Epicutaneously sensitized food-induced anaphylaxis is ameliorated with "oral tolerance" to antigen.

Food allergy is an antigen-specific immunological adverse reaction after exposure to a given food. Multiple clinical studies showed that oral immunotherapy (OIT) is effective for the prevention and treatment for food allergy that is developed in infants and children. However, the effectiveness of OIT for epicutaneously sensitized food allergy remains unclear. Previously, we established a mouse model of epicutaneous-sensitized food allergy. In this model, systemic allergic reaction including intestinal and skin symptoms, such as anaphylaxis, was observed. We treated this model with OIT in two ways (OIT before sensitization or OIT during the sensitization phase) and evaluated the preventive effect of both methods. OIT before sensitization significantly ameliorated mast cell degranulation in sensitized skin, but there was no decrease in rectal temperatures or in mast cell degranulation in the jejunum. However, OIT administered during the sensitization phase significantly ameliorated the decrease in rectal temperature and mast cell degranulation in the skin and jejunum. OIT before sensitization increased the regulatory T cells in mesenteric lymph node (MLN), but not in the spleen, and it reduced antigen-specific IgG, but not IgE, production compared with the non-OIT control. However, OIT during sensitization caused a greater increase in regulatory T cells in both the MLN and spleen and reduced antigen-specific IgE and IgG generation compared with the non-OIT control group. Thus, OIT during the sensitization phase was effective for the prevention of epicutaneous-sensitized food allergy.

Legumain Promotes Atherosclerotic Vascular Remodeling.

Legumain, a recently discovered cysteine protease, is increased in both carotid plaques and plasma of patients with carotid atherosclerosis. Legumain increases the migration of human monocytes and human umbilical vein endothelial cells (HUVECs). However, the causal relationship between legumain and atherosclerosis formation is not clear. We assessed the expression of legumain in aortic atheromatous plaques and after wire-injury-induced femoral artery neointimal thickening and investigated the effect of chronic legumain infusion on atherogenesis in Apoe-/- mice. We also investigated the associated cellular and molecular mechanisms in vitro, by assessing the effects of legumain on inflammatory responses in HUVECs and THP-1 monocyte-derived macrophages; macrophage foam cell formation; and migration, proliferation, and extracellular matrix protein expression in human aortic smooth muscle cells (HASMCs). Legumain was expressed at high levels in atheromatous plaques and wire injury-induced neointimal lesions in Apoe-/- mice. Legumain was also expressed abundantly in THP-1 monocytes, THP-1 monocyte-derived macrophages, HASMCs, and HUVECs. Legumain suppressed lipopolysaccharide-induced mRNA expression of vascular cell adhesion molecule-1 (VCAM1), but potentiated the expression of interleukin-6 (IL6) and E-selectin (SELE) in HUVECs. Legumain enhanced the inflammatory M1 phenotype and oxidized low-density lipoprotein-induced foam cell formation in macrophages. Legumain did not alter the proliferation or apoptosis of HASMCs, but it increased their migration. Moreover, legumain increased the expression of collagen-3, fibronectin, and elastin, but not collagen-1, in HASMCs. Chronic infusion of legumain into Apoe-/- mice potentiated the development of atherosclerotic lesions, accompanied by vascular remodeling, an increase in the number of macrophages and ASMCs, and increased collagen-3 expression in plaques. Our study provides the first evidence that legumain contributes to the induction of atherosclerotic vascular remodeling.

Relationship between duration of sick leave and time variation of words used in return-to-work programs for depression.

BACKGROUND: Return-to-work (RTW) programs are provided as rehabilitation for people who have taken sick leave from work because of mental health problems. However, methods to present this information to workplaces objectively remain limited. OBJECTIVE: This study aimed to conduct an exploratory investigation of the relationship between duration of sick leave and time variation of words used in RTW programs for depression from textual data collected from electronic medical records as a new evaluation indicator. METHODS: The study subjects were those who had taken sick leave because of major depressive or adjustment disorder and had participated in an RTW program. The study data comprised demographic characteristics and texts. Textual data were collected from electronic medical records and classified based on the SOAP note. Thereafter, the textual data were quantified into category scores based on a standard text analysis dictionary. A generalized linear mixed model was used for the statistical analysis, with the score for each category (emotional, social, cognitive, perceptual, biological, motivational, relativity, and informal) as the dependent variable and the duration of sick leave, time, and interaction between the duration of sick leave and time as the independent variables. The level of statistical significance was set at 0.05. RESULTS: In total, 42 participants were included in the analysis. The results revealed a significant interaction between the social (p = 0.001) and emotional (p = 0.002) categories. CONCLUSION: The findings suggest a relationship between word changes in electronic medical records and the duration of sick leave.

Influence of loop diuretics on denosumab-induced hypocalcaemia in osteoporosis: a retrospective observational analysis.

BACKGROUND: We examined whether denosumab-induced hypocalcaemia is evident in osteoporosis when given loop diuretics that promote urinary calcium excretion. METHODS: Japanese Spontaneous Adverse Drug Event Reports was analyzed to examine signals for denosumab-induced hypocalcaemia co-administered loop diuretics. We retrospectively included osteoporotic patients to detect predictors for denosumab-induced hypocalcaemia (corrected calcium level < 8.5 mg/dL) using multivariate logistic regression analysis. We compared differences in corrected calcium levels (ΔCa = nadir-baseline). RESULTS: A significant signal for hypocalcaemia was detected (Reporting odds ratio = 865.8, 95% confidence interval [95% CI]: 596.8 to 1255.9, p < 0.0001). Among 164 patients (hypocalcaemia, 12%), loop diuretics have a significant association with hypocalcaemia (odds ratio [OR] = 6.410, 95% CI: 1.005 to 40.90, p = 0.0494). However, hypocalcaemia was found to be lower in high corrected calcium levels at baseline (OR = 0.032, 95% CI: 0.005 to 0.209, p < 0.0001) and calcium and vitamin D supplementation (OR = 0.285, 95% CI: 0.094 to 0.868, p = 0.0270). In the non-hypocalcaemia, ΔCa decreased significantly in the denosumab plus loop diuretics than in the denosumab alone (-0.9 [-1.3 to -0.7] mg/dL vs. -0.5 [-0.8 to -0.3] mg/dL, p = 0.0156). However, ΔCa remained comparable in the hypocalcaemia despite loop diuretics co-administration (-1.0 [-1.2 to -0.8] mg/dL vs. -0.8 [-1.5 to -0.7] mg/dL, p = 0.7904). CONCLUSIONS: Loop diuretics may predispose to developing denosumab-induced hypocalcaemia.

Impact of body mass index on the severity of bexarotene-associated hypertriglyceridemia: A post hoc analysis of an open-labeled clinical study of combined bexarotene and phototherapy in Japanese patients with cutaneous T-cell lymphoma.

Bexarotene is an effective oral drug for the treatment of cutaneous T-cell lymphoma, but careful management is required due to its various side effects. In particular, hypertriglyceridemia often requires a reduction or even suspension of bexarotene therapy. The risk factors of bexarotene-associated severe hypertriglyceridemia are not clear. Here, we conducted a post hoc analysis of the data from our previous clinical trial, which confirmed the efficacy and safety of combined bexarotene and phototherapy, to evaluate the effect of body mass index on bexarotene-associated hypertriglyceridemia. Twenty-five subjects were divided into two subgroups: normal and underweight (body mass index [BMI] <25 kg/m2 group) and overweight and obese (BMI ≥25 kg/m2 group) patients. The overall incidence of hypertriglyceridemia was 81.3% (13/16) in the BMI <25 kg/m2 group and 88.9% (8/9) in the BMI ≥25 kg/m2 group. The incidence of grade ≥3 hypertriglyceridemia (≥500 mg/dL) was 7.7% (1/13) in the BMI <25 kg/m2 group and 7/8 (87.5%) in the BMI ≥25 kg/m2 group (P < 0.001). Consequently, dose reduction in the BMI ≥25 kg/m2 group was larger than that in the BMI <25 kg/m2 group. The bexarotene-induced change in the serum triglyceride concentration was significantly increased in cutaneous T-cell lymphoma patients with a higher body mass index (ρ = 0.508, P = 0.009). The area under the curve was 0.886 (95% confidence interval 0.748-1.000, P = 0.002). With a body mass index cut-off of 24.85 kg/m2 , the sensitivity and specificity for identifying grade ≥3 hypertriglyceridemia were 0.875 and 0.882, respectively. The present findings suggest that BMI ≥25 kg/m2 is a risk factor for bexarotene-associated severe hypertriglyceridemia, therefore overweight and obese patients treated with bexarotene should receive lipid-lowering drugs prophylactically. Further studies for optimizing the initial bexarotene dose in such patients are required.

Cell cycle-dependent accumulation of histone H3.3 and euchromatic histone modifications in pericentromeric heterochromatin in response to a decrease in DNA methylation levels.

In mammals, DNA methylation is an important epigenetic mark that is associated with gene silencing, particularly in constitutive heterochromatin. However, the effect of DNA methylation on other epigenetic properties of chromatin is controversial. In this study, we show that inhibition of DNA methylation in mouse fibroblast cells affects histone modification and the subnuclear localization of histone H3.3 in a cell cycle-dependent manner. Using a DNA methyltransferase (Dnmt) inhibitor 5-aza-2'-deoxycytidine (5-aza-dC), we found that reduced levels of DNA methylation were associated with the activation of transcription from centromeric and pericentromeric satellite repeats. The de-repressed pericentromeric chromatin was enriched in euchromatic histone modifications such as acetylation of histone H4, and di- and tri-methylation of lysine 4 on histone H3. Spatio-temporal analysis showed that the accumulation of these euchromatic histone modifications occurred during the second S phase following 5-aza-dC treatment, corresponding precisely with a shift in replication timing of the pericentromeric satellite repeats from middle/late S phase to early S phase. Moreover, we found that histone H3.3 was deposited on the pericentromeric heterochromatin prior to the accumulation of the euchromatic histone modifications. These results suggest that DNA CpG methylation is essential for the proper organization of pericentromeric heterochromatin in differentiated mouse cells.

Long-term effects of home-based bench-stepping exercise training on healthcare expenditure for elderly Japanese.

BACKGROUND: We examined the long-term effects of home-based bench-stepping exercise training on total healthcare expenditure (TOHEX) and number of outpatient visits (NOVIS) in elderly adults. METHODS: A total of 189 elderly Japanese (age 73 ± 4 years) participated in this study. They were randomly assigned to either an exercise or control group. TOHEX, NOVIS, and outpatient expenditure (OPEX) were evaluated every 6 months from 1 year before the start to the end of the intervention period, as well as 1 year after the end of the intervention. The exercise group was encouraged to perform home-based bench-stepping exercise training on most, and preferably all, days of the week for 18 months. RESULTS: The exercise group showed significant increases in lactate threshold as compared with pre-intervention values. There were no significant differences in TOHEX, OPEX, or NOVIS between the exercise and control groups 1 year before the start of the intervention, and the values remained similar during the first 12 months of the intervention period. However, at 18 months, TOHEX, NOVIS, and OPEX were significantly lower in the exercise group than in the control group (TOHEX: 170 007 ± 192 072 vs. 294 705 ± 432 314 yen, P = 0.008; NOVIS: 19.2 ± 26.3 vs. 28.2 ± 32.1 days, P = 0.012; OPEX: 132 973 ± 132 016 vs. 187 799 ± 158 167 yen, P = 0.005). CONCLUSIONS: The data indicate that a long-term home-based bench-stepping exercise program can reduce healthcare expenditure in elderly Japanese.

Pulmonary tumor thrombotic microangiopathy of hepatocellular carcinoma: A case report and review of literature.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare condition in patients with hepatocellular carcinoma (HCC); to date, few cases have been reported. While hepatic dysfunction has been focused on the later stages of HCC, the management of symptoms in PTTM is important for supportive care of the cases. For the better understanding of PTTM in HCC, the information of our recent case and reported cases have been summarized. CASE SUMMARY: A patient with HCC exhibited acute and severe respiratory failure. Radiography and computed tomography of the chest revealed the multiple metastatic tumors and a frosted glass-like shadow with no evidence of infectious pneumonia. We diagnosed his condition as acute respiratory distress syndrome caused by the lung metastases and involvement of the pulmonary vessels by tumor thrombus. Administration of prednisolone to alleviate the diffuse alveolar damages including edematous changes of alveolar wall caused by the tumor cell infiltration and ischemia showed mild improvement in his symptoms and imaging findings. An autopsy showed the typical pattern of PTTM in the lung with multiple metastases. CONCLUSION: PTTM is caused by tumor thrombi in the arteries and thickening of the pulmonary arterial endothelium leading to the symptoms of dyspnea in terminal staged patients. Therefore, supportive management of symptoms is necessary in the cases with PTTM and hence we believe that the information presented here is of great significance for the diagnosis and management of symptoms of PTTM with HCC.

Effect of a neural relay on liver regeneration in mice: activation of serotonin release from the gastrointestinal tract.

The development of therapeutic options to promote hepatic regeneration following severe liver injury is essential. While humoral factors have been reported as mechanisms of liver regeneration, the contributions of interorgan communication to liver regeneration have not been reported. In this study, we examined the effect of a neural relay on liver regeneration via activation of serotonin release from the gastrointestinal (GI) tract. Our results demonstrated that the afferent visceral nerve from the liver activates the efferent vagus nerve from the brain, leading to activation of serotonin release from the GI tract and contributing to liver regeneration. While it is difficult to apply these results directly to human health, we believe that this study may represent a step toward developing essential therapeutics to promote liver regeneration.

Angiotensin I converting enzyme gene polymorphism and exercise trainability in elderly women: an electrocardiological approach.

Angiotensin I converting enzyme (ACE) gene Insertion / Deletion (I/D) polymorphism is associated with exercise trainability and exercise induced left ventricular hypertrophy. However, it is unclear whether this polymorphism influences exercise trainability in the elderly, and the electrocardiological alterations by exercise training is unknown among the genotypes. We herein investigated the association between ACE gene insertion/deletion (I/D) polymorphism, exercise trainability and the electrocardiological alternations by exercise in elderly women. Eighty four elderly women participated in this study. In all subjects the leg extension power (LEP) and lactate threshold (LT) were determined in order to evaluate the muscle strength, aerobic capacity and to also select the appropriate training intensity for each individual. They performed bench step exercise training for 12 weeks. A resting electrocardiogram was recorded for the obtained QTc interval in before and after the program. The baseline of aerobic capacity was higher in I/I than that in I/D, and the QTc interval was shorter in I/I than that in I/D. All other characteristics were similar among the genotypes. The QTc interval tended to be shorten only in the D/D. Furthermore, the value of the QTc interval change showed a significant difference between the I/I and D/D genotype after the program. The LT and LEP demonstrated a similar response among the genotypes. The D allele of ACE gene I/D polymorphism may therefore play a role in the electrocardiological aspect during exercise training, however, it was not found to influence the aerobic capacity. Key pointsThe D allele of ACE gene I/D polymorphism may play a role in the electrocardiological aspects during exercise trainingACE gene I/D polymorphism was not determined the aerobic capacity and leg strength in elderly people.The ACE gene I/D polymorphism did not influence aerobic and strength trainability in elderly people.

Peroxisome proliferator-activated receptor gamma co-activator 1 gene Gly482Ser polymorphism is associated with the response of low-density lipoprotein cholesterol concentrations to exercise training in elderly Japanese.

Muscle peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1)α gene expression is influenced by the Gly482Ser gene polymorphism, which is a candidate genetic risk factor for diabetes mellitus and obesity. This study investigated the effects of PGC-1 gene Gly482Ser polymorphisms on alterations in glucose and lipid metabolism induced by exercise training. A 12-week intervention study was performed for 119 participants who were more than 65 years of age and completed exercise training at lactate threshold intensity. Total cholesterol and low-density lipoprotein cholesterol were significantly reduced in Gly/Gly but not in Gly/Ser and Ser/Ser participants after exercise. The Gly/Gly genotype of the PGC-1 gene Gly482Ser polymorphism influences the effects of moderate-intensity exercise training on low-density lipoprotein cholesterol and total cholesterol concentrations in older people.

Effects of bench step exercise on arterial stiffness in post-menopausal women: contribution of IGF-1 bioactivity and nitric oxide production.

OBJECTIVE: To examine the effect of bench step exercise on arterial pulse wave velocity (PWV) and the associated contribution of insulin-like growth factor (IGF)-1 bioactivity and nitric oxide (NO). DESIGN: Twenty-six elderly (post-menopausal) women were randomly allocated to a bench step exercise group or a control group. The participants in the bench step exercise group practiced a 12-week home-based bench step exercise for 10-20min, 3 times daily (i.e., for a total of 140min/week at the intensity level of lactate threshold (LT)). In addition to conventional risk factors of atherosclerosis, PWV, IGF-1/IGF binding protein (IGFBP)-3 molar ratio (an index for IGF-1 bioactivity), and urinary nitrite/nitrate (NO(x)) excretion were measured before and after the intervention. RESULTS: BMI, systolic blood pressure, fasting plasma glucose, low-density lipoprotein cholesterol, LT, and PWV were significantly improved in the bench step exercise group. A significant positive correlation between changes in PWV and IGF-1/IGFBP-3 molar ratio, and a significant negative correlation between changes in IGF-1/IGFBP-3 molar ratio and urinary NO(x) excretion were found in the bench step exercise group. CONCLUSION: The bench step exercise leads to improvements in not only the classical risk factors of atherosclerosis but also the arterial stiffness in elderly women, partly through NO production via IGF-1 bioactivity.

Self-monitoring moderate-vigorous physical activity versus steps/day is more effective in chronic disease exercise programs.

PURPOSE: The effects of self-monitoring number of steps/day versus minutes of moderate to vigorous-intensity physical activity (MVPA/day) were compared to determine which is more effective for increasing physical activity levels. METHODS: A total of 18 participants of a university-based chronic disease prevention program (age 61 +/- 12 years) were enrolled in the 3-week intervention. Subjects were randomly assigned to a group (n = 8) that wore a New Lifestyles accelerometer (NL-1000) and were instructed to increase minutes of MVPA to 30 min/d or more (MIN) or to a group (n = 10) that wore a New Lifestyles pedometer (NL-800) and were instructed to increase the number of steps/day to 10,000 or more (STE). To objectively assess changes in physical activity levels, subjects in both groups simultaneously wore a Lifecorder-EX accelerometer (with display blank) during the intervention. RESULTS: The number of steps increased significantly in the MIN (10,810 +/-3,211 to 13,355 +/- 3,498 steps/day) and STE (11,517 +/- 3,383 to 12,809 +/-2,479 steps/day) from the first to fourth weeks, respectively. However, the time spent in MVPA increased significantly only in MIN group (36 +/- 11 to 52 +/- 15 min/d) but not in the STE group (32 +/- 7 to 37 +/- 11 min/d) from the first to fourth weeks, respectively. CONCLUSION: Data suggest that individuals with chronic disease conditions can more effectively increase levels of physical activity, expressed as both MVPA/day and steps/day, by self-monitoring MIN rather than STE. The effect of self-monitoring physical activity levels for longer periods and/or the effect of increasing minutes of MVPA/day versus steps/day on specific health outcomes have not yet been examined.

rDNA sequence analyses of Streptococcus dysgalactiae subsp. equisimilis isolates from pigs.

The nucleotide sequences of 16S and 23S rRNA genes (rDNA) were determined for 11 isolates of Streptococcus dysgalactiae subsp. equisimilis from slaughtered pigs with endocarditis, arthritis or lymphadenitis and strain ATCC 35666, designated as a strain of subspecies equisimilis. The sequences of each of the genes were compared phylogenetically with the corresponding sequences of S. dysgalactiae subsp. dysgalactiae ATCC 43078(T) and ATCC 27957, which were also determined in this study. Based on the 16S rDNA analysis, the isolates of S. dysgalactiae subsp. equisimilis were divided into two distinct groups, designated groups 1 and 2. S. dysgalactiae subsp. equisimilis ATCC 35666 was closely related to the group 2 strains. The S. dysgalactiae subsp. dysgalactiae strains seemed to be associated with the group 1 strains, which was not consistent with the conventional subspecific classification of S. dysgalactiae. In contrast, the 23S rDNA analysis distinguished S. dysgalactiae subsp. dysgalactiae strains from subsp. equisimilis strains. This inconsistency between phylogenies based on 16S and 23S rDNA indicates that 23S rDNA is a more rigid marker for determining the phylogenetic relationships and taxonomic position of these organisms than is 16S rDNA.