Altered interictal serum histamine and immunoglobulin E but unchanged tryptase levels in individuals with episodic and chronic migraine.

BACKGROUND: Serum histamine, immunoglobulin E, and tryptase are markers of allergic diseases. Despite the reported association between migraine and allergic diseases, differences in these marker levels between episodic and chronic migraines remain unelucidated. METHODS: We investigated serum histamine, immunoglobulin E, and tryptase levels in 97 and 96 participants with episodic migraine and chronic migraine, respectively, and 56 controls according to the presence of allergic diseases. RESULTS: Serum histamine levels in episodic migraine (median and interquartile ranges, 0.78 [0.65-1.25] ng/mL, p < 0.001) and chronic migraine (0.89 [0.67-1.28] ng/mL, p < 0.001) participants were significantly lower than those in healthy controls (1.19 [0.81-2.08] ng/mL) among the 160 participants without allergic diseases. Serum immunoglobulin E levels in episodic migraine and chronic migraine participants with allergic diseases negatively correlated with headache frequency (correlation coefficient = -0.263, p = 0.017). Serum histamine levels in participants with allergic diseases and serum immunoglobulin E levels in participants without allergic diseases were not significantly different among episodic migraine, chronic migraine, and control groups. Serum tryptase levels did not significantly differ among episodic migraine, chronic migraine, and control participants with and without allergic diseases. CONCLUSIONS: Altered serum histamine and immunoglobulin E levels in episodic migraine and chronic migraine and different profiles concerning allergic diseases suggest the involvement of allergic mechanisms in migraine pathogenesis.

Aggravation of asthmatic inflammation by chlorine exposure via innate lymphoid cells and CD11cintermediate macrophages.

BACKGROUND: Chlorine is widely used in daily life as disinfectant. However, chronic exposure to chlorine products aggravates allergic TH 2 inflammation and airway hyperresponsiveness (AHR). Innate lymphoid cells (ILCs) in airways contribute to the inception of asthma in association with virus infection, pollution, and excess of nutrient, but it is not known whether chronic chlorine exposure can activate innate immune cells. The aim of this study was to evaluate the impact of chlorine inhalation on the innate immunity such as ILCs and macrophages in relation with the development of asthma by using murine ovalbumin (OVA) sensitization/challenge model. METHODS: Six-week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low-dose chlorine exposure by inhalation of naturally vaporized gas of 5% sodium hypochlorite solution. AHR, airway inflammatory cells, from BALF and the population of ILCs and macrophages in the lung were evaluated. RESULTS: The mice exposed to chlorine with OVA (Cl + OVA group) showed enhanced AHR and eosinophilic inflammation compared to OVA-treated mice (OVA group). The population of TH 2 cells, ILC2s, and ILC3s increased in Cl + OVA group compared with OVA group. CD11cint macrophages also remarkably increased in Cl + OVA group compared with OVA group. The deletion of macrophages by clodronate resulted in reduction of ILC2s and ILC3s population which was restored by adoptive transfer of CD11cint macrophages. CONCLUSIONS: Chronic chlorine inhalation contributes to the exacerbation of airway inflammation in asthmatic airway by mobilizing pro-inflammatory macrophage into the lung as well as stimulating group 2 and 3 ILCs.

IL-23 secreted by bronchial epithelial cells contributes to allergic sensitization in asthma model: role of IL-23 secreted by bronchial epithelial cells.

IL-23 has been postulated to be a critical mediator contributing to various inflammatory diseases. Dermatophagoides pteronyssinus (Der p) is one of the most common inhalant allergens. However, the role of IL-23 in Der p-induced mouse asthma model is not well understood, particularly with regard to the development of allergic sensitization in the airways. The objective of this study was to evaluate roles of IL-23 in Der p sensitization and asthma development. BALB/c mice were repeatedly administered Der p intranasally to develop Der p allergic sensitization and asthma. After Der p local administration, changes in IL-23 expression were examined in lung tissues and primary epithelial cells. Anti-IL-23p19 antibody was given during the Der p sensitization period, and its effects were examined. Effects of anti-IL-23p19 antibody at bronchial epithelial levels were also examined in vitro. The expression of IL-23 at bronchial epithelial layers was increased after Der p local administration in mouse. In Der p-induced mouse models, anti-IL-23p19 antibody treatment during allergen sensitization significantly diminished Der p allergic sensitization and several features of allergic asthma including the production of Th2 cytokines and the population of type 2 innate lymphoid cells in lungs. The activation of dendritic cells in lung-draining lymph nodes was also reduced by anti-IL-23 treatment. In murine lung alveolar type II-like epithelial cell line (MLE-12) cells, IL-23 blockade prevented cytokine responses to Der p stimulation, such as IL-1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-33, and also bone marrow-derived dendritic cell activation. In conclusion, IL-23 is another important bronchial epithelial cell-driven cytokine which may contribute to the development of house dust mite allergic sensitization and asthma.

Efflux Attenuates the Antibacterial Activity of Q203 in Mycobacterium tuberculosis.

New and improved treatments for tuberculosis (TB) are urgently needed. Recently, it has been demonstrated that verapamil, an efflux inhibitor, can reduce bacterial drug tolerance caused by efflux pump activity when administered in combination with available antituberculosis agents. The aim of this study was to evaluate the effectiveness of verapamil in combination with the antituberculosis drug candidate Q203, which has recently been developed and is currently under clinical trials as a potential antituberculosis agent. We evaluated changes in Q203 activity in the presence and absence of verapamil in vitro using the resazurin microplate assay and ex vivo using a microscopy-based phenotypic assay for the quantification of intracellular replicating mycobacteria. Verapamil increased the potency of Q203 against Mycobacterium tuberculosis both in vitro and ex vivo, indicating that efflux pumps are associated with the activity of Q203. Other efflux pump inhibitors also displayed an increase in Q203 potency, strengthening this hypothesis. Therefore, the combination of verapamil and Q203 may be a promising combinatorial strategy for anti-TB treatment to accelerate the elimination of M. tuberculosis.

Activity of LCB01-0371, a Novel Oxazolidinone, against Mycobacterium abscessus.

Mycobacterium abscessus is a highly pathogenic drug-resistant rapidly growing mycobacterium. In this study, we evaluated the in vitro, intracellular, and in vivo activities of LCB01-0371, a novel and safe oxazolidinone derivative, for the treatment of M. abscessus infection and compared its resistance to that of other oxazolidinone drugs. LCB01-0371 was effective against several M. abscessus strains in vitro and in a macrophage model of infection. In the murine model, a similar efficacy to linezolid was achieved, especially in the lungs. We induced laboratory-generated resistance to LCB01-0371; sequencing analysis revealed mutations in rplC of T424C and G419A and a nucleotide insertion at the 503 position. Furthermore, LCB01-0371 inhibited the growth of amikacin-, cefoxitin-, and clarithromycin-resistant strains. Collectively, our data indicate that LCB01-0371 might represent a promising new class of oxazolidinones with improved safety, which may replace linezolid for the treatment of M. abscessus.

Effect of 1.8-Cineole in Dermatophagoides pteronyssinus-Stimulated Bronchial Epithelial Cells and Mouse Model of Asthma.

1.8-Cineole (eucalyptol) is a phytoncide, a volatile organic compound derived from plants. Phytoncides are known to have an anti-inflammatory effect. However, the effects of 1.8-cineole in house dust mite (HDM)-stimulated bronchial epithelial cells are poorly understood. The objective of this study was to assess the effect of 1.8-cineole in HDM-stimulated bronchial epithelial cells and in the HDM-induced murine asthma model. The purpose of the present study is to evaluate the anti-inflammatory effects and mechanism of 1.8-cineole action in HDM-induced airway inflammation. Human bronchial epithelial cells (HBECs) were cultured with Dermatophagoides pteronyssinus (Der p) and 1.8-cineole. Cytokine protein levels, phosphorylation of protein kinases, and intracellular Toll-like receptor 4 (TLR4) expressions were measured. In the murine model, BALB/C mice were sensitized with Der p and were exposed to Der p via intranasal route during the challenge period. 1.8-Cineole was given by inhalation 6 h before the each challenge. Treatment with 1.8-cineole inhibited the Der p-induced cytokine protein expression, phosphorylation of p38 mitogen-activated protein kinase (MAPK) and Akt and intracellular TLR4 expression in HBECs. In the Der p-induced mouse model, airway hyper-responsiveness (AHR) and the number of eosinophils in bronchoalveolar lavage fluid (BALF) was also significantly reduced by 1.8-cineole treatment. The treatment of 1.8-cineole inhibited the increased production of interleukin (IL)-4, IL-13 and IL-17A in BALF after Der p challenge. These results suggest that 1.8-cineole suppresses Der p-induced IL-8, IL-6 and granulocyte macrophage-colony stimulating factor (GM-CSF) production in HBECs. Finally, we confirmed that 1.8-cineole decreases AHR and eosinophilic airway inflammation in Der p-induced asthma mice.

Mobile-Based Video Learning Outcomes in Clinical Nursing Skill Education: A Randomized Controlled Trial.

Mobile devices are a regular part of daily life among the younger generations. Thus, now is the time to apply mobile device use to nursing education. The purpose of this study was to identify the effects of a mobile-based video clip on learning motivation, competence, and class satisfaction in nursing students using a randomized controlled trial with a pretest and posttest design. A total of 71 nursing students participated in this study: 36 in the intervention group and 35 in the control group. A video clip of how to perform a urinary catheterization was developed, and the intervention group was able to download it to their own mobile devices for unlimited viewing throughout 1 week. All of the students participated in a practice laboratory to learn urinary catheterization and were blindly tested for their performance skills after participation in the laboratory. The intervention group showed significantly higher levels of learning motivation and class satisfaction than did the control. Of the fundamental nursing competencies, the intervention group was more confident in practicing catheterization than their counterparts. Our findings suggest that video clips using mobile devices are useful tools that educate student nurses on relevant clinical skills and improve learning outcomes.

Tranglutaminase 2 contributes to the asthmatic inflammation by modulating activation of alveolar macrophages.

BACKGROUND: Transglutaminase 2 (TG2), a multifunctional calcium-dependent acyltransferase, is upregulated in asthmatic airways and reported to play a role in the pathogenesis of allergic asthma. However, the underlying mechanism is not fully understood. OBJECTIVE: To investigate the role of TG2 in alternative activation of alveolar macrophages by using murine asthma model. METHODS: TG2 expression was assessed in induced sputum of 21 asthma patients and 19 healthy controls, and lung tissue of ovalbumin (OVA)-induced murine asthma model. To evaluate the role of TG2 in asthma, we developed an OVA asthma model in both TG2 null and wild-type mice. The expression of M2 macrophage markers was measured by fluorescence-activated cell sorting (FACS) after OVA sensitization and challenge. To evaluate the effect of TG2 inhibition in vitro, interleukin 4 (IL-4) or IL-13-stimulated expression of M2 macrophage markers was measured in CRL-2456 cells in the presence and absence of a TG2 inhibitor. RESULTS: The expression of both TG2 and M2 markers was increased in the sputum of asthmatics compared with that of healthy controls. The expression of TG2 was increased in macrophages of OVA mice. Airway hyperresponsiveness, and the number of inflammatory cells, including eosinophils, was significantly reduced in TG2 null mice compared with wild-type mice. Enhanced expression of M2 markers in OVA mice was normalized by TG2 knockout. IL-4 or IL-13-stimulated expression of M2 markers in alveolar macrophages was also attenuated by TG2 inhibitor treatment in vitro. CONCLUSION: Our results suggest that TG2-mediated modulation of alveolar macrophage polarization plays important roles in the pathogenesis of asthma.

Role of interleukin-23 in the development of nonallergic eosinophilic inflammation in a murine model of asthma.

Nonallergic eosinophilic asthma (NAEA) is a clinically distinct subtype of asthma. Thus far, the pathophysiologic mechanisms underlying NAEA have not been fully elucidated. This study aimed to determine the role of IL-23 in the pathogenesis of NAEA. We developed a murine model of NAEA using recombinant IL-23 (rIL-23) plus a nonspecific airway irritant [polyinosinic-polycytidylic acid (polyI:C) or diesel exhaust particles (DEPs)] and investigated whether IL-23 plays an important role in the development of NAEA. Intranasal administration of rIL-23 (0.1 µg/mouse) plus polyI:C (0.01 µg/mouse) or DEPs (10 µg/mouse) without allergen resulted in methacholine bronchial hyperresponsiveness and eosinophilic airway inflammation in mice, which are characteristic features of NAEA. rIL-23 plus a low dose nonspecific airway irritants induced the release of innate cytokines from airway epithelium, including IL-33, thymic stromal lymphopoietin and IL-1ß; these factors activated types 2 and 3 innate lymphoid cells (ILC2s and ILC3s). ILC2s and ILC3s, but not CD4+ T cells (i.e., adaptive immune cells), were important in the development of NAEA. In addition, we observed that IL-23 receptor expressions increased in airway epithelial cells, which suggests the existence of a positive autocrine loop in our murine model of NAEA. To our knowledge, this is the first report in which administration of rIL-23 plus a nonspecific airway irritant (polyI:C or DEPs) without allergen resulted in features of NAEA in mice similar to those found in humans. IL-23 may constitute a therapeutic target for NAEA in humans.

Critical role of interleukin-23 in development of asthma promoted by cigarette smoke.

It has been recently reported that cigarette smoke exposure during allergen sensitization facilitates the development of allergic asthma; however, the underlying mechanisms remain elusive. We evaluated the role of interleukin (IL-23) in a cigarette smoke extract (CSE)-induced Dermatophagoides pteronyssinus (Dp)-allergic asthma mouse model. BALB/c mice were exposed to CSE during allergen sensitization period. Anti-IL-23p19 or IL-23R antibody was administered during the sensitization period. And we evaluated several immunological responses. The expression of IL-23 and IL-23 receptor (IL-23R) was examined in lung tissue. IL-23 and IL-23R expression was increased in the airway epithelium of Dp/CSE co-administered mice. CSE administration during the sensitization promoted Dp-allergic sensitization and the development of asthma phenotypes. Additionally, the proportion of innate lymphoid type 2 cells (ILC2) was also increased by CSE and Dp co-instillation. Anti-IL-23 or IL-23R antibody treatment during allergen sensitization significantly diminished phenotypes of allergic asthma and the ILC2 population. The levels of IL-33 and thymic stromal lymphopoietin (TSLP) were also significantly reduced by anti-IL-23 or IL-23R antibody treatment. IL-23 may thus play a significant role in cigarette smoke-induced allergic sensitization and asthma development. Clinically, the increase in allergen sensitization due to cigarette exposure causes onset of asthma, and IL-23 may be important in this mechanism. KEY MESSAGES: IL-23 and IL-23R expression was increased in the lung epithelium of Dp and CSE co-exposed mice during sensitization period. The population of ILC2s was increased in Dp and CSE co-exposed mice during sensitization period. Anti-IL23 or IL-23R antibody treatment with co-administration of CSE and HDM during sensitization period significantly suppresses ILC2. In vitro, IL-23 blockade in Dp and CSE-stimulated epithelial cells suppressed IL-13 expression in ILC2.

[The Influence of Grit on Turnover Intention of University Hospital Nurses: The Mediating Effect of Job Involvement].

PURPOSE: This study aimed to confirm the mediating effect of job involvement in the relationship between grit and turnover intention among nurses working at university hospitals. METHODS: Participants included 437 nurses from university hospitals located in C city, Gyeongnam. Data were collected from January 8 to 19, 2018, using self-report questionnaires. Data were analyzed using the t-test, analysis of variance, Scheffe's test, Pearson's correlation coefficient, and multiple regression, with the SPSS/22.0 program. A mediation analysis was performed according to the Baron and Kenny, and bootstrapping methods. RESULTS: There were significant relationships between grit and job involvement (r=.40, p<.001), grit and turnover intention (r=-.29, p<.001), and turnover intention and job involvement (r=-.52, p<.001). Job involvement showed partial mediating effects in the relationship between grit and turnover intention. CONCLUSION: Grit increased job involvement and lowered turnover intention. Therefore, to reduce nurses' turnover intention, it is necessary to develop a program and strategies to increase their grit.

Correction to: Critical role of interleukin-23 in development of asthma promoted by cigarette smoke.

The original publication of this paper contains a mistake.

Continuous and Quantitative Purification of T-Cell Subsets for Cell Therapy Manufacturing Using Magnetic Ratcheting Cytometry.

T-cell-based immunotherapies represent a growing medical paradigm that has the potential to revolutionize contemporary cancer treatments. However, manufacturing bottlenecks related to the enrichment of therapeutically optimal T-cell subpopulations from leukopak samples impede scale-up and scale-out efforts. This is mainly attributed to the challenges that current cell purification platforms face in balancing the quantitative sorting capacity needed to isolate specific T-cell subsets with the scalability to meet manufacturing throughputs. In this work, we report a continuous-flow, quantitative cell enrichment platform based on a technique known as ratcheting cytometry that can perform complex, multicomponent purification targeting various subpopulations of magnetically labeled T cells directly from apheresis or peripheral blood mononuclear cell (PBMC) samples. The integrated ratcheting cytometry instrument and cartridge demonstrated enrichment of T cells directly from concentrated apheresis samples with a 97% purity and an 85% recovery of magnetically tagged cells. Magnetic sorting of different T-cell subpopulations was also accomplished on chip by multiplexing cell surface targets onto particles with differing magnetic strengths. We believe that ratcheting cytometry's quantitative capacity and throughput scalability represents an excellent technology candidate to alleviate cell therapy manufacturing bottlenecks.

Correction: Unsupervised capture and profiling of rare immune cells using multi-directional magnetic ratcheting.

Correction for 'Unsupervised capture and profiling of rare immune cells using multi-directional magnetic ratcheting' by Coleman Murray et al., Lab Chip, 2018, 18, 2396-2409.

Unsupervised capture and profiling of rare immune cells using multi-directional magnetic ratcheting.

Immunotherapies (IT) require induction, expansion, and maintenance of specific changes to a patient's immune cell repertoire which yield a therapeutic benefit. Recently, mechanistic understanding of these changes at the cellular level has revealed that IT results in complex phenotypic transitions in target cells, and that therapeutic effectiveness may be predicted by monitoring these transitions during therapy. However, monitoring will require unique tools that enable capture, manipulation, and profiling of rare immune cell populations. In this study, we introduce a method of automated and unsupervised separation and processing of rare immune cells, using high-force and multidimensional magnetic ratcheting (MR). We demonstrate capture of target immune cells using samples with up to 1 : 10 000 target cell to background cell ratios from input volumes as small as 25 microliters (i.e. a low volume and low cell frequency sample sparing assay interface). Cell capture is shown to achieve up to 90% capture efficiency and purity, and captured cell analysis is shown using both on-chip culture/activity assays and off-chip ejection and nucleic acid analysis. These results demonstrate that multi-directional magnetic ratcheting offers a unique separation system for dealing with blood cell samples that contain either rare cells or significantly small volumes, and the "sample sparing" capability leads to an expanded spectrum of parameters that can be measured. These tools will be paramount to advancing techniques for immune monitoring under conditions in which both the sample volume and number of antigen-specific target cells are often exceedingly small, including during IT and treatment of allergy, asthma, autoimmunity, immunodeficiency, cell based therapy, transplantation, and infection.

Characteristics of social perception assessed in schizophrenia using virtual reality.

Impairment in social skills is one of the few criteria that all individuals diagnosed with schizophrenia must meet. Successful social skills require the coordination of many abilities, including social perception, which involves the decoding and interpretation of social cues from others. In this study, we examined the potential for virtual reality (VR) in social skill training. We attempted to determine if VR can be used to measure social skills and social perception, and to determine which VR parameters are related to schizophrenic symptoms. Some of these results have clear clinical relevance, while other observations need further study. The VR system appears to be useful in assessing the social perception of schizophrenics and normal people, and could be more widely used in the future for social training and in the assessment of social problem-solving abilities, assertiveness skills, and general social skills.

Thalidomide inhibits alternative activation of macrophages in vivo and in vitro: a potential mechanism of anti-asthmatic effect of thalidomide.

BACKGROUND: Thalidomide is known to have anti-inflammatory and immunomodulatory actions. However, the effect and the anti-asthmatic mechanism of thalidomide in the pathogenesis of asthmatic airways are not fully understood. OBJECTIVE: This study is designed to determine the effect and the potential mechanism of thalidomide in the pathogenesis of asthmatic airways using animal model of allergic asthma. METHODS: Six-week-old female BALB/C mice were sensitized with alum plus ovalbumin (OVA) and were exposed to OVA via intranasal route for 3 days for challenge. Thalidomide 200 mg/kg was given via gavage twice a day from a day before the challenge and airway hyperresponsivenss (AHR), airway inflammatory cells, and cytokines in bronchoalveolar lavage fluids (BALF) were evaluated. The expression levels of pro-inflammatory cytokines and other mediators were evaluated using ELISA, real time (RT)-qPCR, and flow cytometry. CRL-2456, alveolar macrophage cell line, was used to test the direct effect of thalidomide on the activation of macrophages in vitro. RESULTS: The mice with thalidomide treatment showed significantly reduced levels of allergen-induced BALF and lung inflammation, AHR, and the expression of a number of pro-inflammatory cytokines and mediators including Th2 related, IL-17 cytokines, and altered levels of allergen-specific IgG1/IgG2a. Of interesting note, thalidomide treatment significantly reduced expression levels of allergen- or Th2 cytokine-stimulated alternative activation of macrophages in vivo and in vitro. CONCLUSION: These studies highlight a potential use of thalidomide in the treatment of allergic diseases including asthma. This study further identified a novel inhibitory effect of thalidomide on alternative activation of macrophages as a potential mechanism of anti-asthmatic effect of thalidomide.

Chronic low dose chlorine exposure aggravates allergic inflammation and airway hyperresponsiveness and activates inflammasome pathway.

BACKGROUND: Epidemiologic clinical studies suggested that chronic exposure to chlorine products is associated with development of asthma and aggravation of asthmatic symptoms. However, its underlying mechanism was not clearly understood. Studies were undertaken to define the effects and mechanisms of chronic low-dose chlorine exposure in the pathogenesis of airway inflammation and airway hyperresponsiveness (AHR). METHODS: Six week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low dose chlorine exposure of naturally vaporized gas of 5% sodium hypochlorite solution. Airway inflammation and AHR were evaluated by bronchoalveolar lavage (BAL) cell recovery and non-invasive phlethysmography, respectively. Real-time qPCR, Western blot assay, and ELISA were used to evaluate the mRNA and protein expressions of cytokines and other inflammatory mediators. Human A549 and murine epithelial (A549 and MLE12) and macrophage (AMJ2-C11) cells were used to define the responses to low dose chlorine exposure in vitro. RESULTS: Chronic low dose chlorine exposure significantly augmented airway inflammation and AHR in OVA-sensitized and challenged mice. The expression of Th2 cytokines IL-4 and IL-5 and proinflammatory cytokine IL-1ß and IL-33 were significantly increased in OVA/Cl group compared with OVA group. The chlorine exposure also activates the major molecules associated with inflammasome pathway in the macrophages with increased expression of epithelial alarmins IL-33 and TSLP in vitro. CONCLUSION: Chronic low dose exposure of chlorine aggravates allergic Th2 inflammation and AHR potentially through activation of inflammasome danger signaling pathways.