Relationships between circulating irisin levels, cardiorespiratory fitness, and cardiometabolic risk: a cross-sectional study in Japanese adults.

High cardiorespiratory fitness levels achieved through regular aerobic exercise are associated with reduced cardiometabolic risk. The exercise-induced myokine irisin possibly mediates these associations, but these relationships are unclear. This study aimed to clarify the relationships between circulating irisin levels, cardiorespiratory fitness levels, and cardiometabolic risk factors adjusted for sex and age. This cross-sectional study included 328 Japanese participants aged between 18 and 88 yr. We measured serum irisin levels and peak oxygen uptake (V̇o2peak) as cardiorespiratory fitness indicators, and body fat percentage, blood pressure, fasting blood glucose, hemoglobin A1c (HbA1c), high-density lipoprotein (HDL) cholesterol, and triglycerides as cardiometabolic risk factors. Cardiometabolic risk scores were calculated from the z-scores of the cardiometabolic risk factors. Quintiles based on V̇o2peak or irisin values, categorized by sex, showed a gradual increase in HDL cholesterol and a gradual decrease in other cardiometabolic risk factors with an increase in cardiorespiratory fitness levels or irisin. Serum irisin levels were negatively correlated with body fat percentage, blood pressure, fasting blood glucose, HbA1c, triglyceride levels, and cardiometabolic risk score and positively correlated with HDL cholesterol levels and V̇o2peak in both sexes and young, and middle-aged and older adults. The same relationship was observed in all participants after adjusting for sex and age. These results suggest that circulating irisin levels may be involved in the association between cardiorespiratory fitness and cardiometabolic risk factors, regardless of sex and age.NEW & NOTEWORTHY Circulating irisin levels gradually increased, and cardiometabolic risks gradually decreased with increasing cardiorespiratory fitness levels. The fitness levels required to increase irisin levels were moderate for young adults and lower than moderate for middle-aged and older adults. Moreover, circulating irisin levels are correlated with a reduction in cardiometabolic risk and an increase in cardiorespiratory fitness. These data suggest that circulating irisin levels are involved in the association between cardiorespiratory fitness and cardiometabolic risk.

Effects of styrene monomer on a mouse model of atopic dermatitis.

Aim: Styrene monomer (SM) is a basic chemical used as a raw material for polystyrene and unsaturated polyester resins and in the production of synthetic resins, synthetic rubbers, paints, and adhesives. To date, it is unclear whether SM is associated with the aggravation of atopic dermatitis. The aim was to investigate the effects of SM on atopic dermatitis-like skin lesions induced by mite allergen in NC/Nga mice.Methods: Male mice were injected intradermally with mite allergen on their right ears. In the presence of an allergen, SM (3.5 or 350 µg/animal/week) was administered by intraperitoneal injection. We evaluated clinical scores, ear thickening, histologic findings, and the protein expressions of cytokines and chemokines.Results: Macroscopic and microscopic examinations demonstrated that exposure to SM at a dose of 3.5 µg caused an exacerbation of atopic dermatitis-like skin lesions related to mite allergen. These changes were consistent with the level of histamine in the ear tissue as an overall trend. In contrast, 350-µg SM did not show significant enhancement effects.Conclusion: These results indicate that SM exacerbated atopic dermatitis-like skin lesions at hundred-fold lower levels than the level that causes no observed adverse effects as determined by histologic changes in rodent livers. SM could be at least partly responsible for the recent increase in atopic dermatitis.Impact statementStyrene monomer (SM) is classified as an International Agency for Research on Cancer group 2B carcinogen and includes neurotoxicity and respiratory disorders. However, the effects of SM as a chemical substance on existing allergic pathophysiology have not been elucidated yet. This study demonstrated that SM exacerbated murine atopic dermatitis-like skin lesions at hundred-fold lower levels than the level that causes no observed adverse effects as determined by histologic changes in rodent livers, which was concomitant with the local level of histamine. These data hasten a need for comprehensive research to clarify the chemical pollutants' effects of doses much lower than NOAEL on vulnerable pathophysiologies such as allergy/atopy.

Differential Pattern of Cell Death and ROS Production in Human Airway Epithelial Cells Exposed to Quinones Combined with Heated-PM2.5 and/or Asian Sand Dust.

The combined toxicological effects of airborne particulate matter (PM), such as PM2.5, and Asian sand dust (ASD), with surrounding chemicals, particularly quinones, on human airway epithelial cells remain underexplored. In this study, we established an in vitro combination exposure model using 1,2-naphthoquinones (NQ) and 9,10-phenanthroquinones (PQ) along with heated PM (h-PM2.5 and h-ASD) to investigate their potential synergistic effects. The impacts of quinones and heated PM on tetrazolium dye (WST-1) reduction, cell death, and cytokine and reactive oxygen species (ROS) production were examined. Results revealed that exposure to 9,10-PQ with h-PM2.5 and/or h-ASD dose-dependently increased WST-1 reduction at 1 µM compared to the corresponding control while markedly decreasing it at 10 µM. Higher early apoptotic, late apoptotic, or necrotic cell numbers were detected in 9,10-PQ + h-PM2.5 exposure than in 9,10-PQ + h-ASD or 9,10-PQ + h-PM2.5 + h-ASD. Additionally, 1,2-NQ + h-PM2.5 exposure also resulted in an increase in cell death compared to 1,2-NQ + h-ASD and 1,2-NQ + h-PM2.5 + h-ASD. Quinones with or without h-PM2.5, h-ASD, or h-PM2.5 + h-ASD significantly increased ROS production, especially with h-PM2.5. Our findings suggest that quinones, at relatively low concentrations, induce cell death synergistically in the presence of h-PM2.5 rather than h-ASD and h-PM2.5 + h-ASD, partially through the induction of apoptosis with increased ROS generation.

Effects of Streamer Discharge on PM2.5 Containing Endotoxins and Polyaromatic Hydrocarbons and Their Biological Responses In Vitro.

Experimental and epidemiological studies have demonstrated that fine particulate matter with a diameter of <2.5 µm (PM2.5) affects both the respiratory and immune systems. However, effective approaches to reduce PM2.5-induced hazardous effects have not been discovered yet. Streamer discharge is a category of plasma discharge in which high-speed electrons collide with oxygen and nitrogen molecules. Although streamer discharge can reportedly eliminate bacteria, molds, chemical substances, and allergens, its ability to decontaminate PM2.5 has not been previously demonstrated. The present study explored whether streamer discharge treatment could reduce PM2.5-induced inflammatory responses by employing an in vitro system. PM2.5 was collected under four conditions (Bangkok (Sep.−Dec.), Bangkok (Dec.−Mar.), Singapore, and Taipei). Airway epithelial cells and antigen-presenting cells exposed to non-treated PM2.5 in several conditions resulted in inflammatory responses. Streamer-discharged PM2.5 (Bangkok (Sep.−Dec.)) decreased the expression of interleukin (IL)-6 and IL-8 compared to non-treated PM2.5. Moreover, composition analysis demonstrated that streamer discharge reduced some compounds, such as endotoxins and polycyclic aromatic hydrocarbons, included in PM2.5 that can elicit inflammatory responses. Streamer discharge treatment can reduce endotoxins, polycyclic aromatic hydrocarbons, and the subsequent inflammatory responses induced by PM2.5 in vitro.

Esophageal metastasis of renal cell carcinoma resected by endoscopic submucosal dissection: a case report.

BACKGROUND: Esophageal metastasis of renal cell carcinoma (RCC) is extremely rare. We have described herein a case of a 59-year-old man with esophageal metastasis of RCC that was endoscopically resected. CASE PRESENTATION: The case was a 59-year-old man who had undergone left nephrectomy for renal clear cell carcinoma 17 years ago and splenectomy for splenic metastasis 3 years ago. Esophagogastroduodenoscopy (EGD) performed 9 years ago revealed a small reddish elevated lesion with a smooth surface in the middle esophagus; this lesion increased in size 4 years ago. However, no biopsy was performed. The lesion continued to grow in size and was found to have become nodular during the present observation. Biopsy revealed clear cell carcinoma. Endoscopic ultrasound (EUS) revealed that the lesion had not invaded the submucosa, and contrast-enhanced computed tomography did not reveal any other metastasis. The lesion was successfully removed en bloc via endoscopic submucosal dissection (ESD). Pathologically, the tumor was detected in the subepithelium with focal infiltration of the muscularis mucosa. It consisted of monotonous cells with small nuclei and a clear cytoplasm. Immunohistological findings indicated that the tumor was a metastasis of RCC. The lateral and vertical margins were noted to be free. CONCLUSIONS: We have presented herein a case of esophageal metastasis of RCC that had progressed over 9 years and was then resected en bloc through endoscopic submucosal dissection.

Long-term survival analysis of addition of carboplatin to neoadjuvant chemotherapy in HER2-negative breast cancer.

PURPOSE: Addition of carboplatin (CBDCA) to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) has improved pathological complete response (pCR) rates in previous studies. We present long-term survival outcomes (disease-free survival [DFS], pre-planned secondary endpoint; overall survival [OS], post hoc exploratory endpoint) of our randomized study of the addition of CBDCA to NAC for HER2-negative breast cancer. METHODS: Patients with stage II/III, HER2-negative breast cancer (N = 179) were randomly assigned to receive CP-CEF (four 3-week cycles of CBDCA [area under the curve, 5 mg/mL/min, day 1] and weekly paclitaxel [wPTX, 80 mg/m2, day 1, 8, 15] followed by four 3-week cycles of cyclophosphamide, epirubicin, and 5-fluorouracil [CEF, 500/100/500 mg/m2]) or P-CEF (four cycles of wPTX followed by four cycles of CEF) as NAC. DFS and OS were analyzed at each population of pCR status and assigned treatment arm. RESULTS: Of 179 patients, 154 were available for long-term follow-up. At a median follow-up of 6.6 years (range, 0.7-8.0 years), patients who achieved pCR [n = 42, 23.5% (CP-CEF: n = 28, P-CEF: n = 16)] had longer DFS and OS than non-pCR patients [DFS; HR 0.15 (0.04-0.61), P = 0.008, OS; log-rank P = 0.003]. Addition of carboplatin to NAC significantly improved DFS and OS in the subset of patients with TNBC [DFS: HR, 0.22 (0.06-0.82), P = 0.015; OS: HR, 0.12 (0.01-0.96), P = 0.046], but not in the subset of patients with hormone receptor-positive disease or among all patients. CONCLUSIONS: Addition of carboplatin to neoadjuvant chemotherapy significantly improved DFS and OS in patients with TNBC but not in those with hormone receptor-positive, HER2-negative breast cancer.

Physiological effects of brominated flame retardants on NC/Nga mice.

PURPOSE: Brominated flame retardants (BFRs) are used as an additive or reactive components in various materials. Regarding their health concerns, their immunotoxicity have not been clarified yet. MATERIALS AND METHODS: In the current study, we examined the effects of systemic exposure to two types of BFRs, DE71 and DE79, on pathophysiologic traits of murine atopic dermatitis (AD). Male NC/Nga mice were repeatedly injected intraperitoneally with DE71 and DE79 and/or mite allergen (Dermatophagoides pteronyssinus: Dp) into their right ears. Thereafter, clinical scores, macroscopic findings of inflammatory foci, and Ig values in serum were examined. RESULTS: Both DEs significantly aggravated clinical scores induced by mite allergen including skin dryness and edema. Total IgE titer was significantly greater in the Dp + DE79 group than in the Dp group. CONCLUSIONS: Taken together, exposure to BFRs can exacerbate AD-like skin lesions related to mite allergen in mice. The accentuating effects may be mediated, at least in part, through hyperproduction of IgE.

A Pathological Study of Acute Pulmonary Toxicity Induced by Inhaled Kanto Loam Powder.

The frequency and volume of Asian sand dust (ASD) (Kosa) are increasing in Japan, and it has been reported that ASD may cause adverse respiratory effects. The pulmonary toxicity of ASD has been previously analyzed in mice exposed to ASD particles by intratracheal instillation. To study the pulmonary toxicity induced by inhalation of ASD, ICR mice were exposed by inhalation to 50 or 200 mg/m³ Kanto loam powder, which resembles ASD in elemental composition and particle size, for 6 h a day over 1, 3, 6, 9, or 15 consecutive days. Histological examination revealed that Kanto loam powder induced acute inflammation in the whole lung at all the time points examined. The lesions were characterized by infiltration of neutrophils and macrophages. The intensity of the inflammatory changes in the lung and number of neutrophils in both histological lesions and bronchoalveolar lavage fluid (BALF) appeared to increase over time. Immunohistochemical staining showed interleukin (IL)-6- and tumor necrosis factor (TNF)-α-positive macrophages and a decrease in laminin positivity in the inflammatory lesions of the lung tissues. Electron microscopy revealed vacuolar degeneration in the alveolar epithelial cells close to the Kanto loam particles. The nitric oxide level in the BALF increased over time. These results suggest that inhaled Kanto loam powder may induce diffuse and acute pulmonary inflammation, which is associated with increased expression of inflammatory cytokines and oxidative stress.

Environmental pollution and allergies.

Environmental changes are thought to be the main factor in the rapid increase and worsening of allergic diseases. While there have been significant changes in many environmental factors, including in environments such as residential, health and sanitation, food, and water/soil/atmospheric environments, the root of each of these changes is likely an increase in chemical substances. In fact, various environmental pollutants, such as air pollutants and chemical substances, have been shown to worsen various allergies in experimental studies. For example, diesel exhaust particles (DEPs), which are an agglomeration of particles and a wide array of chemical substances, aggravate asthma, primarily due to the principle organic chemical components of DEPs. In addition, environmental chemicals such as phthalate esters, which are commonly used as plasticizers in plastic products, also aggravate atopic dermatitis. It has also become evident that extremely small nanomaterials and Asian sand dust particles can enhance allergic inflammation. While the underlying mechanisms that cause such aggravation are becoming clearer at the cellular and molecular levels, methods to easily and quickly evaluate (screen) the ever-increasing amount of environmental pollutants for exacerbating effects on allergies are also under development. To eliminate and control allergic diseases, medical measures are necessary, but it is also essential to tackle this issue by ameliorating environmental changes.

Serum triglyceride levels in relation to high-density lipoprotein cholesterol (TG-HDL) ratios as an efficient tool to estimate the risk of sleep apnea syndrome in non-overweight Japanese men.

OBJECTIVES: Several studies have reported the association between sleep apnea syndrome and insulin resistance. Being overweight is known risk factor both for sleep apnea syndrome and insulin resistance. However, no studies have reported on the association between serum triglyceride levels in relation to high-density lipoprotein cholesterol (TG-HDL) ratios (a marker of insulin resistance) and sleep apnea syndrome accounting for body mass index (BMI) status. METHODS: Subjects for the present cross-sectional study consisted of 1,528 men aged 30-69 years undergoing pulse oximetry at a sleep disorders clinic for sleep apnea syndrome. Sleep apnea syndrome was diagnosed as a 3 % oxygen desaturation index (ODI) of ≥15 events/h. RESULTS: Among study participants, 241 men were diagnosed with sleep apnea syndrome. Independent of classical cardiovascular risk factors, TG-HDL was significantly positively associated with sleep apnea syndrome in participants with a BMI <25 kg/m2, but not in participants with a BMI ≥25 kg/m2. The multivariable adjusted odds ratio (OR) and 95 % confidence interval (95 % CI) of sleep apnea syndrome per Log TG-HDL was 2.03 (95 % CI: 1.36-3.03) for a BMI <25 kg/m2 and 1.23 (95 % CI: 0.89-1.70) for a BMI ≥25 kg/m2. CONCLUSIONS: An independent positive association between TG-HDL levels and risk of sleep apnea syndrome was observed in participants with a BMI of <25 kg/m2, but not in participants with a BMI ≥25 kg/m2. TG-HDL levels could be an efficient tool to estimate the risk of sleep apnea syndrome in non-overweight Japanese men.

Short stature is an inflammatory disadvantage among middle-aged Japanese men.

OBJECTIVES: A positive association between white blood cell count and carotid atherosclerosis has been reported. Our previous study also found an inverse association between height and carotid atherosclerosis in overweight but not non-overweight men. However, no studies have reported on the association between high white blood cell (WBC) count and height accounting for body mass index (BMI) status. METHODS: We conducted a hospital-based general population cross-sectional study of 3016 Japanese men aged 30-59 years undergoing general health check-ups between April 2013 and March 2014. High WBC count was defined as the highest tertiles of WBC count among total subjects. RESULTS: Independent of classical cardiovascular risk factors, height was found to be inversely associated with high WBC count, especially for subjects with a BMI ≥ 23 kg/m2. The classical cardiovascular risk factors adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) of high WBC count for an increment of one standard deviation (SD) in height (5.7 cm) were 0.91 (0.83-0.99) for total subjects, 1.00 (0.86-1.15) for subjects with a BMI < 23 kg/m2 and 0.86 (0.77-0.96) for subjects with a BMI ≥ 23 kg/m2. CONCLUSION: Independent of classical cardiovascular risk factors, height was found to be inversely associated with high WBC count, especially for those with a BMI ≥ 23 kg/m2. Compared to high stature, short stature appears to convey an inflammatory disadvantage among Japanese men, especially those with a BMI ≥ 23 kg/m2.

The alkylphenols 4-nonylphenol, 4-tert-octylphenol and 4-tert-butylphenol aggravate atopic dermatitis-like skin lesions in NC/Nga mice.

Phthalate esters in plastics act as adjuvants for immunoglobulin production, which aggravates allergic disease. However, the effects of alkylphenols (used as plasticizers and surfactants) on atopic dermatitis have not been studied in detail. Therefore, the goal of the present study was to investigate the effects of the alkylphenols 4-nonylphenol (NP), 4-tert-octylphenol (OP) and 4-tert-butylphenol (BP) in a murine model of atopic dermatitis. NC/Nga mice were intraperitoneally administered NP, OP or BP and were subcutaneously injected with mite allergen in one ear to induce atopic dermatitis-like skin lesions (ADSLs). The condition of the skin was observed, and the levels of immunoglobulin in serum and inflammatory cytokines in lesions were determined. NP exacerbated mite allergen-induced ADSLs according to dose. OP and BP also significantly exacerbated skin lesions but not as a function of dose. Alkylphenols tended to increase the levels of IgE and antigen-specific IgG1 in serum. Further, the treatment of the alkylphenols increased the expression in lesions of inflammatory cytokines, interleukin-4 and monocyte chemotactic protein-3. Thymic stromal lymphopoietin levels increased according to ADSL severity. In contrast, the levels of the T-helper 1 cytokines (interleukin-18 and interferon-gamma) decreased. NP, OP or BP may enhance T-helper 2-type immune responses in NC/Nga mice, which aggravates mite allergen-induced ADSLs. Therefore, the uptake of very low levels of alkylphenols may contribute to the increase in the incidence of atopic dermatitis.

Airborne Suspended Particulate Matter and the Prevalence of Allergic Conjunctivitis in Japan.

Background This study aimed to examine the association of suspended particulate matter (SPM) with outpatient attendance for allergic conjunctivitis. Methodology The information on air pollution, encompassing total hydrocarbons, non-methane hydrocarbons, methane, carbon monoxide, nitrogen oxide, nitric oxide, oxidants, and SPM alongside data concerning daily weather conditions such as temperature, wind speed, and humidity, was gathered. Subsequently, the weekly mean values for outpatient visits, air pollution, and weather parameters were computed. Results The number of outpatient visits for allergic conjunctivitis was significantly associated with SPM levels (r = 0.70, p = 0.0037), oxidant levels (r = 0.70, p = 0.0038), wind speed (r = 0.48, p = 0.0472), and humidity (r = 0.77, p = 0.0009) from January to March, as well as SPM levels (r = 0.53, p = 0.0309) and carbon monoxide (r = 0.56, p = 0.0230) from April to June. Multivariate analysis showed that SPM (odds ratio = 1.37, p = 0.0161) and wind velocity (odds ratio = 1.52, p = 0.0038) were significant predictors of the number of outpatient visits from January to December. Conclusions SPM levels were the only independent predictor of outpatient visits for allergic conjunctivitis, suggesting that SPM contributes to the pathophysiology of this condition.

Organic chemicals in diesel exhaust particles enhance picryl chloride-induced atopic dermatitis in NC/Nga mice.

BACKGROUND: Diesel exhaust particles (DEP) have been reported to worsen allergic airway inflammation in mice. Recently, the organic chemical components of DEP (DEP-OC) were found to be important contributors to the aggravation of allergic airway inflammation in mice. The purpose of this study was to examine the effects of DEP-OC on atopic dermatitis (AD)-like skin lesions induced by picryl chloride (PiCl) in NC/Nga mice. METHODS: DEP were extracted with benzene/ethanol, and the soluble organic fraction formed the DEP-OC. NC/Nga male mice received simultaneous application of DEP-OC and/or PiCl on their ears once a week for 9 or 3 weeks. We evaluated skin lesions by noting scaling, eruption, excoriation, erosion, hemorrhage, pathologic changes, production of cytokines, and IgE level in the serum. RESULTS: PiCl application alone produced progressively severe AD-like skin lesions. The application of PiCl plus DEP-OC resulted in a marked worsening of skin lesions in the early stages of AD. Moreover, mast cell counts significantly increased in the subcutaneous tissue. Administration of PiCl combined with DEP-OC resulted in a greater increase in the local expression of interleukin-4, keratinocyte chemoattractant, and neutrophils in subcutaneous tissue compared with PiCl treatment alone. In contrast, the combination treatment produced lower levels of IFN-γ compared with PiCl treatment alone. CONCLUSIONS: DEP-OC application to the skin aggravated PiCl-induced AD. This aggravation may be due to activation of the Th2-associated immune responses by the organic chemicals in DEP.

Caveolae-mediated endocytosis of intratracheally instilled gold colloid nanoparticles at the air-blood barrier in mice.

Endocytosis is the primary mechanism by which nanoparticles are translocated over the alveolar epithelium. The purpose of this study was to elucidate the association between endocytosis and the translocation of nanoparticles at the air-blood barrier (ABB). Gold colloid particles (diameter, 20 nm) were intratracheally instilled into male ICR mice. Fifteen minutes after instillation, localized accumulation of agglomerated gold particles was observed in the cytoplasm of macrophages, on the surface of alveolar epithelial cells (AECs), and in alveoli. Electron microscopy revealed particles in the vesicles of macrophages, on the surface of AECs, and in caveolae-like vesicles in type 1 AECs. Immunohistochemistry demonstrated positive immunolabeling for caveolin-1 in the ABB of untreated lungs as well as lungs treated with gold particles. Double immunofluorescence and immunoelectron microscopy revealed the presence of caveolin-1 in AECs in the untreated lungs. These results suggest that instilled gold colloid particles are internalized into the alveolar epithelium at the ABB by caveolae-mediated endocytosis, which is regarded as a physiological function of AECs.

Pathological study of chronic pulmonary toxicity induced by intratracheally instilled Asian sand dust (kosa).

Asian sand dust (ASD) events are associated with an increase in pulmonary morbidity and mortality. The number of ASD events has increased rapidly in the east Asian region since 2000. To study the chronic lung toxicity of ASD, saline suspensions of low doses (200 and 400 µg) and high doses (800 and 3,000 µg) of ASD were intratracheally instilled into ICR mice. Animals were sacrificed at 24 hr, 1 week, or 1, 2, or 3 months after instillation. Histopathological examination revealed that ASD induced acute inflammation at 24 hr after instillation. The acute inflammation was transient and subsided at 1 week and 1 month after instillation. At 2 and 3 months after instillation, focal infiltration of lymphocytes with accumulation of epithelioid macrophages, which is a suggestive finding of transformation to granuloma, and granuloma formation were occasionally observed. Aggregation of macrophages containing particles was observed in the pulmonary lymph nodes at 3 months after instillation in high-dose groups. Prolonged inflammatory foci (granuloma) and presence of ASD particles in pulmonary lymph nodes would have a chance to induce immunological modulation leading to adverse health effects in the exposed animals.