Inflammatory Cell Types Research Articles

Matricellular proteins in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is typically characterized by a prominent desmoplastic stroma that is often the most dominant feature of the tumor. This tumor reactive stroma is comprised of a dense fibro-collagenous-enriched extracellular matrix (ECM) surrounding the cancer cells, together with other ECM proteins/peptides, specifically secreted matricellular glycoproteins and proteolytic enzymes, growth factors, and cytokines. Moreover, as enjoined by cholangiocarcinoma cells, this enriched tumor microenvironment is populated by various stromal cell types, most prominently, cancer-associated myofibroblasts (CAFs), along with variable numbers of tumor-associated macrophages (TAMs), inflammatory and vascular cell types. While it is now well appreciated that the interplay between cholangiocarcinoma cells, CAFs, and TAMs in particular play a critical role in promoting cholangiocarcinoma progression, therapeutic resistance, and immune evasion, it is also becoming increasingly evident that over-expression and secretion into the tumor microenvironment of functionally overlapping matricellular glycoproteins, including periostin, osteopontin, tenascin-C, thrombospondin-1, mesothelin and others have an important role to play in regulating or modulating a variety of pro-oncogenic cellular functions, including cholangiocarcinoma cell proliferation, invasion, and metastasis, epithelial-mesenchymal transition, ECM remodeling, and immune evasion. Matricellular proteins have also shown promise as potential prognostic factors for iCCA and may provide unique therapeutic opportunities particularly in relation to targeting iCCA pre-metastatic and metastatic niches, tumor cell dormancy, and immune evasion. This review will highlight timely research and its translational implications for salient matricellular proteins in terms of their structure-function relationships, as modulators of intrahepatic cholangiocarcinoma microenvironment and progression, and potential clinical value for iCCA prognosis and therapy.

Tuberculosis: Role of Nuclear Medicine and Molecular Imaging With Potential Impact of Neutrophil-Specific Tracers.

With Tuberculosis (TB) affecting millions of people worldwide, novel imaging modalities and tools, particularly nuclear medicine and molecular imaging, have grown with greater interest to assess the biology of the tuberculous granuloma and evolution thereof. Much early work has been performed at the pre-clinical level using gamma single photon emission computed tomography (SPECT) agents exploiting certain characteristics of Mycobacterium tuberculosis (MTb). Both antituberculous SPECT and positron emission tomography (PET) agents have been utilised to characterise MTb. Other PET tracers have been utilised to help to characterise the biology of MTb (including Gallium-68-labelled radiopharmaceuticals). Of all the tracers, 2-[18F]FDG has been studied extensively over the last two decades in many aspects of the treatment paradigm of TB: at diagnosis, staging, response assessment, restaging, and in potentially predicting the outcome of patients with latent TB infection. Its lower specificity in being able to distinguish different inflammatory cell types in the granuloma has garnered interest in reviewing more specific agents that can portend prognostic implications in the management of MTb. With the neutrophil being a cell type that portends this poorer prognosis, imaging this cell type may be able to answer more accurately questions relating to the tuberculous granuloma transmissivity and may help in characterising patients who may be at risk of developing active TB. The formyl peptide receptor 1(FPR1) expressed by neutrophils is a key marker in this process and is a potential target to characterise these areas. The pre-clinical work regarding the role of radiolabelled N-cinnamoyl –F-(D) L – F – (D) –L F (cFLFLF) (which is an antagonist for FPR1) using Technetium 99m-labelled conjugates and more recently radiolabelled with Gallium-68 and Copper 64 is discussed. It is the hope that further work with this tracer may accelerate its potential to be utilised in responding to many of the current diagnostic dilemmas and challenges in TB management, thereby making the tracer a translatable option in routine clinical care.

Meteorin-β/Meteorin like/IL-41 attenuates airway inflammation in house dust mite-induced allergic asthma.

We sought to examine the regulatory effect of Meteorin-β (Metrnβ)/Meteorin like (Metrnl)/IL-41 on lung inflammation in allergic asthma. We found that Metrnβ was elevated significantly in asthmatic patients and in mice with allergic asthma induced by house dust mite (HDM) extract. Upon exposure to HDM, Metrnβ was secreted predominantly by airway epithelial cells and inflammatory cells, including macrophages and eosinophils. The increased Metrnβ effectively blocked the development of airway hyperreactivity (AHR) and decreased inflammatory cell airway infiltration and type 2 cytokine production, which was associated with downregulated DC-mediated adaptive immune responses. Moreover, Metrnβ impaired the maturation and function of bone marrow-derived dendritic cells in vitro. Asthmatic mice adoptively transferred with dendritic cells isolated from Metrnβ-treated allergic mice displayed decreased AHR, airway inflammation, and lung injury. Metrnβ also displayed anti-inflammatory properties in immunodeficient SCID mice with allergic asthma and in in vitro 3D ALI airway models. Moreover, blockade of Metrnβ by anti-Metrnβ antibody treatment promoted the development of allergic asthma. These results revealed the unappreciated protective roles of Metrnβ in alleviating DC-mediated Th2 inflammation in allergic asthma, providing the novel treatment strategy of therapeutic targeting of Metrnβ in allergic asthma.

Sanse Powder Essential Oil Nanoemulsion Negatively Regulates TRPA1 by AMPK/mTOR Signaling in Synovitis: Knee Osteoarthritis Rat Model and Fibroblast-Like Synoviocyte Isolates.

Synovitis is the primary driving factor for the occurrence and development of knee osteoarthritis (KOA) and fibroblast-like synoviocytes (FLSs) and plays a crucial role during this process. Our previous works revealed that transient receptor potential ankyrin 1 (TRPA1) ion channels mediate the amplification of KOA synovitis. In recent years, essential oils have been proved to have blocking effect on transient receptor potential channels. Meanwhile, the therapeutic effect of Sanse Powder on KOA synovitis has been confirmed in clinical trials and basic studies; although, the mechanism remains unclear. In the present study, Sanse Powder essential oil nanoemulsion (SP-NEs) was prepared, and then chemical composition, physicochemical properties, and stability were investigated. Besides, both in MIA-induced KOA rats and in LPS-stimulated FLSs, we investigated whether SP-NES could alleviate KOA synovitis by interfering with AMP-activated protein kinase- (AMPK-) mammalian target of rapamycin (mTOR), an energy sensing pathway proved to negatively regulate the TRPA1. Our research shows that the top three substances in SP-NEs were tumerone, delta-cadinene, and Ar-tumerone, which accounted for 51.62% of the total, and should be considered as the main pharmacodynamic ingredient. Less inflammatory cell infiltration and type I collagen deposition were found in the synovial tissue of KOA rats treated with SP-NEs, as well as the downregulated expressions of interleukin (IL)-1β, IL-18, and TRPA1. Besides, SP-NEs increased the phosphorylation level of AMPK and decreased the phosphorylation level of mTOR in the KOA model, and SP-NEs also upregulated expressions of peroxisome proliferator-activated receptor-gamma (PPARγ) and PPARγ coactivator-1α and downstream signaling molecules of AMPK-mTOR in vivo and in vitro. To conclude, a kind of Chinese herbal medicine for external use which is effective in treating synovitis of KOA was extracted and prepared into essential oil nanoemulsion with stable properties in the present study. It may alleviate synovitis in experimental KOA through the negative regulation of TRPA1 by AMPK-mTOR signaling.

Study of haemoflagellates Trypanosoma sp. infection in some fish of Iraq marshes and relationship of leukocytes with inflammatory response

Fresh water fishes infected with different species of genus Trypanosoma parasite that is similar to that same genus in blood of mammals. Trypanosomiasis or sleeping sickness disease that causes by protozoa flagellate parasites which live inside cell called Trypanosoma. Fish parasites play an important role in regulating the population of their hosts. This study was implemented to verify the infection with Trypanosoma sp. report the cellular intervening through inflammatory response in blood smears of infected fishes. A total of 190 fishes of three species Carasobarbus luteus, Aspius vorax and Liza abu were collected from Al-Hamare and Al-Chibayish marsh south of Iraq. The flagellate parasite Trypanosoma sp. observed in blood of Carasobarbus luteus 41.42% and Aspius vorax 12.28% fishes, while no infection was recorded with Trypanosoma sp. in Liza abu fishes. Prevalence and mean intensity of infection were calculated. The different counts and various types of inflammatory cells were monitored, there are increased in lymphocytes in the infected fishes. Statistically, there are significant differences (p<0.05) among species of infected fish with Trypanosoma sp.

The histopathological spectrum of myocardial inflammation in relation to circumstance of death: a retrospective cohort study in clinical and forensic autopsies

Interpreting a myocardial inflammation as causal, contributory or as of no significance at all in the cause of death can be challenging, especially in cases where other pathologic and/or medico-legal findings are also present. To further evaluate the significance of myocardial inflammation as a cause of death we performed a retrospective cohort study of forensic and clinical autopsy cases. We revised the spectrum of histological inflammatory parameters in the myocardium of 79 adult autopsy cases and related these to the reported cause of death. Myocardial slides were reviewed for the distribution and intensity of inflammatory cell infiltrations, the predominant inflammatory cell type, and the presence of inflammation-associated myocyte injury, fibrosis, edema and hemorrhage. Next, the cases were divided over three groups, based on the reported cause of death. Group 1 (n = 27) consisted of all individuals with an obvious unnatural cause of death. Group 2 (n = 29) included all individuals in which myocarditis was interpreted to be one out of more possible causes of death. Group 3 (n = 23) consisted of all individuals in which myocarditis was reported to be the only significant finding at autopsy, and no other cause of death was found. Systematic application of our histological parameters showed that only a diffuse increase of inflammatory cells could discriminate between an incidental presence of inflammation (Group 1) or a potentially significant one (Groups 2 and 3). No other histological parameter showed significant differences between the groups. Our results suggest that generally used histological parameters are often insufficient to differentiate an incidental myocarditis from a (potentially) significant one.

Inhibiting Glucose Metabolism Results in Herpes Simplex Encephalitis.

This report evaluates how HSV enters the brain to cause herpes simplex encephalitis following infection at a peripheral site. We demonstrate that encephalitis regularly occurred when BALB/c mice were infected with HSV and treated daily with 2-deoxy-d-glucose (2DG), which inhibits glucose use via the glycolysis pathway. The outcome of infection in the trigeminal ganglion (TG), the site to which the virus spreads, replicates, and establishes latency, showed marked differences in viral and cellular events between treated and untreated animals. In control-untreated mice, the replicating virus was present only during early time points, whereas in 2DG recipients, replicating virus remained for the 9-d observation period. This outcome correlated with significantly reduced numbers of innate inflammatory cells as well as T cells in 2DG-treated animals. Moreover, T cells in the TG of treated animals were less activated and contained a smaller fraction of expressed IFN-γ production compared with untreated controls. The breakdown of latency was accelerated when cultures of TG cells taken from mice with established HSV latency were cultured in the presence of 2DG. Taken together, the results of both in vivo and in vitro investigations demonstrate that the overall effects of 2DG therapy impaired the protective effects of one or more inflammatory cell types in the TG that normally function to control productive infection and prevent spread of virus to the brain.

Study protocol: effect of infection, Modic and inflammation on clinical outcomes in surgery for radiculopathy (EIMICOR)

BackgroundEvidence indicates that inflammatory processes are involved in radicular pain as well as in resorption of herniated disc tissue. Furthermore there are indications that the presence of vertebral end plate pathology (Modic changes; MC) is associated with a negative effect on inflammation. It is hypothesized that in patients with MC, the (possibly bacterial induced) inflammation will be accompanied by pro inflammatory cytokines that worsen the outcome, and that in patients without MC, the inflammation is accompanied by cytokines that induce a resorption process to accelerate recovery.MethodsThis prospective cohort study will include 160 lumbar and 160 cervical patients (total of 320), which are scheduled for surgery for either a lumbar or cervical herniated disc with ages between 18 and 75. The main and interaction effects of local bacterial infection (culture), inflammatory cells in disc material (immunohistology), MC (MRI), and blood biomarkers indicating inflammation or infection (blood sample evaluation) will be evaluated. Clinical parameters to be evaluated are leg pain on the 11 point NRS pain scale, Oswestry (lumbar spine) or Neck (cervical spine) Disability Index, Global Perceived Recovery, Womac Questionnaire, and medication status, at baseline, and after 6, 16, 26 and 52 weeks.DiscussionGaining insight in the aetiology of pain and discomfort in radiculopathy caused by a herniated disc could lead to more effective management of patients. If the type of inflammatory cells shows to be of major influence on the rate of recovery, new immunomodulating treatment strategies can be developed to decrease the duration and intensity of symptoms. Moreover, identifying a beneficial inflammatory response in the disc through a biomarker in blood could lead to early identification of patients whose herniations will resorb spontaneously versus those that require surgery.Trial registrationprospectively enrolled at trialregister.nl, ID:NL8464.

Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease

Fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), are global health disparities, particularly in the United States, as a result of cultural eating habits and lifestyle. Pathological studies on NAFLD have been mostly focused on hepatocytes and other inflammatory cell types; however, the impact of other biliary epithelial cells (i.e., cholangiocytes) in the promotion of NAFLD is growing. This review article will discuss how cholestatic injury and cholangiocyte activity/ductular reaction influence NAFLD progression. Furthermore, this review will provide informative details regarding the fundamental properties of cholangiocytes and bile acid signaling that can influence NAFLD. Lastly, studies relating to the pathogenesis of NAFLD, cholangiopathies, and ductular reaction will be analyzed to help gain insight for potential therapies.

Inhaled Dual Phosphodiesterase 3/4 Inhibitors for the Treatment of Patients with COPD: A Short Review.

Current pharmacological treatments for chronic obstructive pulmonary disease (COPD) are mostly limited to inhaled bronchodilators and corticosteroids. Azithromycin can contribute to exacerbation prevention. Roflumilast, a phosphodiesterase (PDE) 4 inhibitor administered orally, also prevents exacerbations in selected patients with chronic bronchitis, recurrent exacerbations, severe airflow limitation and concomitant therapy with long-acting inhaled bronchodilators. This outcome likely results from anti-inflammatory effects since PDE4 is expressed by all inflammatory cell types involved in COPD. The use of this agent is, however, limited by side-effects, particularly nausea and diarrhea. To address remaining unmet needs and enrich therapeutic options for patients with COPD, inhaled dual PDE3/4 inhibitors have been developed, with the aim of enhancing bronchodilation through PDE3 inhibition and modulating inflammation and mucus production though PDE4 inhibition, thus producing a potentially synergistic effect on airway calibre. Experimental preclinical data confirmed these effects in vitro and in animal models. At present, RPL554/ensifentrine is the only agent of this family in clinical development. It decreases sputum markers of both neutrophilic and eosinophilic inflammation in patients with COPD. Clinical Phase II trials confirmed its bronchodilator effect and demonstrated clinically meaningful symptom relief and quality of life improvements in these patients. The safety profile appears satisfactory, with less effects on heart rate and blood pressure than salbutamol and no other side effect. Altogether, these data suggest that ensifentrine could have a role in COPD management, especially in addition to inhaled long-acting bronchodilators with or without corticosteroids since experimental studies suggest potentiation of ensifentrine effects by these agents. However, results from ongoing and future Phase III studies are needed to confirm both beneficial effects and favourable safety profile on a larger scale and assess other outcomes including exacerbations, lung function decline, comorbidities and mortality.

Novel Bacterial Cellulose Membrane to Reduce Fibrosis Following Trabeculectomy.

The aim was to evaluate the effectiveness of bacterial cellulose membrane (BCM) in preventing fibrosis in trabeculectomy and the biocompatibility of BCM with conjunctiva and sclera. Twenty-one eyes of 21 adult rabbits underwent fornix-based trabeculectomy. Standard surgery was done to control group (CG, n=7). Mitomycin-C (MMC) (0.3 mg/mL, 3 min) was applied to MMC group only (MMCG, n=7). BCM (~100 µm thick, 10×10 mm, single layer) was covered on the sclerotomy area before conjunctiva was closed in BCM group (BCMG, n=7). Intraocular pressures (IOP) were measured before, and 7, 14, 28, and 45 days after surgery (IOP-POD7, POD14, POD28, POD45). The IOP decrease were expressed as DIOP%-POD7, DIOP%-POD14, DIOP%-POD28, and DIOP%-POD45. The rabbits were sacrificed on the 45th day. Conjunctival vessel number, degrees of fibrosis, total inflammation, foreign body reaction, inflammatory cell types (B cells, T cells, plasma cells), macrophages, bleb spaces and the expression of α-smooth muscle actin were studied using histopathology and immunohistochemistry techniques. The groups were compared using nonparametric tests. There was no statistically significant difference between the groups regarding baseline IOP and DIOP%-POD7 (P>0.05). While DIOP%-POD14, 28 and 45 were similar between BCMG and MMCG, they were significantly lower in CG (P<0.05). The lowest conjunctival vessel number was detected in the MMCG but the difference was not significant. There was no difference between BCMG and CG with regard to the numbers of B cells, T cells, and macrophages, however, these cells were significantly lower in MMCG (P<0.05). Five cases had mild and 2 cases had moderate foreign body reaction in the BCMG. There was mild to moderate inflammation in all BCM cases. While fibrosis and α-smooth muscle actin staining were higher in the CG (P<0.001), they were minimal in the BCM and MMCGs. BCM showed good biocompatibility and provided better control of IOP with minimal fibrosis at the trabeculectomy site compared with the control group.

CD101 genetic variants modify regulatory and conventional T cell phenotypes and functions

SummaryWe recently reported that the risk of sexually acquired HIV-1 infection is increased significantly by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with and without these variants, we demonstrate that CD101 variants modify the prevalence of circulating inflammatory cell types and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T cells. One category of CD101 variants is associated with a reduced capacity of regulatory T cells to suppress T cell cytokine production, resulting in a reduction in the baseline level of immune quiescence. These data are supported by transcriptomics data revealing alterations in the intrinsic regulation of antiviral pathways and HIV resistance genes in individuals with CD101 variants. Our data support the hypothesis that CD101 contributes to homeostatic regulation of bystander inflammation, with CD101 variants altering heterosexual HIV-1 acquisition by facilitating increased prevalence and altered function of T cell subsets.

FC 049A RANDOMISED DOSE RANGING, PLACEBO-CONTROLLED, PHASE II STUDY ASSESSING THE EFFICACY AND SAFETY OF BI 655064, AN ANTAGONISTIC ANTI-CD40 ANTIBODY, IN PATIENTS WITH LUPUS NEPHRITIS

Abstract Background and Aims In patients (pts) with SLE, activation of the CD40–CD40L pathway results in stimulation and proliferation of B cells and other inflammatory cell types. The subsequent generation of autoantibodies and their deposition in the kidney, as well as activation of myeloid and resident kidney cells, result in local inflammation and eventually, kidney injury. Thus, CD40 is an appealing therapeutic target in lupus nephritis (LN). BI 655064 is a humanised anti-CD40 monoclonal antibody that blocks the CD40 pathway in a nanomolar range and downregulates activated B cells. This study assessed the efficacy and safety over 52 weeks (wks) of three doses of subcutaneous BI 655064 compared with placebo, as add-on to mycophenolate and steroids, in pts with active proliferative LN (ClinicalTrials.gov number: NCT02770170). Method Overall, 121 pts with LN were randomised, double blind, in a 2:1:1:2 ratio to placebo or BI 655064 120 mg, 180 mg or 240 mg, and received a weekly loading dose for the first 3 wks, followed by dosing every 2 wks for the 120 and 180 mg doses, and weekly (120 mg) for the 240 mg group. Key inclusion criteria included an active ISN/RPS class III or IV (±V) renal biopsy within 3 months prior to screening and a screening protein/creatinine ratio of ≥1 mg/mg. Randomisation was stratified based on race (Asian vs non-Asian) and screening protein/creatine (UP/UC) ratio (&amp;lt;3 vs ≥3). The primary efficacy endpoint was complete renal response (CRR), defined as 24 h proteinuria &amp;lt;0.5 g/day and stable eGFR at Wk 52. Results The placebo response in this trial was higher than expected (48.3%; Table 1); none of the BI 655064 doses increased rates of CRR at Wk 52 compared with placebo. However, CRR at Wk 52 based on creatinine-adjusted proteinuria, assessed using spot urine, showed a better response in the 180 mg group (50%) vs placebo (42.5%), and the 180 mg dose showed a greater change from baseline over time vs placebo from Wk 4. Time to CRR was shorter in the 180 mg group (17.3 wks) vs placebo (20.4 wks). The 180 mg group also showed improvement vs placebo in total SLEDAI (SELENA) and its subscores. The unexpected high placebo response prompted a post hoc analysis evaluating confirmed CRR (cCRR), whereby confirmation of the endpoint was required at both Wks 46 (penultimate visit on treatment) and 52. A 15.2% higher cCRR in the 180 mg group (44.3%) vs placebo (29.1%) was observed (p=0.26). While based on a small sample size, there were more reports of infection-related severe and serious adverse events and neutropenia in the 240 mg group compared with placebo. Of note, in those who experienced neutropenia, a clinical impact (e.g. increase in infections) was not established. Aside from these observations, safety data were comparable across treatment groups. Larger decreases from baseline were observed in the percentage of CD27−IgD−CD95+, CD27−IgD+CD95+, CD27+IgD+CD95+ and CD27+IgD−CD95+ B-cell subsets in the 180 and 240 mg groups compared with placebo. Treatment-emergent anti-drug antibodies (ADAs) were detected in five pts treated with BI 655054, all at low titre, and in one who received placebo; ADAs had no impact on pharmacokinetics or safety. Conclusion The trial did not meet its primary CRR endpoint. However, when confirmation of CRR was required at both Wks 46 and 52, the resultant decrease in the placebo response generated an effect size of 15.2% and 9.1% in favour of 180 mg and 240 mg BI 655064, respectively.

P137 Preliminary validation of a multi-stage machine learning algorithm to assess histological inflammation in inflammatory bowel disease

Abstract Background The histologic assessment of inflammatory bowel disease (IBD) relies on qualitative grading methods. Although widely accepted, these instruments are time consuming, require specialized training, and suffer from inter-rater disagreement. For these reasons there is a need for more consistent and less biased methods to assess IBD histology. Methods The algorithm was initially developed using hematoxylin and eosin (H&amp;E) stained whole slide images of colon biopsies (238 ulcerative colitis [UC], 30 Crohn’s Disease [CD], and 28 endoscopically normal adjacent [ENA]). The first two stages implement convolutional neural networks (CNN) which segment 11 key anatomical features (Figure 1). The third stage extracts the features and models them for prediction. Results The first stage of the algorithm was validated on an independent test dataset by calculating the intersection-over-union (IoU) for the ground truth and prediction masks, resulting in a value of 0.97. A preliminary validation for stage 2 was performed by randomly selecting 30 unique biopsy sections from the test dataset and applying a 150um x 150um counting frame. An expert gastrointestinal pathologist confirmed correct cell identification by the algorithm for three of the primary inflammatory cell types: plasma cells, eosinophils, and neutrophils which resulted in a sensitivity/specificity of 0.76/0.99, 0.78/1.00, and 1.00/0.98 respectively. The final stage predicts RHI grades which could be directly compared to pathologist reads (Figure 2, 3, and 4). Conclusion This is the first study to demonstrate the value of machine learning to assess histologic activity in IBD. These methods lay the foundations for future work, and we believe stages 1 and 2 can be explored independently to statistically characterize the histologic changes of IBD, enabling the improvement of preexisting grading systems.

POS0687 A RANDOMISED DOSE RANGING, PLACEBO-CONTROLLED, PHASE II STUDY ASSESSING THE EFFICACY AND SAFETY OF BI 655064, AN ANTAGONISTIC ANTI-CD40 ANTIBODY, IN PATIENTS WITH LUPUS NEPHRITIS

POS0687 A RANDOMISED DOSE RANGING, PLACEBO-CONTROLLED, PHASE II STUDY ASSESSING THE EFFICACY AND SAFETY OF BI 655064, AN ANTAGONISTIC ANTI-CD40 ANTIBODY, IN PATIENTS WITH LUPUS NEPHRITIS

Increased intestinal permeability with elevated peripheral blood endotoxin and inflammatory indices for e-waste lead exposure in children

Lead (Pb) entering the body through different channels can damage the function of intestinal mucosal barrier and cause the body stressful inflammatory response to enhance. This study conducted a cross-sectional study to investigate the effects of Pb exposure on intestinal permeability in children by measuring the level of bacterial endotoxin and index of inflammatory cell types in peripheral blood. From November to December 2018, we recruited 187 participants aged 3–6 years by stratified randomization, from an electronic-waste-exposed group (n = 82) and a referent group (n = 105). General demographic information, past history of the digestive system in child, and family situation were informed by children's guardians with questionnaires. Children in the exposed group showed lower weight, height, and body mass index while more diarrhea in a month. Blood Pb and plasma endotoxin were elevated in exposed children than referent children and the positive relationship between them was shown in all children [B (95% CI): 0.072 (0.008, 0.137), P = 0.033]. Peripheral monocyte counts and leukotriene B4 (LTB4) levels were significantly increased in the exposed group. Endotoxin levels were positively correlated with neutrophils, monocytes, and LTB4 [B (95% CI): 0.054 (0.015, 0.093), 0.018 (0.005, 0.031), and 0.049 (0.011, 0.087), respectively, P < 0.05]. To sum up, the exposed children showed lower physical growth levels, poorer gut health, and increased intestinal permeability, which was related to high blood Pb and peripheral inflammatory indices. These results suggest the possible adverse impact of environmental Pb exposure on the intestinal health of children.

Immune-metabolome response to an acute exercise exertion reveals dysfunctional metabolic recovery in heart failure

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): BMBF Background Patients with heart failure with reduced ejection fraction (HFrEF) have an increased inflammatory load and impaired cardiac oxidative lipid phosphorylation. Early dysregulations of pathophysiological alterations may not be detectable if patients are assessed under resting conditions. Purpose We exposed HFrEF patients to a physical exertion challenge by cardiopulmonary exercise testing (CPET) and determined inflammatory and metabolic parameters before, during and 2 hours after the test. Methods A symptom-limited CPET was performed in participants with HFrEF (n = 16) and age and sex matched controls (CON, n = 13). In addition to clinical and physiological parameters, we assessed blood counts of leukocyte subtypes, their morphology, aggregation with platelets and microvesicle release, as well as plasma cytokines and metabolites at baseline (T1), immediately after CPET (T2), and after 2 hours of rest (T3). Inflammatory and metabolic parameters were measured using the ThermoFischer ProcartaPlex Human Inflammation-Panel and Biocrates MxP® Quant 500 kit, respectively. Non-parametric tests were chosen and all multiple tests were adjusted by the Benjamini-Hochberg method. Results Cardiovascular risk profile of HFrEF and CON was similar. In agreement with the definition for HFrEF, these patients had a lower EF and a greater left ventricular enddiastolic diameter compared to CON. There were no differences between groups for leukocyte, cytokine or metabolic parameters at T1. Immediately after CPET, 20 parameters were significantly increased in both groups, including an increase of lactate, natural killer (NK) and NK T cell blood counts. In addition, 131 inflammatory and metabolic parameters were upregulated only in HFrEF, as compared to only 17 in CON. In HFrEF-platelet aggregates with NK cells, CD8+ cytotoxic T cells and "classical" CD14++CD16-monocytes, 58 different phosphatidylcholines and 21 triglycerides were upregulated immediately after exercise. At T3 almost all altered parameters returned to baseline in CON while in HFrEF blood counts and morphological markers of inflammatory effector cell types, including NK cells, CD8+ T cells and neutrophils, as well as genomic nuclear DNA, an indicator of cell death, remained elevated. Moreover, several triglycerides did not return to baseline in HFrEF after a 2-hour resting period. In these patients, but not in CON, the different lipids (i.e. phosphatidylcholine, triglycerides) strongly correlated with pro-inflammatory cytokines and NK cells. Conclusion Our data support the concept of impaired fatty acid utilization and inflammation-mediated metabolic dysregulation in HFrEF. However, the correlations between metabolic and inflammatory parameters were not detected at baseline in comparison to a control group with similar cardiovascular risk profile. Therefore, investigating patients in response to a physical or metabolic challenge might reveal early pathological changes.

Hepatic Histopathology Among Excessive Drinkers Without Advanced Liver Disease.

Alcohol-associated liver disease represents a spectrum of histopathological changes from steatosis to advanced fibrosis and cirrhosis. The major goals of this retrospective study were to characterize the histologic features in patients with excessive alcohol use who presented with an abnormal hepatic panel and/or abnormal radiographic imaging and did not meet the clinical diagnosis of alcoholic hepatitis or cirrhosis. We performed a retrospective study to describe hepatic histology of 62 and 83 excessive drinkers with normal and abnormal serum aspartate transaminase, respectively. The types of inflammatory cells in the liver were characterized by immunohistochemistry for CD4, CD8, CD20, CD68 and myeloperoxidase. Among 62 patients with aspartate aminotransferase (AST)≤50U/L, 37% had histological evidence of steatosis. Of these, we found evidence of hepatocyte ballooning (21%), lobular inflammation (50%), portal inflammation (52%) and fibrosis (14%). For those with AST>50U/L, the presence of hepatic steatosis, lobular inflammation and portal inflammation was observed in 29, 60 and 69% of patients, respectively. Fibrosis was found in 33%, four with bridging fibrosis, and one with cirrhosis. We observed the aggregation of CD68+ macrophages, rather than normally distributed with minimal neutrophilic infiltration. Lobular and portal lymphocytic infiltrations are primarily CD8+ T cells. Abnormal hepatic histopathology occurs in excessive drinkers with normal transaminase activity. Future studies to determine the diagnostic modalities to detect such abnormalities and to better understand its clinical implications and long-term outcome are needed.

Perirenal Adipose Tissue-Current Knowledge and Future Opportunities.

The perirenal adipose tissue (PRAT), a component of visceral adipose tissue, has been recently recognized as an important factor that contributes to the maintenance of the cardiovascular system and kidney homeostasis. PRAT is a complex microenvironment consisting of a mixture of white adipocytes and dormant and active brown adipocytes, associated with predipocytes, sympathetic nerve endings, vascular structures, and different types of inflammatory cells. In this review, we summarize the current knowledge about PRAT and discuss its role as a major contributing factor in the pathogenesis of hypertension, obesity, chronic renal diseases, and involvement in tumor progression. The new perspectives of PRAT as an endocrine organ and recent knowledge regarding the possible activation of dormant brown adipocytes are nowadays considered as new areas of research in obesity, in close correlation with renal and cardiovascular pathology. Supplementary PRAT complex intervention in tumor progression may reveal new pathways involved in carcinogenesis and, implicitly, may identify additional targets for tailored cancer therapy.

Changes of histopathological and hematological characteristics in recurrent chronic rhinosinusitis with nasal polyps

Objective: To investigate the histopathological and hematological changes in reoperation of recurrent chronic rhinosinusitis with nasal polyps (CRSwNP). Methods: A total of 41 patients with CRSwNP who underwent two consecutive endoscopic sinus surgeries in Peking Union Medical College Hospital from February 1999 to April 2019 were included retrospectively, including 25 males and 16 females, aged (40.7±13.6) years at the former surgery and (47.0±13.2) years at the recurrent surgery. The peripheral blood cell count results were collected. Differential inflammatory cells in nasal polyp tissue sections were counted and characteristics of tissue remodeling were scored. Paired t test was used to compare the hematological and histological data of the two surgeries in the same cohort. Spearman's rank correlation coefficient was used to determine the correlation between tissue and peripheral blood eosinophil contents. Results: In histopathological tissue sections of nasal polyps, the mean tissue eosinophil, lymphocyte and total inflammatory cell counts per high power field significantly decreased (54.04±34.67 vs 76.97±65.59, 35.27±16.61 vs 50.01±26.94, 128.88±41.32 vs 176.38±80.59, t value was 2.413, 2.923, 3.445, respectively, all P<0.05), whereas the percentages of different inflammatory cell types remained unchanged when comparing the recurrent surgery with the former surgery. There was a significant reduction of basement membrane thickness and goblet cell hyperplasia score in the recurrent surgery (1.29±0.84 vs 2.00±0.84, 1.81±1.31 vs 2.44±1.10, t value was 5.367, 2.714, respectively, all P<0.05). Subgroup analysis suggested that changes in asthmatic cases, younger cases and cases without previous surgery were more remarkable than non-asthmatics, older cases and cases with previous surgery, respectively. There was no significant change in peripheral white blood cell counts and differential cell percentages, except a small increase of blood monocyte percentage. Correlation analysis showed that tissue eosinophil content correlated positively with blood eosinophil content at each surgery. Conclusions: In the recurrent surgery of CRSwNP, tissue eosinophil, lymphocyte and total inflammatory cell counts decrease significantly compare with that of the former surgery. The histological inflammatory load decreases with improvement of tissue remodeling, which could be attributed to the integrated treatment with surgery and medications.