Bach2 is a transcription factor which represses its target genes and plays important roles in the differentiation of B and T lymphoid cells. Bach2-deficient (KO) mice develop severe pulmonary alveolar proteinosis, which is associated with increased numbers of granulocytes and T cells. Bach2 is essential for the regulation of T cells, but its role in the regulation of granulocytes is not clear. Here, we observed increased numbers of eosinophils but not neutrophils in the bone marrow, spleen, peripheral blood, and bronchoalveolar lavage fluids of Bach2 KO mice compared with those of wild-type (WT) mice. Upon co-transplantation of the bone marrow cells from CD45.2 Bach2 KO and CD45.1/CD45.2 double-positive WT mice to irradiated WT CD45.1/CD45.2 mice, the reconstituted numbers of eosinophils were similar between Bach2 KO and WT cells. These results showed that the deficiency of Bach2 in eosinophils did not directly drive the differentiation of eosinophils. To investigate the effect of Bach2 KO CD4+ T cells upon eosinophils, we analyzed Rag2/Bach2-double deficient (dKO) mice which lack lymphocytes including CD4+ T cells. Rag2/Bach2 dKO mice did not show any increase in the numbers of eosinophils. Importantly, Bach2 KO mice showed an increase of interleukin-5 (Il-5) in the sera compared with WT mice. These results suggest that up-regulated functions of CD4+ T cells including secretion of Il-5 resulted in proliferation and/or migration to peripheral tissues of eosinophils in Bach2 KO mice. We propose that Bach2 controls homeostasis of eosinophils via restricting the production of Il-5 in CD4+ T cells.
Atherosclerotic cardiovascular diseases, such as coronary heart disease, have become a major public health problem all over the world. MicroRNA-29a (miR-29a) modulates expression levels of collagen, inflammatory reaction and other extracellular matrix mRNAs, while adiponectin (APN), a circulating protein secreted by adipocytes, has anti-inflammatory properties. Both play multifaceted roles in angiogenesis or vascular remodelling. However, little is known about plasma miR-29a and APN levels in patients with atherosclerosis. We therefore investigated the relationship between the plasma levels of miR-29a or APN and carotid intima-media thickness (cIMT) in atherosclerosis patients (n = 85, cIMT ≥ 1.2 mm) and the controls (n = 85, cIMT < 1.2 mm). We found that the atherosclerosis group showed higher miR-29a levels (31.15 ± 3.99 vs. 26.39 ± 1.05 Ct, P < 0.001) and lower APN levels (15.93 ± 4.61 vs. 21.80 ± 7.74 ng/ml, P < 0.001), compared with control group. Thus, increased cIMT was associated with higher plasma miR-29a levels (r = 0.688, P < 0.001) and with lower plasma APN levels (r = −0.494, P < 0.001). Furthermore, multiple logistic regression analysis indicated that higher miR-29a levels (OR: 1.136, 95% CI: 1.042-1.240, P = 0.004) increased the risk for atherosclerosis, whereas higher APN levels appeared to be protective (OR: 0.122, 95% CI: 0.055-0.271, P < 0.001). The present study indicates that elevated miR-29a levels and reduced APN levels are associated with atherosclerosis.
In Japan, patients who require home medical care are increasing especially in the elderly. In home medical care settings, devices such as gastrostomy tubes, tracheal cannulas, and urethral catheters are usually replaced by visiting physicians or nurses. However, device replacement services are not always available in Japan. Unless device replacement services are sufficiently provided to patients at home, patients have to suffer various disadvantages, including a forced visit to a hospital for device replacement despite inability to walk. We therefore investigated background factors of clinics and nursing stations providing home-care visits using a cross-sectional postal survey from August to September 2013. We targeted physicians from 5,828 clinics providing home medical care and nurses from 1,798 home-visit nursing stations across six prefectures (Tokyo, Kanagawa, Saitama, Chiba, Miyagi and Iwate). Responses were received from 933 clinics (16.5%) and 552 stations (31.3%). We analyzed the responses using multivariable logistic regression with two models. “Model 1” mainly included the number of full-time staff and the availability of a 24-hour care service system, and “Model 2” mainly included the number of clinics, the number of home-visit nursing stations, and the ratio of the population aged ≥ 65 years to study the influence of medical resources. We thus found that clinic staff numbers and 24-hour care availability were associated with physicians’ replacement of gastrostomy tubes and tracheal cannulas (p < 0.001 for each). In conclusion, single-handed and group practices need to cooperate to ensure the replacement of these devices in home medical care settings.
Adult T-cell leukemia/lymphoma (ATL/ATLL) is one of the most malignant lymphomas with poor prognosis. ATL/ATLL cells express CC chemokine receptor 4, and mogamulizumab (anti-CCR4 monoclonal antibody) exhibits strong cytotoxicity for ATL/ATLL cells. We analyzed plasma samples of 6 patients with ATL/ATLL treated with chemotherapy followed by mogamulizumab therapy (mogatherapy) for changes in the levels of biomarkers in relation to immune-related adverse effects. As treatment is often associated with skin eruptions, we investigated the profiles of inflammatory cytokines, including galectin-9 (Gal-9), which becomes increased in various infectious diseases and allergic patients. Gal-9, soluble interleukin (IL)-2 receptor, tumor necrosis factor-α, and IL-10 levels were increased before chemotherapy, and Gal-9 levels were associated with the sIL-2 receptor, which reflects tumor burden. Inflammatory levels decreased after chemotherapy. After mogatherapy, 5 of 6 patients attained complete remission (CR), whereas 1 patient showed no response (NR) and died. Among 5 patients with CR, the biomarkers remained low during mogatherapy, except for a 3-5-fold increment in Gal-9 (associated with skin eruptions). A skin biopsy showed infiltration by inflammatory cells and Gal-9 synthesis in areas with CD8 cell infiltration. In the patient with NR, increased levels of Gal-9 and the aforementioned biomarkers were noted 3 days after mogatherapy, followed by opportunistic infections resembling immune reconstitution inflammatory syndrome. Therefore, an increased Gal-9 plasma level in ATL/ATLL indicates tumor burden and reflects immune activation by mogatherapy. These findings may indicate that an increase in the Gal-9 level, a novel immune checkpoint molecule, can reflect immune-related adverse effects of various biotherapies.
Insufficient hemoglobin and depression share several symptoms and often occur in the same patients. Here, we sought to clarify their relationship by investigating two indices of oxygenation at the tissue level: mean corpuscular hemoglobin concentration (MCHC) and hemoglobin level. We hypothesized that MCHC would be more informative than hemoglobin levels. This prospective, longitudinal, community-based study included 337 participants (108 men and 229 women; age range, 38-87 years) who received evaluations of MCHC, hemoglobin levels and depressive symptom scores (DSS) during baseline and follow-up examinations, which were performed in 2008-2011 and 2010-2012, respectively. MCHC and hemoglobin levels were measured as part of complete blood counts, while DSS was evaluated using the Beck Depression Inventory. Associations were analyzed using linear regression. We found a statistically significant association between baseline MCHC and follow-up DSS (β = −0.69, p = 0.026), which remained statistically significant after controlling for potential confounders (β = −0.71, p = 0.011). Further, when we analyzed the relationship separately for men and women, we observed that it remained stable for women before (β = −1.00, p = 0.014) and after (β = −1.09, p = 0.003) adjusting for confounders. The stable association indicates that MCHC may be superior to hemoglobin level as a prognostic factor for future depressive symptoms in women. MCHC is easy to measure and low MCHC is usually treatable. Therefore, screening and intervention efforts could be targeted at women with low MCHC, who appear to have elevated risks of developing depressive symptoms.
On March 11, 2011, an earthquake (magnitude 9.0) devastated Japan’s east coast, and the associated tsunami resulted in social and mechanical destruction. Search for the missing people is still ongoing. Surgical implants are common in the general population. Medical implants usually have lot numbers, and their forensic use is common for victim identification. This investigation was conducted mainly in the cities of Kamaishi and Otsuchi, both of which were affected by the tsunami disaster in 2011. We visited 6 mortuaries with the police between March 20 (9 days after the tsunami) and April 20 (40 days after the tsunami) to examine the presence of surgical scars and related information. Unidentified human remains were investigated by visual and tactile examination. We also visited temples where the ashes were preserved. If implants were found, their lot numbers and estimated surgical procedures were recorded to determine positive identification. Ten of 233 sets of unidentified human remains before cremation displayed characteristics of a potential past surgical history. However, only 2 of these 233 sets had orthopedic implants. Instead, non-combustible orthopedic implants were found and recognized in 8 of the 331 sets of unidentified human ashes in the temples after cremation; the lot numbers were fully legible in 2 of the 8 sets. We estimated the surgical procedures, which led to positive identification. In conclusion, lot numbers and the surgical knowledge of orthopedic surgeons could assist with the positive identification of disaster victims. However, the relevant information can be erased after cremation.
Prenatal glucocorticoid therapy is indicated in preterm delivery to prevent respiratory distress. This study was designed to evaluate the age-dependent effects of prenatal dexamethasone (DEX) therapy on the immune system using a rat model. Pregnant Sprague-Dawley rats received an intraperitoneal injection of DEX (0.1 mg/kg/day) or saline (VEH) over gestational days 14-20. Male offspring were sacrificed at postnatal day 7 (D7; infant stage), D120 (young adult stage), and D180 (adult stage) for evaluation of leukocyte subsets and isolation of splenocytes. The production of innate and adaptive immune cytokines was assessed from the culture supernatants of splenocytes, stimulated with lipopolysaccharide and concanavalin A, respectively. For innate cytokines, the levels of interferon gamma inducible protein 10 were significantly higher, but those of tumor necrosis factor-α were significantly lower, in the culture medium of splenocytes prepared from the DEX group at D120 than those in the VEH group. For adaptive cytokines, the levels of interleukin-4 (IL-4) were significantly higher at D7 and those of IL-10 were significantly higher at D120 after prenatal exposure to DEX. We also showed that the expression level of IL-4 mRNA was significantly higher in splenocytes prepared from the DEX group at D7, compared with the VEH group. Importantly, the mRNA expression level of T-bet, a key transcription factor for immune cells, was greatly decreased in the spleen of the DEX group at D7, compared with the VEH group. In conclusion, prenatal dexamethasone exposure shows the greater impact on immune responses of their male offspring in early life.
Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) is a core component of the NCoR/SMRT transcription co-repressor complex, and its role in regulating cancer progression has been reported. Serous epithelial ovarian cancer (EOC) is the most common histological type of EOC. Here we explored the significance of TBL1XR1 expression in predicting outcomes of patients with serous EOC. Real-time quantitative PCR analysis showed that the expression level of TBL1XR1 mRNA was significantly higher in EOC tissues compared with adjacent non-tumorous tissues. The protein levels of TBL1XR1 in EOC tissues were assessed by immunohistochemistry, and the patients were classified into low-expression group (n = 62) and high-expression group (n = 54) according to the immunoreactivity. Prognostic significance of TBL1XR1 was evaluated by univariate and multivariate analyses, showing that over-expression of TBL1XR1 was correlated with poor prognosis. In addition, TBL1XR1 was positively associated with the lymph node metastasis of EOC. Because vascular endothelial growth factor (VEGF)-C is known as a critical mediator of lymph node metastasis, we measured the expression level of VEGF-C mRNA in EOC tissues and thus identified a positive correlation between TBL1XR1 and VEGF-C mRNA levels. Subsequently, using human EOC cell lines, we showed that silencing of TBL1XR1 decreased VEGF-C expression, suggesting that TBL1XR1 may function as an upstream regulator of VEGF-C in EOC. Furthermore, the proliferation and invasion of EOC cells were inhibited by TBL1XR1 silencing. In conclusion, TBL1XR1 overexpression may be an unfavorable prognostic factor for EOC. We also suggest that the TBL1XR1-VEGF-C axis may determine the EOC progression.