Increase In Blood Neutrophils Research Articles

CORONET online risk assessment tool and Charlson comorbidity index in predicting fatalities in cancer patients with COVID-19

Purpose of the study. Сomparing and evaluating the prognostic potential of the CORONET online risk assessment tool and the Charlson Comorbidity Index in predicting mortality in cancer patients with COVID-19.Materials and methods. The results are drawn from the data of 168 case histories of cancer patients who were undergoing inpatient treatment for COVID-19 at the University Clinical Hospitals of Sechenov University between March 2020 and February 2022. The study was conducted as part of the program of the world-class research center “Digital Biodesign and Personalized Healthcare” of Sechenov University, with participation in the ESMO-CoCARE Registry project. Patients with a history of solid or hematologic malignancies were included in the study; their treatment period before the study was 5 years or less. The age ranged from 37 to 100 years, the median age was 69 years. The CORONET online risk assessment tool and the Charlson comorbidity index were used to objectify the severity of multimorbidity status and prognosis of fatal outcomes in cancer patients with COVID-19.Results. It was demonstrated that statistically significant effects on the prognosis of mortality in patients with cancer were: age, percentage of saturation on admission, treatment in intensive care units (ICU), National Early Warning Score 2 (NEWS2) distress syndrome severity scale score, computed tomography (CT) assessment of disease course severity, decreased blood albumin and platelet counts, and increased blood neutrophil counts in both categorical and immediate indicator value formats. In addition, it was determined that as the number of comorbidities increased, the probability of mortality increased significantly, odds ratio (OR) = 2.162 (CI 95 % 1.016–4.600; p = 0.045). The CORONET calculator score yields one of the highest OR values among all established statistically significant predictors,20.410 (CI 95 % 4.894–85.113; p < 0.001). For oncopathology in COVID-19 patients, the Charlson index score shows statistical significance as a predictor of mortality, OR =1.396 (CI 9 5 % 1.105–1.765; p = 0.005).Conclusion. The obtained advantages in using the CORONET online decision support tool over the Charlson comorbidity index in predicting mortality in cancer patients with COVID-19 are recognized as convincing.

Pulmonary exacerbations in early cystic fibrosis lung disease are marked by strong modulation of CD3 and PD-1 on luminal T cells.

In chronic cystic fibrosis (CF) lung disease, neutrophilic inflammation and T-cell inhibition occur concomitantly, partly due to neutrophil-mediated release of the T-cell inhibitory enzyme Arg1. However, the onset of this tonic inhibition of T cells, and the impact of pulmonary exacerbations (PEs) on this process, remain unknown. Children with CF aged 0-5 years were enrolled in a longitudinal, single-center cohort study. Blood (n = 35) and bronchoalveolar lavage (BAL) fluid (n = 18) were collected at stable outpatient clinic visits or inpatient PE hospitalizations and analyzed by flow cytometry (for immune cell presence and phenotype) and 20-plex chemiluminescence assay (for immune mediators). Patients were categorized by PE history into (i) no prior PE, (ii) past history of PE prior to stable visit, or (iii) current PE. PEs were associated with increased concentration of both pro- and anti-inflammatory mediators in BAL, and increased neutrophil frequency and G-CSF in circulation. PE BAL samples showed a trend toward an increased frequency of hyperexocytic "GRIM" neutrophils, which we previously identified in chronic CF. Interestingly, expression levels of the T-cell receptor associated molecule CD3 and of the inhibitory programmed death-1 (PD-1) receptor were respectively decreased and increased on T cells from BAL compared to blood in all patients. When categorized by PE status, CD3 and PD-1 expression on blood T cells did not differ among patients, while CD3 expression was decreased, and PD-1 expression was increased on BAL T cells from patients with current PE. Our findings suggest that airway T cells are engaged during early-life PEs, prior to the onset of chronic neutrophilic inflammation in CF. In addition, increased blood neutrophil frequency and a trend toward increased BAL frequency of hyperexocytic neutrophils suggest that childhood PEs may progressively shift the balance of CF airway immunity towards neutrophil dominance.

Comparison between sevoflurane and propofol on immunomodulation in an in vitro model of sepsis.

Patients with sepsis often require sedation and/or anesthesia. Although the immunomodulatory effects of anesthetics have been increasingly recognized, the molecular mechanisms require better elucidation. We compared the effects of sevoflurane with propofol on the expression of pro- and anti-inflammatory biomarkers released by monocytes/macrophages and blood/bronchoalveolar lavage fluid (BALF) neutrophils, the phagocytic capacity of monocytes/ macrophages, and neutrophil migration, as well as mediators associated with alveolar epithelial and endothelial cells obtained from rats with sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture in nine male Wistar rats. After 48 h, animals were euthanized and their monocytes/alveolar macrophages, blood and BALF neutrophils, as well as alveolar epithelial and endothelial cells were extracted, and then exposed to (1) sevoflurane (1 minimal alveolar concentration), (2) propofol (50 μM), or (3) saline, control (CTRL) for 1 h. Sevoflurane reduced interleukin (IL)-6 mRNA expression in monocytes and alveolar macrophages (p = 0.007, p = 0.029), whereas propofol decreased IL-6 mRNA only in alveolar macrophages (p = 0.027) compared with CTRL. Sevoflurane increased IL-10 expression (p = 0.0002) in monocytes compared with propofol and increased IL-10 mRNA and transforming growth factor (TGF)-β mRNA (p = 0.037, p = 0.045) compared with CTRL. Both sevoflurane and propofol did not affect mRNA expression of IL-10 and TGF-β in alveolar macrophages. The phagocytic capacity of monocytes (p = 0.0006) and alveolar macrophages (p = 0.0004) was higher with sevoflurane compared with propofol. Sevoflurane, compared with CTRL, reduced IL-1β mRNA (p = 0.003, p = 0.009) and C-X-C chemokine receptor 2 mRNA (CXCR2, p = 0.032 and p = 0.042) in blood and BALF neutrophils, and increased CXCR4 mRNA only in BALF neutrophils (p = 0.004). Sevoflurane increased blood neutrophil migration (p = 0.015) compared with propofol. Both sevoflurane and propofol increased zonula occludens-1 mRNA (p = 0.046, p = 0.003) in alveolar epithelial cells and reduced Toll-like receptor 4 mRNA (p = 0.043, p = 0.006) in alveolar endothelial cells compared with CTRL. Only propofol reduced surfactant protein B mRNA (p = 0.028) in alveolar epithelial cells. Sevoflurane, compared with propofol, increased anti-inflammatory biomarkers in monocytes, but not in alveolar macrophages, enhanced monocyte/alveolar macrophage phagocytic capacity and increased neutrophil migration in in vitro experimental sepsis. Both propofol and sevoflurane protected lung epithelial and endothelial cells.

Neutrophil activation may trigger tau burden contributing to cognitive progression of chronic sleep disturbance in elderly individuals not living with dementia

BackgroundTo investigate the complex connection between chronic sleep disturbance (CSD) and cognitive progression.MethodsThe Alzheimer’s Disease Neuroimaging Initiative (ADNI) database was used to assign 784 non-dementia elderly into two groups: a normal sleep group (528 participants) and a CSD group (256 participants) via the Neuropsychiatric Inventory (NPI)-sleep subitem. Blood transcriptomics, blood neutrophil, cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD), and neutrophil-related inflammatory factors were measured. We also investigated gene set enrichment analysis (GSEA), Cox proportional hazards model for risk factors, and mediation and interaction effects between indicators. Cognitive progression is defined as the progression from cognitively normal to mild cognitive impairment (MCI)/dementia or from MCI to dementia.ResultsCSD could significantly affect cognitive function. The activated neutrophil pathways for cognitive progression in CSD were identified by transcriptomics GSEA, which was reflected by increased blood neutrophil level and its correlation with cognitive progression in CSD. High tau burden mediated the influence of neutrophils on cognitive function and exacerbated the CSD-related risk of left hippocampal atrophy. Elevated neutrophil-related inflammatory factors were observed in the cognitive progression of CSD and were associated with brain tau burden.ConclusionsActivated neutrophil pathway triggering tau pathology may underline the mechanism of cognitive progression in CSD.

Neutrophil extracellular traps (NETs) in aortic stenosis: Comparison of methods for assessment of NETs formation

Abstract Introduction We previously showed increased neutrophil extracellular traps (NETs) formation (NETosis) in patients with severe aortic stenosis (AS). Our aim was to comprehensively assess NETosis in AS using a relatively simple and appropriate technique. We investigated circulating NETosis markers by ELISA and assessed the potential of blood neutrophils to release NETs by flow cytometry. Materials and Methods We enrolled 13 patients aged 66 [Q1–Q3, 60–70] years with severe isolated AS without diabetes, chronic kidney disease, and atrial fibrillation. Nine apparently healthy volunteers of similar sex and age served as controls. Serum concentrations of citrullinated histone H3 (citH3), circulating nucleosomes, myeloperoxidase (MPO), and deoxyribonuclease-1 (DNASE1) were measured using ELISAs. Peripheral blood NET-releasing neutrophils were detected by flow cytometry as MPO/citH3-positive cells. Results AS patients compared to controls presented 174% higher concentrations of citH3 (p<0.001), 456% higher nucleosomes (p<0.001), 136% higher MPO (p=0.021) and 19% higher DNASE1 levels (p=0.039), together with 101% elevated percentage of NET-releasing neutrophils assessed by flow cytometry (p=0.003). In AS patients, the proportion of blood NET-releasing neutrophils positively correlated with citH3 (r=0.86, p<0.001) and nucleosome (r=0.58, p=0.041) concentrations but not with MPO or DNASE1. Moreover, we observed a strong association between AS severity, measured as aortic valve area (AVA), and serum citH3 concentrations (r=−0.75, p=0.003), but not the number of NET-releasing neutrophils. Conclusions Our study showed increased blood neutrophil potential to release NETs together with increased levels of serum markers of NETos is in severe AS patients. However, we recommend ELISA to assess NETosis in vivo as simpler technique giving more unequivocal results compared to flow cytometry.

Increased blood neutrophil extracellular traps (NETs) associated with early life stress: translational findings in recent-onset schizophrenia and rodent model

Higher levels of interleukin (IL)-6 and elevated neutrophil counts are consistently reported in the blood of patients with schizophrenia. Stressors during childhood and/or adolescence are major socioenvironmental risk factors for schizophrenia and may contribute to immune dysregulation. Previous studies using blood cytokines to stratify patients with schizophrenia suggest that only a subset presents a low-grade inflammatory state. However, these studies have not addressed whether environmental factors such as childhood maltreatment contributed to identifying inflammatory clusters. Moreover, a neutrophil-related mechanism (Neutrophil Extracellular Traps; NETs) central to both the initiation and chronicity of autoimmune and inflammatory diseases has never been investigated in psychiatry. Elevated NETs in schizophrenia may predispose patients to inflammatory and autoimmune diseases resulting in reduced life expectancy. We, therefore, investigated NETs as a novel mechanism and biological target in early schizophrenia and their role together with IL-6 and childhood maltreatment in identifying cluster subgroups. We found increased NETs in the plasma of patients with early schizophrenia (n = 78) compared to both their unaffected siblings (n = 25) and community controls (n = 78), irrespective of sex, body mass index, psychoactive drug use, or tobacco smoking. Increased NETs in patients were unrelated to antipsychotic treatment, which was further tested in vitro using fresh neutrophils. By applying unsupervised two-step clustering analysis, we integrated values of NETs, IL-6, and childhood maltreatment scores. We identified two main clusters; childhood maltreatment scores and NETs were the most important variables contributing to cluster separation (high-CL1 and low-CL2), while IL-6 was the least contributor. Patients allocated in the high-CL1 (61.5%) had significantly higher childhood maltreatment scores, NETs, and IL-6 levels than the remaining groups (patients low-CL2, siblings, and controls high-CL1 and low-CL2). We complemented these findings with a rat model based on stress exposure during adolescence that results in several schizophrenia-like changes in adulthood. We found that adolescent stressed rats had higher NETs and IL-6 levels in serum compared to non-stressed rats with a tendency to produce more NETs from the bone marrow. Altogether, this study brings a novel cellular-based mechanism in schizophrenia that, combined with early-stress, could be useful to identify subgroups for more personalised treatments.

Neutrophil Depletion Attenuates Acute Liver Stress after Exhaustive Exercise in Mice.

Exhaustive exercise induces acute liver stress; however, the precise mechanisms remain unclear. We investigated the effects of neutrophil depletion in male C57BL/6J mice. Male C57BL/6J mice were divided into four groups: sedentary with control antibody ( n = 20), sedentary with antineutrophil antibody ( n = 20), exhaustive exercise with control antibody ( n = 20), and exhaustive exercise with antineutrophil antibody ( n = 20). Antineutrophil antibodies (1A8) or control antibodies were administered intraperitoneally before running on a treadmill. Immediately and at 24 h after running to exhaustion on a treadmill at a 7% gradient and a speed of 24 m·min -1 , blood neutrophil counts were measured by flow cytometry. Plasma activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also measured. Hematoxylin-eosin staining was performed to calculate the liver stress score, and hepatic tumor necrosis factor-α was measured using enzyme-linked immunosorbent assay. Exercise increased blood neutrophil and neutrophil infiltration into the liver. Plasma AST and ALT activities were significantly higher immediately after exhaustive exercise than after sedentary control (AST, sedentary with control antibody: 52.2 ± 0.4, exhaustive exercise with control antibody: 210.0 ± 19.8; ALT, sedentary with control antibody: 29.8 ± 2.2, exhaustive exercise with control antibody: 87.2 ± 15.8). However, AST and ALT activities were significantly decreased with the 1A8 antibody (AST, 102.2 ± 12.9; ALT, 39.2 ± 4.0). In addition, the liver stress score increased after exercise but was significantly reduced by prior 1A8 antibody administration. The 1A8 antibody treatment also decreased hepatic tumor necrosis factor-α levels after exhaustive exercise. These results suggested that neutrophils play a critical role in increasing liver stress by regulating inflammation.

White blood cell count and chronic obstructive pulmonary disease: A Mendelian Randomization study

Blood leukocyte counts (e.g., eosinophil count) are important biomarkers for the onset, classification, and exacerbation of chronic obstructive pulmonary disease (COPD). The causal relationships between them are necessary for the development of COPD treatment strategy, but remain unclear. Here, we implement two-sample bi-directional univariable Mendelian Randomization (MR) and multivariable MR to investigate the causal relationships. Univariable MR find that elevated blood eosinophil count significantly increases the risk of COPD (odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.14–1.30, P = 1.54 × 10−09) and COPD-related hospitalization (OR = 1.44, 95% CI: 1.15–1.80, P = 1.36 × 10−03). Besides, it also significantly decreases the ratio of forced expiratory volume in the first second over forced vital capacity (FEV1/FVC ratio) (OR = 0.942, 95% CI: 0.914–0.971, P = 1.02 × 10−04). These findings are fully supported by multivariate MR results. Interestingly, univariable MR reveals a weak causal relationship between elevated blood eosinophil count and COPD risk in younger people (<65 years) (OR = 1.39, 95% CI: 1.10–1.75, P = 5.52 × 10−03), but not older individuals (OR = 1.20, 95% CI: 0.926–1.55, P = 0.17). Finally, reverse univariable MR reveals the onset of COPD and the decreased FEV1/FVC ratio both lead to increased blood neutrophil count (OR = 1.03, 95% CI: 1.01–1.05, P = 3.40 × 10−03 and OR = 0.947, 95% CI: 0.91–0.986, P = 8.75 × 10−03 respectively). In summary, this MR study demonstrates that high blood eosinophil count is an independent causal mediator of COPD risk, FEV1/FVC decline, and COPD-related hospitalization. The increase in neutrophil count is induced by COPD onset or FEV1/FVC decline. This suggests eosinophil, but not neutrophil, may be used as a therapeutic target for preventing the onset and exacerbation of COPD and FEV1/FVC decline. Therefore, a non-neutrophil-targeted therapeutic strategy for neutrophilic COPD is required in the future.

Acute Radiation-Induced Hematopoietic Depletion Does Not Alter the Onset or Severity of Pneumonitis in Mice.

Survival from partial-body irradiation (PBI) may be limited by the development of the late lung injury response of pneumonitis. Herein we investigated the hypothesis that acute hematopoietic depletion alters the onset and severity of lung disease in a mouse model. To establish depletion, C3H/HeJ mice received 8 Gy PBI with shielding of only the tibiae, ankles and feet. One week after irradiation, blood lymphocyte and neutrophil counts were each significantly reduced (P < 0.04) in these mice compared to levels in untreated controls or in mice receiving 16 Gy to the whole thorax only. All 8 Gy PBI mice survived to the experimental end point of 16 weeks postirradiation. To determine whether the hematopoietic depletion affects lung disease, groups of mice received 8 Gy PBI plus 8 Gy whole-thorax irradiation (total lung dose of 16 Gy) or 16 Gy whole-thorax irradiation only. The weight loss, survival to onset of respiratory distress (P = 0.17) and pneumonitis score (P = 0.96) of mice that received 8 Gy PBI plus 8 Gy whole-thorax irradiation were not significantly different from those of mice receiving 16 Gy whole-thorax irradiation only. Mice in respiratory distress from PBI plus whole-thorax irradiation had significantly reduced (P = 0.02) blood monocyte counts compared to levels in distressed, whole-thorax irradiated mice, and symptomatic pneumonitis was associated with increased blood neutrophil counts (P = 0.04) relative to measures from irradiated, non-distressed mice. In conclusion, survivable acute hematopoietic depletion by partial-body irradiation did not alter the onset or severity of lethal pneumonitis in the C3H/HeJ mouse model.

Sputum bacterial profile and antibiotics sensitivity pattern in acute exacerbation of chronic obstructive pulmonary disease

ABSTRACT Background: Constant microbiologic screening of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is vital to control the possible alteration of pathogens, as well as their antibiotic resistance. Objective: to identify sputum bacterial profile and antibiotics sensitivity in patients with AECOPD aiming to adjust antibiotics use and reduce antibiotics resistance. Methodology: This cross-sectional study was conducted on 100 patients with AECOPD. The total and differential leucocytic count, spirometric-indices, sputum gram stain, sputum semi-quantitative culture using colony forming unit (CFU) were done for all patients. Additionally, assessments of the sensitivity of the isolated pathogenic bacterial species were done for 25 antibiotics by disk diffusion method. Results: by sputum semi-quantitative culture 28% of the studied patients have non-pathogenic bacterial growth (i.e., growth of normal flora) and 72% have pathogenic bacterial growth. Amongthose with pathogenic bacterial growth the isolated bacterial species in descending order were klebsiella (40.3%), staphylococcus aureus (19.4%), pseudomonas (12.5%), streptococcal pneumoniae, E. coli (8.3% each), acinetobacter (6.9%), citrobacter (2.8%) and enterobacter (1.4%). The most predictive factors for bacterial etiology in AECOPD in descending orders were decreased blood eosinophils % (B = - 0.16), increased blood neutrophils % (B = 0.04), increased blood lymphocytes (B = 0.02), and lower FEV1% (B = - 0.01). Levofloxacin was the most sensitive antibiotics (91.7%), followed by amikacin (88.9%), ciprofloxacin (87.5%) and gentamycin (87.5%) then imipenem (81.7%) and ofloxacin (76.4%). On the other hand, linezolid and vancomycin were the most resistant antibiotics (95.8% each), followed by clindamycin and cefotaxime (91.7% each) then colistin sulphate and tetracycline (90.3% each). Conclusion: Gram-negative bacterial species especially klebsiella was the most prevalent organism’s in AECOPD. The isolated bacterial species were sensitive mainly to quinolones, gentamycin, amikacin, and imipenem, while it was mainly resistant to clindamycin, cefotaxime, colistin sulphate, tetracycline.

Sex‐dependent effects of tranexamic acid on blood‐brain barrier permeability and the immune response following traumatic brain injury in mice

BackgroundTranexamic acid (TXA) is an anti‐fibrinolytic agent used to reduce bleeding in various conditions including traumatic brain injury (TBI). As the fibrinolytic system also influences the central nervous system and the immune response, TXA may also modulate these parameters following TBI. ObjectivesTo determine the effect of TXA on blood‐brain barrier (BBB) integrity and changes in immune and motor function in male and female mice subjected to TBI. MethodsWild‐type and plasminogen deficient (plg−/−) mice were subjected to TBI then administered either TXA/vehicle. The degree of BBB breakdown, intracerebral hemorrhage (ICH), motor dysfunction, and changes in inflammatory subsets in blood and brain were determined. Results and conclusionsTranexamic acid significantly reduced BBB breakdown, and increased blood neutrophils in male mice 3 hours post‐TBI. In contrast, TXA treatment of female mice increased BBB permeability and ICH but had no effect on blood neutrophils at the same time‐point. TXA improved motor function in male mice but still increased BBB breakdown in female mice 24 hours post‐TBI. Brain urokinase‐type plasminogen activator (u‐PA) antigen and activity levels were significantly higher in injured females compared to males. Because TXA can promote a pro‐fibrinolytic effect via u‐PA, these sex differences may be related to brain u‐PA levels. TXA also increased monocyte subsets and dendritic cells in the injured brain of wild‐type male mice 1 week post‐TBI. Plg−/− mice of both sexes had reduced BBB damage and were protected from TBI irrespective of treatment indicating that TXA modulation of the BBB is plasmin‐dependent. In conclusion, TXA is protective post‐TBI but only in male mice.

SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis

BackgroundGenome wide association studies (GWAS) identified SLC44A2 as a novel susceptibility gene for venous thrombosis (VT) and previous work established that SLC44A2 contributed to clot formation upon vascular injury. ObjectiveTo further investigate the role of SLC44A2 in VT by utilizing SLC44A2 deficient mice (Slc44a2−/−) in two representative disease models. MethodsMice were included in a hypercoagulability model driven by siRNA‐mediated hepatic gene silencing of anticoagulants Serpinc1 (antithrombin) and Proc (protein C) and a flow restriction (stenosis) model induced by partial ligation of the inferior vena cava. ResultsIn the hypercoagulability model, no effect in onset was observed in Slc44a2−/− animals; however, a drop in plasma fibrinogen and von Willebrand factor coinciding with an increase in blood neutrophils was recorded. In the neutrophil dependent stenosis model after 48 hours, Slc44a2−/− mice had significantly smaller thrombi both in length and weight with less platelet accumulation as a percentage of the total thrombus area. During the initiation of thrombosis at 6 hours post‐stenosis, Slc44a2−/− mice also had smaller thrombi both in length and weight, with circulating platelets remaining elevated in Slc44a2−/− animals. Platelet activation and aggregation under both static‐ and venous and arterial shear conditions were normal for blood from Slc44a2−/− mice. ConclusionsThese studies corroborate the original GWAS findings and establish a contributing role for SLC44A2 during the initiation of VT, with indications that this may be related to platelet‐neutrophil interaction. The precise mechanism however remains elusive and warrants further investigation.

Particle Depletion Does Not Remediate Acute Effects of Traffic-related Air Pollution and Allergen. A Randomized, Double-Blind Crossover Study.

Rationale: Diesel exhaust (DE), an established model of traffic-related air pollution, contributes significantly to the global burden of asthma and may augment the effects of allergen inhalation. Newer diesel particulate-filtering technologies may increase NO2 emissions, raising questions regarding their effectiveness in reducing harm from associated engine output.Objectives: To assess the effects of DE and allergen coexposure on lung function, airway responsiveness, and circulating leukocytes, and determine whether DE particle depletion remediates these effects.Methods: In this randomized, double-blind crossover study, 14 allergen-sensitized participants (9 with airway hyperresponsiveness) underwent inhaled allergen challenge after 2-hour exposures to DE, particle-depleted DE (PDDE), or filtered air. The control condition was inhaled saline after filtered air. Blood sampling and spirometry were performed before and up to 48 hours after exposures. Airway responsiveness was evaluated at 24 hours.Measurements and Main Results: PDDE plus allergen coexposure impaired lung function more than DE plus allergen, particularly in those genetically at risk. DE plus allergen and PDDE plus allergen each increased airway responsiveness in normally responsive participants. DE plus allergen increased blood neutrophils and was associated with persistent eosinophilia at 48 hours. DE and PDDE each increased total peripheral leukocyte counts in a manner affected by participant genotypes. Changes in peripheral leukocytes correlated with lung function decline.Conclusions: Coexposure to DE and allergen impaired lung function, which was worse after particle depletion (which increased NO2). Thus, particulates are not necessarily the sole or main culprit responsible for all harmful effects of DE. Policies and technologies aimed at protecting public health should be scrutinized in that regard.Clinical trial registered with www.clinicaltrials.gov (NCT02017431).

Retraction: Disruption of the NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Gene in Mice Causes Myelogenous Hyperplasia.

NAD(P)H:quinone oxidoreductase1 (NQO1) is a cytosolic protein that reduces and detoxifies quinones and their derivatives, thus protecting cells against redox cycling and oxidative stress. Disruption of the NQO1 gene in mice caused myeloid hyperplasia of bone marrow and highly significant increases in blood neutrophils, eosinophils, and basophils. NQO1-null mice also showed a decrease in lymphocytes and WBCs as compared with wild-type mice. Various techniques also demonstrated an increase in megakaryocytes without an increase in blood platelets. Histological analysis of liver, kidney, spleen, and thymus did not demonstrate a difference between wild-type and NQO1-null mice or a sign of infection. Blood cultures and urine analysis also did not demonstrate any sign of infection in NQO1-null and wild-type mice. Additional analysis of the bone marrow from NQO1-null mice revealed that loss of NQO1 alters the intracellular redox status because of accumulation of NAD(P)H, cofactors for NQO1. This causes a reduction in the levels of pyridine nucleotides and tumor suppressor proteins p53 and p73, and a decrease in apoptosis. The decrease in apoptosis causes myelogenous hyperplasia in NQO1-null mice. These results demonstrate that NQO1 acts as an endogenous factor in the protection against myelogenous hyperplasia. This is significant because 2-4% of human individuals without known abnormalities, and >25% of individuals with benzene poisoning and acute myelogenic leukemia are homozygous for a mutant allele (P187S) of NQO1 and lack NQO1 protein/activity.

Prenatal Intra-Amniotic Endotoxin Induces Fetal Gut and Lung Immune Responses and Postnatal Systemic Inflammation in Preterm Pigs

Prenatal inflammation is a major risk for preterm birth and neonatal morbidity, but its effects on postnatal immunity and organ functions remain unclear. Using preterm pigs as a model for preterm infants, we investigated whether prenatal intra-amniotic (IA) inflammation modulates postnatal systemic immune status and organ functions. Preterm pigs exposed to IA lipopolysaccharide (LPS) for 3days were compared with controls at birth and postnatal day 5 after formula feeding. IA LPS induced mild chorioamnionitis but extensive intra-amniotic inflammation. There were minor systemic effects at birth (increased blood neutrophil counts), but a few days later, prenatal LPS induced delayed neonatal arousal, systemic inflammation (increased blood leukocytes, plasma cytokines, and splenic bacterial counts), altered serum biochemistry (lower albumin and cholesterol and higher iron and glucose values), and increased urinary protein and sodium excretion. In the gut and lungs, IA LPS-induced inflammatory responses were observed mainly at birth (increased LPS, CXCL8, and IL-1β levels and myeloperoxidase-positive cell density, multiple increases in innate immune gene expressions, and reduced villus heights), but not on postnatal day 5 (except elevated lung CXCL8 and diarrhea symptoms). Finally, IA LPS did notaffect postnatal gut brush-border enzymes, hexose absorption, permeability, or sensitivity to necrotizing enterocolitis on day 5. Short-term IA LPS exposure predisposes preterm pigs to postnatal systemic inflammation after acute fetal gut and lung inflammatory responses.

Nanoparticles in the lungs of old mice: Pulmonary inflammation and oxidative stress without procoagulant effects

Pulmonary exposure to nanoparticles (NPs) has been shown to induce pulmonary as well as cardiovascular toxicity. These effects might be enhanced in elderly subjects as a result of a compromised immunity and/or declined organ functions. To study the adverse in vivo effects of NPs in a model for the elderly, we exposed 18-month-old C75Bl/6 mice to multi-walled carbon nanotubes (MWCNTs) or ZnO NPs by intratracheal instillation once a week during 5 consecutive weeks. Pulmonary and hemostatic toxicity was determined 24 h (T1) and 8 weeks (T2) after the last administration.Both NP types significantly increased the pulmonary macrophages at both time points. The MWCNTs and ZnO NPs also induced a pulmonary influx of neutrophils, which was even larger at T2 compared to T1. All NPs induced only a modest increase of pulmonary IL-1β, IL-6 and KC levels. Both types of NPs also increased blood neutrophils. Red blood cells were not significantly affected. Both NPs significantly increased coagulation factor VIII levels at both time points. Histological analysis revealed the presence of MWCNTs in the alveolar macrophages up to 8 weeks after the last administration and the ZnO NPs induced a pronounced alveolar inflammation.In these 18-month-old mice, NPs caused pulmonary inflammation (without evidence of oxidative stress) accompanied by large increases in coagulation factor VIII up to 8 weeks after the last NP exposure. The persistence of the MWCNTs in the lungs resulted in translocation from the lungs to the left heart and the ZnO NPs induced a fibrosis-like pathology.

Body mass index status and peripheral airway obstruction in school-age children: a population-based cohort study

BackgroundFew large prospective studies have investigated the impact of body mass index (BMI) on lung function during childhood.MethodsUsing data collected between 2002 and 2013, we analysed associations between BMI status...

Synthesis and characterization of heparosan-granulocyte-colony stimulating factor conjugates: a natural sugar-based drug delivery system to treat neutropenia.

Many injectable drugs require delivery strategies for enhancing their pharmacokinetics due to rapid loss via renal filtration if possess low molecular weight (<60-70 kDa) and/or clearance by the body's components (e.g., proteases, antibodies, high-efficiency receptors) in their native form. FDA-approved polyethylene glycol (PEG) is a vehicle for improving therapeutics, but artificial polymers have potential biocompatibility and immunogenicity liabilities. Here, we utilized a natural vertebrate carbohydrate, heparosan (HEP), the biosynthetic precursor of heparan sulfate and heparin, to enhance performance of a biologic drug. The HEP polysaccharide was stable with a long half-life (~8 days for 99-kDa chain) in the nonhuman primate bloodstream, but was efficiently degraded to very short oligosaccharides when internalized by cells, and then excreted into urine and feces. Several HEP-modified human granulocyte-colony stimulating factor (G-CSF) conjugates were synthesized with defined quasi-monodisperse HEP polysaccharide chains. Single dosing of 55- or 99-kDa HEP-G-CSF in rats increased blood neutrophil levels comparable to PEG-G-CSF conjugates. Repeated dosing of HEP-G-CSF or HEP alone for 2 weeks did not cause HEP-specific toxic effects in rats. HEP did not possess the anticoagulant behavior of its daughter, heparin, based on testing in rats or clinical diagnostic assays with human plasma. Neither anti-HEP IgG nor IgM antibodies were detected in a long-term (9 doses over 7 months) immunogenicity study of the HEP-drug conjugate with rats. These proof-of-concept experiments with HEP-G-CSF indicate that it is a valid drug candidate for neutropenia and suggest the potential of this HEP-based platform as a safe alternative delivery vehicle for other therapeutics.

Pulmonary challenge with carbon nanoparticles induces a dose-dependent increase in circulating leukocytes in healthy males

BackgroundInhalation of particulate matter, as part of air pollution, is associated with increased morbidity and mortality. Nanoparticles (< 100 nm) are likely candidates for triggering inflammatory responses and activation of coagulation pathways because of their ability to enter lung cells and pass bronchial mucosa. We tested the hypothesis that bronchial segmental instillation of carbon nanoparticles causes inflammation and activation of coagulation pathways in healthy humans in vivo.MethodsThis was an investigator-initiated, randomized controlled, dose-escalation study in 26 healthy males. Participants received saline (control) in one lung segment and saline (placebo) or carbon nanoparticles 10 μg, 50 μg, or 100 μg in the contra-lateral lung. Six hours later, blood and bronchoalveolar lavage fluid (BALF) was collected for inflammation and coagulation parameters.ResultsThere was a significant dose-dependent increase in blood neutrophils (p = 0.046) after challenge with carbon nanoparticles. The individual top-dose of 100 μg showed a significant (p = 0.05) increase in terms of percentage neutrophils in blood as compared to placebo.ConclusionsThis study shows a dose-dependent effect of bronchial segmental challenge with carbon nanoparticles on circulating neutrophils of healthy volunteers. This suggests that nanoparticles in the respiratory tract induce systemic inflammation.Trial registrationDutch Trial Register no. 2976. 11 July 2011. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2976

Predictors of prolonged stay in patients with community-acquired pneumonia and complicated parapneumonic effusion.

Development of CPE in CAP is associated with prolonged hospital stay and it may increase the morbidity and mortality. We aimed to identify microbiological and clinical factors that predicate a prolonged hospital admission in patients treated with a tube thoracostomy to control CPE. This retrospective cohort included patients with CPE requiring chest tube drainage in a tertiary referral Korean hospital from 1 January 2004 to 30 July 2012. After dichotomous grouping according to the mean duration of hospital stay, clinical, laboratory and microbiological parameters were compared. The final analysis included 158 patients with CPE. The majority were male (130, 85.0%), and the mean age was 62.8 years. The mean duration of hospital stay was 17.7 (±10.2) days. The mean duration of chest tube drainage was 9.6 (±6.7) days. Streptococcus viridans (48.4%) was the most common pathogen. Intrapleural fibrinolysis was performed in 85 (53.8%); additional tube insertion was needed in 40 (25.3%) patients. In the multivariate analysis after adjusting for covariates, a prolonged hospital stay was associated with fever (aOR: 3.42, P = 0.02), lower PaO2 (aOR: 4.89, P = 0.007) and haemoglobin (aOR: 4.90, P = 0.003) levels, and an increased blood neutrophil fraction (aOR: 3.83, P = 0.01) on admission as well as the identification of microbes in CPE (aOR: 4.14, P = 0.03), and ineffective pleural drainage (aOR: 3.28, P = 0.03). This study suggests that physicians should note the clinical symptoms and laboratory findings of severe infection and effectiveness of pleural drainage to predicate which patients with a CAP needing thoracostomy for CPE will have a prolonged hospital stay.