STAT6 gain-of-function variant exacerbates multiple allergic symptoms.

BACKGROUND: Allergic diseases were long considered to be complex multifactorial disorders. However, recent findings indicate that severe allergic inflammation can be caused by monogenic immune defects. OBJECTIVES: We sought to clarify the molecular pathogenesis of a patient with early-onset multiple allergic diseases, a high serum IgE level, hypereosinophilia, treatment-resistant severe atopic dermatitis with increased dermal collagen fiber deposition, and eosinophilic gastrointestinal disorder with numerous polypoid nodules. METHODS: A missense variant in STAT6 was identified, and its function was examined using peripheral blood, transfected HEK293 cells, lymphoblastoid cell lines, and knock-in mice with the corresponding mutation. RESULTS: Whole-exome sequencing identified a de novo heterozygous missense variant in signal transducer and activator of transcription 6 (STAT6) (p.Asp419Asn). Luciferase reporter assay revealed that the transcriptional activity of this STAT6 mutant was upregulated even without IL-4 stimulation. Phosphorylation of STAT6 was not observed in either the patient's TH2 cells or lymphoblastoid cell lines without stimulation, whereas it was induced more strongly in both by IL-4 stimulation compared with healthy controls. STAT6 protein was present in the nuclear fraction of the lymphoblastoid cell lines of the patient even in the absence of IL-4 stimulation. The patient's gastric mucosa showed upregulation of STAT6-, fibrosis-, and germinal center formation-related molecules. Some of the knock-in mice with the corresponding mutation spontaneously developed dermatitis with skin thickening and eosinophil infiltration. Moreover, serum IgE levels and mRNA expression of type 2 cytokines were increased in the knock-in mice-with or without development of spontaneous dermatitis-compared with the wild-type mice. CONCLUSIONS: A novel STAT6 gain-of-function variant is a potential cause of primary atopic disorders.

Laundry detergents and surfactants-induced eosinophilic airway inflammation by increasing IL-33 expression and activating ILC2s.

INTRODUCTION: Epidemiological studies demonstrated that cleaning work and frequent use of cleaning products are risk factors for asthma. Laundry detergents have been reported to have epithelial barrier-opening effects. However, whether laundry detergents directly induce airway inflammation and its mechanisms in vivo remain to be elucidated. METHODS: Two commercial laundry detergents and two commonly used surfactants for cleaning and cosmetics (sodium lauryl sulfate and sodium dodecyl benzene sulfonate) were intranasally administered to mice. Lungs were analyzed using flow cytometry, histology, ELISA, and quantitative PCR. Human bronchial epithelial cells were stimulated with laundry detergents and analyzed using quantitative PCR and western blotting. Involvement of oxidative stress was assessed using an antioxidant. Dust samples from homes were analyzed to determine their detergent content by measuring their critical micelle concentration (CMC). RESULTS: The administered laundry detergents and surfactants-induced eosinophilic airway inflammation accompanied by increased IL-33 expression and activation of group 2 innate lymphoid cells (ILC2s). Detergent-induced eosinophilic airway inflammation was significantly attenuated in Rag2-/- Il2rg-/- , Il33-/- mice, and also in wild-type mice treated with NAC. Detergent-induced IL-33 expression in airways was attenuated by NAC treatment, both in vivo and in vitro. CMCs were found in all of the tested dust extracts, and they differed significantly among the homes. CONCLUSION: The laundry detergents and surfactants-induced eosinophilic airway inflammation in vivo through epithelial cell and ILC2 activation. They induced IL-33 expression in airway epithelial cells through oxidative stress. Furthermore, detergent residues were present in house dust and are presumably inhaled into the airway in daily life.

Direct platelet adhesion potentiates group 2 innate lymphoid cell functions.

BACKGROUND: Platelets are thought to be involved in the pathophysiology of asthma, presumably through direct adhesion to inflammatory cells, including group 2 innate lymphoid cells (ILC2s). Here, we tried to elucidate the effects of platelet adhesion to ILC2s in vitro and in vivo, as well as the mechanisms involved. METHODS: Alternaria-induced ILC2-dependent airway inflammation models using wild-type and c-mpl-/- mice were evaluated. Both purified CD41+ and CD41- ILC2s were cultured with IL-2 and IL-33 to determine in vitro Type 2 (T2) cytokine production and cell proliferation. RNA-seq data of flow-cytometry-sorted CD41+ and CD41- ILC2s were used to isolate ILC2-specific genes. Flow cytometry was performed to determine the expression of CD41 and adhesion-related molecules on ILC2s in both mouse and human tissues. RESULTS: T2 inflammation and T2 cytokine production from ILC2s were significantly reduced in the c-mpl-/- mice compared to wild-type mice. Platelet-adherent ILC2s underwent significant proliferation and showed enhanced T2 cytokine production when exposed to IL-2 and IL-33. The functions of ILC2-specific genes were related to cell development and function. Upstream regulator analysis identified 15 molecules, that are thought to be involved in ILC2 activation. CD41 expression levels were higher in ILC2s from human PBMCs and mouse lung than in those from secondary lymphoid tissues, but they did not correlate with the P-selectin glycoprotein ligand-1 or CD24 expression level. CONCLUSION: Platelets spontaneously adhere to ILC2s, probably in the peripheral blood and airways, thereby potentiating ILC2s to enhance their responses to IL-33.

Assessment of appropriate body mass index cut-off points for long-term mortality among ST-elevation myocardial infarction survivors in Asian population using machine learning algorithm.

Low body mass index (BMI) is a predictor of adverse events in patients with ST-elevated myocardial infarction (STEMI) in Western countries. Because the average BMI of Asians is significantly lower than that of the Western population, the appropriate cut-off BMI value and its role in long-term mortality are unclear in Asian patients. Between January 2006 and December 2017, 1215 patients who underwent percutaneous coronary intervention (PCI) for acute STEMI and were alive at discharge (mean age, 67.7 years; male, 75.4%) were evaluated. The cut-off BMI value, which could predict all-cause mortality within 10 years, was detected using a survival classification and regression tree (CART) model. The causes of death according to the BMI value were evaluated in each group. Based on the CART model, the patients were divided into three groups (BMI < 18 kg/m2: 54 patients, 18 kg/m2 ≤ BMI ≤ 20 kg/m2: 109 patients, and BMI > 20 kg/m2: 1052 patients). The BMI decreased with age; with an increased BMI, patients with dyslipidemia, diabetes mellitus, and smoking habit increased. During the study period (median, 4.9 years), 194 patients (26.8%) died (cardiac death, 59 patients; non-cardiac death, 135 patients). All-cause mortality was more frequent as the BMI decreased (BMI < 18 kg/m2; 72.8%, 18 kg/m2 ≤ BMI ≤ 20 kg/m2; 40.5%, and BMI > 20 kg/m2; 22.8%; log-rank p < 0.001). Non-cardiac deaths were more frequent than cardiac deaths in all groups, and the dominance of non-cardiac death was highest in the lowest BMI group. Cut-off BMI values of 18 kg/m2 and 20 kg/m2 can predict long-term mortality after PCI in Asian STEMI survivors, whose cut-off value is lower than that in the Western populations. The main causes of death in this cohort differed according to the BMI values.

Eating behaviour characteristics and dietary intake among Japanese junior high school students: A cross-sectional study.

BACKGROUND: Psychological characteristics of eating behaviour may be related to dietary habits. AIM: We investigated the association between eating behaviour characteristics and nutrition and food intake adequacy in Japanese adolescents. METHODS: This cross-sectional survey was conducted among 136 junior high school students (boys: 90, girls: 46) at a junior high school in Tokyo, Japan. Eating behaviour was categorised into three types (emotional, external, and restrained) using scores on the Japanese version of the Dutch Eating Behaviour Questionnaire. Dietary intake was assessed using a validated, brief self-administered diet history questionnaire. Inadequate nutrient intake was determined by counting the number of nutrients not meeting the dietary reference intake (DRI) for the Japanese population. The statistical analyses included Wilcoxon signed-rank tests, Spearman's rank correlation coefficient, and multiple regression analysis using JMP ver.14 (SAS Institute Inc., Cary, NC, USA). All reported p values are two-tailed, and p < 0.05 was regarded as statistically significant. RESULTS: Multiple regression analysis showed that restrained eating score was inversely associated with the number of nutrients not meeting the DRI (ß = - 0.28; p = 0.0027) and with total weight of snack intake (ß = - 0.30; p = 0.0010). Neither emotional nor external eating was significantly associated with the number of nutrients not meeting the DRI and with total weight of snack intake. CONCLUSIONS: These results suggest that adolescents with low restrained eating scores may have less self-control over their eating behaviour and may therefore have inadequate dietary intake.

Pathophysiology and Treatment of Diabetic Cardiomyopathy and Heart Failure in Patients with Diabetes Mellitus.

There is a close relationship between diabetes mellitus and heart failure, and diabetes is an independent risk factor for heart failure. Diabetes and heart failure are linked by not only the complication of ischemic heart disease, but also by metabolic disorders such as glucose toxicity and lipotoxicity based on insulin resistance. Cardiac dysfunction in the absence of coronary artery disease, hypertension, and valvular disease is called diabetic cardiomyopathy. Diabetes-induced hyperglycemia and hyperinsulinemia lead to capillary damage, myocardial fibrosis, and myocardial hypertrophy with mitochondrial dysfunction. Lipotoxicity with extensive fat deposits or lipid droplets is observed on cardiomyocytes. Furthermore, increased oxidative stress and inflammation cause cardiac fibrosis and hypertrophy. Treatment with a sodium glucose cotransporter 2 (SGLT2) inhibitor is currently one of the most effective treatments for heart failure associated with diabetes. However, an effective treatment for lipotoxicity of the myocardium has not yet been established, and the establishment of an effective treatment is needed in the future. This review provides an overview of heart failure in diabetic patients for the clinical practice of clinicians.

A nutritional intervention that promotes increased vegetable intake in Japanese with non-alcoholic fatty liver disease: a six-month trial.

The aim of this study was to investigate whether a nutritional intervention motivating increased vegetable consumption would be an effective treatment and diet therapy for patients with non-alcoholic fatty liver disease. We examined 15 patients with this disease (5 men and 10 women). During the 6-month intervention period, all participants received a small amount of vegetables twice a month as a nutritional education tool aimed at increasing vegetable consumption. They also received nutritional counseling and underwent ultrasound and blood biochemical examinations at baseline and 3 and 6 months after initiation of the intervention. Moreover, they were requested to submit dietary records for any 2 days. Green, white, and total vegetable intakes were significantly higher at 3 and 6 months than at baseline in 8 patients. These patients had significantly lower alanine amino-transferase and triglyceride concentrations than those whose vegetable intake did not increase. Additionally, green vegetable intake significantly negatively correlated with weight at 3 and 6 months (r = -0.617, p = 0.032 and r = -0.848, p = 0.008, respectively). These results suggest that our nutritional approach effectively increased vegetable consumption in at least some patients with non-alcoholic fatty liver disease, consequently improving their condition.

[Usefulness of Mohs Paste Against Breast Cancer with Skin Invasion].

We report with the addition of literature because we have experienced 3 cases of locally advanced breast cancer with skin invasion that have alleviated symptoms and improved quality of life by using Mohs paste. In Case 1, Mohs paste reduced exposed tumors, exudation, and bleeding. In Case 2, bleeding, which had been the cause of the marked anemia, was controlled, and tumor shrinkage and epithelialization were observed. Case 3 had a poor prognosis due to systemic metastasis, but the QOL improved for a certain period of time as exudation, bleeding, and foul odor were controlled. From the viewpoint of palliative care, Mohs paste is a safe and effective treatment method against various symptoms such as large amounts of exudation, bleeding, and foul odor caused by breast cancer skin invasion, and depending on the case, prognosis can be expected to be extended by shrinking the tumor. The cooperation of not only doctors but also palliative care teams including pharmacists and nurses is essential for use.

Myocardial salvage after ST-segment-elevation myocardial infarction: comparison between prasugrel and clopidogrel in the presence or absence of high-residual platelet reactivity.

BACKGROUND: The effect of prasugrel over clopidogrel on myocardial salvage in ST-segment-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (p-PCI) is not fully elucidated. METHODS: Among 854 consecutive STEMI patients who underwent p-PCI, 446 patients were evaluated by two-phase (7 days and 3 months) single-photo emission computed tomography (SPECT). Patients were divided into two groups based on the loading P2Y12 inhibitor. The clopidogrel group was further divided based on the result of platelet function testing. Thus, the prasugrel group included 227 patients; the clopidogrel without high-residual platelet reactivity (HRPR) group, 109 patients; and the clopidogrel with HRPR group, 107 patients. The primary endpoint was the Myocardial Salvage Index (MSI), determined by SPECT. RESULTS: The incidence of final TIMI 0/1 and TIMI myocardial perfusion grade 0/1 was higher in the clopidogrel with HRPR group (0.9%, 1.8%, and 7.5%, P =  .002; 19.8%, 29.4%, and 41.1%, P = .0002, in the prasugrel, clopidogrel without HRPR, and clopidogrel with HRPR groups, respectively). The MSI was significantly lower in the clopidogrel with HRPR group (48% [27-66], 44% [30-72], and 36% [15-55], P =  .006, respectively). CONCLUSIONS: Prasugrel in STEMI patients was associated with an increased MSI compared with clopidogrel in the presence of HRPR.

Impact of the use of hydroxyethyl starch in granulocyte apheresis using Spectra Optia.

OBJECTIVES: To determine the impact of the use of hydroxyethyl starch (HES) in granulocyte apheresis using Spectra Optia. BACKGROUND: Granulocyte transfusion (GT) is a therapeutic option for neutropenic patients with severe bacterial or fungal infections. Recent studies in emergency medicine have shown the potential risk of using HES, which is routinely used in granulocyte apheresis to increase yield by sedimenting red blood cells. We hypothesized that the use of a newer device (Spectra Optia) would spare the need for HES. METHODS: We retrospectively compared granulocyte apheresis with HES (HES group, n = 89) and without HES (non-HES group, n = 36) using Spectra Optia. RESULTS: The granulocyte yield was significantly higher in the HES group (7.3 × 1010 vs. 2.0 × 10, p < 0.01) and was attributed to the difference in collection efficiency (36% vs. 7.7%, p < 0.01). The absolute neutrophil count on the following morning of GT was significantly higher in the HES group than in the non-HES group (2460/µl vs. 505/µl, p < 0.01). There were no significant differences in the occurrence of adverse events between the HES and non-HES groups. The renal function was unchanged in both groups after apheresis. CONCLUSIONS: We demonstrated that the advantage of using HES remained unchanged in granulocyte apheresis using Spectra Optia.

Electron Microscopy Revealed Massive Lipid Droplets in Cardiomyocytes in a Patient with Cardiogenic Shock Following a Fulminant Type 1 Diabetes Mellitus.

A 52-year-old man with consciousness disorder following a 2-day history of general fatigue, diarrhea, vomiting and excessive thirst was admitted to our hospital. Severe hyperglycemia (1,739 mg/dL) with a slightly elevated HbA1c level (6.9%), ketonuria and low C-peptide level (0.07 ng/mL) confirmed the diagnosis of fulminant type 1 diabetes mellitus (FT1DM). Following sudden unexplained cardiogenic shock shortly after the initiation of insulin therapy with no evidence of myocardial ischemia assessed by coronary angiography, the patient was supported with percutaneous venoarterial extracorporeal membrane oxygenation. Electron microscopic analysis of the myocardium revealed massive lipid droplets without the infiltration of inflammatory cells. His left ventricular function began to recover during the following days and returned to a normal level on day 14. Currently, the impact of FT1DM on intramyocardial lipid deposition is poorly understood. However, this case suggests that even short-term exposure to high concentrations of glucose can be responsible for lipotoxicity followed by severe cardiac dysfunction.

[Clinical experience of leukapheresis for CD19 CAR-T cell therapy].

To perform chimeric antigen receptor T (CAR-T) cell therapy in heavily pretreated patients with progressive disease and depleted lymphocytes, an optimized leukapheresis protocol must be established. To probe the effects of patient-related parameters on the collection efficiency of CD3+ cells, we retrospectively analyzed patients with relapsed/refractory diffuse large B-cell lymphoma who underwent leukapheresis for tisagenlecleucel at two centers. A total of 51 patients were analyzed, with a median age at apheresis of 59 years, and precollection hemoglobin levels, CD3+ cell counts, and platelet counts of 9.2 g/dl, 574/µl, and 15.8×104/µl, respectively. A median of 3.0×109 (0.7-8.4) CD3+ cells were harvested with 8.7 (4.0-15.7) l apheresis volume. The collection efficiency 2 (CE2) for CD3+ cells was 61.0% (21.0-127.3). One-day apheresis was sufficient to obtain the designated cell numbers in all cases. Lower hemoglobin levels, higher CD3+ cell counts, and higher platelet counts before apheresis were significantly associated with lower CE2 for CD3+ cells. These results suggest a need to increase the apheresis volume in anemic, lymphocyte- or platelet-rich patients due to an expected low CE2. Erythrocyte transfusions before or during apheresis may be a reasonable option for patients with anemia.

Muscle quality characteristics of muscles in the thigh, upper arm and lower back in elderly men and women.

PURPOSE: The ratio of fat within skeletal muscle is an important parameter that is indicative of muscle quality, and can be assessed using ultrasonography to measure echo intensity (EI). Muscle EI indicates muscle strength and risk of physical dysfunction; however, this observation was determined following examinations of only selected muscle. The purpose of this study was to investigate the EI characteristics of muscles in several regions in elderly men and women, using physical function tests and serum cholesterol levels. METHODS: Twenty-two men and women (age 78 ± 8 years) participated in this study. The EIs were calculated from rectus femoris (RF), biceps femoris (BF) triceps brachii (TB) and multifidus (MF) using B-mode transverse ultrasound images. Seven functional tests (isometric knee-extension peak torque, functional reach, sit-to-stand, 5-m normal/maximal speed walking, handgrip strength and timed up-and-go) and blood lipid components including adipocytokines were measured in all participants. RESULTS: A statistically significant correlation between EI of the RF, TB and BF was observed (r = 0.46-0.50, P < 0.05), but not between EI of the MF and that of other muscles. EI of muscles of the limbs, which was averaged EI for RF, TB and BF, was negatively correlated with leptin levels (adjusted R2 = 0.27, P < 0.01), and EI of the MF was correlated with muscle mass and performance in the timed up-and-go test (adjusted R2 = 0.61, P < 0.01). CONCLUSION: These results suggest that EI might be influenced by specific parameters depending on the location of the muscle.

HCN4-Overexpressing Mouse Embryonic Stem Cell-Derived Cardiomyocytes Generate a New Rapid Rhythm in Rats with Bradycardia.

A biological pacemaker is expected to solve the persisting problems of an artificial cardiac pacemaker including short battery life, lead breaks, infection, and electromagnetic interference. We previously reported HCN4 overexpression enhances pacemaking ability of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) in vitro. However, the effect of these cells on bradycardia in vivo has remained unclear. Therefore, we transplanted HCN4-overexpressing mESC-CMs into bradycardia model animals and investigated whether they could function as a biological pacemaker. The rabbit Hcn4 gene was transfected into mouse embryonic stem cells and induced HCN4-overexpressing mESC-CMs. Non-cardiomyocytes were removed under serum/glucose-free and lactate-supplemented conditions. Cardiac balls containing 5 × 103 mESC-CMs were made by using the hanging drop method. One hundred cardiac balls were injected into the left ventricular free wall of complete atrioventricular block (CAVB) model rats. Heart beats were evaluated using an implantable telemetry system 7 to 30 days after cell transplantation. The result showed that ectopic ventricular beats that were faster than the intrinsic escape rhythm were often observed in CAVB model rats transplanted with HCN4-overexpressing mESC-CMs. On the other hand, the rats transplanted with non-overexpressing mESC-CMs showed sporadic single premature ventricular contraction but not sustained ectopic ventricular rhythms. These results indicated that HCN4-overexpressing mESC-CMs produce rapid ectopic ventricular rhythms as a biological pacemaker.

Comparisons of dietary intake in Japanese with non-alcoholic fatty liver disease and type 2 diabetes mellitus.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease that involves a complex interaction between genetics, diet, and lifestyle, all of which combine to form the NAFLD phenotype. In Japan, medical nutrition therapy for NAFLD has not yet been established, so NAFLD patients are instructed in the dietary modifications used for type 2 diabetes mellitus (T2DM). Because points of difference may exist in the effects of dietary choices on NAFLD and T2DM, the present study aimed to compare and assess the dietary intake of Japanese individuals with NAFLD and T2DM. This cross-sectional study involved 219 patients (77 NAFLD subjects; 33 males, 44 females; 142 T2DM subjects: 76 males, 66 females) aged 40-79 years. Dietary intake was assessed using a validated self-administered diet history questionnaire. Among the results, the most notable in NAFLD patients relative to T2DM patients were: 1) the low intake of vegetables that can reduce the overall energy density; 2) the high consumption of fruits and confectionery containing simple carbohydrates such as fructose; and 3) BMI may be higher. We demonstrated differences in dietary selection between the two groups. NAFLD patients were more likely to have dietary habits that promote fat accumulation in the body.

Isolation of Japanese encephalitis virus and a novel insect-specific flavivirus from mosquitoes collected in a cowshed in Japan.

Cattle do not generally appear to develop severe viremia when infected with Japanese encephalitis virus (JEV), and they can be infected without showing clinical signs. However, two cattle in Japan recently died from JEV infection. In this study, we investigated the presence of different species of mosquitoes and flavivirus in a cowshed in the southwest region of Japan. In this cowshed, the two most common species of mosquitoes collected were Culex tritaeniorhynchus (including Culex pseudovishnui) and Anopheles sinensis. We performed virus isolation from the collected mosquitoes and obtained two flaviviruses: JEV and a novel insect-specific flavivirus, tentatively designated Yamadai flavivirus (YDFV). Phylogenetic analysis revealed that all three JEV isolates belonged to JEV genotype I and were closely related to a JEV strain that was isolated from the brains of cattle exhibiting neurological symptoms in Japan. Genetic characterization of YDFV revealed that the full genome RNA (10,863 nucleotides) showed homology with the Culex-associated insect-specific flaviviruses Quang Binh virus (79% identity) and Yunnan Culex flavivirus (78% identity), indicating that YDFV is a novel insect-specific flavivirus.

pH-responsive fluorescence chemical sensor constituted by conjugated polymers containing pyridine rings.

Poly(p-pyridinium phenylene ethynylene)s (PPyPE) functionalized with alternating donor-acceptor repeat units were synthesized by a Pd-catalyzed Sonogashira coupling reaction between diethynyl monomer and di-iodopyridine for use as a pH-responsive fluorescence chemical sensor. The synthesized PPyPE, containing pyridine units, was characterized by FT-IR, (1)H and (13)C NMR, UV-visible and fluorescence spectroscopies. We investigated the relationship between changes of optical properties and protonation/deprotonation of PPyPE containing pyridine units in solution. Addition of HCl decreased and red-shifted the fluorescence intensity of the conjugated polymers that contained pyridine rings; fluorescence intensity of the polymers increased upon addition of NaOH solution. The synthesized PPyPE was found to be an effective and reusable chemical sensor for pH sensing.

Effect of vildagliptin, a dipeptidyl peptidase 4 inhibitor, on cardiac hypertrophy induced by chronic beta-adrenergic stimulation in rats.

BACKGROUND: Heart failure with left ventricular (LV) hypertrophy is often associated with insulin resistance and inflammation. Recent studies have shown that dipeptidyl peptidase 4 (DPP4) inhibitors improve glucose metabolism and inflammatory status. We therefore evaluated whether vildagliptin, a DPP4 inhibitor, prevents LV hypertrophy and improves diastolic function in isoproterenol-treated rats. METHODS: Male Wistar rats received vehicle (n = 20), subcutaneous isoproterenol (2.4 mg/kg/day, n = 20) (ISO), subcutaneous isoproterenol (2.4 mg/kg/day + oral vildagliptin (30 mg/kg/day, n = 20) (ISO-VL), or vehicle + oral vildagliptin (30 mg/kg/day, n = 20) (vehicle-VL) for 7 days. RESULTS: Blood pressure was similar among the four groups, whereas LV hypertrophy was significantly decreased in the ISO-VL group compared with the ISO group (heart weight/body weight, vehicle: 3.2 ± 0.40, ISO: 4.43 ± 0.39, ISO-VL: 4.14 ± 0.29, vehicle-VL: 3.16 ± 0.16, p < 0.05). Cardiac catheterization revealed that vildagliptin lowered the elevated LV end-diastolic pressure observed in the ISO group, but other parameters regarding LV diastolic function such as the decreased minimum dp/dt were not ameliorated in the ISO-VL group. Histological analysis showed that vildagliptin attenuated the increased cardiomyocyte hypertrophy and perivascular fibrosis, but it did not affect angiogenesis in cardiac tissue. In the ISO-VL group, quantitative PCR showed attenuation of increased mRNA expression of tumor necrosis factor-α, interleukin-6, insulin-like growth factor-l, and restoration of decreased mRNA expression of glucose transporter type 4. CONCLUSIONS: Vildagliptin may prevent LV hypertrophy caused by continuous exposure to isoproterenol in rats.

Differential association of visceral adipose tissue with coronary plaque characteristics in patients with and without diabetes mellitus.

BACKGROUND: Excess visceral adipose tissue (VAT) is closely associated with the presence of coronary artery plaques that are vulnerable to rupture. Patients with diabetes mellitus (DM) have more VAT than patients without DM, but the extent to which VAT contributes to the characteristics of coronary plaques before and after the development of DM is not fully understood. METHODS: We retrospectively evaluated 456 patients (60% male, age 64 ± 16 years) who were suspected to have cardiovascular disease and underwent 64-slice computed tomography angiography (CTA). Seventy-one (16%) patients had vulnerable plaques (CT density < 50 Hounsfield Units, positive remodeling index > 1.05, and adjacent spotty areas of calcification). RESULTS: Patients were divided into tertiles according to the VAT area. There were stepwise increases in noncalcified and vulnerable plaques with increasing tertiles of VAT area in patients without DM, but not in patients with DM. Multivariate analysis showed that a larger VAT area was significantly associated with a higher risk of vulnerable plaque in patients without DM (odds ratio 3.17, 95% confidence interval 1.08-9.31, p = 0.04), but not in patients with DM. CONCLUSIONS: The VAT area is associated with the characteristics of coronary plaques on CTA in patients without DM, but not in patients with DM. VAT may be a significant cardiometabolic risk factor that is associated with plaque vulnerability before the development of DM. CTA findings may help to improve risk stratification in such patients.

Associations between brain-derived neurotrophic factor and estradiol in women's saliva.

OBJECTIVE: The aim of this study was to assess the relationship between brain-derived neurotrophic factor (BDNF) and sex hormones (estradiol [E2] and progesterone), using saliva samples obtained from healthy women. METHODS: Forty female dental hygienist students were divided into groups according to being in the follicular phase or luteal phase. Saliva BDNF, E2, and progesterone levels were measured using a sandwich ELISA system. The correlation between these factors was analyzed using Spearman's index, and fluctuations of these levels in the whole menstrual cycle were investigated classifying the subjects by every 4 days according to the phase of their menstrual cycle. RESULTS: Saliva BDNF variations strongly correlated with saliva E2 levels in the follicular phase (r = 0.721, p = 0.000) and luteal phase (r = 0.770, p = 0.000). The correlation coefficient showing the relationship between progesterone and BDNF levels in the luteal phase (r = 0.371, p = 0.157) was lower than that in the follicular phase (r = 0.631, p = 0.001). Moreover, the fluctuation of BDNF levels in the menstrual cycle followed a similar pattern to that of E2. CONCLUSIONS: We found that saliva BDNF and E2 levels were closely related in healthy young women. In particular, for first time, that correlation was investigated throughout the menstrual cycle. Monitoring of saliva BDNF may yield insight into women's reproductive and mental health.