Analytical evaluation of serum non–transferrin-bound iron and its relationships with oxidative stress and cardiac load in the general population

Excessive iron accumulation provokes toxic effects, especially in the cardiovascular system. Under iron overload, labile free non–transferrin-bound iron (NTBI) can induce cardiovascular damage with increased oxidative stress. However, the significance of NTBI in individuals without iron overload and overt cardiovascular disease has not been investigated. We aimed to examine the distribution of serum NTBI and its relationship with oxidative stress and cardiac load under physiological conditions in the general population.We enrolled individuals undergoing an annual health check-up and measured serum NTBI and derivatives of reactive oxygen metabolites (d-ROM), an oxidative stress marker. In addition, we evaluated serum levels of B-type natriuretic peptide (BNP) to examine cardiac load. We excluded patients with anemia, renal dysfunction, cancer, active inflammatory disease, or a history of cardiovascular disease.A total of 1244 individuals (57.8 ± 11.8 years) were enrolled, all of whom had detectable serum NTBI. d-ROM and BNP showed significant trends across NTBI quartiles. Multivariable regression analysis revealed that serum iron and low-density lipoprotein cholesterol were positively associated with NTBI but that age, d-ROM, and BNP showed an inverse association with this measure. In logistic regression analysis, NTBI was independently associated with a combination of higher levels of both d-ROM and BNP than the upper quartiles after adjustment for possible confounding factors.Serum NTBI concentration is detectable in the general population and shows significant inverse associations with oxidative stress and cardiac load. These findings indicate that serum NTBI in physiological conditions does not necessarily reflect increased oxidative stress, in contrast to the implications of higher levels in states of iron overload or pathological conditions.     

Dual targeting of transformed and untransformed HTLV-1-infected T cells by DHMEQ, a potent and selective inhibitor of NF-kappaB, as a strategy for chemoprevention and therapy of adult T-cell leukemia

Human T-cell leukemia virus type I (HTLV-1) causes adult T-cell leukemia (ATL), a fatal T-cell leukemia resistant to chemotherapy, after more than 50 years of clinical latency from transmission through breast-feeding. Polyclonal expansion of virus-infected T cells predisposes them to transformation. Constitutive activation of nuclear factor-kappaB (NF-kappaB) in the leukemic cells is essential for their growth and survival. Blocking NF-kappaB has been shown to be a potential strategy to treat ATL. We tested this approach using a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), and also examined its application to chemoprevention by selective purging of the HTLV-1-infected cells. DHMEQ inhibited NF-kappaB activation in primary ATL cells and cell lines derived from them and induced apoptotic cell death. NF-kappaB inhibition down-regulated expression of genes involved in antiapoptosis or cell-cycle progression. DHMEQ protected severe combined immunodeficiency (SCID) mice inoculated with HTLV-1-transformed cells from death. In addition, DHMEQ selectively targeted HTLV-1-infected cells in the peripheral blood of virus carriers in vitro, resulting in a decreased number of infected cells. We conclude that NF-kappaB is a potential molecular target for treatment and prevention of ATL. As a potent NF-kappaB inhibitor, DHMEQ is a promising compound allowing the translation of this strategy into clinical medicine.     

Soluble interleukin-6 receptor in rheumatoid arthritis

To investigate the pathophysiologic role of soluble interleukin-6 receptor (sIL-6R) in patients with rheumatoid arthritis (RA), serum sIL-6R levels were measured in 15 RA patients and 15 healthy control subjects using a sandwich enzyme-linked immunosorbent assay. Correlation analysis was performed between sIL-6R levels and clinical variables such as joint score, Lansbury’s index, C-reactive protein and platelet counts. Levels of sIL-6R and IL-6 were also measured in paired samples of serum and synovial fluid obtained at the same time from nine RA patients. Serum sIL-6R levels in RA patients (153.9±56.9 ng/ml) were significantly higher than those of control subjects (115.1±19.1 ng/ml;P<0.05). However, sIL-6R levels did not correlate with any clinical characteristic of RA. sIL-6R was detectable in synovial fluid, but was invariably lower than in serum, in contrast to IL-6 (i.e. much higher in synovial fluid). It correlated neither with total cell nor neutrophil number in synovial fluid. Serum C-reactive protein levels were significantly correlated with IL-6 in synovial fluid, but not with sIL-6R in synovial fluid. These results indicate that serum sIL-6R levels are increased in RA patients. High levels of serum sIL-6R did not seem to be derived from the site of local inflammation. The readily detectable sIL-6R in synovial fluid may co-operate with IL-6 in the pathogenesis of synovitis in RA.     

Synergistic interaction between job control and social support at work on depression,burnout, and insomnia among Japanese civil servants

Purpose

To elucidate whether low job control and low social support at work have synergistic interaction on mental health. The synergistic interaction was also analyzed after stratification by high and low job demands.

Methods

Participants were 2,121 local government employees in Asahikawa city, Japan. The Brief Job Stress Questionnaire was used to assess job demands, job control, and social support. Depression was assessed using the Patient Health Questionnaire-9. The Maslach Burnout Inventory-General Survey was used to assess burnout. Insomnia was assessed using the Athens Insomnia Scale. Possible confounder-adjusted logistic regression analyses were performed to obtain odds ratios for depression, burnout, and insomnia, and synergy indices between job control and social support at work were assessed.

Results

The synergy indices among men and women, respectively, were 2.08 (80 % confidence interval: 1.01, 4.27) and 1.98 (0.67, 5.89) for depression, 1.79 (1.28, 2.51) and 2.62 (1.07, 6.40) for burnout, and 1.92 (1.22, 3.02) and 2.77 (0.43, 18.01) for insomnia. Men with high job demands had higher synergistic interaction on depression and burnout, compared to men with low job demands, and women with low job demands had higher synergistic interaction between job control and social support at work on burnout and insomnia, compared to women with high job demands.

Conclusions

There were more-than-additive interactions of job control and social support at work on depression, burnout, and insomnia. After stratification by job demands, the synergistic interaction may be different between men and women. To assess job stress, it is necessary to consider the interactive effect of not only job demands and job control but also job control and social support at work.

     

Heat-related mortality risk model for climate change impact projection

Objectives

We previously developed a model for projection of heat-related mortality attributable to climate change. The objective of this paper is to improve the fit and precision of and examine the robustness of the model.

Methods

We obtained daily data for number of deaths and maximum temperature from respective governmental organizations of Japan, Korea, Taiwan, the USA, and European countries. For future projection, we used the Bergen climate model 2 (BCM2) general circulation model, the Special Report on Emissions Scenarios (SRES) A1B socioeconomic scenario, and the mortality projection for the 65+-year-old age group developed by the World Health Organization (WHO). The heat-related excess mortality was defined as follows: The temperature–mortality relation forms a V-shaped curve, and the temperature at which mortality becomes lowest is called the optimum temperature (OT). The difference in mortality between the OT and a temperature beyond the OT is the excess mortality. To develop the model for projection, we used Japanese 47-prefecture data from 1972 to 2008. Using a distributed lag nonlinear model (two-dimensional nonparametric regression of temperature and its lag effect), we included the lag effect of temperature up to 15 days, and created a risk function curve on which the projection is based. As an example, we perform a future projection using the above-mentioned risk function. In the projection, we used 1961–1990 temperature as the baseline, and temperatures in the 2030s and 2050s were projected using the BCM2 global circulation model, SRES A1B scenario, and WHO-provided annual mortality. Here, we used the “counterfactual method” to evaluate the climate change impact; For example, baseline temperature and 2030 mortality were used to determine the baseline excess, and compared with the 2030 excess, for which we used 2030 temperature and 2030 mortality. In terms of adaptation to warmer climate, we assumed 0 % adaptation when the OT as of the current climate is used and 100 % adaptation when the OT as of the future climate is used. The midpoint of the OTs of the two types of adaptation was set to be the OT for 50 % adaptation.

Results

We calculated heat-related excess mortality for 2030 and 2050.

Conclusions

Our new model is considered to be better fit, and more precise and robust compared with the previous model.     

Late-evening snack with branched-chain amino acids improves liver function after radiofrequency ablation for hepatocellular carcinoma

Aim: This prospective study was designed to examine whether consumption of a branched‐chain amino acid (BCAA)‐enriched nutrient mixture as a late‐evening snack (LES) helps maintain and/or improve liver functioning in liver cirrhosis (LC) patients who have undergone radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). Methods: An equal number (10) of 30 LC patients who had undergone RFA for HCC was randomly assigned to a standard diet group (control) group, a morning BCAA (M‐BCAA) administration group, or a LES with BCAA (LES‐BCAA) administration group. Liver function testing was performed and Child–Pugh scores (CPS) calculated for each group to assess the improvement at 1, 4 and 12 weeks post‐RFA. Results: Compared to the control and M‐BCAA groups, the LES‐BCAA group experienced a rapid and significant improvement in albumin and total serum bilirubin levels and in CPS that began during the initial post‐RFA period. These results indicate that LES with BCAA supplementation significantly improved the CPS of the LES‐BCAA group at 4 and 12 weeks post‐RFA. Although no patients experienced serious adverse effects, two patients who had been diagnosed with diabetes mellitus before undergoing RFA required blood sugar management to improve glycemic control and one subject withdrew due to supplement‐induced vomiting. Conclusion: LES with BCAA supplementation significantly and rapidly improves liver functioning and CPS in LC patients who have undergone RFA for HCC. Control of blood sugar levels is necessary when calorie‐containing BCAA is administrated to LC patients with impaired glucose tolerance.     

Signaling through the interleukin-18 receptor α attenuates inflammation in cisplatin-induced acute kidney injury

Interleukin (IL)-18 is produced by leukocytes and renal parenchymal cells (tubular epithelial cells, podocytes, and mesangial cells). The IL-18 receptor (IL-18R) is expressed on these cells in cisplatin-induced acute kidney injury, but the role of IL-18R is unknown. To help define this, we compared IL-18Rα knockout with wild-type mice in cisplatin-induced acute kidney injury and found deteriorated kidney function, tubular damage, increased accumulation of leukocytes (CD4(+) and CD8(+) T-cells, macrophages, and neutrophils), upregulation of early kidney injury biomarkers (serum TNF, urinary IL-18, and KIM-1 levels), and increased expression of pro-inflammatory molecules downstream of IL-18. In vitro, leukocytes from the spleen and kidneys of the knockout mice produced greater amounts of pro-inflammatory cytokines upon stimulation with concanavalin A compared to that in wild-type mice. Levels of the suppressor of cytokine signaling 1 and 3 (negative regulators of cytokine signaling) were reduced in the spleen and kidneys of IL-18Rα-deficient compared to wild-type mice. Adoptive transfer of wild-type splenocytes by IL-18Rα-deficient mice led to decreased cisplatin nephrotoxicity compared to control IL-18Rα-deficient mice. In contrast, anti-IL-18Rα and anti-IL-18Rβ antibody treatment tended to increase cisplatin nephrotoxicity in wild-type mice. Thus, signaling through IL-18Rα activates both inflammation-suppressing and pro-injury pathways in cisplatin-induced acute kidney injury.