Higher Inflammatory Response Research Articles

Use of disease-modifying anti-rheumatic drugs in the therapy of osteoarthritis

Osteoarthritis (OA) is a heterogeneous disease with varying degrees of inflammatory responses, structural changes, functional insufficiency, and disease progression as a whole. Some OA phenotypes are characterized by a high local inflammatory response, persistent pain, persistent synovitis, and severe functional limitation. As a rule, the use of traditional nonsteroidal anti-inflammatory drugs in these patients and the injection of glucocorticoids into the joint show no substantial effect. Taking into account the important role of inflammation and the involvement of immune responses in the pathogenesis of OA, the existence of its erosive forms, the use of some disease-modifying anti-rheumatic drugs could be a rational solution of the problem in the therapy of this disease.The paper reviews data on the efficiency and safety of using methotrexate and hydroxychloroquine in OA.

Distinct release strategies are required to modulate macrophage phenotype in young versus aged animals

The role of innate immunity and macrophages in the host response to biomaterials has received renewed attention. A context-dependent spectrum of macrophage phenotypes are shown to affect tissue integration and performance of implanted biomaterials and medical devices. Recent studies by our group demonstrated that the host response in aged animals was characterized by delayed macrophage recruitment, differences in marker expression and a shifted pro-inflammatory (M1) response, associated with an unresolved host response in the long-term. The present work sought to study the effects of single and sequential cytokine delivery regimens in aged mice to restore delayed recruitment of macrophages and shift the inflammatory host response towards an M2-like phenotype, using MCP-1 (macrophage chemotactic protein-1) and IL-4 (interleukin-4), respectively. Implantation of cytokine-eluting implants showed a preserved response to MCP-1 in both young and aged animals, restoring delayed macrophage recruitment in aged mice. However, the response elicited by IL-4, sequential delivery of MCP-1/IL-4 and coating components was distinct in young versus aged mice. While single delivery of IL-4 did not counteract the high inflammatory response observed in aged mice, the sequential delivery of MCP-1/IL-4 was capable of restoring both recruitment and shifting the macrophage response towards an M2-like phenotype, associated with decreased implant scarring in the long-term. In young mice, sequential delivery was not as effective as IL-4 alone at promoting an M2-like response, but did result in a reduction of M1 macrophages and capsule deposition downstream. These results demonstrate that a proper understanding of patient/context-dependent biological responses are needed to design biomaterial-based therapies with improved outcomes in the setting of aging.

Lymphopenic community-acquired pneumonia is associated with a dysregulated immune response and increased severity and mortality

ObjectivesLymphopenic (<724 lymphocytes/µL) community-acquired pneumonia (L-CAP) is an immunophenotype with an increased risk of mortality. We aimed to characterize the l-CAP immunophenotype though lymphocyte subsets and the inflammatory response and its relationship with severity at presentation and outcome. MethodsProspective study of 217 immunocompetent patients hospitalized for CAP. Lymphocyte subsets (CD4+, CD8+, CD19+, and natural killer [NK] cells) and inflammatory cytokines were analyzed on days 1 and 4, and immunoglobulin subclasses were analyzed on day 1 in a nested group. Results39% of patients showed l-CAP, with decreased levels of all lymphocyte subsets with a partial recovery of CD4+ and CD8+ cells by day 4. l-CAP patients exhibited higher initial severity and systemic levels of interleukin (IL)-8, IL-10, granulocyte colony-stimulating factor, and monocyte chemoattractant protein-1. Initial IgG2 levels were lower in patients with <724 lymphocytes/µL and positively correlated with ALC, CD4+, and CD19+ cell counts. Low CD4+ counts (<129 cells/µL) also independently predicted 30-day mortality after adjusting for age, gender, and the CURB-65 score. Conclusionsl-CAP is characterized by CD4+ depletion, a higher inflammatory response, and low IgG2 levels that correlated with greater severity at presentation and worse prognosis. l-CAP is an immunophenotype useful for rapidly recognizing severity.

Toll-like receptor 4 promotes high glucose-induced catabolic and inflammatory responses in chondrocytes in an NF-κB-dependent manner

Diabetes is an independent risk factor for knee osteoarthritis (OA), and hyperglycaemia-induced inflammation is considered to play an important role in their connection. The Toll-like receptor 4 (TLR4) regulates inflammatory responses in several pathological conditions including diabetes and OA. However, its role in diabetes-associated OA is poorly understood. In this study, we found that TLR4 expression was higher in OA cartilage from patients with type 2 diabetes mellitus (T2DM) than that from non-T2DM patients. Similarly, its expression was induced in primary mouse chondrocytes treated with high glucose, which suggests that TLR4 upregulation in T2DM-associated OA cartilage may originate from hyperglycaemia stimulation. We further discovered that TLR4 promoted high glucose-induced catabolic and inflammatory responses in chondrocytes, and mechanistically, these effects could be explained by the exacerbated activation of the transcription factor nuclear factor kappa B (NF-κB) pathway, since its inhibition by Bay 11-7082 abrogated TLR4 effects on high glucose-treated chondrocytes. Taken together, these findings may reveal a promotive role of TLR4 in regulating hyperglycaemia-induced catabolism and inflammation in T2DM-associated OA, and also implicate that TLR4 inhibition might be of therapeutic significance in treating T2DM-associated OA.

Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response.

AIRmax and AIRmin mouse strains phenotypically selected for high and low acute inflammatory responsiveness (AIR) are, respectively, susceptible or resistant to developing hepatocellular carcinoma (HCC) induced by the chemical carcinogens urethane and diethylnitrosamine (DEN). Early production of TNF-α, IL-1β, and IL-6 in the liver after DEN treatment correlated with tumor development in AIRmax mice. Transcriptome analysis of livers from untreated AIRmax and AIRmin mice showed specific gene expression profiles in each line, which might play a role in their differential susceptibility to HCC. Linkage analysis with SNP markers in F2 (AIRmax×AIRmin) intercross mice revealed two quantitative trait loci (QTL) in chromosomes 2 and 9, which are significantly associated with the number and progression of urethane-induced liver tumors. An independent linkage analysis with an intercross population from A/J and C57BL/6J inbred mice mapped regions in chromosomes 1 and 7 associated with the progression of urethane-induced liver tumors, evidencing the heterogeneity of HCC genetic control.

Papaverine identified as an inhibitor of high mobility group box 1/receptor for advanced glycation end-products interaction suppresses high mobility group box 1-mediated inflammatory responses

The interaction of high mobility group box 1 (HMGB1), which is secreted from immune and dying cells during cellular infection and injury, and receptor for advanced glycation end-products (RAGE) appears to be critical for acute and chronic inflammatory disorders. Here we designed a unique cyclic β-hairpin peptide (Pepb2), which mimics the predicted RAGE-binding domain of HMGB1. Pepb2 competitively inhibited HMGB1/RAGE interaction. We then identified papaverine as a Pepb2 mimetic by in silico 3D-structural similarity screening from the DrugBank library. Papaverine was found to directly inhibit HMGB1/RAGE interaction. It also suppressed the HMGB1-mediated production of pro-inflammatory cytokines, IL-6 and TNF-α, in mouse macrophage-like RAW264.7 cells and bone marrow-derived macrophages. In addition, papaverine attenuated mortality in cecal ligation puncture-induced sepsis model mice. Taken together, these findings indicate that papaverine could become a useful therapeutic against HMGB1/RAGE-mediated sepsis and other inflammatory diseases.

Abstract # 3158 Stress indirectly links to ex vivo inflammatory responses via depressive symptoms and is moderated by gender

Although research has linked stress to depression and inflammation, the extent to which gender alters relationships between stress, depression, and inflammation is relatively unknown. In theory-driven exploratory analyses based on recent work (Majd et al., 2018), depressive affect was investigated as a statistical mediator of stress and inflammation in cross-sectional data; gender was examined as a moderator in this model. Participants (n = 162; 25–65 years old; 67% women; 87% non-white) reported depressive symptoms (PROMIS short-form), recent stressors (life events [past year]; perceived stress [past month]), and cumulative stress severity from EMA (past 2 weeks), and lifetime stressors. Inflammatory responses were determined from lipopolysaccharide (LPS) stimulated cytokines in blood collected at the end of the EMA period. Recent stress and inflammatory responses were indirectly linked via depressive symptoms; gender significantly moderated the depression-immune path (IL-6: w = 0.070, 95%CI[0.02, 0.15]; IL-10: w = 0.059, 95%CI[−0.004, 0.13]; TNF α : w = 0.064, 95%CI[0.02, 0.13]). Recent stress related to greater depressive symptoms for men and women; greater depressive symptoms in turn related to higher inflammatory responses in men, but reduced responses in women. Similar patterns were evident for other recent stress measures; weaker effects were evident for lifetime stress measures. This research suggests that the relationship between recent stress and stimulated inflammatory responses may be accounted for by depressive symptoms, and that the direction of the relationship between depression and inflammation may be dependent on gender.

Challenges in severe community-acquired pneumonia: a point-of-view review.

PurposeSevere community-acquired pneumonia (SCAP) is still associated with substantial morbidity and mortality. In this point-of-view review paper, a group of experts discuss the main controversies in SCAP: the role of severity scores to guide patient settings of care and empiric antibiotic therapy; the emergence of pathogens outside the core microorganisms of CAP; viral SCAP; the best empirical treatment; septic shock as the most lethal complication; and the need for new antibiotics.MethodsFor all topics, the authors describe current controversies and evidence and provide recommendations and suggestions for future research. Evidence was based on meta-analyses, most recent RCTs and recent interventional or observational studies. Recommendations were reached by consensus of all the authors.Results and conclusionsThe IDSA/ATS criteria remain the most pragmatic tool to predict ICU admission. The authors recommend a combination of a beta-lactam/beta-lactamase inhibitor or a third G cephalosporin plus a macrolide in most SCAP patients, and to empirically cover PES (P. aeruginosa, extended spectrum beta-lactamase producing Enterobacteriaceae, methicillin-resistant S. aureus) pathogens when at least two specific risk factors are present. In patients with influenza CAP, the authors recommend the use of oseltamivir and avoidance of the use of steroids. Corticosteroids can be used in case of refractory shock and high systemic inflammatory response.

Prognostic Significance Of Serum Urea Concentration at Admission in older patients with hip fracture

Background:There are unmet needs in objective prognostic indicators for Hip Fracture (HF) outcomes.Objectives:To evaluate the determinants and prognostic impact of elevated serum urea, a key factor of nitrogen homeostasis, in predicting hospital mortality, inflammatory complications and length of stay in HF patients.Methods:In 1819 patients (mean age 82.8±8.1 years; 76.4% women) with osteoporotic HF, serum urea level at admission along with 22 clinical and 35 laboratory variables were analysed and outcomes recorded. The results were validated in a cohort of 455 HF patients (age 82.1±8.0 years, 72.1% women).Results:Elevated serum urea levels (&gt;7.5mmol/L) at admission were prevalent (44%), independently determined by chronic kidney disease, history of myocardial infarction, anaemia, hyperparathyroidism, advanced age and male gender, and significantly associated with higher mortality (9.4% vs. 3.3%, p&lt;0.001), developing a high postoperative inflammatory response (HPIR, 22.1% vs.12.1%, p=0.009) and prolonged hospital stay (&gt;20 days: 31.2% vs. 26.2%, p=0.021). The predictive value of urea was superior to other risk factors, most of which lost their discriminative ability when urea levels were normal. Patients with two abnormal parameters at admission, compared to subjects with the normal ones, had 3.6-5.6 -fold higher risk for hospital mortality, 2.7-7.8-fold increase in risk for HPIR and 1.3-1.7-fold higher risk for prolonged hospital stay. Patients with increased admission urea and a high inflammatory response had 9.7 times greater mortality odds compared to patients without such characteristics.Conclusion:In hip fracture patients admission serum urea is an independent and valuable predictor of hospital outcomes, in particular, mortality.

Effect of Combined β-Lactam/Macrolide Therapy on Mortality According to the Microbial Etiology and Inflammatory Status of Patients With Community-Acquired Pneumonia

Antibiotic combinations that include macrolides have shown lower mortality rates than β-lactams in monotherapy or combined with fluoroquinolones in patients with community-acquired pneumonia (CAP). However, this effect has not been studied according to the levels of C-reactive protein in CAP with identified microbial cause. In patients with CAP and known microbial cause we aimed to evaluate 30-day mortality of a β-lactam plus macrolide (BL+ M) compared with a fluoroquinolone alone or with a β-lactam (FQ ± BL). We analyzed a prospective observational cohort of patients with CAP admitted to the Hospital Clinic of Barcelona between 1996 and 2016. We included only patients with known microbial cause. Of 1,715 patients (29%) with known etiology, a total of 932 patients (54%) received BL+ M. Despite lower crude mortality in the BL+ M group in the overall population (BL+ M, 5%vsFQ ± BL, 8%; P= .015), after adjustment by a propensity score and baseline characteristics, the combination of BL+ M had a protective effect on mortality only in patients with high inflammatory response (C-reactive protein, > 15mg/dL) and pneumococcal CAP (adjusted OR, 0.28; 95%CI, 0.09-0.93). No benefits on mortality were observed for the population without high inflammatory response and pneumococcal CAP or with other etiologies. The combination of a β-lactam with a macrolide was associated with decreased mortality in patients with pneumococcal CAP and in patients with high systemic inflammatory response. When both factors occurred together, BL+ M was protective for mortality in the multivariate analysis.

Long-term implantation of acoustic transmitters induces chronic inflammatory cytokine expression in adult rainbow trout (Oncorhynchus mykiss)

Telemetry transmitters are frequently used in studies of wild fish migration and behavior. Although the effects of surgically implanted transmitters on survival, tag retention, healing and growth have been studied, there has been little research regarding the potential immune response induced by these transmitters. In the current study, mature rainbow trout received either surgical implantation of an acoustic transmitter or a sham surgical procedure. These fish were then sampled over a 10-week period so that pro-inflammatory cytokine expression in the spleen, peritoneal cavity lymphocytes and muscle at the surgical site could be analyzed. There were no significant differences in transcript expression for the spleen and muscle tissue between fish that had a transmitter and those that received the surgical procedure alone. However, transmitter presence significantly increased the expression of IL-6, IL-1β and TNFα in the peritoneal cells at 10 weeks indicating that tagged fish may be coping with chronic inflammation. Furthermore, tagged male fish had a higher inflammatory response in 10-week peritoneal lavage samples when compared to their tagged mature female counterparts, providing some evidence that mature female rainbow trout may have suppressed immune function when sexually mature. Externally, fish appeared to heal at similar rates regardless of the presence or absence of the transmitter, but the tag itself was prone to encapsulation and adhesion to the body wall and/or surgical site. This suggests that fish tagged with large intraperitoneal implants may not behave similarly to their wild counterparts. This research could aid in the development of improved telemetry tags that are more biocompatible, economical and better able to track fish behavior/movement.

P34 Identification of the Genetic Determinants of Susceptibility to Lung Cancer in a Moroccan Cohort

Lung cancer is the most common cause of death from cancer worldwide, estimated to be responsible 1.59 million deaths, representing 19.4% of all cancer types. Representing 80–85% of all cases non–small cell lung cancer (NSCLC) is the most predominant type of lung cancer. Lung cancer has been recognized as a complex multifactorial disease resulting from the interactions between various genetic and environmental factors. Identification of genes involved in the occurrence and development of lung cancer could contribute to further understanding of the underlying mechanisms, and even a very important additional appropriate prevention strategies and targeted treatments for reducing lung cancer burden. Many studies have suggested that key cytokines in inflammation pathways may exert important roles in the etiology of lung cancer. The aim of this study was to investigate whether common variants in inflammatory and immune response genes influence lung cancer risk in Moroccan patients. Using a candidate gene approach, 6 single nucleotide polymorphisms (SNPs) in 4 genes were assessed in 117controls and 117 lung cancer patients. Genotyping was performed with the TaqMan® allelic discrimination technology. The results were analysed using SPSS 24.0 software. Among the 5 studied genes, we found a significant association for the MIF (rs755622) (OR=1.63; 95% confidence interval 1.04-2.56; p =0.03), IL-6 (rs2069840) (OR=1.63; 95% confidence interval 1.08-2.47; p =0.01) and STAT3. No significant association was observed for the remaining SNPs in the following genes: IL17A rs7747909, IL-6R_rs2228145, IL6ST_rs2228044. The results founded suggest the important role of genetically determined high inflammatory response in the pathogenesis of lung cancer in the Moroccan population.

Association of low skeletal muscle index with increased systematic inflammatory responses and interferon γ-induced protein 10 levels in patients with colon cancer.

BackgroundSkeletal muscle depletion is a prognostic factor in patients with cancer. Here, we evaluated the association between the skeletal muscle index (SMI) and local and systemic responses in patients with colon cancer.Patients and methodsWe analyzed the relationships of the SMI with neutrophil, lymphocyte, monocyte, and platelet counts; the neutrophil-to-lymphocyte ratio; albumin levels; and C-reactive protein levels in a cohort of 561 patients, and with the circulating levels of 39 cytokines in a cohort of 125 patients. We also studied the association between the SMI and tumor local inflammatory response and the effect of SMI on survival.ResultsThe median SMIs for male and female subjects were 44.1 and 34.2 cm2/m2, respectively. We observed positive correlations of the SMI with neutrophil (p=0.022), lymphocyte (p=0.001), and monocyte counts (p=0.003). A low SMI correlated significantly with an increased platelet count (p=0.017), decreased albumin level (p=0.006), neutrophil-to-lymphocyte ratio >3 (p=0.021), and an increased interferon γ-induced protein 10 level (IP-10, r = −0.276, p=0.002). The SMI did not correlate significantly with local inflammatory reactions or the C-reactive protein level. Finally, the SMI was a significant prognosticator in patients with stage III colon cancer (3-year disease-free survival rates: 35.1% for the low SMI arms versus 46.0% in the high SMI arms; HR =2.036; p=0.034).ConclusionThis study highlights the association of a low SMI with a high systematic inflammatory response and IP-10 levels. Furthermore, low SMI is a predictor of poor disease-free survival in patients with stage III colon cancer.

Dysregulated Immune Response in Lymphopenic Community-Acquired Pneumonia Increases Mortality

Introduction: Lymphopenic community-acquired pneumonia (L-CAP) is an immunophenotype with an increased risk of mortality but little is known about its immunological profile in CAP. We aimed to characterize the immunophenotypes of lymphopenic and non-lymphopenic CAP by analyzing lymphocyte subsets and the inflammatory response. Methods: This was a prospective study of immunocompetent patients hospitalized for CAP. Lymphocyte subsets (CD4 , CD8 , CD19 , and natural killer [NK] cells) and inflammatory cytokines were analyzed on days 1 and 4, and immunoglobulin subclasses were analyzed on day 1 in a nested group. Findings: We recruited 217 patients of whom 59% showed lymphopenia (absolute lymphocyte count [ALC] <1000 cells/μL), with decrease in CD4 , CD8 , CD19 , and NK cells although there was a partial recovery on day 4. ALC was strongly correlated with CD4 counts (rho 0.91). The L-CAP group showed initial higher levels of interleukin (IL)-2, IL-8, IL-10, IL-17, granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1, and macrophage inflammatory protein-1 beta (MIP-1β) with persistence on day 4 of IL-8 and MIP-1β. Initial IgG2 levels were positively correlated with ALC, CD4 , and CD19 cell counts. Low CD4 counts (<129 cells/μL) also independently predicted 30-day mortality (Odds ratio 5.07 [1.12-23.01, 95% confidence interval]) after adjusting for age, gender, and the CURB-65 score. Conclusions: L-CAP presents features of dysregulated immune response, characterized principally by CD4 cell depletion, with a higher inflammatory response. Low lymphocyte count correlated with low IgG2 levels and is ultimately associated with a worse prognosis. Better immunoprofiling could contribute to personalize treatment in CAP. Funding Statement: This work was supported by Grant from Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) [2012/145, 2014/72]; Sociedad Valenciana de Neumologia (SVN) [2013, 2015]. The funders of the study had no role in the design, data collection, data analysis, data interpretation, writing, review, or approval of the manuscript. The first author and the corresponding author have had full access to all the data in the study and had final responsibility for the decision to submit for publication. Declaration of Interest: All authors declare that they have no conflicts of interest regarding this submission, and each has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Ethics Approval Statement: The local ethics committee approved the study (code: 2011/0859) and patients or their next of kin provided written informed consent.

ASSESSMENT OF SYSTEMIC INFLAMMATION MARKERS IN HIV INFECTED OPIATE USERS

Interleukin 6 and D-dimer known as chronic systemic inflammation markers shown prognostic significance in course of HIVdisease. Association between opioid use and systemic inflammation response are still elucidate. Objective: аssess plasma levels of IL-6 and D-dimer in HIV-positive patients in groups formed on the base of opiate use activity. Materials and methods. Crosssectional study of 346 HIV-positive ART-naive individuals. Participants were categorized into 3 groups according to their history of opioid use: 1) current opioid use — past 30 day opioid use; 2) «ever» opioid use — no use in past 30 days; 3) «never» opioid use. Results. Рarticipants with current opioid use had higher log-transformed IL-6 (0,4 [ s 1,0]; p&lt;0,0001) and D-dimer (-0,6 [ s 0,9]; p&lt;0,0001) levels than participants who reported «ever» (-0,1 [ s 1,0] and -0,9 [ s 0,8]), or «never» (-0,4 [ s 0,7] and 1,3 [ s 0,7]) opioid use. Conclusion. Оpioid use in HIV-positive participants is associated with higher inflammatory response.

LncRNA MALAT1 promotes high glucose-induced inflammatory response of microglial cells via provoking MyD88/IRAK1/TRAF6 signaling

Although a large number of studies have confirmed from multiple levels that diabetes mellitus (DM) promotes cerebral ischemic reperfusion (I/R) injury, but the precise mechanism is still unclear. A cerebral I/R injury model in diabetic rats was established. The neurological deficit scores and brain edema were monitored at 24 and 72 hours after injury. The peri-infarct cortical tissues of rats were isolated for molecular biology detection. The rat primary microglia and microglia line HAPI were cultured to establish the cell model of DM-I/R by high glucose (HG) and hypoxia-reoxygenation (H/R). The endogenous expression of MALAT1 and MyD88 was regulated by the transfection with pcDNA-MALAT1, si-MALAT1 and si-MyD88, respectively. The cerebral I/R injury model in diabetic rats had more severe neuronal injury as shown by the significantly higher neurological deficit scores and an obvious increasing brain edema at 24 and 72 hours after injury. Moreover, the microglia were activated and induced a large number of inflammatory cytokines TNF-α, IL-1β and IL-6 in the peri-infarct cortical tissues during cerebral I/R injury associated with DM. The expression of MALAT1, MyD88, IRAK1 and TRAF6 protein were significantly up-regulated by DM-I/R in vitro and in vivo. Furthermore, the HG-H/R-induced MALAT1 promoted the inflammatory response in microglia via MyD88/IRAK1/TRAF6 signaling. Our results suggested that MALAT1 mediated the exacerbation of cerebral I/R injury induced by DM through triggering the inflammatory response in microglia via MyD88 signaling.

NOD2-mediated downregulation of the TLR pathways contributes to protection against colitis and colorectal tumorigenesis

Abstract NOD-like receptor family member NOD2, which activates the NF-kB and MAPK signaling pathways in response to the bacterial cell wall component MDP, is the first identified inflammatory bowel disease (IBD) susceptibility gene. IBD is a risk factor for colorectal tumorigenesis. However, the role of NOD2 in colorectal tumorigenesis has not been studied adequately and the precise mechanism of NOD2-mediated protection against IBD is elusive. We studied the role of NOD2 in colorectal tumorigenesis using azoxymethane plus dextran sulfate sodium-induced colorectal tumorigenesis in mice. We found that Nod2-deficient mice are highly susceptible to colorectal tumorigenesis with increased tumor burden as compared to wild-type mice. Interestingly, increased tumorigenesis in Nod2−/− mice was independent of gut microbial composition. Increased tumorigenesis in Nod2-deficient mice was associated with higher inflammatory responses and activation of the inflammatory signaling pathways, such as NF-kB, ERK, and STAT3. Consistently, in vitro studies demonstrate that while NOD2 activates NF-kB and ERK in response to MDP, it inhibits TLR-mediated activation of NF-kB and ERK, and production of inflammatory mediators. Notably, NOD2-mediated downregulation of TLR signaling pathways is independent of MDP-mediated activation of NOD2. We further explored the underlying mechanism of NOD2-mediated downregulation of TLR signaling and revealed that NOD2 induces IRF4 which negatively regulates TLR-NF-kB signaling axis. Taken together, this study therefore shed light on a novel function of NOD2 which may be implicated in genetic association of NOD2 mutations with IBD and colorectal cancer.

Bacillus licheniformis in geogenic dust induces inflammation in respiratory epithelium

Exposure to environmental geogenic (or earth-derived) dust can lead to more frequent and severe infections in the human airway. Particulate matter < 10 µm (PM10) is the component of air pollution that is commonly associated with the exacerbation of respiratory diseases. We have previously demonstrated that mice exposed to geogenic dust PM10 experienced an exacerbation of inflammatory responses to influenza A virus. Whether geogenic dust PM10 also exacerbates respiratory bacterial infection is not yet known, nor are the components of the dust that drive these responses.We treated airway bronchial epithelial cells (NuLi-1) with UV-irradiated geogenic dust PM10 from six remote Western Australian towns. High levels of IL-6 and IL-8 production were observed, as well as persistent microbial growth. 16 S rRNA sequencing of the growth identified the microbe as Bacillus licheniformis, a spore-forming, environmentally abundant bacterium. We next investigated the interaction of B. licheniformis with respiratory epithelium in vitro to determine whether this exacerbated infection with a bacterial respiratory pathogen (non-typeable Haemophilus influenzae, NTHi).Heat treatment (100 °C) of all PM10 samples eliminated B. licheniformis contamination and reduced epithelial inflammatory responses, suggesting that heat-labile and/or microbial factors were involved in the host response to geogenic dust PM10. We then exposed NuLi-1 epithelium to increasing doses of the isolated Bacillus licheniformis (multiplicity of infection of 10:1, 1:1 or 0.1:1 bacteria: cells) for 1, 3, and 24 h. B. licheniformis and NTHi infection (association and invasion) was assessed using a standard gentamicin survival assay, and epithelial release of IL-6 and IL-8 was measured using a bead based immunoassay.B. licheniformis was cytotoxic to NuLi-1 cells at 24 h. At 3 h post-challenge, B. licheniformis elicited high IL-6 and IL-8 inflammatory responses from NuLi-1 cells compared with cells treated with heat-treated geogenic dust PM10 (p < 0.0001). Whilst treatment of cells with B. licheniformis increased inflammation, this did not make the cells more susceptible to NTHi infection. This study highlights that geogenic dust PM10 can harbour viable bacterial spores that induce inflammation in respiratory epithelium. The impact on respiratory health from inhalation of bacterial spores in PM10 in arid environments may be underestimated. Further investigation into the contribution of B. licheniformis and the wider dust microbiome to respiratory infection is warranted.

Environmental exposure to polycyclic aromatic hydrocarbons, kitchen ventilation, fractional exhaled nitric oxide, and risk of diabetes among Chinese females.

Diabetes is related to exposure to polycyclic aromatic hydrocarbons (PAHs), inflammation in the body, and housing characters. However, associations of urinary monohydroxy-PAHs (OH-PAHs) or fractional exhaled nitric oxide (FeNO) with diabetes risk in relation to housing characters are unclear. In this study, 2645 individuals were drawn from the baseline survey of the Wuhan-Zhuhai Cohort Study. Associations of diabetes with urinary OH-PAHs or FeNO among cooking participants were estimated using logistic regression models. Among women with self-cooking meals, urinary OH-PAH levels were positively associated with diabetes risk (P<.05); the cooking women with high FeNO (≥25ppb) had a 59% increase in the risk of diabetes (OR: 1.59, 95% CI: 1.06, 2.38), compared with those with low FeNO (<25ppb). The cooking women with use of kitchen exhaust fans/hoods had a 52% decrease in the risk of diabetes (OR: 0.48, 95% CI: 0.27, 0.84), compared with those with nonuse of kitchen exhaust fans/hoods. The results indicated that the cooking women had an elevated risk of diabetes, which may be partly explained by an increase in the PAH body burden and higher inflammatory responses. Use of kitchen exhaust fan/hood can be associated with a lower risk of diabetes.

Bone Turnover Status: Classification Model and Clinical Implications.

Aim: To develop a practical model for classification bone turnover status and evaluate its clinical usefulness.Methods: Our classification of bone turnover status is based on internationally recommended biomarkers of both bone formation (N-terminal propeptide of type1 procollagen, P1NP) and bone resorption (beta C-terminal cross-linked telopeptide of type I collagen, bCTX), using the cutoffs proposed as therapeutic targets. The relationships between turnover subtypes and clinical characteristic were assessed in1223 hospitalised orthogeriatric patients (846 women, 377 men; mean age 78.1±9.50 years): 451(36.9%) subjects with hip fracture (HF), 396(32.4%) with other non-vertebral (non-HF) fractures (HF) and 376 (30.7%) patients without fractures.Resalts: Six subtypes of bone turnover status were identified: 1 - normal turnover (P1NP>32 μg/L, bCTX≤0.250 μg/L and P1NP/bCTX>100.0[(median value]); 2- low bone formation (P1NP ≤32 μg/L), normal bone resorption (bCTX≤0.250 μg/L) and P1NP/bCTX>100.0 (subtype2A) or P1NP/bCTX<100.0 (subtype 2B); 3- low bone formation, high bone resorption (bCTX>0.250 μg/L) and P1NP/bCTX<100.0; 4- high bone turnover (both markers elevated ) and P1NP/bCTX>100.0 (subtype 4A) or P1NP/bCTX<100.0 (subtype 4B). Compared to subtypes 1 and 2A, subtype 2B was strongly associated with nonvertebral fractures (odds ratio [OR] 2.0), especially HF (OR 3.2), age>75 years and hyperparathyroidism. Hypoalbuminaemia and not using osteoporotic therapy were two independent indicators common for subtypes 3, 4A and 4B; these three subtypes were associated with in-hospital mortality. Subtype 3 was associated with fractures (OR 1.7, for HF OR 2.4), age>75 years, chronic heart failure (CHF), anaemia, and history of malignancy, and predicted post-operative myocardial injury, high inflammatory response and length of hospital stay (LOS) above10 days. Subtype 4A was associated with chronic kidney disease (CKD), anaemia, history of malignancy and walking aids use and predicted LOS>20 days, but was not discriminative for fractures. Subtype 4B was associated with fractures (OR 2.1, for HF OR 2.5), age>75 years, CKD and indicated risks of myocardial injury, high inflammatory response and LOS>10 days.Conclusions: We proposed a classification model of bone turnover status and demonstrated that in orthogeriatric patients altered subtypes are closely related to presence of nonvertebral fractures, comorbidities and poorer in-hospital outcomes. However, further research is needed to establish optimal cut points of various biomarkers and improve the classification model.