Th2 Suppressor Cells Are More Susceptible to Sphingosine Than Th1 Cells in Murine Contact Photosensitivity

Murine contact photosensitivity (CPS) to 3,3',4',5-tetrachlorosalicylanilide (TCSA) is a cutaneous delayed-type hypersensitivity reaction in which both positive and negative regulatory pathways exist. The latter pathway is mediated by antigen-specific, CD4+ suppressor T cells (CPS-Ts) that are Th2 cells. We examined the effects of sphingosine and synthetic cell-permeable analogs of ceramide on the cellular kinetics of CPS-Ts and immune lymph node cells from TCSA-photosensitized mice (CPS-LNC), along with other murine T-cell populations. The addition of sphingosine at 10 or 3 μM to in vitro cultures suppressed DNA synthesis of CPS-Ts and Th2 clones, including D10 cells and 24-2 cells, but not that of CPS-LNC or Th1 clones, including 23-1-8 and 28-4 cells. This suggested that sphingosine exerts its inhibitory effects preferentially on the proliferation of Th2 cells. Although suppressing DNA synthesis, sphingosine augmented the production and mRNA expression of interleukin-4 (IL-4) and enhanced the expression of the IL-4 receptor in CPS-Ts. In addition, the ability of sphingosine to induce signal transduction of CPS-Ts was confirmed by elevation of the intracellular free Ca++ concentration. Because CPS-Ts exposed to sphingosine exhibited a lower G2M/G1 ratio than control, these seemingly ambivalent phenomena may be caused by retardation of the G1 to S phase progression, a cell-cycle dysregulation known to augment cytokine production. In contrast to sphingosine, cell-permeable ceramide did not affect the proliferation of these cells when stimulated with mitogen/antigen and did not augment IL-4 production by CPS-Ts. Our study suggests that sphingosine modifies the Th1/Th2 balance by preferentially affecting the cellular kinetics of Th2

Micronutrient Adequacy in the Diet of Reproductive-Aged Adolescent Girls and Adult Women in Rural Bangladesh

Micronutrient deficiencies remain a serious nutritional concern in Bangladesh, especially among rural women of reproductive age (WRA). This study assesses the diet quality of reproductive-aged adolescent girls and adult women (referred to together as WRA in this study), including socio-demographic factors associated with their diet quality. The diet quality of adolescent girls was compared with that of adult women to assess which group was most at risk. The diet quality was measured by calculating the nutrient adequacy ratio (NAR), using the preceding 24 h dietary recall method. The mean adequacy ratio (MAR) was calculated as an overall measure of diet quality using the NAR. Nearly three quarters of WRA (adolescents: 73.1–88.5%; adult women: 72.9–86.4%) had an inadequate intake of calcium, vitamin A, folic acid, and vitamin B12. The prevalence of inadequate dietary intakes of calcium, zinc, and energy was significantly higher in adolescent girls (p < 0.001) than in adult women. Overall diet quality was significantly better in adult women (0.51 ± 0.21, p < 0.001) than in adolescent girls (0.49 ± 0.22). Age, marital status, educational level, and monthly household income were important factors associated with the diet quality of WRA. Micronutrient inadequacy is widely prevalent in the diets of WRA in Bangladesh, and adolescent girls with poor socio-economic status and lower educational levels are at higher risk

Treatment of T Lymphocytes with 8-Methoxypsoralen Plus Ultraviolet A Induces Transient but Biologically Active Th1-Skewing Cytokine Production

8-Methoxypsoralen plus ultraviolet A light is suggested to shift T lymphocytes from Th2 to Th1 cells. To clarify this issue, we examined the effects of 8-methoxypsoralen/ultraviolet A on the expression/production of cytokines in peripheral blood mononuclear cells from normal subjects and a Sézary syndrome patient. 8-Methoxypsoralen/ultraviolet A augmented the expression of mRNAs for interferon-γ and interleukin-2 and reduced those for interleukin-4 and interleukin-10. It seems that this enhancement of Th1 cytokines is caused by increment of cytokine production by Th1 cells but not by conversion of Th2 cells to produce Th1 cytokines. The number of interferon-γ-secreting lymphocytes was markedly increased in 8-methoxypsoralen/ultraviolet A-treated peripheral blood mononuclear cells 20 h after treatment, whereas that of Th2 cytokine-producing cells was decreased. Accordingly, the amount of interferon-γ was elevated in culture supernatants from 8-methoxypsoralen-phototreated peripheral blood mononuclear cells, whereas interleukin-4 was significantly reduced. This enhanced production of interferon-γ, however, was found only until 3 d after 8-methoxypsoralen phototreatment and was declined by 5 d after treatment. Finally, 8-methoxypsoralen/ultraviolet A treatment of T cells regulated their ability to induce keratinocyte CD54 expression. Our results show that 8-methoxypsoralen/ultraviolet A has a transient but biologically active Th1-skewing action in human T cells, suggesting that 8-methoxypsoralen/ultraviolet A exerts a beneficial therapeutic effect on Th2-mediated or Th2-malignant diseases

Resection of Metachronous Lymph Node Metastases from Hepatocellular Carcinoma after Hepatectomy: Report of Four Cases

We report 4 cases of surgical resection of metachronous lymph node (LN) metastases from hepatocellular carcinoma (HCC) following hepatectomy. Clinicopathological features and results of LN dissection were investigated in the 4 patients. One patient was found to have a single metastasis in the mediastinal LNs, another had multiple metastases in the mediastinal and abdominal LNs, and the other 2 had single metastases in the abdominal LN. The locations of the abdominal LN metastases were behind the pancreas head in 2 patients and around the abdominal aorta in 1 patient. They all underwent surgical resection of metastatic LNs and had no postoperative complications. The 3 patients whose LN metastases were solitary have been alive for more than 2 years after LN resection, and one of them is free from recurrence. The patient with multiple LN metastases died 13 months after LN resection due to carcinomatosis. With the expectation of long-term survival, a single metachronous LN metastasis from HCC after hepatectomy should be resected in patients without uncontrollable intrahepatic or extrahepatic tumors

Promotion of clinical trials before / after CTA

Background : Enforcement of the 2018 Clinical Trials Act (CTA) in Japan resulted in strict and complicated regulations surrounding intervention studies. Few Japan-specific measures have been developed to promote intervention studies in Japan despite concerns about CTA’s negative influence on such studies. Therefore, this study examined the changes in academic investigators’ interest in conducting clinical studies before and after enforcement of the CTA to determine measures to promote specified clinical trials. Methods : We conducted a questionnaire survey with investigators belonging to the Institute of Biomedical Sciences, Tokushima University Graduate School, before and after enforcement of the CTA. Results : Investigators had lesser interest in intervention studies in the post-questionnaire survey (post) group than in the pre-questionnaire survey (pre) group. Their desire for “project management” was significantly higher in the post-group than in the pre-group. Their desire for “support for preparing documents when conducting specified clinical trials” was significantly higher in the group interested in conducting specified clinical trials than that in the not-interested group. Conclusion : We revealed that investigators were highly interested in “project management” and “support for preparing documents when conducting specified clinical trials” after enforcement of the CTA. Measures for these desires may promote specified clinical trials

Effect of dapagliflozin on 24-hour glycemic variables in Japanese patients with type 2 diabetes mellitus receiving basal insulin supported oral therapy (DBOT) : a multicenter, randomized, open-label, parallel-group study

Introduction: This study aimed to evaluate the impacts of dapagliflozin on 24-hour glucose variability and diabetes-related biochemical variables in Japanese patients with type 2 diabetes who had received basal insulin supported oral therapy (BOT). Research design and methods: Changes in mean daily blood glucose level before and after 48–72 hours of add-on or no add-on of dapagliflozin (primary end point) and diabetes-related biochemical variables and major safety variables during the 12 weeks (secondary end point) were evaluated in the multicenter, randomized, two-arm, open-label, parallel-group comparison study. Results: Among 36 participants, 18 were included in the no add-on group and 18 were included in the dapagliflozin add-on group. Age, gender, and body mass index were comparable between the groups. There were no changes in continuous glucose monitoring metrics in the no add-on group. In the dapagliflozin add-on group, mean glucose (183–156mg/dL, p=0.001), maximum glucose (300–253, p<0.01), and SD glucose (57–45, p<0.05) decreased. Time in range increased (p<0.05), while time above the range decreased in the dapagliflozin add-on group but not in the no add-on group. After 12-week treatment with dapagliflozin add-on, 8-hydroxy-2’-deoxyguanosine (8OHdG), as well as hemoglobin A1c (HbA1c), decreased. Conclusions: This study showed that the mean daily blood glucose and other daily glucose profiles were amended after 48–72 hours of dapagliflozin add-on in Japanese patients with type 2 diabetes who received BOT. The diabetes-related biochemical variables such as HbA1c and urinary 8OHdG were also obtained during the 12 weeks of dapagliflozin add-on without major adverse events. A preferable 24-hour glucose profile in ‘time in ranges’ and an improvement in reactive oxygen species by dapagliflozin warrant us to evaluate these benefits in larger clinical studies

Antagonist of sphingosine 1-phosphate receptor 3 reduces cold injury of rat donor hearts for transplantation

Cold storage is widely used to preserve an organ for transplantation; however, a long duration of cold storage negatively impacts graft function. Unfortunately, the mechanisms underlying cold exposure remain unclear. Based on the sphingosine-1-phosphate (S1P) signal involved in cold tolerance in hibernating mammals, we hypothesized that S1P signal blockage reduces damage from cold storage. We used an in vitro cold storage and rewarming model to evaluate cold injury and investigated the relationship between cold injury and S1P signal. Compounds affecting S1P receptors (S1PR) were screened for their protective effect in this model and its inhibitory effect on S1PRs was measured using the NanoLuc Binary Technology (NanoBiT)-β-arrestin recruitment assays. The effects of a potent antagonist were examined via heterotopic abdominal rat heart transplantation. The heart grafts were transplanted after 24-hour preservation and evaluated on day 7 after transplantation. Cold injury increased depending on the cold storage time and was induced by S1P. The most potent antagonist strongly suppressed cold injury consistent with the effect of S1P deprivation in vitro. In vivo, this antagonist enabled 24-hour preservation, and drastically improved the beating score, cardiac size, and serological markers. Pathological analysis revealed that it suppressed the interstitial edema, inflammatory cell infiltration, myocyte lesion, TUNEL-positive cell death, and fibrosis. In conclusion, S1PR3 antagonist reduced cold injury, extended the cold preservation time, and improved graft viability. Cold preservation strategies via S1P signaling may have clinical applications in organ preservation for transplantation and contribute to an increase in the donor pool

Impact of Parenting Style on Clinically Significant Behavioral Problems Among Children Aged 4–11 Years Old After Disaster: A Follow-Up Study of the Great East Japan Earthquake

Objective: The purpose of this study was to investigate the influence of parenting style on children's behavior problems after the Great East Japan Earthquake in 2011.Methods: Participants were children exposed to the 2011 disaster at preschool age (n = 163). Data were collected from August 2012 to March 2013, and from July 2014 to March 2015 (2 and 4 years, respectively, after the earthquake), thus participants were aged 4–11 years when assessed. Parenting style was assessed by caregivers using the Alabama Parenting Questionnaire (APQ), which measures parental involvement, positive parenting, poor monitoring/supervision, inconsistent discipline, and corporal punishment in the second year after the disaster. Behavior problems were assessed by caregivers using the Child Behavior Checklist (CBCL), which identifies internalizing, externalizing, and total problems in the second and fourth year after the disaster.Results: The results show that corporal punishment in the second year after the disaster had negative influence on CBCL internalizing score (coefficient: 0.78, 95%CI: 0.12–1.45, p = 0.023), externalizing score (coefficient: 0.74, 95%CI: 0.09–1.39, p = 0.025), and total score in the fourth year after the disaster (coefficient: 0.85, 95%CI: 0.16–1.55, p = 0.016), after adjusted for children's age, sex, the number of trauma experiences, maternal education, the number of siblings, temporally housing experience, and CBCL each scores in the second year after the disaster. Other parenting style did not affect children's behavioral problems.Conclusion: The result suggests that inadequate rearing after a natural disaster had negative impact on the behavior problems of the affected children in 4 years later of the disaster. Specifically, corporal punishment had negative influence on children's behavior problems

Splenic artery syndrome after living donor liver transplantation with ligation of the splenic artery : A case report

After orthotopic liver transplantation, splenic artery syndrome (SAS), a phenomenon by which the main blood flow of the impaired hepatic artery is shifted to the splenic artery or gastroduodenal artery despite the absence of a structural lesion involving the anastomosis, has occasionally been observed. We report a 20-year-old women who developed SAS with pancytopenia and refractory ascites after living donor liver transplantation despite intraoperative ligation of the splenic artery as a prophylactic treatment for SAS. In this case SAS was diagnosed by digital subtraction angiography (DSA). A celiac trunk angiogram showed relative hypoperfusion of the hepatic artery together with augmentation of the blood flow toward the spleen with the unique collateral circulation through the left gastric artery, stomach and short gastric artery, and distal splenic artery. Embolization of one of the two left gastric arteries was performed. After embolization the hepatic artery perfusion showed significant improvement, but reduced again the next day. We ultimately conducted splenectomy. This case showed portal hyperperfusion and portal hypertension, consistent with previous reports that have described an association of SAS with portal hyperperfusion. After splenectomy, there was significant improvement in the hepatic artery perfusion, ascites disappeared promptly, and pancytopenia was significantly improved