Fugacity model incorporating computational fluid dynamics for analyzing the behavior of an insecticide sprayed indoors.

Fugacity models are used widely to predict the time-dependent behaviors of chemicals in environments containing several media (e.g., air, sediment, soil, and water). However, these fugacity models work on the assumption that the concentration of a chemical in each medium is uniform, so they cannot describe the spatial distribution of the chemical. We developed a new fugacity model, termed InPestCFD, incorporating computational fluid dynamics to describe both the time-dependent distribution and the spatial distribution of a chemical in a medium. InPestCFD was used to calculate the behavior of an insecticide released from an aerosol canister in a room. Indoor airflow and aerosol particle behavior were calculated via computational fluid dynamics and using a Lagrangian dispersion model. Transport of the insecticide among media (aerosol particles, air, ceiling, floor, and walls) was calculated using the fugacity model. The time-dependent distributions and spatial distributions of the insecticide in the media agreed well with real measurements.

Utility of contrast-enhanced 3D STIR FLAIR imaging for evaluating pituitary adenomas at 3 Tesla.

Purpose: To assess the usefulness of contrast-enhanced 3D STIR FLAIR imaging for evaluation of pituitary adenomas. Methods: Patients with pituitary adenomas underwent MR examinations including contrast-enhanced 3D STIR FLAIR and 2D T1-weighted (T1W) imaging. We subjectively compared the two techniques in terms of 10 categories. In addition, images were rated by side-by-side comparisons into three outcomes: 3D STIR FLAIR imaging superior, equal, or 2D T1W imaging superior. Additionally, the added value of 3D STIR FLAIR imaging for adenoma detection over conventional MR imaging was assessed. Results: Twenty-one patients were included in this study. 3D STIR FLAIR imaging offered significantly better images than 2D T1W imaging in terms of three categories, including overall visualization of the cranial nerves in the cavernous sinus (mean 4.0 vs. 2.8, p < 0.0001), visualization of the optic nerves and chiasm (mean 4.0 vs. 2.6, p < 0.0001), and severity of susceptibility artifacts (mean 0.0 vs. 0.4, p = 0.004). In the side-by-side comparison, 3D STIR FLAIR imaging was judged to be significantly superior to 2D T1W imaging for overall lesion conspicuity (62% vs. 19%, p = 0.049) and border between the adenoma and the pituitary gland (67% vs. 19%, p = 0.031). The addition of 3D STIR FLAIR imaging significantly improved the adenoma detection of conventional MR imaging. Conclusion: 3D STIR FLAIR imaging improved overall lesion conspicuity compared to 2D T1W imaging. We suggest that 3D STIR FLAIR imaging is recommended as a supplemental technique when pituitary adenomas are invisible or equivocal on conventional imaging.

Clinical Efficacy of Pre-Hospital Electrocardiogram Transmission in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction.

Rapid reperfusion by primary percutaneous coronary intervention (pPCI) is an established strategy for the treatment of patients with ST-segment elevation myocardial infarction (STEMI). Pre-hospital electrocardiogram (PH-ECG) transmission by the emergency medical services (EMS) facilitates timely reperfusion in these patients. However, evidence regarding the clinical benefits of PH-ECG in individual hospitals is limited.This retrospective, observational study investigated the clinical efficacy of PH-ECG in STEMI patients who underwent pPCI. Of a total of 382 consecutive STEMI patients, 237 were enrolled in the study and divided into 2 groups: a PH-ECG group (n = 77) and non-PH-ECG group (n = 160). Door-to-balloon time (D2BT) was significantly shorter in the PH-ECG group (66 [52-80] min), compared to the non-PH-ECG group (70 [57-88] minutes, P = 0.01). The 30-day all-cause mortality rate was 6% in the PH-ECG group, which was significantly lower than that in the non-PH-ECG group (16%) (P = 0.037, hazard ratio [HR]: 0.38, 95% CI: 0.15-0.98). This trend was particularly evident in severely ill patients when stratified by GRACE score.The use of PH-ECG improved the survival rate of STEMI patients undergoing pPCI due to the improved pre-arrival preparation based on the EMS information. Coordination between EMS and PCI-capable institutes is essential for the management of PH-ECG.

ACTH-independent Cushing's syndrome due to ectopic endocrinologically functional adrenal tissue caused by a GNAS heterozygous mutation: a rare case of McCune-Albright syndrome accompanied by central amenorrhea and hypothyroidism: a case report and literature review.

In a small number of cases, the development of ectopic residual adrenal lesions during embryogenesis causing Cushing's syndrome due to the production of excess cortisol has been reported. A 29-year-old woman was admitted to our hospital for fatigue and recent amenorrhea. Her plasma ACTH was <1.5 pg/mL, and her serum cortisol was 21.4 pg/mL after the 8 mg dexamethasone suppression test, revealing the presence of ACTH-independent Cushing's syndrome; however, her bilateral adrenal glands were atrophied. Abdominal CT revealed a 40-mm round tumor on the right renal hilum and remarkably accumulated 131I-labelled adosterol. CT and bone scintigraphy showed that 99mTc-methylene diphosphonate had accumulated in her dissymmetric skull at the right-frontoparietal region. The tumor on the right renal hilum was laparoscopically removed. Her cortisol levels rapidly decreased to below the normal range, and glucocorticoids were administered to rescue adrenal insufficiency. The resected tumor was yellowish in appearance and 4.5×3.0×2.8 cm in size. Immunohistochemical staining for SF-1, P450scc, CYP17A, CYP21A, and CYP11B1 indicated that this tumor produced cortisol. Exome sequencing analysis revealed that the GNAS heterozygous mutation (c.601C>T, p. Arg201Cys; accession number, NM_000516.5) was found in approximately 20% of the adrenal tumor sample. A mutation of GNAS, encoding the Gsα subunit that mediates GPCR signaling, causes the constitutive activation of adenylyl cyclase, resulting in hypersecretion of hormones regulated by the GPCR. GNAS mutation is one of the major genetic causes of cortisol-producing adrenal tumors independent of ACTH secretion. Considering the combination of GNAS mutation with one of the typical clinical triad characteristics, fibrous dysplasia of bone, we diagnosed this patient with McCune-Albright syndrome accompanied by ACTH-independent Cushing's syndrome caused by an ectopic residual adrenal tumor due to GNAS mutation. This case highlights that GNAS involves a previously unknown pathological mechanism in which inhibition of the natural elimination of remnant tissue leads to ectopic endocrine hypersecretion.

Contrast Enhancement of the Normal Infundibular Recess Using Heavily T2-weighted 3D FLAIR.

PURPOSE: The purpose of the present study was to evaluate contrast enhancement of the infundibular recess in the normal state using heavily T2-weighted 3D fluid-attenuated inversion recovery (FLAIR) (HT2-FLAIR). METHODS: Twenty-six patients were retrospectively recruited. We subjectively assessed overall contrast enhancement of the infundibular recess between postcontrast, 4-hour (4-h) delayed postcontrast, and precontrast HT2-FLAIR images. We also objectively conducted chronological and spatial comparisons by measuring the signal intensity (SI) ratio (SIR). Chronological comparisons were performed by comparing SI of the infundibular recess/SI of the midbrain (SIRIR-MB). Spatial comparisons were conducted by comparing SI on postcontrast HT2-FLAIR/SI on precontrast HT2-FLAIR (SIRPost-Pre) of the infundibular recess with that of other cerebrospinal fluid (CSF) spaces, including the superior part of the third ventricle, lateral ventricles, fourth ventricle, and interpeduncular cistern. RESULTS: In the subjective analysis, all cases showed contrast enhancement of the infundibular recess on both postcontrast and 4-h delayed postcontrast HT2-FLAIR, and showed weaker contrast enhancement of the infundibular recess on 4-h delayed postcontrast HT2-FLAIR than on postcontrast HT2-FLAIR. In the objective analysis, SIRIR-MB was the highest on postcontrast images, followed by 4-h delayed postcontrast images. SIRPost-Pre was significantly higher in the infundibular recess than in the other CSF spaces. CONCLUSION: The present results demonstrated that the infundibular recess was enhanced on HT2-FLAIR after an intravenous gadolinium injection. The infundibular recess may be a potential source of the leakage of intravenously administered gadolinium into the CSF.

Thyroid crisis caused by metastatic thyroid cancer: an autopsy case report.

BACKGROUND: Thyroid crisis is a life-threatening condition in thyrotoxic patients. Although differentiated thyroid cancer is one of the causes of hyperthyroidism, reports on thyroid crisis caused by thyroid cancer are quite limited. Here, we describe a case of thyroid crisis caused by metastatic thyroid cancer. CASE PRESENTATION: A 91-year-old woman was admitted to our hospital because of loss of appetite. Two years prior to this hospitalization, she presented with subclinical thyrotoxicosis and was diagnosed with histologically unidentified thyroid cancer with multiple metastases, and she refused aggressive medical interventions. On admission, she exhibited extreme thyrotoxicosis, and the presence of fever, severe tachycardia, impaired consciousness, and heart failure revealed the presence of thyroid crisis. All thyroid autoantibodies were negative. Multidisciplinary conservative treatment was initiated; however, she died on the fifth day after admission. Autopsy revealed the presence of primary anaplastic thyroid carcinoma and multiple metastatic foci arising from follicular thyroid carcinoma. Both primary and metastatic follicular thyroid carcinoma likely induced thyrotoxicosis, which could have been exacerbated by anaplastic thyroid carcinoma. CONCLUSIONS: Even though the trigger of thyroid crisis in this patient is not clear, the aggravated progression of her clinical course suggests that careful monitoring of thyroid hormones and appropriate intervention are essential for patients with thyroid cancer.

Signal and morphological changes in the endolymph of patients with vestibular schwannoma on non-contrast 3D FLAIR at 3 Tesla.

BACKGROUND: Non-contrast FLAIR revealed increased signal within the inner ear in patients with vestibular schwannoma, which is generally assumed to occur in the perilymph; however, the majority of previous studies did not differentiate between the endolymph and perilymph. Therefore, endolymph signal changes have not yet been investigated in detail. The purpose of the present study was three-fold: (1) to assess perilymph signal changes in patients with vestibular schwannoma on heavily T2-weighted (T2W) 3D FLAIR, also termed positive perilymphatic images (PPI), (2) to evaluate signal and morphological changes in the endolymph on PPI, and (3) to establish whether vertigo correlates with the signal intensity ratios (SIR) of the vestibular perilymph or vestibular endolymphatic hydrops. METHODS: Forty-two patients with unilateral vestibular schwannoma were retrospectively recruited. We semi-quantitatively and qualitatively evaluated the perilymph signal intensity on the affected and unaffected sides. We also quantitatively examined the signal intensity of the vestibular perilymph and assessed the relationship between vertigo and the SIR of the vestibular perilymph on the affected side. We semi-quantitatively or qualitatively evaluated the endolymph, and investigated whether vestibular hydrops correlated with vertigo. RESULTS: The perilymph on the affected side showed abnormal signal more frequently (signal intensity grade: overall mean 1.45 vs. 0.02; comparison of signal intensity: overall mean 36 vs. 0 cases) and in more parts (the entire inner ear vs. the basal turn of the cochlea and vestibule) than that on the unaffected side. No significant difference was observed in the SIR of the vestibular perilymph with and without vertigo (5.54 vs. 5.51, p = 0.18). The endolymph of the vestibule and semicircular canals showed the following characteristic features: no visualization (n = 4), signal change (n = 1), or vestibular hydrops (n = 10). A correlation was not observed between vestibular hydrops and vertigo (p = 1.000). CONCLUSIONS: PPI may provide useful information on signal and morphological changes in the endolymph of patients with vestibular schwannoma. Further research is warranted to clarify the relationship between vertigo and the MR features of the inner ear.

A case of insulin-like growth factor 2-producing gastrointestinal stromal tumor with severe hypoglycemia.

BACKGROUND: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome that secretes incompletely processed high molecular weight insulin growth factor 2 (big-IGF2), which results in stimulation of the insulin receptor and subsequently induces hypoglycemia. Gastrointestinal stromal tumor (GIST) is a common intestinal mesenchymal neoplasm of the gastrointestinal tract. The most frequent site of GIST is the stomach; NICTH induced by IGF2-producing stomach GISTs is rare. CASE PRESENTATION: An 84-year-old man was admitted to the hospital due to impaired consciousness (JCS II-10) in the morning. At the time of admission, his serum glucose was 44 mg/dL; his consciousness was restored with 20 ml of 50% glucose. To avoid hypoglycemia, a continuous intravenous infusion of glucose as well as dietary intervention was required. At the time of hypoglycemia, the levels of insulin and C-peptide were suppressed. Additionally, IGF1 levels were below the normal range. Abdominal computed tomography revealed that he had a large lobulated mass (116 × 70 × 72 mm) around the gastric corpus. Pathological analysis of biopsy specimens identified disarray of spindle cells and positivity for c-kit as well as strong positivity for DOG-1. Further analysis revealed high levels of Ki-67 (Mib-1 index: 15.5%) and mitotic index (7/50HPF); the tumor was diagnosed as high-risk GIST, and complete surgical resection was performed. Hypoglycemia resolved immediately after tumor resection. The resected tumor specimen was positive for IGF2 staining, and big-IGF2 (11-18 kDa) was detected in preoperative serum and tumor samples; the patient was diagnosed with NICTH due to an IGF2-producing tumor. CONCLUSIONS: NICTH is rare in GIST of the stomach; however, the large GIST could produce big-IGF2 and subsequently cause severe hypoglycemia, requiring prompt evaluation and complete tumor resection.

Lymphatic Vessel Thrombosis in a Patient with Secondary Lymphedema.

Lymphatic thrombosis is rarer than venous thrombosis. This case report describes a patient with secondary lymphedema, who was found to have lymphatic thrombosis during lymphaticovenous anastomosis (LVA). A 51-year-old woman underwent hysterectomy and pelvic lymph node dissection for uterine cancer when she was 48 years old, and lymphedema developed in the left leg soon after the operation. She was diagnosed with lymphedema based on lymphoscintigraphic finding. Preoperative echography showed 2 hypoechoic circles measuring about 0.5 mm in diameter that did not collapse with pressure from the probe, although the veins collapsed with pressure. We diagnosed the 2 hypoechoic circles as lymphatic vessels based on the location and longitudinal continuity. During LVA, we identified 2 parallel white vessels beneath the superficial fascia. After they were cut, white material was extruded. A diagnosis of lymphatic thrombosis was made, and we ligated the lymphatic vessels, closed the wound at this site, and performed LVA at other sites (4 sites in the left and 1 site in the right leg). The postoperative course was uneventful. Histopathological examination showed hyperplasty of fibroblasts and organization in the thrombus. Lymphatic thrombosis is sometimes found in the lymphedema-affected extremities. On retrospective consideration, lymphatic thrombosis can be detected with preoperative echography.

Successful reduction of ACTH secretion in a case of intractable Cushing's disease with pituitary Crooke's cell adenoma by combined modality therapy including temozolomide.

Crooke's cell adenoma (CCA) is an aggressive subtype of corticotroph adenoma; however, CCA is associated with a high incidence of low expression of methyl guanine methyl transferase (MGMT), suggesting that temozolomide (TMZ) treatment might be effective for this tumor type. The case of a 56-year-old woman with Cushing's disease caused by a pituitary CCA is presented. At the age of 38 years, the patient presented to our hospital with polyuria and a visual field defect. MRI and laboratory studies showed a 4.5-cm-diameter pituitary tumor with plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels of more than 500 pg/mL and 40 µg/dL, respectively. At 39 years of age, the patient underwent a craniotomy, and her plasma ACTH and cortisol levels decreased to less than 200 pg/mL and 10 µg/dL, respectively; however, these hormone levels increased gradually to 3,940 pg/mL and 70 µg/dL, respectively, by the time the patient was 56 years old. Histopathological re-examination of the previously resected specimen showed that the pituitary tumor was MGMT-negative CCA. TMZ treatment after the second operation decreased the plasma ACTH levels from 600-800 pg/mL to 70-300 pg/mL. No signs of recurrence were observed in the seven years following these treatments with added prophylactic radiation therapy. These clinical findings suggest that TMZ treatment to patients with CCA accompanied with elevated ACTH may be good indication to induce lowering ACTH levels and tumor shrinkage.

Insulin-Like Growth Factor-I Protects Against the Detrimental Effects of Advanced Glycation End Products and High Glucose in Myoblastic C2C12 Cells.

Previous studies suggested that advanced glycation end products (AGEs) and insulin-like growth factor-I (IGF-I) are involved in the mechanism of diabetes-induced sarcopenia. In this study, we examined effects of treatments with AGEs and/or IGF-I for 24 h on myogenic differentiation and apoptosis in mouse myoblastic C2C12 cells. Real-time PCR and Western blot were performed to investigate mRNA and protein expressions, and apoptosis was examined by using a DNA fragment detection ELISA kit. AGE3 significantly decreased mRNA and protein expressions of MyoD and Myogenin, whereas IGF-I significantly increased them and attenuated the effects of AGE3. AGEs significantly decreased endogenous IGF-I mRNA expression and suppressed IGF-I-induced Akt activation. High glucose (22 mM) significantly increased mRNA expression of Rage, a receptor for AGEs, while IGF-I significantly decreased it. DNA fragment ELISA showed that AGE2 and AGE3 significantly increased apoptosis of C2C12 cells, whereas IGF-I significantly suppressed the AGE2- and AGE3-induced apoptosis. In contrast, high glucose enhanced AGE3-induced apoptosis. IGF-I significantly attenuated the effects of high glucose plus AGE3 on the mRNA and protein expressions of MyoD and Myogenin as well as the apoptosis. These findings indicate that AGEs inhibit myogenic differentiation and increase apoptosis in C2C12 cells, and that high glucose increases RAGE and enhances the AGE3-induced apoptosis, suggesting that AGEs and high glucose might contribute to the reduction of muscle mass and function. Moreover, IGF-I attenuated the detrimental effects of AGEs and high glucose in myoblastic cells; thus, IGF-I-Akt signal could be a therapeutic target of DM-induced sarcopenia.

Late-onset isolated adrenocorticotropic hormone deficiency caused by nivolumab: a case report.

BACKGROUND: Immune checkpoint inhibitors including nivolumab, an anti-programmed cell death protein 1 antibody, are recently developed cancer immunotherapy agents. Immune checkpoint inhibitors are known to cause autoimmune-related side effects including endocrine dysfunctions. However, there are few reports on late-onset isolated adrenocorticotropic hormone (ACTH) deficiency caused by nivolumab. CASE PRESENTATION: The patient was a 72-year-old female. When she was 64 years old, she was diagnosed with malignant melanoma of the left thigh accompanied by left inguinal lymph node metastases, and she received several courses of chemotherapy for malignant melanoma followed by the resection of these lesions. At 71 years of age, multiple metastases were found and treatment with nivolumab 2 mg/kg every 3 weeks was initiated. Six months later, replacement with levothyroxine was started because of hypothyroidism following mild transient thyrotoxicosis. Eleven months after the beginning of nivolumab, the treatment was discontinued because of tumor expansion. Four months after the discontinuation of nivolumab, general malaise and appetite loss worsened, and 2 months later, hyponatremia (Na; 120-127 mEq/L) and hypoglycemia (fasting plasma glucose; 62 mg/dL) appeared. Her ACTH and cortisol levels were extremely low (ACTH; 9.6 pg/mL, cortisol; undetectable). Challenge tests for anterior pituitary hormones showed that responses of ACTH and cortisol secretion to corticotropin-releasing hormone were disappeared, although responses of other anterior pituitary hormones were preserved. Thus, she was diagnosed with isolated ACTH deficiency. Her symptoms were improved after treatment with hydrocortisone. CONCLUSIONS: The present report showed a case of late-onset isolated ACTH deficiency accompanied by hyponatremia, which was diagnosed 6 months after the discontinuation of nivolumab. The effects of nivolumab last for a long time and the side effects of nivolumab can also appear several months after discontinuation of the drug. Repeated monitoring of serum sodium levels may be a beneficial strategy to find the unexpected development of adrenal insufficiency even after discontinuation of nivolumab.

Nerve conduction velocity is negatively associated with intima-media thickness and brachial-ankle pulse wave velocity in men with type 2 diabetes mellitus.

OBJECTIVE: Previous studies suggest that the presence of diabetic peripheral polyneuropathy (DPN) is associated with atherosclerotic diseases; however, little is known about the relationship between diabetic nerve conduction velocity (NCV) versus arterial stiffness and atherosclerosis parameters. METHODS: The subjects in this study were 292 men with type 2 diabetes mellitus (T2DM). All subjects underwent NCV examination at median and tibial nerves as motor nerve (MCV) as well as median and sural nerves as sensory nerve (SCV). Brachial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (IMT) were evaluated as arterial stiffness and atherosclerosis parameters. RESULTS: Pearson's correlation coefficient showed that NCV at all sites negatively correlated with baPWV, maximal and mean IMT (IMT-Max and IMT-Mean), and plaque score (all p values p<0.01 at least). Multiple regression analyses adjusted for confounding factors such as age, duration of diabetes, body mass index, HbA1c, fasting C-peptide, systolic blood pressure, HDL-cholesterol, LDL-cholesterol and albuminuria showed that the association of NCV with IMT-Max, ITM-Mean, and plaque score remained significant (all p values p<0.05 at least) except that between SCV at median and IMT-Max. Moreover, SCV at median (forearm) and sural were significantly associated with baPWV (p = 0.023 and p = 0.027, respectively). CONCLUSION: The present study showed that DPN estimated by quantitative NCV is linearly associated with the deterioration of arterial stiffness and atherosclerosis parameters in T2DM independently of various diabetic and atherosclerotic factors.

Visceral fat accumulation is associated with increased plasma sphingosine-1-phosphate levels in type 2 diabetes mellitus.

OBJECTIVE: Accumulating evidence has shown that sphingosine-1-phosphate (S1P) plays roles in glucose and fat metabolism. However, the association between plasma S1P levels and fat mass, especially visceral fat mass, remains unknown. METHODS: In this cross-sectional study, 80 men with type 2 diabetes mellitus (T2DM) were recruited to investigate the association of plasma S1P levels with body fat parameters. Visceral (VFA) and subcutaneous fat (SFA) areas were evaluated by performing computed tomography scan, and fat mass (FM) and lean body mass (LBM) were examined by whole body dual-energy X-ray absorptiometry. RESULTS: Multiple regression analysis adjusted for age, T2DM duration, serum creatinine, and body mass index (BMI) showed that S1P was significantly and positively associated with fasting plasma glucose (ß = 0.25, p = 0.027), HbA1c (ß = 0.28, p = 0.012), and urine C-peptide (ß = 0.29, p = 0.014). Moreover, multiple regression analysis adjusted for age, T2DM duration, serum creatinine, HbA1c, and urine C-peptide showed that BMI (ß = 0.32, p = 0.008), VFA (ß = 0.33, p = 0.008), SFA (ß = 0.26, p = 0.039), FM (ß = 0.37, p = 0.003), and LBM (ß = 0.35, p = 0.01). FM was significantly and positively associated with S1P after additional adjustment for LBM (ß = 0.29, p = 0.028), whereas LBM was not after adjustment for FM. Moreover, VFA was significantly and positively associated with S1P after additional adjustment for SFA (ß = 0.27, p = 0.039), whereas SFA was not after adjustment for VFA. CONCLUSION: This is the first study to show that increased plasma S1P levels are associated with blood glucose levels and accumulation of fat mass, especially visceral fat mass, in men with T2DM.

The Association Between Osteocalcin and Chronic Inflammation in Patients with Type 2 Diabetes Mellitus.

Osteocalcin acts as an endocrine hormone to regulate energy homeostasis. Although several in vivo and in vitro studies suggest that osteocalcin is involved in chronic inflammation, the association between osteocalcin and chronic inflammation in humans is unknown. In this cross-sectional study, 246 patients with type 2 diabetes mellitus (T2DM) were recruited to investigate the association of bone turnover markers with chronic inflammation parameters such as high-sensitive C-reactive protein (hsCRP), ferritin, and leukocyte subtype counts. Bone-specific alkaline phosphatase (BAP), total osteocalcin (OC), undercarboxylated OC (ucOC), and urinary N-terminal cross-linked telopeptide of type-I collagen (uNTX) were measured. Multiple regression analysis adjusted for age, duration of diabetes, body mass index, estimated glomerular filtration rate, and hemoglobin A1c showed that serum OC levels were significantly and negatively associated with hsCRP, ferritin, basophil count, and monocyte count (ß = - 0.18, p = 0.013; ß = - 0.22, p = 0.031; ß = - 0.14, p = 0.038; and ß = - 0.17, p = 0.012, respectively). Moreover, serum ucOC levels were significantly and negatively associated with hsCRP, ferritin, total leukocyte count, neutrophil count, and monocyte count (ß = - 0.24, p = 0.007; ß =- 0.37, p = 0.003; ß = - 0.21, p = 0.007; ß = - 0.24, p = 0.002; and ß = - 0.20, p = 0.011, respectively). The ratio of ucOC to OC was significantly and negatively associated with ferritin (ß = - 0.31, p = 0.014). However, neither BAP nor uNTX was associated with any chronic inflammation parameters. This is the first study to show that serum OC and ucOC levels were negatively associated with chronic inflammation parameters such as hsCRP, ferritin, and leukocyte subtypes in patients with T2DM. Therefore, OC could be a therapeutic target for protecting against chronic inflammation.

Long-term efficacy and safety of vildagliptin add-on therapy in type 2 diabetes mellitus with insulin treatment.

BACKGROUND: The use of dipeptidyl peptidase (DPP)-4 inhibitors in patients with type 2 diabetes treated with insulin may be beneficial. However, the long-term efficacy and safety of vildagliptin add-on therapy in these patients remains unclear. SUBJECTS AND METHODS: A total of 73 patients with type 2 diabetes treated with insulin were randomly assigned to receive either add-on therapy of vildagliptin (n=37) or conventional therapy without DPP-4 inhibitors (n=36) for glucose control. Hemoglobin A1c (HbA1c) levels, dose and number of insulin injections, number of hypoglycemia episodes, and liver and renal function were monitored for 2years. RESULTS: The baseline characteristics of subjects, including age, dose of insulin injections, or HbA1c levels, did not differ between the two groups. In the vildagliptin group, HbA1c levels significantly decreased and the significance of HbA1c reduction was maintained for 24months (from 8.0±1.2% to 7.4±1.0%, p<0.05, at the end of observational period). In addition, the dose and number of insulin injections significantly reduced (-5.6units, p<0.01, and -0.9 times, p<0.001). However, these parameters were unchanged in the control group. The number of patients who experienced three or more episodes of hypoglycemia per year was significantly lower in the vildagliptin group (n=4) than in the control group (n=11) (odds ratio, 0.28; 95% confidence interval, 0.08-0.97; p<0.05). CONCLUSION: Vildagliptin as an add-on to insulin treatment for 24months was well tolerated and led to sustained reductions in HbA1c, the dose and number of insulin injections, and the risk of hypoglycemia.

Advanced Glycation End-Products Induce Apoptosis of Vascular Smooth Muscle Cells: A Mechanism for Vascular Calcification.

Vascular calcification, especially medial artery calcification, is associated with cardiovascular death in patients with diabetes mellitus and chronic kidney disease (CKD). To determine the underlying mechanism of vascular calcification, we have demonstrated in our previous report that advanced glycation end-products (AGEs) stimulated calcium deposition in vascular smooth muscle cells (VSMCs) through excessive oxidative stress and phenotypic transition into osteoblastic cells. Since AGEs can induce apoptosis, in this study we investigated its role on VSMC apoptosis, focusing mainly on the underlying mechanisms. A rat VSMC line (A7r5) was cultured, and treated with glycolaldehyde-derived AGE-bovine serum albumin (AGE3-BSA). Apoptotic cells were identified by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. To quantify apoptosis, an enzyme-linked immunosorbent assay (ELISA) for histone-complexed DNA fragments was employed. Real-time PCR was performed to determine the mRNA levels. Treatment of A7r5 cells with AGE3-BSA from 100 µg/mL concentration markedly increased apoptosis, which was suppressed by Nox inhibitors. AGE3-BSA significantly increased the mRNA expression of NAD(P)H oxidase components including Nox4 and p22(phox), and these findings were confirmed by protein levels using immunofluorescence. Dihydroethidisum assay showed that compared with cBSA, AGE3-BSA increased reactive oxygen species level in A7r5 cells. Furthermore, AGE3-induced apoptosis was significantly inhibited by siRNA-mediated knockdown of Nox4 or p22(phox). Double knockdown of Nox4 and p22(phox) showed a similar inhibitory effect on apoptosis as single gene silencing. Thus, our results demonstrated that NAD(P)H oxidase-derived oxidative stress are involved in AGEs-induced apoptosis of VSMCs. These findings might be important to understand the pathogenesis of vascular calcification in diabetes and CKD.

Visceral fat obesity increases serum DPP-4 levels in men with type 2 diabetes mellitus.

OBJECTIVE: The relationship between serum DPP-4 level and visceral fat mass is still unclear in type 2 diabetes mellitus (T2DM). This study thus aimed to examine the association of visceral fat accumulation and metabolic syndrome with serum DPP-4 levels in T2DM. METHODS: Visceral and subcutaneous fat areas were evaluated by performing computed tomography scan in 135 men with T2DM, who had never taken DPP-4 inhibitors or GLP-1 receptor agonists. We investigated the association between serum DPP-4 levels and visceral fat area as well as the presence of metabolic syndrome. RESULTS: Multiple regression analysis adjusted for age, duration of T2DM, body mass index, serum creatinine, and HbA1c showed that serum DPP-4 levels were positively associated with visceral fat area (ß=0.25, p=0.04), but not subcutaneous fat area (ß=-0.18, p=0.13). In logistic regression analyses adjusted for the confounding factors described above, serum DPP-4 levels were positively associated with visceral fat obesity and metabolic syndrome [odds ratio (OR)=1.63, 95% confidence interval (CI)=1.00-2.66 per standard deviation (SD) increase, p=0.04; OR=1.77, 95%CI=1.09-2.88 per SD increase, p=0.02, respectively]. CONCLUSIONS: The present study showed that serum DPP-4 level was positively and specifically associated with accumulation of visceral fat and the presence of metabolic syndrome in men with T2DM.

Serum dipeptidyl peptidase-4 is associated with multiple vertebral fractures in type 2 diabetes mellitus.

OBJECTIVE: Patients with type 2 diabetes mellitus (T2DM) have a high risk of fracture although they have slightly higher bone mineral density (BMD). There is no evidence that dipeptidyl peptidase-4 (DPP-4) is involved in the bone fragility of the patients. The aim of this study was to investigate the association between serum DPP-4 levels and vertebral fractures (VFs) in men with T2DM. DESIGN: We conducted a cross-sectional study and investigated the relationships between serum DPP-4 levels vs BMD at lumbar spine, femoral neck and radius, bone turnover markers and presence of VFs in 204 Japanese male patients. RESULTS: Multiple regression analyses adjusted for confounders such as age, duration of diabetes, body mass index, serum creatinine, HbA1c, serum albumin, log(alanine transaminase), and log(C-reactive protein) showed that serum DPP-4 was positively associated with bone formation markers (bone-specific alkaline phosphatase and osteocalcin) as well as a bone resorption marker [tartrate-resistant acid phosphatase 5b (TRACP-5b)] (ß = 0·25, P < 0·01; ß = 0·17, P < 0·05; and ß = 0·30, P < 0·01, respectively), but not BMD at each site. Multivariate logistic regression analyses adjusted for the confounders described above revealed that serum DPP-4 levels were associated with the presence of multiple VFs (odds ratio 1·61, 95% confidential interval 1·05-2·49 per SD increase, P < 0·05). This association was still significant after additional adjustment for any sites of BMD or bone turnover markers except for TRACP-5b. CONCLUSIONS: We firstly showed that high level of serum DPP-4 is associated with prevalent multiple VFs independently of BMD and bone formation in men with T2DM.

Structure and molecular characterization of barley nudix hydrolase genes.

Putative nudix hydrolase (NUDX) genes, which encode amino acid sequences showing homology with those of Arabidopsis NUDXs and conserve nudix motif, were identified from barley. The 14 deduced barley NUDXs (HvNUDX1-14) were classified into established subfamilies, except for 8-oxo-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) pyrophosphohydrolase and mRNA decapping enzyme subfamilies, and three substrate-unknown subfamilies. Drought and UV-C stresses, respectively, up-regulated 7 and 4 HvNUDX genes, but some homologs of Arabidopsis NUDXs showed different responses to abiotic stress. HvNUDX12 gene, belonging to diadenosine tetraphosphates (Ap4A) pyrophosphohydrolase subfamily gene and up-regulated by UV-C, was expressed in Escherichia coli cells. The recombinant protein showed 8-oxo-dGTP, Ap4A, and guanosine-3',5'-tetraphosphate (ppGpp) pyrophosphohydrolase activities, and the suppression of the lacZ amber mutation in a mutT-deficient E. coli cells caused by the incorporation of 8-oxo-GTP into mRNA was prevented to a significant degree. These results suggest that barley NUDXs have unique constitution and response of NUDX to abiotic stress.