Serum H‐ficolin levels: Clinical association with interstitial lung disease in patients with systemic sclerosis

Ficolins, a group of oligomeric lectins consisting of three isoforms (H‐, L‐ and M‐ficolin), contribute to innate immunity via activating the complement pathway and/or acting directly as opsonins against pathogens and apoptotic cells. Because apoptotic cells likely drive the development of systemic sclerosis (SSc) partly through innate immunity, we assessed the clinical association of serum H‐ficolin levels in SSc patients. Despite no difference in serum H‐ficolin levels between SSc and control subjects, SSc patients with decreased serum H‐ficolin levels tended to have a higher prevalence of interstitial lung disease (ILD). More importantly, serum H‐ficolin levels inversely correlated with ground‐glass opacity score on chest computed tomography in SSc‐ILD patients. Therefore, H‐ficolin‐related innate immunity may be involved in SSc‐ILD development.     

Induced histamine regulates Ni elution from an implanted Ni wire in mice by downregulating neutrophil migration

Histamine regulates various inflammatory reactions. We have reported that the expression of histidine decarboxylase (HDC) was induced by subcutaneous implantation of nickel (Ni) wire. However, the source and functions of histamine in Ni elution and Ni wire‐induced inflammation have not been completely studied. We aimed to elucidate the effects of de novo synthesized histamine on leucocyte infiltration and Ni elution. Implantation of Ni wire induced an increase in the Ni ion content of the surrounding tissues and serum and in the mRNA levels of HDC, a histamine‐producing enzyme, macrophage inflammatory protein‐2 (MIP‐2), a chemoattractant for neutrophils, and monocyte chemoattractant protein‐1 (MCP‐1), a chemoattractant for monocytes. The Ni wire induced HDC expression even in mast cell‐deficient WBB6F1‐W/W^V mice. In HDC knockout (HDC KO) mice, the Ni wire‐induced increase in MIP‐2 mRNA expression was significantly higher than that in wild‐type mice but not MCP‐1. MIP‐2 expression was enhanced in histamine H2 receptor knockout (H2R KO) mice but not in WBB6F1‐W/W^V mice. Histamine inhibited NiCl₂‐induced MIP‐2 mRNA expression in mouse bone marrow‐derived macrophages (BMDMs) obtained from wild‐type mice; this inhibition was not observed in BMDMs from H2R KO mice. Ni elution increased in HDC KO mice, in which leucocyte infiltration also increased, and was suppressed in mice treated with neutrophil‐specific antibody. These results suggest that the Ni wire induced HDC expression in non‐mast cells and that, in the chronic phase of inflammation, endogenous histamine reduced Ni elution, probably through regulation of MIP‐2 expression and neutrophil migration.     

Predominance of influenza A(H3N2) virus genetic subclade 3C.2a1 during an early 2016/17 influenza season in Europe – Contribution of surveillance data from World Health Organization (WHO) European Region to the WHO vaccine composition consultation for northern hemisphere 2017/18

During the European 2016/17 influenza season, A(H3N2) viruses have predominated and the majority clustered in genetic subclade 3C.2a1. Genetic analyses showed that circulating viruses have undergone considerable genetic diversification of the haemagglutinin gene from the current vaccine virus A/Hong Kong/4801/2014 (clade 3C.2a), but the antigenic data that is limited by the challenges with the antigenic characterisation of currently circulating A(H3N2) viruses, showed no clear evidence of antigenic change. The recommended A(H3N2) vaccine component for the northern hemisphere 2017/18 influenza season remained unchanged. However, early and mid-season vaccine effectiveness (VE) estimates were suggestive of reduced VE against A(H3N2) viruses.     

Analysis of cellular response to isocyanate using N‐succinimidyl N‐methylcarbamate exposure in cultured mammalian cells

Isocyanates (R? N?C?O), one of the highly reactive industrial intermediates, possess the capability to modulate the bio‐molecules by forming toxic metabolites and adducts which may cause adverse health effects. Some of their toxic degradations have previously been unknown and overlooked; of which, molecular repercussions underlying their genetic hazards upon occupational/accidental exposures still remain as an intricate issue and are hitherto unknown. To assess the genotoxic potential of methyl isocyanate in cultured mammalian cells after in vitro exposure, we performed a study in three different normal cell lines MM55.K (mouse kidney epithelial), B/CMBA.Ov (mouse ovarian epithelial), and NIH/3T3 (primary mouse embryonic fibroblast). Cellular DNA damage response was studied for qualitative phosphorylation states of ATM, γH2AX proteins and quantitative state of p53 phosphorylation; DNA cell cycle analysis and measure of cellular apoptotic index before and after treatment were also investigated. Our results demonstrate that methyl isocyanate by negatively regulating the DNA damage response pathway, might promote cell cycle arrest, and apoptosis in cultured mammalian cells suggestive of causing genetic alterations. We anticipate that these data along with other studies reported in the literature would help to design better approaches in risk assessment of occupational and accidental exposure to isocyanates. We also predict that increasing knowledge on DNA damage‐triggered signaling leading to cell death could provide new strategies for investigating the effects of DNA repair disorders and decreased repair capacity on the toxicity and carcinogenic properties of environmental toxins. Environ. Mol. Mutagen., 2009. © 2009 Wiley‐Liss, Inc.     

Clinical characteristics and biomarkers of breast cancer associated with choline concentration measured by 1H MRS

This study investigated the association between the total choline (tCho) concentration and the clinical characteristics and biomarker status of breast cancer. Sixty‐two patients with breast cancer, 1.5 cm or larger in size on MR images, were studied. The tCho concentration was correlated with the MRI features, contrast enhancement kinetics, clinical variables and biomarkers. Pairwise two‐tailed Spearman's nonparametric test was used for statistical analysis. The tCho concentration was higher in high‐grade than moderate‐/low‐grade tumors (p = 0.04) and in tumors with higher K_trans and k_ep (p < 0.001 for both). The association of tCho concentration with age (p = 0.05) and triple negative biomarker (p = 0.09) approached significance. tCho was not detected in 17 patients, including 15 with invasive ductal cancer and two with infiltrating lobular cancer. Fifteen of the 17 patients had moderate‐ to low‐grade cancers, and 11 had human epidermal growth factor‐2‐negative cancer, suggesting that these two factors might lead to false‐negative choline. Higher tCho concentration in high‐grade tumors and tumors with higher K_trans and k_ep indicates that choline is associated with cell proliferation and tumor angiogenesis. The higher choline level in younger women may be caused by their more aggressive tumor type. The results presented here may aid in the better interpretation of ¹H MRS for the diagnosis of breast lesions. Copyright © 2010 John Wiley & Sons, Ltd.     

Therapy With m‐TOR Inhibitors Decreases the Response to the Pandemic Influenza A H1N1 Vaccine in Solid Organ Transplant Recipients

Concern has been raised regarding the response to vaccination in solid organ transplant recipients (SOTR) undergoing immunosuppressant regimens and the possibility of rejection related to the immune response associated with pandemic influenza H1N1–2009 vaccination. The goal of this study was to assess the immunogenicity, efficacy and safety of the pandemic vaccine in SOTR. We performed a multicenter prospective study in SOTR receiving the pandemic vaccine. Immunological response was determined in serum 5 weeks after vaccination by microneutralization assays, and immunoglobulins were measured by ELISA. Three hundred and forty‐six SOTR were included. Preexisting seroprotection was detected in 13.6% of cases and rates of seroconversion and seroprotection after vaccination were 73.1% and 82.9%, respectively. Patients with baseline antibody titers had better geometric mean titers (GMT)‐post after pandemic vaccination (339.4 vs. 121.4, p < 0.001). Younger age, liver disease and m‐TOR inhibitor therapy were independently associated with lower seroprotection and GMT‐post. There were no major adverse effects or rejection episodes. Pandemic vaccine was safe in SOTR and elicited an adequate response, although lower than in healthy individuals. This is the first study describing a decreased response after vaccination in patients receiving mTOR inhibitors who presented lower seroprotection rates and lower GMT‐post.     

Role of Histamine H1 Receptors in Vestibular Nucleus in Motion Sickness

Objectives To investigate the expression of histamine H1 receptors (H1R) in the vestibular nucleus of brainstem in rats and the role of H1R in motion sickness (MS). Methods A total of 24 healthy Sprague-Dawley rats were divided randomly into four groups (n=6 each) which determined if the animals would receive induction of MS or drug (promethazine) treatment: MS(-)/Drug(-); MS(+)/Drug(-); MS(-)/Drug(+ at 0.25 mg); and MS(+)/Drug(+). MS was induced by complex motion stimulation and the conditioned taste aversion was used as a behavioral indicator of MS. The volume of 0.15% sodium saccharin solution (SS) intake within 45 minutes after motion stimulation was measured. H1R in the vestibular nucleus was examined by immunofluorescence staining. The expression of H1R protein in brainstem tissue at vestibular nucleus level was detected by western blot. Results The mean SS intake volume in the MS(+)/Drug(-) group (8.8 ml) was significantly less than that of the MS(-)/Drug(-) group (15.1 ml) (P < 0.01). The mean SS intake volume of the MS(-)/Drug(+) group (14.8 ml) was similar to that of the MS(-)/Drug(-) group. The mean SS intake volume (9.6 ml) of the MS(+)/Drug(+) group was more than that of the MS(+)/Drug(-)group (P < 0.01), but less than that of the MS(-)/Drug(-) group or MS(-)/Drug(+) group (P < 0.01). Immunofluorescence staining showed positive expression of H1R in the vestibular nucleus of brainstem and the expression was enhanced by motion stimulation. Western blot analysis showed that H1R protein expressed in the brainstem tissue at vestibular nucleus level and the expression also increased significantly after motion stimulation. The MS-induced increase of H1R was not affected significantly by promethazine. Conclusions H1Rs exist in the vestibular nucleus in rats and H1R expression is up-regulated by motion stimulation, but not affected by promethazine. The findings indicate that the histaminergic system is involved in MS. Promethazine, as an H1R blocker, may play its anti-MS role by competing the binding site on H1Rs with histamine rather than inhibiting H1R expression.     

Na+/H+ exchanger mediates TNF-α-induced hepatocyte apoptosis via the calpain-dependent degradation of Bcl-xL

Background and Aim:  It is well known that tumor necrosis factor-α (TNF-α) induces hepatocyte apoptosis and contributes to liver diseases. However, the exact mechanisms are not well understood.
Methods:  In the present study, we reported that Na⁺/H⁺ exchanger (NHE) is involved in TNF-α-induced hepatocyte apoptosis.
Results:  TNF-α time dependently induced an increase in NHE activity in hepatocytes, but cariporide, an NHE inhibitor, blocked the TNF-α-induced increase of NHE activity in a dose-dependent manner. Increased NHE activity induced by TNF-α was associated with increased intracellular calcium (Ca²⁺_i) concentration and calpain activity. Cariporide reversed these effects induced by TNF-α. In addition, TNF-α downregulated Bcl-xL, an anti-apoptotic protein, but not mRNA levels. The inhibition of either calpain or NHE blocked the TNF-α-induced decrease of the Bcl-xL protein. TNF-α did not change the pro-apoptotic Bax and Bak protein levels. Cariporide, calcium remover 1,2-bis (2-aminophenoxy) ethane-N,N,N0,N0–tetraacetic acid, or calpain inhibitor benzyloxycarbonyl-leucyl-leucinal attenuated TNF-α-induced hepatocyte apoptosis.
Conclusion:  TNF-α via NHE results in hepatocyte apoptosis through the calcium/calpain/Bcl-xL pathway.