Filling gaps between exposure modeling and the analysis of urinary biomarkers using personal air monitoring: An intervention study of permethrin used in home insecticide spray.

Permethrin is one of the most widely used active ingredients in spray-type home insecticides. However, indoor permethrin exposure resulting from the use of home insecticides is not well-characterized, as measured permethrin concentrations in indoor environmental and biological media with a known application rate are scarce. We conducted an intervention study with four participants for seven days. We conducted personal air monitoring and collected 24-h urine samples in which we quantified time-weighted average (TWA) permethrin concentrations in indoor air (Cair ) and urinary concentrations of two permethrin metabolites, 3-phenoxybenzoic acid (3-PBA) and cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis/trans-DCCA). We also estimated (1) TWA Cair using a simple indoor air model and (2) urinary excreted (UE) mass using a simple excretion model with both estimated and measured TWA Cair . Measurements of TWA Cair from personal air monitoring were lower than those estimated from the indoor model by a factor of 2.9 to 49.4. The ratio of estimated to measured UE mass ranged 3.5-18.2 when using estimated TWA Cair and 1.1-2.9 when using measured TWA Cair . Smaller ratios in estimating internal permethrin exposure from personal air monitoring suggest that personal air monitoring could reduce uncertainties in permethrin exposure assessment resulting from the use of spray-type insecticides.

Development of a personal passive air sampler for estimating exposure to effective chlorine while using chlorine-based disinfectants.

With an increasing use of indoor disinfectants such as chlorine (Cl2 ) and hypochlorous acid, a convenient sampler for estimating exposure to oxidants, such as effective chlorine, is necessary. Here, we developed a personal passive air sampler (PPAS) composed of a redox dye, o-dianisidine, in a polydimethylsiloxane (PDMS) sheet. o-Dianisidine readily reacts with gaseous oxidants generated by bleach usage, and its color changes as the reaction progresses; hence, personal exposure to effective chlorine could be easily detected by the naked eye, while cumulative exposure could be determined by measuring concentrations of o-dianisidine reacting with it. The PPAS was calibrated, and a sampling rate of 0.00253 m3 /h was obtained using a small test chamber. The PPAS was tested with the help of ten volunteers whose personal exposure to Cl2 -equivalent gas was estimated after bathrooms were cleaned using spray and liquid-type household disinfection products, and the accumulated exposure-gas concentrations ranged from 69 to 408 ppbv and 148 to 435 ppbv, respectively. These PPAS-derived exposure concentrations were approximately two orders lower than those estimated using ConsExpo, suggesting a significant overestimation by prevailing screening models, possibly due to the ignorance of transformation reactions.

Targeting of Phospholipase D1 Ameliorates Collagen-Induced Arthritis via Modulation of Treg and Th17 Cell Imbalance and Suppression of Osteoclastogenesis.

Phospholipase D1 (PLD1) plays a crucial role in various inflammatory and autoimmune diseases. Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease. However, the role of PLD1 in the pathogenesis of RA remains unknown. Here, we first investigated the role and effects of PLD1 in collagen-induced arthritis (CIA) and found that genetic and pharmacological inhibition of PLD1 in DBA1/J mice with CIA reduced the incidence of CIA, decreased the clinical score, and abrogated disease symptoms including infiltration of leukocytes, synovial inflammation, bone erosion, and cartilage destruction. Moreover, ablation and inhibition of PLD1 suppressed the production of type II collagen-specific IgG2a autoantibody and proinflammatory cytokines, accompanied by an increase in the regulatory T (Treg) cell population and a decrease in the Th17 cell population in CIA mice. The PLD1 inhibitor also promoted differentiation of Treg cells and suppressed differentiation of Th17 cells in vitro. Furthermore, the PLD1 inhibitor attenuated pathologic bone destruction in CIA mice by suppressing osteoclastogenesis and bone resorption. Thus, our findings indicate that the targeting of PLD1 can ameliorate CIA by modulating the imbalance of Treg and Th17 cells and suppressing osteoclastogenesis, which might be a novel strategy to treat autoimmune diseases, such as RA.

Impact of a delirium prevention project among older hospitalized patients who underwent orthopedic surgery: a retrospective cohort study.

BACKGROUND: Postoperative delirium (POD) is a common clinical syndrome with significant negative outcomes. Thus, we aimed to evaluate the feasibility and effectiveness of a delirium screening tool and multidisciplinary delirium prevention project. METHODS: A retrospective cohort study was conducted at a single teaching center in Korea. A cohort of patients who underwent a delirium prevention program using a simple delirium screening tool from December 2018 to February 2019 (intervention group, N = 275) was compared with the cohort from the year before implementation of the delirium prevention program (December 2017 to February 2018) (control group, N = 274). Patients aged ≥65 years who were admitted to orthopedic wards and underwent surgery were included. The incidence rates of delirium before and after implementation of the delirium prevention program, effectiveness of the delirium screening tool, change in the knowledge score of nurses, and length of hospital stay were assessed. RESULTS: The sensitivity and specificity of the screening tool for the incidence of POD were 94.1 and 72.7%, respectively. The incidence rates of POD were 10.2% (control group) and 6.2% (intervention group). The odds ratio for the risk reduction effect of the project related to the incidence of POD was 0.316 (95% confidence interval: 0.125-0.800, p = 0.015) after adjustment for possible confounders. The delirium knowledge test score increased from 40.52 to 43.24 out of 49 total points (p < 0.001). The median length of hospital stay in the intervention and control groups was 6.0 (interquartile range, 4-9) and 7.0 (interquartile range, 4-10) days, respectively (p = 0.062). CONCLUSION: The screening tool successfully identified patients at a high risk of POD at admission. The POD prevention project was feasible to implement, effective in preventing delirium, and improved knowledge regarding delirium among the medical staff. TRIAL REGISTRATION: None.

Serum levels of IgG antibodies against alpha-enolase are increased in patients with Behçet's disease and are associated with the severity of oral ulcer, erythrocyte sedimentation rates, and C-reactive protein.

OBJECTIVES: Behçet's disease (BD) is a chronic inflammatory disease of unknown etiology, characterised by recurrent oral and genital ulcers, skin lesions, uveitis, and arthritis. It is regarded as vasculitis and anti-endothelial cell antibodies (AECA) are found in patients with BD. One of the endothelial cell antibodies was reported to recognise alpha-enolase. This study aimed to investigate expression of alpha-enolase in the surface of peripheral blood cells and serum anti-alpha-enolase antibody (AEA), and their association with clinical manifestations or disease activity of BD. METHODS: Cell surface alpha-enolase expression was examined from several cell types of peripheral blood, including lymphocytes, monocytes, and neutrophils using flow cytometry in patients with BD and healthy controls (HCs). IgG AEA levels were measured by enzyme-linked immunosorbent assay (ELISA) in sera from 110 patients with BD, and age/sex matched 110 HCs. Association of alpha-enolase or AEA with clinical manifestation was analysed. RESULTS: The frequency of surface alpha-enolase-expressing cells was increased in BD in lymphocytes and monocytes. Serum AEA levels were in- creased in BD patients (median [IQR], 0.360 [0.268-0.482], p < 0.0001), particularly with mucocutaneous involvement (0.367 [0.273-0.490], p < 0.0001) compared to HCs (0.274 [0.231-0.357]). The levels of AEA were correlated with the number of oral ulcer, ESR, and CRP. There was no association between serum levels of AEA and other clinical manifestations. CONCLUSIONS: Serum AEA was increased in BD patients and correlated with oral ulcer, ESR and CRP.

Asterixis in the leg induced by anterior cerebral artery infarction.

Asterixis commonly occurs in a patient with metabolic encephalopathy, whereas focal brain lesions such as thalamus, cerebellum, or frontal area also cause focal or unilateral asterixis in the arms. We report a novel case of asterixis in the leg after unilateral anterior cerebral artery territory infarction. A 76-year-old man was admitted with sudden-onset mild right leg weakness and postural instability due to knee buckling. He was diagnosed with ischemic stroke in the left prefrontal area and cingulated gyrus by brain magnetic imaging. Needle electromyography of the right vastus lateralis muscle while standing showed intermittent periods of EMG silence, consistent with asterixis. There were no abnormal involuntary movements in the upper extremities. This case suggests that gait disturbance or postural instability after structural lesions in the prefrontal area may be directly related to asterixis in the leg, not in the arm associated with postural failure.

Tandem Diels-Alder and retro-ene reactions of 1-sulfenyl- and 1-sulfonyl-1,3-dienes as a traceless route to cyclohexenes.

A pericyclic approach for the synthesis of six-membered ring structures is described. The method employs 1,3-dienes with a 1-sulfur substituent in a tandem sequence of Diels-Alder and retro-ene reactions. In this pairing of [4 + 2] cycloaddition and 1,5-sigmatropic rearrangement, 1-sulfenyl-1,3-dienes engage in Diels-Alder reactions with electron-deficient dienophiles. Subsequently, the sulfenyl group of the cycloadducts is oxidized and unmasked to form allylic sulfinic acids, which undergo sterospecific reductive transposition via sulfur dioxide extrusion. The sequence can also include an inverse electron demand Diels-Alder reaction by using a 1-sulfonyl-1,3-diene. This combination of two pericyclic events offers novel stereocontrolled access to cyclohexenes that are inaccessible via a direct [4 + 2] cycloaddition route.

CRIF1 deficiency induces FOXP3LOW inflammatory non-suppressive regulatory T cells, thereby promoting antitumor immunity.

Recently identified human FOXP3lowCD45RA- inflammatory non-suppressive (INS) cells produce proinflammatory cytokines, exhibit reduced suppressiveness, and promote antitumor immunity unlike conventional regulatory T cells (Tregs). In spite of their implication in tumors, the mechanism for generation of FOXP3lowCD45RA- INS cells in vivo is unclear. We showed that the FOXP3lowCD45RA- cells in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in Tregs bore Foxp3lowINS-Tregs with mitochondrial dysfunction and metabolic reprograming. The enhanced glutaminolysis activated α-ketoglutarate-mTORC1 axis, which promoted proinflammatory cytokine expression by inducing EOMES and SATB1 expression. Moreover, chromatin openness of the regulatory regions of the Ifng and Il4 genes was increased, which facilitated EOMES/SATB1 binding. The increased α-ketoglutarate-derived 2-hydroxyglutarate down-regulated Foxp3 expression by methylating the Foxp3 gene regulatory regions. Furthermore, CRIF1 deficiency-induced Foxp3lowINS-Tregs suppressed tumor growth in an IFN-γ-dependent manner. Thus, CRIF1 deficiency-mediated mitochondrial dysfunction results in the induction of Foxp3lowINS-Tregs including FOXP3lowCD45RA- cells that promote antitumor immunity.

De novo fatty-acid synthesis protects invariant NKT cells from cell death, thereby promoting their homeostasis and pathogenic roles in airway hyperresponsiveness.

Invariant natural-killer T (iNKT) cells play pathogenic roles in allergic asthma in murine models and possibly also humans. While many studies show that the development and functions of innate and adaptive immune cells depend on their metabolic state, the evidence for this in iNKT cells is very limited. It is also not clear whether such metabolic regulation of iNKT cells could participate in their pathogenic activities in asthma. Here, we showed that acetyl-coA-carboxylase 1 (ACC1)-mediated de novo fatty-acid synthesis is required for the survival of iNKT cells and their deleterious functions in allergic asthma. ACC1, which is a key fatty-acid synthesis enzyme, was highly expressed by lung iNKT cells from WT mice that were developing asthma. Cd4-Cre::Acc1fl/fl mice failed to develop OVA-induced and HDM-induced asthma. Moreover, iNKT cell-deficient mice that were reconstituted with ACC1-deficient iNKT cells failed to develop asthma, unlike when WT iNKT cells were transferred. ACC1 deficiency in iNKT cells associated with reduced expression of fatty acid-binding proteins (FABPs) and peroxisome proliferator-activated receptor (PPAR)γ, but increased glycolytic capacity that promoted iNKT-cell death. Furthermore, circulating iNKT cells from allergic-asthma patients expressed higher ACC1 and PPARG levels than the corresponding cells from non-allergic-asthma patients and healthy individuals. Thus, de novo fatty-acid synthesis prevents iNKT-cell death via an ACC1-FABP-PPARγ axis, which contributes to their homeostasis and their pathogenic roles in allergic asthma.

N-formyl-methionyl-leucyl-phenylalanine (fMLP) promotes osteoblast differentiation via the N-formyl peptide receptor 1-mediated signaling pathway in human mesenchymal stem cells from bone marrow.

Binding of N-formyl-methionyl-leucyl-phenylalanine (fMLP) to its specific cell surface receptor, N-formyl peptide receptor (FPR), triggers different cascades of biochemical events, eventually leading to cellular activation. However, the physiological role of fMLP and FPR during differentiation of mesenchymal stem cells is unknown. In this study, we attempted to determine whether fMLP regulates differentiation of mesenchymal stem cells derived from bone marrow. Analysis by quantitative-PCR and flow cytometry showed significantly increased expression of FPR1, but not FPR2 and FPR3, during osteoblastic differentiation. fMLP, a specific ligand of FPR1, promotes osteoblastic commitment and suppresses adipogenic commitment under differentiation conditions. Remarkably, fMLP-stimulated osteogenesis is associated with increased expression of osteogenic markers and mineralization, which were blocked by cyclosporine H, a selective FPR1 antagonist. In addition, fMLP inhibited expression of peroxisome proliferator-activated receptor-γ1, a major regulator of adipocytic differentiation. fMLP-stimulated osteogenic differentiation was mediated via FPR1-phospholipase C/phospholipase D-Ca(2+)-calmodulin-dependent kinase II-ERK-CREB signaling pathways. Finally, fMLP promoted bone formation in zebrafish and rabbits, suggesting its physiological relevance in vivo. Collectively, our findings provide novel insight into the functional role of fMLP in bone biology, with important implications for its potential use as a therapeutic agent for treatment of bone-related disorders.

Colon-targeted cell-permeable NFκB inhibitory peptide is orally active against experimental colitis.

For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP-NIP). The most potent CPP-NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP-NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP-NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP-NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP-NIP (CPP-NIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD.

MsrB1-regulated GAPDH oxidation plays programmatic roles in shaping metabolic and inflammatory signatures during macrophage activation.

Classically activated pro-inflammatory macrophages are generated from naive macrophages by pro-inflammatory cues that dynamically reprogram their fuel metabolism toward glycolysis. This increases their intracellular reactive oxygen species (ROS) levels, which then activate the transcription and release of pro-inflammatory mediators. Our study on mice that lack methionine sulfoxide reductase (Msr)-B1 shows that the resulting partial loss of protein methionine reduction in pro-inflammatory macrophages creates a unique metabolic signature characterized by altered fuel utilization, including glucose and pyruvate. This change also associates with hyper-inflammation that is at least partly due to sustained oxidation of an exposed methionine residue (M44) on glyceraldehyde 3-phosphate dehydrogenase (GAPDH), thereby inducing GAPDH aggregation, inflammasome activation, and subsequent increased interleukin (IL)-1ß secretion. Since MsrB1-knockout mice exhibit increased susceptibility to lipopolysaccharide (LPS)-induced sepsis, the MsrB1-GAPDH axis may be a key molecular mechanism by which protein redox homeostasis controls the metabolic profile of macrophages and thereby regulates their functions.

Impact of malnutrition evaluated by the mini nutritional assessment on the prognosis of acute hospitalized older adults.

Background: Malnutrition is prevalent among hospitalized older patients. Therefore, this study aimed to investigate the association between nutritional status [assessed using the Mini Nutritional Assessment (MNA) and serum albumin levels] and adverse outcomes in hospitalized older patients. We also aimed to compare the predictive utility of our findings. Methods: This retrospective cohort study was conducted between January 2016 and June 2020. In total, 808 older patients (aged ≥ 65 years, mean age 82.8 ± 6.70 years, 45.9% male) admitted to the acute geriatric unit were included in our sample. Comprehensive geriatric assessments, including the MNA, were performed. Malnutrition and risk of malnutrition were defined as MNA < 17, albumin < 3.5 g/dL and 17 ≤ MNA ≤ 24, 3.5 g/dL ≤ albumin < 3.9 g/dL, respectively. The primary outcome was that patients could not be discharged to their own homes. The secondary outcomes were overall all-cause mortality, 3-month all-cause mortality, and incidence of geriatric syndrome, including delirium, falls, and newly developed or worsening pressure sores during hospitalization. Results: Poor nutritional status was associated with older age; female sex; admission from the emergency room; high risk of pressure sores and falls; lower physical and cognitive function; higher depressive score; and lower serum albumin, protein, cholesterol, and hemoglobin levels. In the fully adjusted model, malnutrition assessed using the MNA predicted discharge to nursing homes or long-term care hospitals [odds ratio (OR) 5.822, 95% confidence interval (CI): 2.092-16.199, P = 0.001], geriatric syndrome (OR 2.069, 95% CI: 1.007-4.249, P = 0.048), and 3-month mortality (OR 3.519, 95% CI: 1.254-9.872, P = 0.017). However, malnutrition assessed using albumin levels could only predict 3-month mortality (OR 3.848, 95% CI: 1.465-10.105, P = 0.006). The MNA predicted 3-month mortality with higher precision than serum albumin levels (P = 0.034) when comparing the areas under the receiver operating characteristic curve. Conclusion: Nutritional risk measured by the MNA was an independent predictor of various negative outcomes in hospitalized older patients. Poor nutritional status assessed by serum albumin levels, the most widely used biochemical marker, could predict mortality, but not the development of geriatric syndrome or discharge location reflecting functional status.

Gene expression profile during chondrogenesis in human bone marrow derived mesenchymal stem cells using a cDNA microarray.

Mesenchymal stem cells (MSCs) have the capacity to proliferate and differentiate into multiple connective tissue lineages, which include cartilage, bone, and fat. Cartilage differentiation and chondrocyte maturation are required for normal skeletal development, but the intracellular pathways regulating this process remain largely unclear. This study was designed to identify novel genes that might help clarify the molecular mechanisms of chondrogenesis. Chondrogenesis was induced by culturing human bone marrow (BM) derived MSCs in micromass pellets in the presence of defined medium for 3, 7, 14 or 21 days. Several genes regulated during chondrogenesis were then identified by reverse transcriptase-polymerase chain reaction (RT-PCR). Using an ABI microarray system, we determined the differential gene expression profiles of differentiated chondrocytes and BM-MSCs. Normalization of this data resulted in the identification of 1,486 differentially expressed genes. To verify gene expression profiles determined by microarray analysis, the expression levels of 10 genes with high fold changes were confirmed by RT-PCR. Gene expression patterns of 9 genes (Hrad6B, annexinA2, BMP-7, contactin-1, peroxiredoxin-1, heat shock transcription factor-2, synaptotagmin IV, serotonin receptor-7, Axl) in RT-PCR were similar to the microarray gene expression patterns. These findings provide novel information concerning genes involved in the chondrogenesis of human BM-MSCs.

Aged Microglia in Neurodegenerative Diseases: Microglia Lifespan and Culture Methods.

Microglia have been recognized as macrophages of the central nervous system (CNS) that are regarded as a culprit of neuroinflammation in neurodegenerative diseases. Thus, microglia have been considered as a cell that should be suppressed for maintaining a homeostatic CNS environment. However, microglia ontogeny, fate, heterogeneity, and their function in health and disease have been defined better with advances in single-cell and imaging technologies, and how to maintain homeostatic microglial function has become an emerging issue for targeting neurodegenerative diseases. Microglia are long-lived cells of yolk sac origin and have limited repopulating capacity. So, microglial perturbation in their lifespan is associated with not only neurodevelopmental disorders but also neurodegenerative diseases with aging. Considering that microglia are long-lived cells and may lose their functional capacity as they age, we can expect that aged microglia contribute to various neurodegenerative diseases. Thus, understanding microglial development and aging may represent an opportunity for clarifying CNS disease mechanisms and developing novel therapies.

Current Understanding of the Roles of CD1a-Restricted T Cells in the Immune System.

Cluster of differentiation 1 (CD1) is a family of cell-surface glycoproteins that present lipid antigens to T cells. Humans have five CD1 isoforms. CD1a is distinguished by the small volume of its antigen-binding groove and its stunted A' pocket, its high and exclusive expression on Langerhans cells, and its localization in the early endosomal and recycling intracellular trafficking compartments. Its ligands originate from self or foreign sources. There are three modes by which the T-cell receptors of CD1a-restricted T cells interact with the CD1a:lipid complex: they bind to both the CD1a surface and the antigen or to only CD1a itself, which activates the T cell, or they are unable to bind because of bulky motifs protruding from the antigen-binding groove, which might inhibit autoreactive T-cell activation. Recently, several studies have shown that by producing TH2 or TH17 cytokines, CD1a-restricted T cells contribute to inflammatory skin disorders, including atopic dermatitis, psoriasis, allergic contact dermatitis, and wasp/bee venom allergy. They may also participate in other diseases, including pulmonary disorders and cancer, because CD1a-expressing dendritic cells are also located in non-skin tissues. In this mini-review, we discuss the current knowledge regarding the biology of CD1a-reactive T cells and their potential roles in disease.

Efficacy of novel bispecific antibody targeting TNF-α/CXCL10 in the treatment of experimental arthritis.

This study was aimed at generating and investigating the efficacy of a novel monoclonal bispecific antibody (BsAb) for the combined inhibition of tumor necrosis factor-α (TNF-α) and CXCL10 as a treatment option for rheumatoid arthritis (RA). A novel BsAb targeting TNF-α and CXCL10 was generated by conjugating a single-chain variable fragment (scFv) of the anti-CXCL10 monoclonal antibody to the Fc region of adalimumab (ADA). The effects of the BsAb on the inflammatory response in the in vitro and in vivo development of arthritis and joint destruction were evaluated in human TNF transgenic (hTNF-Tg) mice, and K/BxN serum transfer arthritis models. The BsAb inhibited CXCL10-mediated CD8+ T cell migration. The binding affinity of the BsAb to TNF-α was comparable to that of ADA and suppressed TNF-α induced cell death and inhibited TNF-α induced ICAM-1 and VCAM-1 in RA fibroblast-like synoviocytes (FLSs). The BsAb decreased the expression of TNFSF11 and the production of IL-6 in RA-FLS cells stimulated with TNF-α and CXCL10. Treatment with the BsAb attenuated the development of arthritis in hTNF-Tg mice and suppressed LPS-induced bone erosion. In the K/BxN serum transfer model, BsAb effectively attenuated ankle swelling, synovial inflammation, cartilage damage, and bone destruction, reducing the activation of osteoclasts. The additional neutralization of TNF-α and CXCL10 from treatment with the novel BsAb was more effective than TNF-α inhibition alone in the in vitro and in vivo models of RA. Thus, the BsAb, targeting both TNF-α and CXCL10, may provide a new therapeutic opportunity for RA patients who fail to respond to the blockade of a single cytokine.

Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis.

BACKGROUND: To investigate the effects of inhibiting histone deacetylase (HDAC) 6 on inflammatory responses and tissue-destructive functions of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). METHODS: FLS from RA patients were activated with interleukin (IL)-1ß in the presence of increasing concentrations of M808, a novel specific HDAC6 inhibitor. Production of ILs, chemokines, and metalloproteinases (MMPs) was measured in ELISAs. Acetylation of tubulin and expression of ICAM-1 and VCAM-1 were assessed by Western blotting. Wound healing and adhesion assays were performed. Cytoskeletal organization was visualized by immunofluorescence. Finally, the impact of HDAC6 inhibition on the severity of arthritis and joint histology was examined in a murine model of adjuvant-induced arthritis (AIA). RESULTS: HDAC6 was selectively inhibited by M808. The HDAC6 inhibitor suppressed the production of MMP-1, MMP-3, IL-6, CCL2, CXCL8, and CXCL10 by RA-FLS in response to IL-1ß. Increased acetylation of tubulin was associated with decreased migration of RA-FLS. Inhibiting HDAC6 induced cytoskeletal reorganization in RA-FLS by suppressing the formation of invadopodia following activation with IL-1ß. In addition, M808 tended to decrease the expression of ICAM-1 and VCAM-1. In the AIA arthritis model, M808 improved the clinical arthritis score in a dose-dependent manner. Also, HDAC6 inhibition was associated with less severe synovial inflammation and joint destruction. CONCLUSION: Inhibiting HDAC6 dampens the inflammatory and destructive activity of RA-FLS and reduces the severity of arthritis. Thus, targeting HDAC6 has therapeutic potential.

Exposure to permethrin used as a home insecticide: A case study comparing model predictions and excretion of metabolites.

Pyrethroids have been widely used as an active ingredient in home insecticide products since the 1960 s. Although their occurrence in indoor environments has been studied, the contribution of home insecticide application to the aggregate exposure to pyrethroids is not well known. The objective of this study was to estimate the consumer exposure to permethrin, a representative pyrethroid, via the use of home insecticide spray during the summer season using biomonitoring and personal exposure modeling. Exposure to permethrin was assessed by analyzing its urinary metabolites, 3-phenoxybenzoic acid (3-PBA) and cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropan carboxylic acid (cis/trans-DCCA), for a group of consumers (n = 27). The levels of metabolites were also compared with those predicted by a screening exposure model considering personal exposure parameters. The levels of metabolites in 15 participants increased significantly (p < 0.05) with the application of home insecticide products, thereby suggesting that the heavy use of home insecticides during summer could be an important exposure route of permethrin in addition to other sources, such as food consumption. The total amount of excreted 3-PBA and cis/trans-DCCA was lower than the amount estimated by the exposure model for most participants by a factor of 0.9-861.0. These differences could be attributed to the rapid loss of permethrin after application, including sorption to indoor surfaces, reaction with indoor substances, individual biological variations, and ventilation during application. However, the screening exposure model used for the initial safety assessment of biocidal products generally performed well because it did not underestimate the personal exposure to permethrin during the application of home insecticide spray.

Impact of Social Support and Social Trust on Public Viral Risk Response: A COVID-19 Survey Study.

Public health has been under continuous threat worldwide in recent years. This study examined the impact of social support and social trust on the activities and efficacy of the public's risk response in the case of COVID-19. We conducted an online survey over eight days with 620 Korean adult participants. Data were analyzed using structural equation modelling and K-means cluster analysis. Our results showed that public support had a positive impact on response efficacy, while response efficacy had a positive impact on sanitation, distancing, and purchasing activities. In addition, social support positively moderated the impact of public and individual support on response efficacy, while response efficacy negatively moderated the impact on sanitation activities. These results suggest that, first, amid viral risk, governments should proactively supply tools and information for infection-prevention, and deliver messages that encourage and support infection-prevention activities among the public. Second, when viral risk occurs, governments, along with all other members of society, must engage in aggressive risk response measures. Third, there is a need for risk communication that further emphasizes the importance of personal sanitation activities in the face of viral risk.