Subjective perceptions that affect the continued employment of persons with mental disabilities in Japan: A mixed-methods study.

BACKGROUND: Among people with mental disabilities in Japan, 50.7% have left employment within a year despite the provision of employment support. Their subjective perceptions are likely relevant, as many causes for leaving employment are personal. However, thus far, employment continuity assessment has been based on objective indicators, while subjective evaluation remains underdeveloped. OBJECTIVE: We conducted a mixed-methods study to identify the subjective characteristics that impact the ability of persons with mental disabilities to continue working while receiving employment support. METHODS: In total, 41 participants with mental disabilities in continuous employment were included in the study, and data were collected using a demographic and employment status questionnaire and the Worker's Role Interview. Further, to clarify the constructs related to subjective perceptions of work continuity, the step for coding and theorization (SCAT) method was utilized. RESULTS: The results revealed five overarching superordinate concepts and 12 subordinate concepts of subjective perceptions regarding maintaining the current work and the future for participants who continue to work. These perceptions may be related to the participants' experience and the time course of work continuity. Subjective perceptions of difficulty levels were found to be the most and the least difficult for a reasonable accommodation without specific rules and awareness of the effects of work concepts, respectively. CONCLUSION: This research could facilitate the development of an employment support system based on people with mental disabilities' subjective needs, thus contributing to their continued employment.

2-Deoxy-d-glucose induces deglycosylation of proinflammatory cytokine receptors and strongly reduces immunological responses in mouse models of inflammation.

Anti-proinflammatory cytokine therapies against interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1 are major advancements in treating inflammatory diseases, especially rheumatoid arthritis. Such therapies are mainly performed by injection of antibodies against cytokines or cytokine receptors. We initially found that the glycolytic inhibitor 2-deoxy-d-glucose (2-DG), a simple monosaccharide, attenuated cellular responses to IL-6 by inhibiting N-linked glycosylation of the IL-6 receptor gp130. Aglycoforms of gp130 did not bind to IL-6 or activate downstream intracellular signals that included Janus kinases. 2-DG completely inhibited dextran sodium sulfate-induced colitis, a mouse model for inflammatory bowel disease, and alleviated laminarin-induced arthritis in the SKG mouse, an experimental model for human rheumatoid arthritis. These diseases have been shown to be partially dependent on IL-6. We also found that 2-DG inhibited signals for other proinflammatory cytokines such as TNF-α, IL-1ß, and interferon -γ, and accordingly, prevented death by another inflammatory disease, lipopolysaccharide (LPS) shock. Furthermore, 2-DG prevented LPS shock, a model for a cytokine storm, and LPS-induced pulmonary inflammation, a model for acute respiratory distress syndrome of coronavirus disease 2019 (COVID-19). These results suggest that targeted therapies that inhibit cytokine receptor glycosylation are effective for treatment of various inflammatory diseases.

Virus-infection in cochlear supporting cells induces audiosensory receptor hair cell death by TRAIL-induced necroptosis.

Although sensorineural hearing loss (SHL) is relatively common, its cause has not been identified in most cases. Previous studies have suggested that viral infection is a major cause of SHL, especially sudden SHL, but the system that protects against pathogens in the inner ear, which is isolated by the blood-labyrinthine barrier, remains poorly understood. We recently showed that, as audiosensory receptor cells, cochlear hair cells (HCs) are protected by surrounding accessory supporting cells (SCs) and greater epithelial ridge (GER or Kölliker's organ) cells (GERCs) against viral infections. Here, we found that virus-infected SCs and GERCs induce HC death via production of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Notably, the HCs expressed the TRAIL death receptors (DR) DR4 and DR5, and virus-induced HC death was suppressed by TRAIL-neutralizing antibodies. TRAIL-induced HC death was not caused by apoptosis, and was inhibited by necroptosis inhibitors. Moreover, corticosteroids, the only effective drug for SHL, inhibited the virus-induced transformation of SCs and GERCs into macrophage-like cells and HC death, while macrophage depletion also inhibited virus-induced HC death. These results reveal a novel mechanism underlying virus-induced HC death in the cochlear sensory epithelium and suggest a possible target for preventing virus-induced SHL.

Proactive Community Occupational Therapy Service for Social Participation Development of Thai Adults with Depression: A Grounded Theory Study from Occupational Therapists' Perspective.

INTRODUCTION: Depression in adulthood decreases social participation in the workplace, family, and community, which further results in decreased work performance and cessation and social isolation. There is a high statistic of outpatient consultation and readmission of Thais with depression, yet the mental health support for remission in community life and social participation remains limited and unclear. Further, due to the lack of mental health professional resources, particularly occupational therapists, there is much to be known regarding how such therapists work to support the development of social participation in Thai adults with depression. OBJECTIVE: This research was aimed at understanding the process of how occupational therapists work to redevelop the social participation of community-dwelling Thai adults with depression. METHOD: The grounded theory methodology was used in this study. Data were collected through interviews and nonparticipatory observations of 14 participants who had experience providing mental health care in community services. The constant comparative analysis method was employed. RESULT: Three concepts illustrated a proactive community occupational therapy service for depression (PCOTS-D), namely, integrating depression care in community occupational therapy service (COTS), supporting meaningful participation, and forming collaborative networks. The PCOTS-D supported the reconnection of social participation by leading from proactive depression care service to COTS and then working to support meaningful participation toward the patient's self-management and building collaborative networks with inter- and intraprofessional teams simultaneously. CONCLUSION: The PCOTS-D presented a holistic view of working with community-dwelling Thai adults with depression by considering the importance of the community and researchers' network to redevelop social participation, promote health and recovery, build teams in depression care, and encourage research evidence to enhance the supportive advocacy policy for Thai people with depression.

Nonpharmacological Treatment for Supporting Social Participation of Adults with Depression.

BACKGROUND: Social withdrawal is predominantly seen among adults with depression. However, a dearth of reviews exists that explore nonpharmacological treatments, especially occupational therapy (OT) interventions and their effect in promoting social participation. The aim of this research was to review what intervention programs are conducted to support the social participation of adults with depression and their effectiveness. METHOD: A systematic review was performed wherein relevant articles were searched in PubMed, CINAHL, Wiley Online Library, PsycINFO, and OTseeker databases and AJOT, BJOT, SJOT, and OTMH journals. Only English articles published from January 2010 to December 2018, which tackled intervention for adults aged 20-60 years with depression, were considered. Ten out of 918 studies met the screening criteria. RESULT: Among the ten studies, the effective intervention programs were categorized as either occupation-based intervention (OBI) or cognitive behavioral therapy-based intervention (CBT-BI). These programs sought the following outcomes: behavioral change in social participation (n = 4), reduction of depression or depressive symptoms (n = 13), life satisfaction (n = 4), and quality of life (QoL) (n = 1). Studies showed moderate (n = 3) to strong (n = 7) level of certainty, whereas they also revealed high to unclear (n = 3) and low (n = 7) risk of bias. CONCLUSION: Both OBI such as animal-assisted therapy and CBT-BI such as behavioral change program and health education have a strong level of certainty and low risk of bias in promoting social participation by supporting positive behavioral change and reducing depressive symptoms. Furthermore, the sport and exercise program of OBI was popular in encouraging participation and engagement with other people. Other programs were suggested for combined interventions to support social participation, life satisfaction, and QoL.

MYD88 signals induce tumour-initiating cell generation through the NF-κB-HIF-1α activation cascade.

Tumour-promoting inflammation is a hallmark of cancer, and chronic inflammatory disease increases the risk of cancer. In this context, MYD88, a downstream signalling molecule of Toll-like receptors that initiates inflammatory signalling cascades, has a critical role in tumour development in mice and its gene mutation was found in human cancers. In inflammation-induced colon cancer, tumour suppressor p53 mutations have also been detected with high frequency as early events. However, the molecular mechanism of MYD88-induced cancer development is poorly understood. Here, we demonstrated that MYD88 induced the protein accumulation of the transcription factor HIF-1α through NF-κB in p53-deficient cells. HIF-1α accumulation was not caused by enhanced protein stability but by NF-κB-mediated transcriptional activation, the enhanced translation of HIF-1α and JNK activation. In contrast, MYD88-induced mRNA expressions of HIF-1α and HIF-1-target genes were attenuated in the presence of p53. Furthermore, constitutively active forms of MYD88 induced tumour-initiating cell (TIC) generation in p53-deficient cells, as determined by tumour xenografts in nude mice. TIC generating activity was diminished by the suppression of NF-κB or HIF-1α. These results indicate that MYD88 signals induce the generation of TICs through the NF-κB-HIF-1α activation cascade in p53-deficient cells and suggest this molecular mechanism underlies inflammation-induced cancer development.

Cochlear supporting cells function as macrophage-like cells and protect audiosensory receptor hair cells from pathogens.

To protect the audiosensory organ from tissue damage from the immune system, the inner ear is separated from the circulating immune system by the blood-labyrinth barrier, which was previously considered an immune-privileged site. Recent studies have shown that macrophages are distributed in the cochlea, especially in the spiral ligament, spiral ganglion, and stria vascularis; however, the direct pathogen defence mechanism used by audiosensory receptor hair cells (HCs) has remained obscure. Here, we show that HCs are protected from pathogens by surrounding accessory supporting cells (SCs) and greater epithelial ridge (GER or Kölliker's organ) cells (GERCs). In isolated murine cochlear sensory epithelium, we established Theiler's murine encephalomyelitis virus, which infected the SCs and GERCs, but very few HCs. The virus-infected SCs produced interferon (IFN)-α/ß, and the viruses efficiently infected the HCs in the IFN-α/ß receptor-null sensory epithelium. Interestingly, the virus-infected SCs and GERCs expressed macrophage marker proteins and were eliminated from the cell layer by cell detachment. Moreover, lipopolysaccharide induced phagocytosis of the SCs without cell detachment, and the SCs phagocytosed the bacteria. These results reveal that SCs function as macrophage-like cells, protect adjacent HCs from pathogens, and provide a novel anti-infection inner ear immune system.

Alteration of adipokines during peripheral blood stem cell mobilization induced by granulocyte colony-stimulating factor.

Adipokines, soluble mediators produced by adipocytes, have been shown to play a role in various physiological and pathological conditions. We investigated the involvement of adipokines in granulocyte colony-stimulating factor (G-CSF)-induced mobilization of hematopoietic stem cells in 21 healthy donors. We found that serum visfatin and resistin levels, but not leptin and adiponectin levels, were significantly elevated by G-CSF treatment. G-CSF treatment activated signaling proteins like extracellular signal-regulated kinase and stimulated secretion of visfatin from 3T3-L1 adipocytes. These findings suggest that some adipokines may play a role in G-CSF-induced mobilization of stem cells from the bone marrow into systemic circulation.

The anti-apoptotic role of the unfolded protein response in Bcr-Abl-positive leukemia cells.

To define the role of the unfolded protein response (UPR) in leukemogenesis, we investigated UPR activation in the cells expressing the representative oncogene Bcr-Abl (B-A). The expression of UPR-related proteins and mRNAs, namely, X-box-binding protein (XBP1) and glucose-regulated protein 78 (GRP78) was increased in B-A. UPR inhibition using inositol-requiring enzyme 1alpha (IRE1alpha) or activating transcription factor 6 (ATF6) dominant-negative mutants diminished the ability of Bcr-Abl to protect the cells from etoposide- and imatinib-induced apoptosis. We also noted that the expression of UPR-related genes in primary leukemia cells from Philadelphia chromosome (Ph)-positive cells was higher than that in the control by quantitative RT-PCR assay. Thus, our results suggested that UPR is a downstream target of Bcr-Abl and plays an anti-apoptotic role in Ph-positive leukemia cells.

Elevation of serum high-mobility group box 1 protein during granulocyte colony-stimulating factor-induced peripheral blood stem cell mobilisation.

High mobility group box 1 (HMGB1) is a non-histone protein involved in maintaining the architecture of chromatin. HMGB1 also acts extracellularly as a cytokine, in processes such as inflammation, cell migration and stem cell recruitment. The involvement of HMGB1 in granulocyte colony-stimulating factor (G-CSF)-induced mobilisation of haematopoietic stem cells was investigated in 21 healthy donors. G-CSF treatment significantly elevated serum HMGB1 levels, which increased from 1.16 +/- 0.86 ng/ml, before treatment, to 31.1 +/- 5.99 ng/ml, after treatment. These findings suggest HMGB1 may play a role during the mobilisation of stem cells from the bone marrow into the systemic circulation.