testosterone promotes the differentiation of hematopoietic progenitors into the myeloid lineage. These findings have potential mechanistic, therapeutic, and safety implications.
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Gamma tocopherol effect on LPS-induced sputum neutrophilia is not modified by BMI or GSTM1 genotype.
Sood, AK, Burbank, AJ, Duran, CG, Enders, K, Zhou, H, Peden, DB, Hernandez, ML
The Journal of allergy and clinical immunology. 2019;(5):1937-1939
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Gamma tocopherol may be beneficial as a primary or complementary therapeutic agent in conditions with neutrophilic airway inflammation. Its effects are not modified by BMI or GSTM1 genotype, allowing for its use in a broader population.
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Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial.
Ebrahimi, F, Giaglis, S, Hahn, S, Blum, CA, Baumgartner, C, Kutz, A, van Breda, SV, Mueller, B, Schuetz, P, Christ-Crain, M, et al
The European respiratory journal. 2018;(4)
Abstract
Neutrophil extracellular traps (NETs) are a hallmark of the immune response in inflammatory diseases. However, the role of NETs in community-acquired pneumonia (CAP) is unknown. This study aims to characterise the impact of NETs on clinical outcomes in pneumonia.This is a secondary analysis of a randomised controlled, multicentre trial. Patients with CAP were randomly assigned to either 50 mg prednisone or placebo for 7 days. The primary end-point was time to clinical stability; main secondary end-points were length of hospital stay and mortality.In total, 310 patients were included in the analysis. Levels of cell-free nucleosomes as surrogate markers of NETosis were significantly increased at admission and declined over 7 days. NETs were significantly associated with reduced hazards of clinical stability and hospital discharge in multivariate adjusted analyses. Moreover, NETs were associated with a 3.8-fold increased adjusted odds ratio of 30-day mortality. Prednisone treatment modified circulatory NET levels and was associated with beneficial outcome.CAP is accompanied by pronounced NET formation. Patients with elevated serum NET markers were at higher risk for clinical instability, prolonged length of hospital stay and 30-day all-cause mortality. NETs represent a novel marker for outcome and a possible target for adjunct treatments of pneumonia.
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Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO.
Dell'Aquila, E, Cremolini, C, Zeppola, T, Lonardi, S, Bergamo, F, Masi, G, Stellato, M, Marmorino, F, Schirripa, M, Urbano, F, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2018;(4):924-930
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BACKGROUND Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial. PATIENTS AND METHODS Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution. RESULTS NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05-1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25-1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14-1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95-1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64-1.08)] and high [HR 0.73 (95% CI 0.54-0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62-1.12) for low NLR; HR 0.82 (95% CI 0.59-1.12) for high NLR]. CONCLUSION This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.
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Neutrophil and Monocyte Bactericidal Responses to 10 Weeks of Low-Volume High-Intensity Interval or Moderate-Intensity Continuous Training in Sedentary Adults.
Bartlett, DB, Shepherd, SO, Wilson, OJ, Adlan, AM, Wagenmakers, AJM, Shaw, CS, Lord, JM
Oxidative medicine and cellular longevity. 2017;:8148742
Abstract
Neutrophils and monocytes are key components of the innate immune system that undergo age-associated declines in function. This study compared the impact of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on immune function in sedentary adults. Twenty-seven (43 ± 11 years) healthy sedentary adults were randomized into ten weeks of either a HIIT (>90% maximum heart rate) or MICT (70% maximum heart rate) group training program. Aerobic capacity (VO2peak), neutrophil and monocyte bacterial phagocytosis and oxidative burst, cell surface receptor expression, and systemic inflammation were measured before and after the training. Total exercise time commitment was 57% less for HIIT compared to that for MICT while both significantly improved VO2peak similarly. Neutrophil phagocytosis and oxidative burst and monocyte phagocytosis and percentage of monocytes producing an oxidative burst were improved by training similarly in both groups. Expression of monocyte but not neutrophil CD16, TLR2, and TLR4 was reduced by training similarly in both groups. No differences in systemic inflammation were observed for training; however, leptin was reduced in the MICT group only. With similar immune-enhancing effects for HIIT compared to those for MICT at 50% of the time commitment, our results support HIIT as a time efficient exercise option to improve neutrophil and monocyte function.
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Interval and continuous exercise regimens suppress neutrophil-derived microparticle formation and neutrophil-promoted thrombin generation under hypoxic stress.
Chen, YC, Ho, CW, Tsai, HH, Wang, JS
Clinical science (London, England : 1979). 2015;(7):425-36
Abstract
Acute hypoxic exposure increases vascular thrombotic risk. The release of procoagulant-rich microparticles from neutrophils accelerates the pathogenesis of inflammatory thrombosis. The present study explicates the manner in which interval and continuous exercise regimens affect neutrophil-derived microparticle (NDMP) formation and neutrophil/NDMP-mediated thrombin generation (TG) under hypoxic condition. A total of 60 sedentary males were randomized to perform either aerobic interval training [AIT; 3-min intervals at 40% and 80% V̇O2max (maximal O2 consumption)] or moderate continuous training (MCT; sustained 60% V̇O2max) for 30 min/day, 5 days/week for 5 weeks, or to a control (CTL) group who did not receive any form of training. At rest and immediately after hypoxic exercise test (HE, 100 W under 12% O2 for 30 min), the NDMP characteristics and dynamic TG were measured by flow cytometry and thrombinography respectively. Before the intervention, HE (i) elevated coagulant factor VIII/fibrinogen concentrations and shortened activated partial thromboplastin time (aPTT), (ii) increased total and tissue factor (TF)-rich/phosphatidylserine (PS)-exposed NDMP counts and (iii) enhanced the peak height and rate of TG promoted by neutrophils/NDMPs. Following the 5-week intervention, AIT exhibited higher enhancement of V̇O2max than did MCT. Notably, both MCT and AIT attenuated the extents of HE-induced coagulant factor VIII/fibrinogen elevations and aPTT shortening. Furthermore, the two exercise regimens significantly decreased TF-rich/PS-exposed NDMP formation and depressed neutrophil/NDMP-mediated dynamic TG at rest and following HE. Hence, we conclude that AIT is superior to MCT for enhancing aerobic capacity. Moreover, either AIT or MCT effectively ameliorates neutrophil/NDMP-promoted TG by down-regulating expression of procoagulant factors during HE, which may reduce thrombotic risk evoked by hypoxia. Moreover, either AIT or MCT effectively ameliorates neutrophil/NDMP-promoted TG by down-regulating expression of procoagulant factors during HE, which may reduce thrombotic risk evoked by hypoxia.
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Neutrophil:lymphocyte ratio is positively related to type 2 diabetes in a large-scale adult population: a Tianjin Chronic Low-Grade Systemic Inflammation and Health cohort study.
Guo, X, Zhang, S, Zhang, Q, Liu, L, Wu, H, Du, H, Shi, H, Wang, C, Xia, Y, Liu, X, et al
European journal of endocrinology. 2015;(2):217-25
Abstract
AIM: It is widely known that inflammation is related to type 2 diabetes (T2D), but few studies have shown a direct relationship between the immune system and T2D using a reliable biomarker. Neutrophil:lymphocyte ratio (NLR) is an easy-to-analyze inflammation biomarker, but few studies have assessed the relationship between NLR and T2D. In order to evaluate how NLR is related to T2D, we designed a large-scale cross-sectional and prospective cohort study in an adult population. SUBJECTS AND METHODS Participants were recruited from the Tianjin Medical University General Hospital-Health Management Centre. Both a baseline cross-sectional (n=87,686) and a prospective (n=38,074) assessment were performed. Participants without a history of T2D were followed up for ∼ 6 years (with a median follow-up of 2.7 years). Adjusted logistic and Cox proportional hazards regression models were used to assess relationships between the quintiles of NLR and T2D (covariates: age, sex, BMI, smoking status, drinking status, hypertension, hyperlipidemia, and family history of cardiovascular disease, hypertension, hyperlipidemia, or diabetes). RESULTS The prevalence and incidence of T2D were 4.9% and 6.8/1000 person-years respectively. The adjusted odds ratio and hazard ratio (95% CI) of the highest NLR quintile were 1.34 (1.21, 1.49) and 1.39 (1.09, 1.78) (both P for trend <0.01) respectively as compared to the lowest quintile of NLR. Leukocyte, neutrophil, and lymphocyte counts do not significantly predict the eventual development of T2D. CONCLUSION The present study demonstrates that NLR is related to the prevalence and incidence of T2D, and it suggests that NLR may be an efficient and accurate prognostic biomarker for T2D.
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Effects of carbohydrate ingestion on acute leukocyte, cortisol, and interleukin-6 response in high-intensity long-distance running.
Ihalainen, JK, Vuorimaa, T, Puurtinen, R, Hämäläinen, I, Mero, AA
Journal of strength and conditioning research. 2014;(10):2786-92
Abstract
The purpose of this study was to investigate the effect of ingestion of fluids with different carbohydrate concentrations (0, 1.5, and 7%) on the acute immune stress responses after high-intensity long-distance running. Continuous 18- to 20-km run was performed at 75% of maximal oxygen uptake with carbohydrate supplementation (CHO7%, 7% carbohydrate solution) and low-carbohydrate supplementation (lowCHO1.5%, 1.5% carbohydrate solution) in a randomized, double-blind, placebo (PLA) controlled design. Seven recreational runners (4 men and 3 women) completed all 3 trials. Blood was collected at baseline (PRE) and immediately after the run (POST). The running task induced significant (p ≤ 0.05) increases in leukocyte (white blood cells), neutrophil, and interleukin-6 (IL-6) counts in every trial. There was a significant (p ≤ 0.05) increase in cortisol with PLA and lowCHO1.5% but not with CHO7%. Increase in total leukocyte and neutrophil concentration was significantly lower with CHO7% compared with PLA (p ≤ 0.05). Postexercise IL-6 levels were significantly elevated when compared with baseline in all conditions (p ≤ 0.05). Interleukin-6 (IL-6) concentrations did not differ significantly between trials. LowCHO1.5% sport drink did not significantly differ from PLA in measured variables, which indicated that the amount and rate of carbohydrate ingestion (15 g, 10 g·h) in low-carbohydrate sport drink was not enough to significantly protect from the stress induced by high-intensity long-distance running, whereas the ingestion of CHO7% (45 g·h) blunted the significant cortisol response and significantly decreased the leukocyte response.
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Remote ischaemic preconditioning down-regulates kinin receptor expression in neutrophils of patients undergoing heart surgery.
Saxena, P, Aggarwal, S, Misso, NL, Passage, J, Newman, MA, Thompson, PJ, d'Udekem, Y, Praporski, S, Konstantinov, IE
Interactive cardiovascular and thoracic surgery. 2013;(4):653-8
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OBJECTIVES Remote ischaemic preconditioning (RIPC) may protect distant organs against ischaemia-reperfusion injury. We investigated the impact of RIPC on kinin receptor expression in neutrophils following RIPC in patients undergoing coronary artery bypass grafting (CABG). METHODS Patients undergoing elective CABG with cardiopulmonary bypass (CPB) were randomized to RIPC (n = 15) or control (n = 15) groups. The study group underwent RIPC by inflation of a blood pressure cuff on the arm. Expression of kinin receptors, plasma concentrations of IL-6, IL-8, IL-10, TNF-α and neutrophil elastase were determined at baseline (before RIPC/sham), immediately before surgery (after RIPC/sham) and 30 min and 24 h after surgery. Plasma bradykinin levels were assessed before and after RIPC/sham, and at 30 min, 6, 12 and 24 h after surgery. Serum creatine kinase (CK), troponin I, C-reactive protein (CRP) and lactate levels were measured immediately prior to surgery and 30 min, 6, 12, 24 and 48 h after surgery. RESULTS Kinin B2 receptor expression did not differ between the groups at baseline (pre-RIPC), but was significantly lower in the RIPC group than in the control group after RIPC/sham (P < 0.05). Expressions of both kinin B1 and B2 receptors were significantly down-regulated in the RIPC group, and this persisted to 24 h after surgery (P < 0.001). Neutrophil elastase levels were significantly increased after surgery. There were no differences in CK, CRP, cytokine, lactate or troponin I levels between the groups. CONCLUSIONS RIPC down-regulated the expression of kinin B1 and B2 receptors in neutrophils of patients undergoing CABG.