Different Levels Of Inflammation Research Articles

Transcriptomic profiles in major depressive disorder: the role of immunometabolic and cell-cycle-related pathways in depression with different levels of inflammation.

Transcriptomic profiles are important indicators for molecular mechanisms and pathways involved in major depressive disorder (MDD) and its different phenotypes, such as immunometabolic depression. We performed whole-transcriptome and pathway analyses on 139 individuals from the observational, case-control, BIOmarkers in DEPression (BIODEP) study, 105 with MDD and 34 controls. We divided MDD participants based on levels of inflammation, as measured by serum high-sensitivity C-reactive protein (CRP), in n = 39 'not inflamed' (CRP < 1 mg/L), n = 31 with 'elevated CRP' (1-3 mg/L), and n = 35 with 'low-grade inflammation' (>3 mg/L). We performed whole-blood RNA sequencing using Illumina NextSeq 550 and statistical analyses with the Deseq2 package for R statistics (RUV-corrected) and subsequent pathway analyses with Ingenuity Pathway Analysis. Immunometabolic pathways were activated in individuals with CRP > 1 mg/L, although surprisingly the CRP 1-3 group showed stronger immune activation than the CRP > 3 group. The main pathways identified in the comparison between CRP < 1 group and controls were cell-cycle-related, which may be protective against immunometabolic abnormalities in this 'non-inflamed' depressed group. We further divided MDD participants based on exposure and response to antidepressants (n = 47 non-responders, n = 37 responders, and n = 22 unmedicated), and identified specific immunomodulatory and neuroprotective pathways in responders (especially vs. non-responders), which could be relevant to treatment response. In further subgroup analyses, we found that the specific transcriptional profile of responders is independent of CRP levels, and that the inhibition of cell-cycle-related pathways in MDD with CRP < 1 mg/L is present only in those who are currently depressed, and not in the responders. The present study demonstrates immunometabolic and cell-cycle-related transcriptomic pathways associated with MDD and different (CRP-based and treatment-based) MDD phenotypes, while shedding light on potential molecular mechanisms that could prevent or facilitate an individual's trajectory toward immunometabolic depression and/or treatment-non-responsive depression. The recognition and integration of these mechanisms will facilitate a precision-medicine approach in MDD.

Biological Evaluation of Oral Care Products Using 3D Tissue-Engineered In Vitro Models of Plaque-Induced Gingivitis.

The aim of this study was to investigate and visualize the anti-inflammatory and anti-bacterial effects of different oral care products using an infected and inflamed 3D tissue-engineered gingival mucosal model. A 3D full-thickness oral mucosal model was engineered inside tissue culture inserts using collagen hydrogels populated with human gingival fibroblasts and THP-1 monocytes and layered with oral epithelial cell lines. Oral saliva bacteria were cultured and added to the surface of the models and inflammation was further simulated with lipopolysaccharide (LPS) of Escherichia coli. The 3D models were exposed to three different types of toothpastes, a chlorhexidine antiseptic mouthwash, different antibiotics, and a mechanical rinse with phosphate-buffered saline (PBS) prior to biological evaluation using the PrestoBlue tissue viability assay, histology, optical coherence tomography (OCT), confocal microscopy, and measurement of the release of the inflammatory markers IL-1β, IL-6, and IL-8 with ELISA. Multiple-endpoint analyses of the infected oral mucosal models treated with different anti-bacterial agents showed consistent outcomes in terms of tissue viability, histology, OCT, and confocal microscopy findings. In terms of anti-inflammatory testings, the positive control group showed the highest level of inflammation compared with all other groups. Depending on the anti-bacterial and anti-inflammatory potential of the test groups, different levels of inflammation were observed in the test groups. The inflamed 3D oral mucosal model developed in this study has the potential to be used as a suitable in vitro model for testing the biocompatibility, anti-inflammatory, and anti-bacterial properties of oral care products including mouthwashes and toothpastes. The results of this study indicate that the chlorhexidine mouthwash has both anti-bacterial and cytotoxic effects on the 3D oral mucosal model. Hyaluronic-acid-containing toothpaste has significant anti-bacterial and anti-inflammatory effects on the 3D oral mucosal model.

4-Octyl itaconate alleviates experimental autoimmune prostatitis by inhibiting the NLRP3 inflammasome-induced pyroptosis through activating Nrf2/HO-1 pathway.

Chronic prostatitis demonstrates a prevalence rate of nearly 5%-10% among young and middle-aged individuals, significantly affecting their daily lives. Researchers have obtained significant outcomes investigating the anti-inflammatory properties of itaconic acid (IA) and its derivative, 4-Octyl itaconate (4-OI), against diverse chronic inflammatory disorders, such as osteoarthritis and airway inflammation. Nevertheless, whether IA can also exert anti-inflammatory effects in chronic prostatitis requires extensive research and validation. Human prostate tissues obtained through transurethral prostate resection (TURP) from individuals were divided into three groups based on different levels of inflammation using hematoxylin and eosin staining (H&E). Subsequently, immunohistochemistry (IHC) was employed to detect the expression of immune-responsive gene 1 (IRG-1) in these different groups. The animal experiment of this study induced experimental autoimmune prostatitis (EAP) in nonobese diabetic mice through intradermal prostate antigen injection and complete Freund's adjuvant. Then, the experimental group received intraperitoneal injections of different doses of 4-OI, while the control group received injections of saline. Western blot (WB), H&E staining, and TUNEL staining helped analyze the prostate tissues, while enzyme-linked immunosorbent assay (ELISA) helped evaluate serum inflammatory factors. Reactive oxygen species, superoxide dismutase (SOD), and malondialdehyde (MDA) were assessed for oxidative stress across experimental groups. IHC analysis of human prostate tissue depicts that IRG-1 expression enhances as prostate inflammation worsens, highlighting the critical role of IA in human prostatitis. The application of 4-OI increased Nrf2/HO-1 expression while inhibited NLRP3 expression following the WB results, and its application resulted in a decrease in cell pyroptosis in prostate tissue, demonstrated by the results of TUNEL staining. Administering a Nrf2 inhibitor ML385 1 h before intraperitoneal injection of 50 mg/kg 4-OI reversed the previous conclusion, further confirming the above conclusion from another perspective. Meanwhile, the ELISA results of serum inflammatory factors (IL-1β, IL-6, and TNF-α), as well as the measurements of oxidative stress markers MDA and SOD, further confirmed the specific anti-inflammatory effects of 4-OI in EAP. The present study indicates that 4-OI can alleviates EAP by inhibiting the NLRP3 inflammasome-induced pyroptosis through activating Nrf2/HO-1 pathway, which may facilitate a novel approach toward prostatitis treatment.

Clinical efficacy of conbercept injection on neovascular age-related macular degeneration under different levels of inflammation.

Age-related macular degeneration (AMD) is considered one of the most common causes of irreversible blindness among elderly patients. Neovascular AMD, which accounts for 10% of all AMD cases, can cause devastating vision loss due to choroidal neovascularization (CNV). The clinical effects and safety of intravitreal injection of conbercept in patients suffering from neovascular AMD have not been fully evaluated. The aim of the study was to evaluate the efficacy and safety of intravitreal injection of conbercept in patients with neovascular AMD with different levels of inflammation. A total of 120 consecutive patients with neovascular AMD who underwent intravitreal injection of conbercept (3 injections per month + pro re nata (3 + PRN)) were included and stratified based on the intraocular level of high-sensitivity C-reactive protein (hs-CRP). The level of inflammation was defined as low, medium or high, based on the concentration of hs-CRP prior to injection. Before and after conbercept injections, best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were compared, respectively. Moreover, cytokine markers as well as the frequency of injections and adverse events (AEs) were measured. There were significant differences in BCVA and CRT between low, medium and high tertiles. Compared to the baseline, improved BCVA was observed, and CRT declined significantly after operation. Adverse events were most observed in high tertiles. A significant decrease in vascular endothelial growth factor (VEGF), interleukin (IL)-6 and IL-8 was observed after 1 year. The effectiveness of conbercept on neovascular AMD varies depending on the level of inflammation, which could be achieved by administering different injection frequencies at different levels of inflammation. Furthermore, conbercept is associated with the reduction of inflammatory factor (IL-6 and IL-8) levels after intravitreal injection, which suggests that suppressing inflammatory response might contribute to the clinical efficacy of anti-VEGF treatment. Our results provide a novel mechanism for conbercept in patients with neovascular AMD.

Virtual screening indicates potential inhibitors of the P2X7 receptor

Anti-inflammatory agents can be synthetic or natural compounds and are often used to attenuate different levels of inflammation. Inflammatory diseases, due to the involvement of multiple systems, are becoming difficult to treat, involve long durations of therapy where applicable, have a high cost of management and have a deleterious impact on public health. The search for natural and synthetic compounds with anti-inflammatory activity is an important strategy in drug design. Bioactive synthetic drugs may be repurposed for other pharmacological applications, and natural product chemical structures offer unlimited opportunities for new drug discoveries due to the unparalleled availability of chemical diversity. Virtual screening of 2774 molecules on the mouse P2X7 protein showed that potential ligands are composed of five flavonoids (narirutin, diosmin, complanatuside, hesperidin, and oroxin B) and other drugs such as velpatasvir, itacitinib and lifitegrast. In vitro studies in mouse cells confirmed the inhibitory activity of the indicated ligands on the P2X7 receptor by applying virtual screening. The behavior of protein bonded to the ligands was verified by analysis of the molecular dynamic simulation trajectories for four of the most potent inhibitor compounds, indicating that the ligands velpatasvir, itacitinib, lithospermic acid and narirutin remained in the binding site indicated by molecular docking.

Regional differences in the level of inflammation between right and left sided coronary arteries: a cardiac CT study of epicardial fat attenuation index

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): The CARDIOCOV project - Prototype for personalized assessment of cardiovascular risk and post-Covid myocarditis based on artificial intelligence, advanced medical imaging and cloud computing - financed by UEFISCDI PN-III-P2-2.1-PTE-2021-0450 (Contract Number 108PTE/2022). Background Pericoronary fat attenuation index is a novel CT-derived marker used to quantify vascular inflammation at the level of coronary vessels. It has prognostic value for major adverse cardiovascular events and provides improvements in cardiac risk assessment beside classical risk factors and coronary artery calcium score. However, the influence of local factors related to coronary circulation in the right versus left coronary bed, on the development of pericoronary inflammation, has not been elucidated so far. Purpose The aim of the study was to evaluate the regional differences in the level of inflammation between right and left sided coronary arteries. Methods In total, 153 patients (mean age 62 years, male patients 70.5%) who underwent clinically indicated coronary computed tomography angiography (CCTA) were included in the study. All the plaque features classically associated with vulnerability were evaluated for identification of high-risk plaques. Fat attenuation index (FAI) and the corresponding FAI score (which takes into consideration the risk factors and age) were calculated for all cases at the level of the left anterior descending artery (LAD), circumflex artery (Cx) and right coronary artery (RCA). Results A total of 459 coronary arteries were included in the analysis and both FAI and FAI score were higher at the level of RCA compared with LAD and Cx. FAI score was 15.23±11.97 at RCA vs 10.55±6.78 at LAD and 11.48±6.5 for Cx, p = 0.02. Also, a significantly higher value of FAI at the level of RCA was noted in comparison with the other two coronary arteries: −76±7.68 HU for RCA compared to −73.04±8.9 HU for LAD and −71.25±7.47 HU for Cx, p&amp;lt;0.0001. This difference was maintained in all the study sub-group analysis: for patients undergoing CT scan after COVID infection (−75.49±7.62 HU for RCA vs -72.89±9.40 HU for Cx and −71.28 ±7.82 HU for LAD, p = 0.01), or patients with high-risk plaques (20.98±16.29 for RCA vs 11.77±7.68 for Cx and 12.83±6.47 for LAD, p = 0.03). Conclusion Plaques located in different coronary territories exhibit different vulnerability patterns and different levels of inflammation. RCA seems to have a more pronounced susceptibility to inflammation, right coronary plaques exhibiting higher scores of inflammation in the territories surrounding coronary plaques.

Effects of temperature on success of scale autografts and allografts in Poecilia reticulata

Abstract Acceptance or rejection of transplanted tissues is dependent upon both genetic and environmental factors. We used guppy fish, Poecilia reticulata, as a model for studying those factors impacting the immune response to transplanted scale tissues. Scale tissue acceptance is observed when blood has begun to circulate throughout the grafted tissue and rejection can occur at different time intervals due to the degree of genetic difference between donor and recipient. Individual fish were genotyped for MHC class I (UBA) and MHC class II (DAA and DAB) similarity and underwent both autografts and genetically distinct allografts, followed by a recovery period with different environmental temperatures. Fish exhibit behavioral fever under infection and stress models, and were expected to show different levels of inflammation and graft success at different environmental temperatures. We set tank temperatures at 20, 23, and 26 degrees Celsius (n = 5 fish per tank) and monitored subjects for five weeks following the graft procedure to observe for signs of chronic rejection. Typically, chronic rejection takes two to three weeks to become evident, fish were monitored longer to confirm acceptance or rejection of the grafts. We observed signs of rejection, including necrosis and loss of pigmentation, at higher rates in allografts than in autografts.

Pharmacokinetic and pharmacodynamic considerations of antibiotics and antifungals in liver transplantation recipients.

The liver plays a major role in drug metabolism. Liver transplantation impacts the intrinsic metabolic capability and extrahepatic mechanisms of drug disposition and elimination. Different levels of inflammation and oxidative stress during transplantation, the process of liver regeneration, and the characteristics of the graft alter the amount of functional hepatocytes and activity of liver enzymes. Binding of drugs to plasma proteins is affected by the hyperbilirubinemia status and abnormal synthesis of albumin and alpha-1-acid glycoproteins. Postoperative intensive care complications such as biliary, circulatory, and cardiac also impact drug distribution. Renally eliminated antimicrobials commonly present reduced clearance due to hepatorenal syndrome and the use of nephrotoxic immunosuppressants. In addition, liver transplantation recipients are particularly susceptible to multidrug-resistant infections due to frequent manipulation, multiple hospitalizations, invasive devices, and frequent use of empiric broad-spectrum therapy. The selection of appropriate anti-infective therapy must consider the pathophysiological changes after transplantation that impact the pharmacokinetics and pharmacodynamics of antibiotics and antifungal drugs.

Maternal leucocyte trajectory across pregnancy associated with offspring's growth.

Leucocytes for individuals during pregnancy may form into different trajectory patterns. Since no studies have been conducted, we aim to examine the associations between leucocyte trajectory across pregnancy and offspring's birth outcomes and growth during the first 2 years. We conducted a retrospective study enrolled 1070 singleton pregnancies aged 21-46 years old between 2014 and 2018 in Huazhong University of Science and Technology Union Shenzhen Hospital, China. Leucocyte trajectories were modelled using growth mixture modelling and four trajectories were identified: moderate-increasing (n = 41), low-stable (n = 828), high-decreasing (n = 145) and low-increasing (n = 56). Relative to the low-stable group, logistic regression analysis after adjusting for covariates indicated that the odds ratios of preterm were 3.06 (95% confidence interval (CI): 1.43-6.23) for moderate-increasing, 0.78 (95% CI: 0.38-1.47) for high-decreasing and 0.68 (95% CI: 0.23-1.61) for the low-increasing group, respectively. By using generalized estimating equation analysis, we observed that infants in the moderate-increasing and low-increasing group had -0.35 and -0.21 (P &lt; 0.01) lower head circumference z-score compared with the low-stable group, respectively. No significant association of leucocyte trajectory with other birth weight measures or anthropometric measure z-scores was found. Changes in leucocytes across pregnancy affected the occurrence of preterm and offspring's head circumference during the first 2 years of life. Previous researches on the association of leucocytes with pregnancy outcomes mainly focused on leucocytes in a specific trimester. No studies until now have been conducted to assess the influences of the leucocyte trajectories on the growth and development of infants. Changes in leucocytes across pregnancy affected the occurrence of preterm and offspring's head circumference during the first 2 years of life. Our study will positively contribute to the dialogue regarding the treatment of pregnancies with different levels of inflammation in each trimester to minimize adverse pregnancy outcomes and optimize brain growth.

Defective Notch Activation in Mesenchymal Cells Contributes to Myeloproliferative Neoplasm in Aged Mice

Increasing evidence supports important roles of the bone marrow (BM) microenvironment in the development of hematological malignancies. Recently, the non-cell autonomous role of Notch signaling has emerged as one of the key regulators of normal and malignant hematopoiesis. By using a Mx1 - Cre -mediated Rbpj gene deletion in mice (Mx1 - Cre ; R bpjf/f) as a genetic model of Notch loss-of function, we have previously discovered that loss of Rbpj in microenvironment leads to a myeloproliferative neoplasm (MPN)-like disease, which is driven by increased miR-155 expression, NF-kB activation, and inflammatory cytokine production (Wang et al . Cell Stem Cell, 2014). The Mx1 promoter is active in hematopoietic cells as well as in non-hematopoietic cells. In vitro analysis of the impact of Mx1 - Cre -induced R bpj gene deletion on BM endothelial cells (EC), mesenchymal stem cells (MSC), bone cells, andhematopoietic cells showed a greater increase of miR-155 expression in EC and MSC compared to other cell types, leading to higher production of inflammatory cytokines, in particular G-CSF and TNF-a. Comparative in vivo studies showed that EC-specific R bpj knockout mice (Tie2 - CreER ;Rbpjf/f) developed an inflammation and MPN-like disease like Mx1 - Cre ; R bpjf/f mice. However, the disease affected 80% of Tie2 - CreER ;Rbpjf/f mice (compared to 100% of Mx1 - Cre ; R bpjf/f), took longer time to develop (8-12 months vs. 4 months), and was less aggressive than in Mx1 - Cre ; R bpjf/f mice.To further dissect the individual contribution of different stromal cell types to the regulation of myelopoiesis, we used an Osterix (Osx)-Cre -mediated loss-of-function approach to inactivate Rbpj in mesenchymal cells in vivo . We found that the impact of Osx -driven Notch loss-of-function in mice is age-dependent. 5-month-old Osx-Cre ; Rbpjf/f mice showed no abnormal hematologic features compared to controls, as they exhibited similar numbers and percentages of white blood cells (WBC), lymphocytes, neutrophils, red blood cells, and platelets, and comparable percentages of Gr-1+CD11b+ granulocytes, B220+ B cells, and CD3+ T cells in their BMs and spleens. Age-dependent myeloid skewing was shown in wild-type (WT) control mice, but interestingly, was more accentuated in Osx-Cre ; Rbpjf/f mice. Osx-Cre ; Rbpjf/f mice between 11 and 18 months of age showed significantly increased WBC counts in their blood due to increases in neutrophils, lymphocytes and monocytes, but exhibited similar percentages of hematopoietic populations in their BMs and spleens. However, 2 out of 7 mice in the oldest cohort between 17 and 18 months of age showed significant hematological differences in terms of numbers and percentages of hematopoietic cells in their blood, BMs and spleens compared to age-matched controls. Detailed analysis of individual mice revealed that the 2 mutant mice showed an MPN-like disease with circulating myeloid progenitors, splenomegaly and increased granulocyte-macrophage progenitors (GMP) in the BM. In summary, the deletion of Rb pj induced a MPN-like disease in 15% of Osx-Cre ; Rbpjf/f mice and was age-dependent.Cytokine analysis revealed an overall increase of inflammatory cytokines in WT mice during aging; G-GSF and GM-CSF were detected only in the blood of aged (11- to 18-month-old) mice but not young (5-month-old), and C5/C5a was 14-fold increased. Interestingly, in the young Osx-Cre ; Rbpjf/f mice, the levels of many cytokines, such as TIMP-1, IL-16, TNF-a, M-CSF, C5/C5a, IP-10/CXCL10, and CCL2/MCP-1, were already more elevated (1.5- to 20-fold) than in age-matched controls. Importantly, the Osx-Cre ; Rbpjf/f mice that developed MPN showed specific increases of CXCL13/BCA-1, IL-1RA, IL-16, and TIMP-1, which were approximately 2- to 5-fold higher than in age-matched WT control and non-MPN mutant mice, indicating that these cytokines are strongly associated with the MPN phenotype. These data suggest that changes in the BM niche and inflammatory cytokines due to loss of Notch signaling in mesenchymal cells may cooperate with the physiological increase of inflammation occurring during aging in the development of MPN. Collectively, these observations show that loss of Notch signaling leads to different levels of inflammation and has a different biological impact depending on the specific niche cell type. DisclosuresNo relevant conflicts of interest to declare.

Increase of Tpo Levels in Patients with Acute Inflammatory States

Thrombopoietin (TPO) is a growth factor for platelet/megakaryocytic lineage and may also have a protective effect in other cell types such as heart and neural cells (Li et al, Circulation, 2006). In this study, we investigated the changes of TPO levels in patients with acute inflammatory response disease of different etiologies. In the case-control study, 65 patients with acute inflammatory response disease were enrolled in the case group (15 patients with acute myocardial infarction, 15 patients with acute cerebral infarction, 25 patients with acute trauma and 10 patients with acute pneumonia), and 65 healthy subjects were selected as the control group. The levels of TPO in peripheral blood and blood cell counts between the case group and the control group were compared by Student's t test for examing whether the level of TPO in acute inflammation states was higher than that in healthy people. And, by using Kruskal-Wallis H test and Nemenyi test, subsequent subgroup comparison was performed to assess whether there was a difference in TPO levels under the condition of inflammation of different etiologies and at different levels. Compared with the control group, serum TPO levels in case group were significantly higher (181.11±35.38 vs 96.13± 9.7 pg/ml, P<0.001), and the white blood cell count in case group (9.64±3.43) ×109/L was higher than that in control group (7.35±1.49) ×109/L (P<0.001), but the platelet count in the case group was not statistically different from that in the control group (P=0.313). In the further subgroup analysis, it was found that changes in TPO levels were different in different levels of inflammation. The level of TPO in patients with inflammatory disease of high level (acute trauma, acute pneumonia) was greatly higher than that in patients with inflammatory disease of low level (acute myocardial infarction, acute cerebral infarction) (P <0.05), and there was no statistically significant difference in platelet count among subgroups. In acute inflammation states, serum TPO levels increase do not correlate with platelet counts but inflammation levels, and TPO may act as an acute response protein to protect the heart and neural cells. DisclosuresNo relevant conflicts of interest to declare.

Precision targeting of the plasminogen activator inhibitor-1 mechanism increases efficacy of fibrinolytic therapy in empyema.

Plasminogen activator inhibitor‐1 (PAI‐1) is an endogenous irreversible inhibitor of tissue‐type (tPA) and urokinase (uPA) plasminogen activators. PAI‐1‐targeted fibrinolytic therapy (PAI‐1‐TFT) is designed to decrease the therapeutic dose of tPA and uPA, attenuating the risk of bleeding and other complications. Docking site peptide (DSP) mimics the part of the PAI‐1 reactive center loop that interacts with plasminogen activators, thereby affecting the PAI‐1 mechanism. We used DSP for PAI‐1‐TFT in two rabbit models: chemically induced pleural injury and Streptococcus pneumoniae induced empyema. These models feature different levels of inflammation and PAI‐1 expression. PAI‐1‐TFT with DSP (2.0 mg/kg) converted ineffective doses of single chain (sc) tPA (72.5 µg/kg) and scuPA (62.5 µg/kg) into effective ones in chemically induced pleural injury. DSP (2.0 mg/kg) was ineffective in S. pneumoniae empyema, where the level of PAI‐1 is an order of magnitude higher. DSP dose escalation to 8.0 mg/kg resulted in effective PAI‐1‐TFT with 0.25 mg/kg sctPA (1/8th of the effective dose of sctPA alone) in empyema. There was no increase in the efficacy of scuPA. PAI‐1‐TFT with DSP increases the efficacy of fibrinolytic therapy up to 8‐fold in chemically induced (sctPA and scuPA) and infectious (sctPA) pleural injury in rabbits. PAI‐1 is a valid molecular target in our model of S. pneumoniae empyema in rabbits, which closely recapitulates key characteristics of empyema in humans. Low‐dose PAI‐1‐TFT is a novel interventional strategy that offers the potential to improve fibrinolytic therapy for empyema in clinical practice.

Protective effects of glucocorticoid on liver injury in a rat sepsis model.

Sepsis is one of the leading causes of death with unsatisfactory current treatments. The present study assessed the liver protective effect of glucocorticoids on different levels of inflammation in septic shock rats. A rat septic shock model was established by lipopolysaccharide (LPS) injection. Rats were divided into control (Control), high-inflammation treated with hydrocortisone (HT), high-inflammation non-treatment (HNT), low-inflammation treated with hydrocortisone (LT) and low-inflammation non-treatment (LNT) groups according to the levels of serum C-reactive protein (CRP), interleukin (IL)-6 and interferon (IFN)-γ. The mean arterial pressure and heart rate changes were continuously monitored and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured by an automatic biochemical analyzer. Hematoxylin and eosin (H&E) staining was performed to observe the pathological changes of liver tissue. Western blot analysis was used to detect the expression of p38 mitogen-activated protein kinase (MAPK) and NF-κB protein. The results demonstrated that following 7 days of treatment, there were no obvious differences in the serum CRP, IL-6 and IFN-γ levels between the HT group and the control group, whilst the HNT group, LT group and LNT group were significantly different compared with the HT and control groups. H&E staining demonstrated that the liver cells in the HT group were homogeneous following 7 days of treatment. Western blot analysis determined that the phosphorylation levels of p38MAPK and NF-κB in HT group were reduced significantly compared with the LT group, while there was no obvious difference with the control group after 7 days treatment. The present results indicated that glucocorticoids have better therapeutic effect on septic shock rats with high-inflammation compared with low-inflammation rats. The present study provides a novel approach for glucocorticoid treatment of septic shock.

Severe bronchial asthma in children: a review of novel biomarkers used as predictors of the disease.

Severe asthma or therapy-resistant asthma in children is a heterogeneous disease that affects all age-groups. Given its heterogeneity, precision in diagnosis and treatment has become imperative, in order to achieve better outcomes. If one is thus able to identify specific patient phenotypes and endotypes using the appropriate biomarkers, it will assist in providing the patient with more personalized and appropriate treatment. However, there appears to be a huge diagnostic gap in severe asthma, as there is no single test yet that accurately determines disease phenotype. In this paper, we review the published literature on some of these biomarkers and their possible role in bridging this diagnostic gap. We also highlight the cellular and molecular mechanisms involved in severe asthma, in order to show the basis for the novel biomarkers. Some markers useful for monitoring therapy and assessing airway remodeling in the disease are also discussed. A review of the literature was conducted with PubMed to gather baseline data on the subject. The literature search extended to articles published within the last 40 years. Although biomarkers specific to different severe asthma phenotypes have been identified, progress in their utility remains slow, because of several disease mechanisms, the variation of biomarkers at different levels of inflammation, changes in relying on one test over time (eg, from sputum eosinophilia to blood eosinophilia), and the degree of invasive tests required to collect biomarkers, which limits their applicability in clinical settings. In conclusion, several biomarkers remain useful in recognizing various asthma phenotypes. However, due to disease heterogeneity, identification and utilization of ideal and defined biomarkers in severe asthma are still inconclusive. The development of novel serum/sputum-based biomarker panels with enhanced sensitivity and specificity may lead to prompt diagnosis of the disease in the future.

Comparison of renal interstitial fibrosis induced by different animal models of urinary tract infection

Objectives: To identify a better animal model that more closely mimics early renal interstitial fibrosis induced by long-term recurrent urinary tract infection (UTI), as occurs in humans, three different murine models were compared. Methods: Three different murine models of upper UTI were established, including direct injection of bacteria into renal tissues, ascending urinary infection with partial unilateral ureteric obstruction, and repeated infusion of bacteria into the bladder. The histopathology of the kidneys was assessed by hematoxylin and eosin staining. Masson's trichrome staining and immunohistochemistry for α-smooth muscle actin (α-SMA) expression were used for the detection of fibrosis. Results: All three models developed different levels of inflammation in the kidney. However, in contrast to the severe renal interstitial fibrosis in the other two models, the model of repeated infusion of bacteria into the bladder demonstrated early renal interstitial fibrosis by Masson's trichrome staining and immunohistochemistry for α-SMA. Conclusions: The model of repeated infusion of bacteria into the bladder developed low levels of renal interstitial fibrosis, which resembles the early tissue damage in the kidney induced by recurrent UTI s in humans. This model may therefore offer a better way to study the early therapeutic intervention of renal interstitial fibrosis caused by inflammation.

Plastic and micro-evolutionary responses of a nematode to the host immune environment

Parasitic organisms have to cope with the defences deployed by their hosts and this can be achieved adopting immune evasion strategies or optimal life history traits according to the prevailing pattern of immune-mediated mortality. Parasites often encounter variable immune environments both within and between hosts, promoting the evolution of plastic strategies instead of fixed responses. Here, we explored the plasticity and micro-evolutionary responses of immunomodulatory mechanisms and life history traits to the immune environment provided by the host, using the parasitic nematode Heligmosomoides polygyrus. To test if the parasite responds plastically to the immune environment, we stimulated the systemic inflammatory response of mice and we assessed i) the expression of two genes with candidate immunomodulatory functions (Hp-Tgh2 and Hp-CPI); ii) changes in the number of eggs shed in the faeces. To test if the immune environment induces a micro-evolutionary response in the parasite, we maintained the nematode in mice whose inflammatory response was up- or down-regulated during four generations. We found that H. polygyrus plastically responded to a sudden rise of pro-inflammatory cytokines, up-regulating the expression of two candidate genes involved in the process of immune modulation, and enhancing egg output. At the micro-evolutionary level, parasites maintained in hosts experiencing different levels of inflammation did not have differential expression of Hp-Tgh2 and Hp-CPI genes when infecting unmanipulated, control, mice. However, parasites maintained in mice with an up-regulated inflammation shed more eggs compared to the control line. Overall, our study shows that H. polygyrus can plastically adjust the expression of immunomodulatory genes and life history traits, and responds to selection exerted by the host immune system.

Changes of Thrombopoietin Levels in Patients with Acute Inflammatory Disease and Its Significance

To investigate the changes of TPO levels in patients with acute inflammatory response disease of different etiologies. In the case -control study, 65 patients with acute inflammatory response disease were enrolled in the case group (15 patients with acute myocardial infarction, 15 patients with acute cerebral infarction, 25 patients with acute trauma and 10 patients with acute pneumonia), and 42 healthy subjects were selected as the control group. The levels of TPO in peripheral blood and blood cell counts between the case group and the control group were compared by Student's t test for examing whether the level of TPO in acute inflammation states was higher than that in healthy people. And, by using Kruskal-Wallis H test and Nemenyi test, subsequent subgroup compaison was performed to assess whether there was a difference in TPO levels under the condition of inflammation of different etiologies and at different levels. Compared with the control group,serum TPO levels in case group were significantly higher (181.11±35.38 vs 96.13±9.7 pg/ml)(P<0.001), and the white blood cell count in case group (9.64±3.43)×109/L was higher than that in control group(7.35±1.49)×109/L(P<0.001), but the platelet count in the case group was not statistically different from that in the control group (P=0.313). In the further subgroup analysis, it was found that changes in TPO level were different in different levels of inflammation. The level of TPO in patients with inflammatory disease of high level(acute trauma, acute pneumonia) was greatly higher than that in patients with inflammatory disease of low level(acute myocardial infarction, acute cerebral infarction) (P<0.05), and there was no statistically significant difference in platelet count among subgroups. In acute inflammation states, the increase of serum TPO levels does not correlate with platelet counts, but correlates with inflammation levels, and TPO may act as an acute response protein to protect the body.

Forns index and 'FIB4' for staging of fibrosis in adults with chronic hepatitis C

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the diagnostic test accuracy of Forns index and 'FIB4' in diagnosing people with chronic hepatitis C virus, using liver biopsy as the reference standard. To compare the diagnostic accuracy of the pre-defined cut-off values, used in the original publications, versus the accuracy of other published cut-off values, used in the included studies. To compare the diagnostic accuracy of Forns index and 'FIB4' in people with chronic hepatitis C. To explore potential sources of heterogeneity: serum levels of alanine transferase activity (Dufour 2000); different levels of inflammation according to liver biopsy; different quality of liver biopsy sample (based on length and number of portal tracts); people with and without HIV co-infection; studies with high methodological quality compared to studies with low or unclear methodological quality, applying the QUADAS-2 tool (Whiting 2011). serum levels of alanine transferase activity (Dufour 2000); different levels of inflammation according to liver biopsy; different quality of liver biopsy sample (based on length and number of portal tracts); people with and without HIV co-infection; studies with high methodological quality compared to studies with low or unclear methodological quality, applying the QUADAS-2 tool (Whiting 2011).

What Causes Eye Pain?

Eye pain is an unpleasant sensory and emotional experience including sensory-discriminative, emotional, cognitive, and behavioral components and supported by distinct, interconnected peripheral and central nervous system elements. Normal or physiological pain results of the stimulation by noxious stimuli of sensory axons of trigeminal ganglion (TG) neurons innervating the eye. These are functionally heterogeneous. Mechano-nociceptors are only excited by noxious mechanical forces. Polymodal nociceptors also respond to heat, exogenous irritants, and endogenous inflammatory mediators, whereas cold thermoreceptors detect moderate temperature changes. Their distinct sensitivity to stimulating forces is determined by the expression of specific classes of ion channels: Piezo2 for mechanical forces, TRPV1 and TRPA1 for heat and chemical agents, and TRPM8 for cold. Pricking pain is evoked by mechano-nociceptors, while polymodal nociceptors are responsible of burning and stinging eye pain; sensations of dryness appear to be mainly evoked by cold thermoreceptors. Mediators released by local inflammation, increase the excitability of eye polymodal nociceptors causing their sensitization and the augmented pain sensations. During chronic inflammation, additional, long-lasting changes in the expression and function of stimulus-transducing and voltage-sensitive ion channels develop, thereby altering polymodal terminal’s excitability and evoking chronic inflammatory pain. When trauma, infections, or metabolic processes directly damage eye nerve terminals, these display aberrant impulse firing due to an abnormal expression of transducing and excitability-modulating ion channels. This malfunction evokes ‘neuropathic pain’ which may also result from abnormal function of higher brain structures where ocular TG neurons project. Eye diseases or ocular surface surgery cause different levels of inflammation and/or nerve injury, which in turn activate sensory fibers of the eye in a variable degree. When inflammation dominates (allergic or actinic kerato-conjunctivitis), polymodal nociceptors are primarily stimulated and sensitized, causing pain. In uncomplicated photorefractive surgery and moderate dry eye, cold thermoreceptors appear to be mainly affected, evoking predominant sensations of unpleasant dryness.

Molecular Imaging of Inflammation in Inflammatory Bowel Disease with a Clinically Translatable Dual-Selectin–targeted US Contrast Agent: Comparison with FDG PET/CT in a Mouse Model

To develop and test a molecular imaging approach that uses ultrasonography (US) and a clinically translatable dual-targeted (P- and E-selectin) contrast agent (MBSelectin) in the quantification of inflammation at the molecular level and to quantitatively correlate selectin-targeted US with fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and computed tomography (CT) in terms of visualization and quantification of different levels of inflammation in a murine acute colitis model. Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. MBSelectin was developed by covalently binding an analog of the naturally occurring binding ligand P-selectin glycoprotein ligand 1 fused to a human fragment crystallizable(or Fc) domain onto the lipid shell of perfluorobutane and nitrogen-containing MBs. Binding specificity of MBSelectin was assessed in vitro with a flow chamber assay and in vivo with a chemically induced acute colitis murine model. US signal was quantitatively correlated with FDG uptake at PET/CT and histologic grade. Statistical analysis was performed with the Student t test, analysis of variance, and Pearson correlation analysis. MBSelectin showed strong attachment to both human and mouse P- and E-selectin compared with MBControl in vitro (P ≤ .002). In vivo, US signal was significantly increased (P < .001) in mice with acute colitis (173.8 arbitrary units [au] ± 134.8 [standard deviation]) compared with control mice (5.0 au ± 4.5). US imaging signal strongly correlated with FDG uptake on PET/CT images (ρ = 0.89, P < .001). Ex vivo analysis enabled confirmation of inflammation in mice with acute colitis and high expression levels of P- and E-selectin in mucosal capillaries (P = .014). US with MBSelectin specifically enables detection and quantification of inflammation in a murine acute colitis model, leveraging the natural pathway of leukocyte recruitment in inflammatory tissue. US imaging with MBSelectin correlates well with FDG uptake at PET/CT imaging.