Involvement and Possible Role of Eosinophils in Asthma Exacerbation

Eosinophils are involved in the development of asthma exacerbation. Recent studies have suggested that sputum and blood eosinophil counts are important factors for predicting asthma exacerbation. In severe eosinophilic asthma, anti-interleukin (IL)-5 monoclonal antibody decreases blood eosinophil count and asthma exacerbation frequency. However, even in the absence of IL-5, eosinophilic airway inflammation can be sufficiently maintained by the T helper (Th) 2 network, which comprises a cascade of vascular cell adhesion molecule-1/CC chemokines/eosinophil growth factors, including granulocyte-macrophage colony-stimulating factor (GM-CSF). Periostin, an extracellular matrix protein and a biomarker of the Th2 immune response in asthma, directly activates eosinophils in vitro. A major cause of asthma exacerbation is viral infection, especially rhinovirus (RV) infection. The expression of intercellular adhesion molecule (ICAM)-1, a cellular receptor for the majority of RVs, on epithelial cells is increased after RV infection, and adhesion of eosinophils to ICAM-1 can upregulate the functions of eosinophils. The expressions of cysteinyl leukotrienes (cysLTs) and CXCL10 are upregulated in virus-induced asthma. CysLTs can directly provoke eosinophilic infiltration in vivo and activate eosinophils in vitro. Furthermore, eosinophils express the CXC chemokine receptor 3, and CXCL10 activates eosinophils in vitro. Both eosinophils and neutrophils contribute to the development of severe asthma or asthma exacerbation. IL-8, which is an important chemoattractant for neutrophils, is upregulated in some cases of severe asthma. Lipopolysaccharide (LPS), which induces IL-8 from epithelial cells, is also increased in the lower airways of corticosteroid-resistant asthma. IL-8 or LPS-stimulated neutrophils increase the transbasement membrane migration of eosinophils, even in the absence of chemoattractants for eosinophils. Therefore, eosinophils are likely to contribute to the development of asthma exacerbation through several mechanisms, including activation by Th2 cytokines, such as IL-5 or GM-CSF or by virus infection-related proteins, such as CXCL10, and interaction with other cells, such as neutrophils

Japan useful medication program for schizophrenia (JUMPs)-long-term study on discontinuation rate, resolution and remission, and improvement in social functioning rate associated with atypical antipsychotic medications in patients with schizophrenia

Background: It is desirable to establish evidence for the selection of antipsychotics from the viewpoint of recovery of social activity in individual patient with schizophrenia receiving medication. From this perspective, awareness of the importance of studies about drug effectiveness on treatment discontinuation rate, remission rate, and improvement in QOL has grown recently. In Western countries, numerous reports are available in effectiveness studies, which are related to olanzapine and risperidone primarily, whereas evidence for other second-generation antipsychotics (SGAs) is poor. In Japan, no effectiveness study has been reported: thus, it is desirable to collect data that will serve as evidence for selection of the 3 SGAs approved after olanzapine. Methods: The present study was a long-term effectiveness study under healthcare setting in Japan. It was designed as an open-label, multicenter, randomized, comparative study involving 104-week oral treatment with 1 of the 3 drugs (aripiprazole, blonanserin, and paliperidone) in patients with schizophrenia aged 20 years or over who required antipsychotic medication or switching of the current medication to others for reasons such as lack of efficacy and intolerability. The primary endpoint is treatment discontinuation rate for any causes. The secondary endpoints include remission rate, improvement of social activity, alleviation, aggravation or recurrence of psychiatric symptoms, and safety. The target number of subjects was set at 300. Discussion: Because this study is expected to yield evidence regarding the selection of antipsychotics for facilitating the recovery of social activity in patients with schizophrenia, it is considered highly valuable to perform this effectiveness study under ordinary healthcare setting in Japan

Mismatch Negativity as a Psychophysiological Index of Cognitive Function in Schizophrenia

It is now widely accepted that cognitive deficits, beyond other psychiatric symptoms (e.g., delusion, hallucination, emotional flattening, social withdrawal and apathy), is far most relevant to social functional outcome in schizophrenia. Accordingly, the treatment target has been shifted to the area, developing new drugs that facilitate cognitive function and building up new psychosocial rehabilitation programs that directly approach the cognitive deficits. Despite the desirability to target these deficits, no standard neuropsychological test batteries exist for assessing the level of cognitive function. Mismatch negativity (MMN), an auditory event-related potential component, is a measure of preattentive information processing and its amplitude has repeatedly been demonstrated to be reduced in schizophrenia. MMN deficits are a robust feature in chronic schizophrenia and indicate abnormalities in automatic context-dependent auditory information processing and auditory sensory memory in schizophrenia. Moreover, the deficits have been related to poor social functioning level and social skills acquisition, hypofunction of NMDA system, and illness duration, which indicate the validity of accepting MMN as a biomarker of the disease. In this article, we present a summary of the discussions about the plausibility of MMN to be used as a neurobiological index for assessing the cognitive function and also its predictability of social functional outcome in schizophrenia

Safety and Feasibility of Transcranial Direct Current Stimulation for Cognitive Rehabilitation in Patients With Mild or Major Neurocognitive Disorders: A Randomized Sham-Controlled Pilot Study

Introduction: Transcranial direct current stimulation (tDCS) is a potentially novel strategy for cognitive enhancement in patients with mild or major neurocognitive disorders. This study aims to assess the safety and efficacy of tDCS during cognitive training on cognitive functioning in patients with mild or major neurocognitive disorders.Methods: This study was primarily a single arm for safety, secondary a two-arm, parallel, randomized, and sham-controlled trial for potential efficacy. Patients with mild or major neurocognitive disorders were recruited. The participants and raters were blinded to the group assignment. The participants in the active arm received tDCS (anodal; F3, cathodal, Fp2, 2A, 20 min) twice daily for five consecutive days, whereas those in the sham arm received the same amount of sham-tDCS. Calculation and reading tasks were conducted in both arms as a form of cognitive intervention for 20 min during tDCS. The primary outcome was the attrition rate during the trial in the active arm, which is expected to be less than 10%. The secondary outcomes were the between-group differences of adjusted means for several cognitive scales from baseline to post-intervention and follow-up.Results: Twenty patients [nine women (45%)], with a mean (standard deviation) age of 76.1 years participated; nine patients (45%) with minor neurocognitive disorders and 11 (55%) with major neurocognitive disorders were randomized, and 19 of them completed the trial. The attrition rate in the active arm was 0%, with no serious adverse events. Further, in the Intention-to-Treat analysis, patients in the active arm showed no statistically significant improvement compared with those who received the sham in the mean change scores of the mini-mental state examination [0.41; 95% CI (−1.85; 2.67) at day five, 1.08; 95% CI (−1.31; 3.46) at follow-up] and Alzheimer’s disease assessment scale – cognition subscale [1.61; 95% CI (−4.2; 0.98) at day 5, 0.36; 95%CI (−3.19; 2.47) at follow-up].Conclusion: These findings suggest that tDCS is safe and tolerable but causes no statistically significant cognitive effects in patients with mild or major neurocognitive disorders. Additional large-scale, well-designed clinical trials are warranted to evaluate the cognitive effects of tDCS as an augmentation to cognitive training.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03050385

Neural correlates for intrinsic motivational deficits of schizophrenia; implication for therapeutics of cognitive impairment

The ultimate goal of the treatment of schizophrenia is recovery, a notion related to improvement of cognitive and social functioning. Cognitive remediation therapies (CRT), one of the most effective cognition enhancing methods, have been shown to moderately improve social functioning. For this purpose, intrinsic motivation, related to internal values such as interest and enjoyment, has been shown to play a key role. Although the impairment of intrinsic motivation is one of the characteristics of schizophrenia, its neural mechanisms remain unclear. This is related to the lack of feasible measures of intrinsic motivation, and its response to treatment. According to the self-determination theory (SDT), not only intrinsic motivation, but extrinsic motivation has been reported to enhance learning and memory in healthy subjects to some extent. This finding suggests the contribution of different types of motivation to potentiate the ability of the CRT to treat cognitive impairment of schizophrenia. In this paper, we provide a review of psychological characteristics, assessment methods, and neural correlates of intrinsic motivation in healthy subjects and patients with schizophrenia. Particularly, we focus on neuroimaging studies of intrinsic motivation, including our own. These considerations are relevant to enhancement of functional outcomes of schizophrenia

The feasibility and effectiveness of remote cognitive training on cognitive function and work performance in workers

ObjectivesWe aimed to determine whether remote cognitive training (CT) is feasible and has the potential to improve cognitive function and work performance in Japanese workers.MethodsFrom June to September 2020, this intervention time series study enrolled workers aged 18–65 years from 10 companies located in a metropolitan area of Japan. Cognitive function tests and self-administered questionnaires were completed by the participants three times: at baseline, after 12 weeks of CT, and after a further 12 weeks following cessation. We measured work performance with the question: “How would you rate your performance (compared with your optimum performance) over the past 4 weeks?” Responses were made via a visual analog scale (0–100). Cognitive function was assessed using the THINC-integrated tool, which is a brief, objective computerized cognitive assessment battery. For our computerized remote CT intervention, BrainHQ was used on the basis of our scientific rationale and the empirical literature. We recommended three 20-min sessions of BrainHQ per week and sent participants three reminders.ResultsIn total, 119 participants were recruited to this study. Only 22.7% of the subjects achieved the recommended training time of 720 min over 12 weeks. The median training time was used to divide participants into long and short- training groups. The long-training group showed a greater improvement in attention and executive function than the short-training group but there was no significant improvement in work performance after CT compared to baseline.ConclusionOur results suggest that although remote CT was not feasible enough, the effects on cognitive function can be expected by increasing training time and motivation

Possible Mechanisms of Eosinophil Accumulation in Eosinophilic Pneumonia

Eosinophilic pneumonia (EP), including acute EP and chronic EP, is characterized by the massive pulmonary infiltration of eosinophils into the lung. However, the mechanisms underlying the selective accumulation of eosinophils in EP have not yet been fully elucidated. We reported that bronchoalveolar lavage fluid (BALF) from EP patients induced the transmigration of eosinophils across endothelial cells in vitro. The concentrations of eotaxin-2 (CCL24) and monocyte chemotactic protein (MCP)-4 (CCL13), which are CC chemokine receptor (CCR) 3 ligands, were elevated in the BALF of EP patients, and anti-CCR3 monoclonal antibody inhibited the eosinophil transmigration induced by the BALF of EP patients. The concentration of macrophage inflammatory protein 1β (CCL4), a CCR5 ligand that induces eosinophil migration, was increased in the BALF of EP patients. Furthermore, the concentration of interleukin (IL) 5 was increased in the BALF of EP patients, and it has been reported that anti-IL-5 antibody treatment resulted in remission and the reduction of glucocorticoid use in some cases of chronic EP. The concentrations of lipid mediators, such as leukotriene (LT) B4, damage-associated molecular pattern molecules (DAMPs), such as uric acid, or extracellular matrix proteins, such as periostin, were also increased in the BALF of EP patients. These findings suggest that chemokines, such as CCR3/CCR5 ligands, cytokines, such as IL-5, lipid mediators, such as LTB4, DAMPs, and extracellular matrix proteins may play roles in the accumulation or activation of eosinophils in EP

Role of Allergen Immunotherapy in Asthma Treatment and Asthma Development

Allergen immunotherapy may modify the natural course of allergic diseases and induce remission. It includes subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). For asthma, allergen immunotherapy using house dust mite (HDM) improves clinical symptoms and airway hyperresponsiveness and decreases drug requirements. Furthermore, it has been suggested that allergen immunotherapy also has the following effects: (1) the effect can be maintained for more than a year even if the treatment is terminated, (2) the remission rate of childhood asthma can be increased, (3) new allergen sensitization can be suppressed, and (4) asthma development can be prevented if allergen immunotherapy was performed in the case of pollinosis. Allergen immunotherapy differs from conventional drug therapy, in particular the effect of modifying the natural course of allergic diseases and the effect of controlling complicated allergic diseases such as rhinoconjunctivitis. The general indication for HDM-SCIT in asthma is HDM-sensitized atopic asthma with mild-to-moderate disease and normal respiratory function. HDM allergens should be involved in the pathogenesis of asthma, and a duration of illness of less than 10 years is desirable. HDM-SLIT is available for allergic rhinitis but not for asthma in Japan. However, as the efficacy of SLIT for asthma has been fully proven internationally, SLIT is also applied in asthmatics with complicated allergic rhinitis in Japan