Introduction
First responders to disasters are at risk of developing post-traumatic stress disorder (PTSD). The trajectories of post-traumatic stress symptom severity differ among individuals, even ...if they are exposed to similar events. These trajectories have not yet been reported in non-Western first responders.
Objectives
We aimed to explore post-traumatic stress symptom severity trajectories and their risk factors in first responders to the 2011 Great East Japan Earthquake (GEJE)— a historically large earthquake that resulted in a tsunami and a nuclear disaster.
Methods
56 388 Japan Ground Self-Defense Force (JGSDF) personnel dispatched to the GEJE were enrolled in this seven-year longitudinal cohort study. PTSD symptom severity was measured using the Impact of Event Scale-Revised (IES-R). Trajectories were identified using latent growth mixture models (LGMM). Nine potential risk factors for the symptom severity trajectories were analyzed using multinomial logistic regression.
Results
Five symptom severity trajectories were identified: “resilient” (54.7%), “recovery” (24.5%), “incomplete recovery” (10.7%), “late-onset” (5.7%), and “chronic” (4.3%). The main risk factors for the four non-resilient trajectories were older age, personal disaster experiences, and working conditions. These working conditions included duties involving body recovery or radiation exposure risk, longer deployment length, later or no post-deployment leave, and longer post-deployment overtime.
Conclusions
The majority of first responders to GEJE were resilient and developed few or no PTSD symptoms. A substantial minority experienced late-onset and chronic symptom severity trajectories. The identified risk factors can inform policies for prevention, early detection, and intervention in individuals at risk of developing symptomatic trajectories.
Disclosure
No significant relationships.
Dendritic cells (DCs) are professional antigen-presenting cells involved in the initiation of immune responses. We generated a tolerogenic DC (tolDC) line that constitutively secretes interleukin-10 ...(IL10-DCs), expressed lower levels of co-stimulatory and MHCII molecules upon stimulation, and induced antigen-specific proliferation of T cells. Vaccination with IL10-DCs combined with another tolDC line that secretes IL-35, reduced antigen-specific local inflammation in a delayed-type hypersensitivity assay independently on regulatory T cell differentiation. In an autoimmune model of rheumatoid arthritis, vaccination with the combined tolDCs after the onset of the disease impaired disease development and promoted recovery of mice. After stable memory was established, the tolDCs promoted CD4 downregulation and induced lymphocyte activation gene 3 (LAG-3) expression in reactivated memory T cells, reducing T cell activation. Taken together, our findings indicate the benefits of combining anti-inflammatory cytokines in an antigen-specific context to treat excessive inflammation when memory is already established.
Summary
We showed recently that M3 muscarinic acetylcholine receptor (M3R)‐reactive CD3+ T cells play a pathogenic role in the development of murine autoimmune sialadenitis (MIS), which mimics ...Sjögren's syndrome (SS). The aim of this study was to determine the effectiveness and mechanism of action of retinoic acid‐related orphan receptor‐gamma t (RORγt) antagonist (A213) in MIS. Splenocytes from M3R knockout (M3R–/–) mice immunized with murine M3R peptide mixture were inoculated into recombination‐activating gene 1 knockout (Rag‐1–/–) mice (M3R–/–→Rag‐1–/–) with MIS. Immunized M3R–/– mice (pretransfer treatment) and M3R–/–→Rag‐1–/– mice (post‐transfer treatment) were treated with A213 every 3 days. Salivary volume, severity of sialadenitis and cytokine production from M3R peptide‐stimulated splenocytes and lymph node cells were examined. Effects of A213 on cytokine production were analysed by enzyme‐linked immunosorbent assay (ELISA) and on T helper type 1 (Th1), Th17 and Th2 differentiation from CD4+ T cells by flow cytometry. Pretransfer A213 treatment maintained salivary volume, improved MIS and reduced interferon (IFN)‐γ and interleukin (IL)‐17 production significantly compared with phosphate‐buffered saline (PBS) (P < 0·05). These suppressive effects involved CD4+ T cells rather than CD11c+ cells. Post‐transfer treatment with A213 increased salivary volume (P < 0·05), suppressed MIS (P < 0·005) and reduced IFN‐γ and IL‐17 production (P < 0·05). In vitro, A213 suppressed IFN‐γ and IL‐17 production from M3R‐stimulated splenocytes and CD4+ T cells of immunized M3R–/– mice (P < 0·05). In contrast with M3R specific responses, A213 suppressed only IL‐17 production from Th17 differentiated CD4+ T cells without any effect on Th1 and Th2 differentiation in vitro. Our findings suggested that RORγt antagonism is potentially suitable treatment strategy for SS‐like sialadenitis through suppression of IL‐17 and IFN‐γ production by M3R‐specific T cells.
RORγt antagonist (A213) increased salivary volume, suppressed sialadenitis, and reduced IFN‐γ and IL‐17 production in M3 muscarinic acetylcholine receptor‐induced Sjögren's syndrome (SS)‐like sialadenitis (MIS).
RORγt antagonism is a potentially suitable treatment strategy for SS‐like sialadenitis, through suppression of IL‐17 and IFN‐γ production by M3R‐specific‐T cells.
Sickle cell disease (SCD) is an inherited blood disorder that leads to a variety of complications, including stroke. The use of hydroxyurea (HU) is reported to lessen the frequency and burden of ...stroke in SCD patients. However, less is known about the prevalence of stroke in SCD patients pre- and during the use of HU in sub-Saharan African (SSA) countries. Therefore, the study assessed stroke prevalence before and during uses of hydroxyurea among SCD patients in Tanzania. A hospital-based descriptive cross-sectional study was conducted at the sickle cell clinics in Dar es Salaam, Tanzania, from April 2023 to May 2023. A total of 228 participants were recruited, and data on demographic and clinical characteristics, HU use, and history of stroke were collected using a checklist from the respective patients’ medical records and verbal communication with the patients or caregivers. Data analysis was done using SPSS software version 25, and findings are summarized using frequency and percentages. Out of 228 enrolled SCD patients, 124 (54.4%) were females, 109 (47.8%) were aged between 6 and 12 years, 226 (99.1%) were not married, 181 (79.4%) had primary education, and 209 (95%) were unemployed. The prevalence of stroke pre-HU use was 28 (12.3%) and 6 (2.6%) after starting using HU. Out of 6 with stroke after starting using HU, 3 (50%) had a history of stroke pre-HU uses. The study showed that the prevalence of stroke among SCD patients is significantly reduced after HU use. The findings suggest the need for stakeholders to implement measures to ensure eligible SCD patients are kept on HU.
Background and purpose
The detection rate of diffusion‐weighted (DWI) hyperintense lesions varies widely in patients with transient global amnesia (TGA). The aim was to examine the association of ...hyperintense lesions on DWI magnetic resonance imaging (MRI) with patient characteristics, precipitating factors, clinical presentation and MRI settings in patients with TGA.
Methods
In this multicenter retrospective observational study, using the standardized diagnosis entry system of electronic health records of four tertiary medical centers in the Kansai district of Japan, TGA patients (n = 261) who underwent brain MRI within 28 days of onset were examined. When the onset time was unavailable, the discovery time was used.
Results
Diffusion‐weighted hyperintense lesions were observed in 79 patients (30%). There were no significant differences in age, sex, vascular risk factors, precipitating factors or clinical presentation between patients with and without DWI lesions. The detection rate increased linearly 24 h after onset and then reached a plateau of 60%–80% by 84 h. After 84 h, the detection rate decreased rapidly. In a multivariate logistic regression model, MRI examination 24–84 h after onset (odds ratio 7.00, 95% confidence interval 3.50–13.99) and a thin‐slice (≤3 mm) DWI sequence (odds ratio 7.59, 95% confidence interval 3.05–18.88) were independent predictors of DWI lesions.
Conclusions
This study suggests that DWI hyperintense lesions in TGA are not associated with patient characteristics and clinical presentation. Brain MRI examination 24–84 h after onset and thin‐slice DWI sequences enhance the detection of DWI lesions in TGA patients.
The role of Epithelial to Mesenchymal Transition (EMT) factor Zeb1 is well defined in metastasis and cancer progression but it's importance in dendritic cells (DCs) is unexplored until now. For the ...first time we report here that Zeb1 controls immunogenic responses of CD8α
conventional Type-I (cDC1) DCs. We found that ZEB1 expression increases significantly after TLR9 stimulation and its depletion impairs activation, co-stimulation and secretion of important cytokines like IL-6, IL-10 and IL-12 in cDC1 MutuDC line. We further confirmed our findings in primary cDC1 DCs derived from bone marrow. Co-culture of these Zeb1 knock down (KD) DCs with OT-II CD4
T helper cells skewed their differentiation toward Th2 subtype. Moreover, adoptive transfer of activated Zeb1 KD DCs cleared intestinal worms in helminth infected mice by increasing Th2 responses
. Integrative genomic analysis showed Zeb1 as an activator of immune response genes in cDC1 MutuDCs as compared to other pathway genes. In addition, differentially regulated genes in Zeb1 KD RNA-seq showed significant enrichment of Th2 activation pathways supporting our
findings. Mechanistically, we showed that decreased IL-12 secreted by Zeb1 KD DCs is the plausible mechanism for increased Th2 differentiation. Collectively our data demonstrate that Zeb1 could be targeted in DCs to modulate T-cell mediated adaptive immune responses.
OxLDL is recognized by macrophage scavenger receptors, including CD36; we have recently found that Platelet-Activating Factor Receptor (PAFR) is also involved. Since PAFR in macrophages is associated ...with suppressor function, we examined the effect of oxLDL on macrophage phenotype. It was found that the presence of oxLDL during macrophage differentiation induced high mRNA levels to IL-10, mannose receptor, PPARγ and arginase-1 and low levels of IL-12 and iNOS. When human THP-1 macrophages were pre-treated with oxLDL then stimulated with LPS, the production of IL-10 and TGF-β significantly increased, whereas that of IL-6 and IL-8 decreased. In murine TG-elicited macrophages, this protocol significantly reduced NO, iNOS and COX2 expression. Thus, oxLDL induced macrophage differentiation and activation towards the alternatively activated M2-phenotype. In murine macrophages, oxLDL induced TGF-β, arginase-1 and IL-10 mRNA expression, which were significantly reduced by pre-treatment with PAFR antagonists (WEB and CV) or with antibodies to CD36. The mRNA expression of IL-12, RANTES and CXCL2 were not affected. We showed that this profile of macrophage activation is dependent on the engagement of both CD36 and PAFR. We conclude that oxLDL induces alternative macrophage activation by mechanisms involving CD36 and PAFR.
ABSTRACT In the late stages of nuclear burning for massive stars (M > 8 M ), the production of neutrino-antineutrino pairs through various processes becomes the dominant stellar cooling mechanism. As ...the star evolves, the energy of these neutrinos increases and in the days preceding the supernova a significant fraction of emitted electron anti-neutrinos exceeds the energy threshold for inverse beta decay on free hydrogen. This is the golden channel for liquid scintillator detectors because the coincidence signature allows for significant reductions in background signals. We find that the kiloton-scale liquid scintillator detector KamLAND can detect these pre-supernova neutrinos from a star with a mass of 25 M at a distance less than 690 pc with 3 significance before the supernova. This limit is dependent on the neutrino mass ordering and background levels. KamLAND takes data continuously and can provide a supernova alert to the community.
Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of ...morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.
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