RAGE in circulating immune cells is fundamental for hippocampal inflammation and cognitive decline in a mouse model of latent chronic inflammation.

BACKGROUND: Latent chronic inflammation has been proposed as a key mediator of multiple derangements in metabolic syndrome (MetS), which are increasingly becoming recognized as risk factors for age-related cognitive decline. However, the question remains whether latent chronic inflammation indeed induces brain inflammation and cognitive decline. METHODS: A mouse model of latent chronic inflammation was constructed by a chronic subcutaneous infusion of low dose lipopolysaccharide (LPS) for four weeks. A receptor for advanced glycation end products (RAGE) knockout mouse, a chimeric myeloid cell specific RAGE-deficient mouse established by bone marrow transplantation and a human endogenous secretory RAGE (esRAGE) overexpressing adenovirus system were utilized to examine the role of RAGE in vivo. The cognitive function was examined by a Y-maze test, and the expression level of genes was determined by quantitative RT-PCR, western blot, immunohistochemical staining, or ELISA assays. RESULTS: Latent chronic inflammation induced MetS features in C57BL/6J mice, which were associated with cognitive decline and brain inflammation characterized by microgliosis, monocyte infiltration and endothelial inflammation, without significant changes in circulating cytokines including TNF-α and IL-1ß. These changes as well as cognitive impairment were rescued in RAGE knockout mice or chimeric mice lacking RAGE in bone marrow cells. P-selectin glycoprotein ligand-1 (PSGL-1), a critical adhesion molecule, was induced in circulating mononuclear cells in latent chronic inflammation in wild-type but not RAGE knockout mice. These inflammatory changes and cognitive decline induced in the wild-type mice were ameliorated by an adenoviral increase in circulating esRAGE. Meanwhile, chimeric RAGE knockout mice possessing RAGE in myeloid cells were still resistant to cognitive decline and brain inflammation. CONCLUSIONS: These findings indicate that RAGE in inflammatory cells is necessary to mediate stimuli of latent chronic inflammation that cause brain inflammation and cognitive decline, potentially by orchestrating monocyte activation via regulation of PSGL-1 expression. Our results also suggest esRAGE-mediated inflammatory regulation as a potential therapeutic option for cognitive dysfunction in MetS with latent chronic inflammation.

JNK and ATF4 as two important platforms for tumor necrosis factor-α-stimulated shedding of receptor for advanced glycation end products.

Soluble receptor for advanced glycation end products (sRAGE), shed from cell surfaces, is found in human circulation and has been implicated in cardiovascular disease. Its pathophysiological regulation and underlying mechanisms are scarcely understood. In endothelium-specific human RAGE transgenic mice, human sRAGE was detected in circulation, whereas its level was markedly increased after LPS treatment. That increase was preceded by a rapid rise in TNF-α level. Treatment with TNF-α also significantly increased serum sRAGE. In human microvascular endothelial cells or human umbilical vein endothelial cells with RAGE overexpression, TNF-α markedly induced RAGE shedding, which was dependent on MMP9 and ADAM10. TNF-α-stimulated MMP9 expression was completely dependent on JNK activation, with its inhibition partially effective in suppressing TNF-α-induced RAGE shedding. In contrast, TNF-α transiently induced activation transcription factor (ATF)4, a major component in unfolded protein response (UPR), whereas knockdown of ATF4 abrogated TNF-α-stimulated RAGE shedding. Protein levels of the pro and activated forms of ADAM10 were also decreased by ATF4 knockdown, whereas inhibition of other components of UPR, including XBP1 and ATF6, failed to block TNF-α-stimulated RAGE shedding. Although the endoplasmic reticulum stressors thapsigargin and tunicamycin induced markedly and sustained expression of ATF4 and XBP-1, they did not induce RAGE shedding to the same level as TNF-α, suggesting that ATF4 is necessary but not sufficient alone for TNF-α-mediated RAGE shedding. ATF4 inhibition did not affect TNF-α-stimulated MMP9 expression, whereas inhibition of JNK activity did not influence ADAM10 activation. Thus, inflammatory cascades including TNF-α induced RAGE shedding in endothelial cells in vivo and in vitro. JNK and ATF4 may be 2 platforms for regulation of TNF-α-stimulated RAGE shedding.-Miyoshi, A., Koyama, S., Sasagawa-Monden, M., Kadoya, M., Konishi, K., Shoji, T., Inaba, M., Yamamoto, Y., Koyama, H. JNK and ATF4 as two important platforms for tumor necrosis factor-α-stimulated shedding of receptor for advanced glycation end products.

Overestimation of glomerular filtration rate calculated from serum creatinine as compared with cystatin C in patients with subclinical hypercortisolism: Hyogo Adrenal Metabolic Registry.

The skeletal muscle mass are decreased in the patients with hypercortisolism. Glomerular filtration rate (eGFR) is not accurately evaluated by calculation from serum creatinine (eGFRcre) in these patients. However, it is not known whether it applies to patients with subclinical hypercortisolism. We investigated the dissociation between eGFRcre and eGFR calculated from cystatin C (eGFRcys) in patients with subclinical hypercortisolism and its association with the skeletal muscle mass. This cross-sectional study includes 23 patients with overt Cushing's syndrome (CS), 84 patients with possible autonomous cortisol secretion (pACS) and 232 patients with non-functioning adenomas (NFA). eGFRcre, eGFRcys, the ratio of eGFRcre to eGFRcys (eGFRcre/eGFRcys) were calculated. Skeletal muscle index (SMI) was measured by a direct segmental multi-frequency bioelectrical impedance body composition analyzer. eGFRcre/eGFRcys was significantly higher (p < 0.01) in pACS (mean ± standard error: 1.15 ± 0.02) than NFA (1.06 ± 0.01). In multiple linear regression analysis, the presence of pACS (ß = 0.162, p < 0.01), and post 1 mg-DST cortisol levels (ß = 0.190, p < 0.01) were significantly associated with eGFRcre/eGFRcys independent of age, gender, BMI and diabetes. eGFRcre/eGFRcys was significantly and inversely associated with SMI (r = -0.164, p = 0.02). Furthermore, post 1 mg-DST cortisol levels was significantly associated with SMI in simple (r = -0.177, p = 0.01) and multiple (ß = -0.089, p = 0.01) regression analyses. In conclusion, dissociation between eGFRcre and eGFRcys was observed in patients with subclinical hypercortisolism at least partly explained by muscle mass. Our findings raise an important clinical point that eGFRcre value should be carefully evaluated even in the phase of subclinical hypercortisolism.

Plasma leptin level is associated with cardiac autonomic dysfunction in patients with type 2 diabetes: HSCAA study.

BACKGROUND: It has been shown that visceral fat accumulation is associated with autonomic dysfunction, though the precise mechanism remains unclear. A recent basic study found that leptin can directly modulate autonomic function through the dorsomedial hypothalamus in relation to obesity. Here, we investigated the mutual relationships among plasma leptin, visceral fat accumulation, and cardiac autonomic dysfunction in patients with type 2 diabetes. METHODS: This cross-sectional study included 100 diabetic patients, and 100 age- and gender-matched non-diabetic patients with cardiovascular risk factors. Plasma leptin and soluble leptin receptor levels, visceral fat area (VFA), and heart rate variability (HRV) were determined in addition to classical cardiovascular risk factors. RESULTS: In the type 2 diabetic patients, VFA was significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = -0.243; SDANN5: r = -0.238), while the plasma level of leptin, but not soluble leptin receptor, was also significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = -0.243; SDANN5: r = -0.231). Multiple regression analysis showed that plasma leptin was significantly associated with SDNN and SDANN5 independent of other factors, including age, gender, presence of hypertension and dyslipidemia, duration of diabetes, HbA1c, and eGFR. Furthermore, the relationship of leptin with SDNN and SDANN5 (ß = -0.279 and -0.254, respectively) remained significant (p < 0.05) after adjustment for VFA. In patients without diabetes, no significant associations were observed between leptin and any of the HRV parameters. CONCLUSIONS: Hyperleptinemia may be involved in cardiac autonomic dysfunction in patients with type 2 diabetes and visceral obesity.

Rho-associated coiled-coil-containing kinase 2 deficiency in bone marrow-derived cells leads to increased cholesterol efflux and decreased atherosclerosis.

BACKGROUND: Macrophages play a central role in the development of atherosclerosis. However, the signaling pathways that regulate their function are not well understood. The Rho-associated coiled-coil-containing kinases (ROCK1 and ROCK2) are serine-threonine protein kinases that are involved in the regulation of the actin cytoskeleton. Recent studies suggest that ROCK1 in macrophages and bone marrow-derived cells mediates atherogenesis. However, a similar role for ROCK2 in the pathogenesis of atherosclerosis has not been determined. METHODS AND RESULTS: The bone marrows from wild-type, ROCK2(+/-), and ROCK2(-/-) mice were transplanted into irradiated recipient low-density lipoprotein receptor(-/-) mice, and atherosclerosis was induced with a 16-week high-cholesterol diet. Compared with wild-type bone marrow-transplanted mice, ROCK2(+/-) bone marrow-transplanted and ROCK2(-/-) bone marrow-transplanted mice showed substantially less lipid accumulation in the aorta (8.46±1.42% and 9.80±2.34% versus 15.64±1.89%; P<0.01 for both) and decreased atherosclerotic lesions in the subaortic sinus (158.1±44.4 and 330.1±109.5×10(3)µm(2) versus 520.2±125.7×10(3)µm(2); P<0.01 for both). These findings correlated with decreased foam cell formation (2.27±0.57 versus 4.10±0.3; P<0.01) and increased cholesterol efflux (17.65±0.6 versus 9.75±0.8; P<0.05) in ROCK2-deficient mice that are mediated, in part, through the peroxisome proliferator-activated receptor-γ/liver X receptor/ATP-binding cassette transporter A1 pathway in macrophages. CONCLUSIONS: ROCK2 contributes to atherosclerosis, in part, by inhibiting peroxisome proliferator-activated receptor-γ-mediated reverse cholesterol transport in macrophages, which contributes to foam cell formation. These findings suggest that inhibition of ROCK2 in macrophages may have therapeutic benefits in preventing the development of atherosclerosis.

Relationship between serum allantoin and urate in healthy subjects and effects of benzbromarone in gout patients.

BACKGROUND: Although hyperuricemia is suggested to increase allantoin production in both pro- and antioxidant manners, it remains undetermined whether it increases the serum concentration of allantoin. In addition, since uric acid has both pro- and antioxidant actions, a decrease in the serum concentration of uric acid may have an effect on the pro-oxidant-antioxidant balance. METHODS: To examine whether serum allantoin is correlated with serum urate, we measured those levels as well as other parameters in 63 healthy subjects. In addition, to determine whether serum allantoin is correlated with reactive oxygen species (ROS) biomarkers, we measured 8-hydroxy deoxyguanosine and 15-F2t-isoprostane, markers of ROS, in urine samples from 30 gout patients before and 1 year after benzbromarone treatment (50 mg/d). RESULTS: The serum concentration of allantoin was correlated with that of urate in healthy subjects (R = 0.27, p < 0.05). Benzbromarone treatment in the patients decreased the concentrations of allantoin and urate in serum by 17% (p < 0.05) and 49% (p < 0.05), respectively, and the benzbromarone-induced change in serum allantoin was correlated with that in serum urate (R = 0.39, p < 0.05). However, benzbromarone treatment did not change the ratios of 8-hydroxydeoxyguanosine/creatinine or 15-F2t-isoprostane/creatinine in urine. CONCLUSIONS: Our findings suggest that hyperuricemia contributes to an increase in serum concentration of allantoin, though they do not indicate that hyperuricemia is a major factor for controlling oxidative stress in vivo.

Xanthine oxidoreductase activity is correlated with hepatic steatosis.

The enzyme xanthine oxidoreductase (XOR) catalyzes the synthesis of uric acid (UA) from hypoxanthine and xanthine, which are products of purine metabolism starting from ribose-5-phosphate. Several studies suggested a relationship between hyperuricemia and hepatic steatosis; however, few previous studies have directly examined the relationship between XOR activity and hepatic steatosis. A total of 223 subjects with one or more cardiovascular risk factors were enrolled. The liver-to-spleen (L/S) ratio on computed tomography and the hepatic steatosis index (HSI) were used to assess hepatic steatosis. We used a newly developed highly sensitive assay based on [13C2, 15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry to measure plasma XOR activity. Subjects with the L/S ratio of < 1.1 and the HSI of < 36 had increased XOR activity and serum UA levels. Independent of insulin resistance and serum UA levels, multivariate logistic regression analysis revealed that plasma XOR activity was associated with the risk of hepatic steatosis as assessed by the L/S ratio and HSI. According to the findings of this study, plasma XOR activity is associated with hepatic steatosis independent of insulin resistance and serum UA levels.

Sleep Apnea and Physical Movement During Sleep, But Not Sleep Duration, Are Independently Associated With Progression of Left Ventricular Diastolic Dysfunction: Prospective Hyogo Sleep Cardio-Autonomic Atherosclerosis Cohort Study.

Background Although co-occurrence of sleep disorder with heart failure is known, it is not clear whether that condition is a cause or consequence of heart failure. The present study was conducted as a longitudinal examination of the predictive value of sleep parameters on progression of left ventricular diastolic dysfunction. Methods and Results Four-hundred fifty-two subjects were followed for a mean of 34.7 months. An outcome of diastolic dysfunction was defined as increase in early inflow velocity/early diastolic tissue velocity >14. Sleep apnea-hypopnea index, minimal oxygen saturation, sleep duration, and activity index (physical movement during sleep time, a potential parameter of poor sleep quality) were determined using apnomonitor and actigraphy findings, while heart rate variability was measured with a 24-hour active tracer device. Sixty-six of the patients developed diastolic dysfunction during the follow-up period, with a median time of 25 months. Kaplan-Meier analysis results revealed that those with sleep apnea classified as moderate (apnea-hypopnea index 15 to <30, P<0.01 versus none) or severe (apnea-hypopnea index ≥30, P<0.01 versus none), and with a high activity index (Q3 or Q4, P<0.01 versus Q1), but not short sleep duration (P=0.27) had a significantly greater risk for a diastolic dysfunction event. Results of multivariable Cox proportional hazards regression analysis indicated that moderate to severe sleep apnea after a follow-up period of 3 years (hazard ratio [HR], 9.26 [95% CI, 1.89-45.26], P<0.01) and high activity index (HR, 1.85 [95% CI, 1.01-3.39], P=0.04) were significantly and independently associated with future diastolic dysfunction. Moreover, significant association of high activity index with the outcome was not confounded by either minimal oxygen saturation or heart rate variability. Conclusions Sleep apnea and physical movement during sleep, but not sleep duration and autonomic nervous dysfunction, are independent important predictors for progression of left ventricular diastolic dysfunction.

Sleep quality, autonomic dysfunction and renal function in diabetic patients with pre-CKD phase.

Diabetes has been established as a strong risk factor for chronic kidney disease (CKD). Sleep apnea, poor sleep quality (PSQ), and autonomic imbalance are also considered to be potential risk factors for decline in renal function, though no known study has examined their integrated predictive value in diabetic and non-diabetic patients without CKD. The present cohort consisted of 754 serial patients (diabetes; n = 231, non-diabetes; n = 523) without CKD registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) study. Patients underwent examinations to determine respiratory event index and objective sleep quality using actigraphy, as well as heart rate variability (HRV). Renal outcome was defined as a decline in estimated glomerular filtration rate to less than 60 ml/min/1.73 m2 for more than 3 months. Kaplan-Meier analysis showed that diabetic patients with PSQ or low HRV, but not sleep apnea, had a significantly increased risk for renal outcome. Furthermore, Cox proportional hazards analysis revealed that PSQ was significantly associated with elevated risk of renal outcome (HR: 2.57; 95% CI: 1.01-6.53, p = 0.045) independent of sleep apnea and classical risk factors. Low HRV tended to be, but not significantly (p = 0.065), associated with the outcome. In non-diabetic patients, PSQ was also significantly and independently associated with renal outcome, whereas sleep apnea and low HRV were not. In conclusion, PSQ and low HRV appear to be important predictors of decline in renal function in diabetic patients without CKD.

Dialysis modality is independently associated with circulating endothelial progenitor cells in end-stage renal disease patients.

BACKGROUND: Numbers of endothelial progenitor cells (EPC) have been shown to be decreased in subjects with end-stage renal disease (ESRD). It is not clear, however, whether dialysis modality affects circulating EPCs in ESRD subjects. METHODS: We examined the number of circulating EPCs in 67 continuous ambulatory peritoneal dialysis (CAPD) patients and age- and gender-matched 142 haemodialysis (HD) patients, and 78 subjects without chronic kidney disease. Arterial stiffness was analysed as pulse-wave velocity (PWV) for these patients, and their mutual relationship with circulating EPCs was examined. EPCs were measured as CD34(+) CD133(+) CD45(low) VEGFR2(+) cells determined by flow cytometry. RESULTS: The EPC numbers exhibited a strong correlation (R(2) = 0.866) with endothelial-colony forming units on culture assay. The levels of EPCs in HD or CAPD subjects were significantly lower than those in control subjects. Among ESRD subjects, the levels of EPC were significantly higher in CAPD subjects than those in HD subjects. In ESRD subjects, PWV levels tended to be associated with EPCs (Rs = -0.131, P = 0.058). However, the significant relationship between dialysis modality and circulating EPCs was independent of the levels of PWV. The association of circulating EPCs with dialysis modality was significant even after adjusting for other potential confounders, including age, gender, blood pressure, history of cardiovascular diseases, presence of diabetes, blood haemoglobin level and treatments with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker or statin. CONCLUSIONS: CAPD treatment could be a positive regulator of number of circulating EPCs in subjects with ESRD, with the relationship independent of the status of arteriosclerosis.

Associations of sleep quality, sleep apnea and autonomic function with insulin secretion and sensitivity: HSCAA study.

RATIONALE AND PURPOSE: Although sleep disorders are shown to be involved in occurrence of diabetes, impacts of several quantitative parameters related to sleep on insulin secretion and sensitivity is yet to be elucidated. We cross-sectionally examined relationships among quantitative sleep quality, sleep apnea, and autonomic function with insulin secretion and sensitivity in 399 patients without previous diagnosed diabetes who underwent 75-g oral glucose tolerance test (75gOGTT). METHOD: Poor sleep quality (PSQ) was defined as an activity index ≥50 by actigraphy. Sleep apnea was measured by apnomonitor, while standard deviation of all normal-to-normal R-R intervals (SDNN) was measured by active tracer. Parameters of insulin secretion and sensitivity were measured by 75gOGTT. RESULTS: Patients with PSQ exhibited significantly lower insulinogenic index (r = 0.155, p < 0.01), a parameter of insulin secretion, with the association independent of other clinical factors including apnea and SDNN (ß = -0.156, p < 0.01). In contrast, presence of sleep apnea (r = -0.143, p < 0.05) and the lower SDNN (r = -0.150, p < 0.01) were significantly and inversely associated with BIGTT-S, an insulin sensitivity parameter, with the association of SDNN with BIGTT-S remaining significant even after adjustments for PSQ and sleep apnea (ß = -0.111, p < 0.05). CONCLUSION: Poor sleep quality is an independent predictor of pancreatic ß-cell function, which could be involved in occurrence of type 2 diabetes.

Subclinical decrease in cardiac autonomic and diastolic function in patients with metabolic disorders: HSCAA study.

Heart failure due to decreased diastolic function, HFpEF, is a growing health concern with rising prevalence. We examined subclinical cardiac autonomic and diastolic functions in 605 patients with metabolic diseases classified as pre-heart failure. Presence of glucose intolerance or diabetes, or visceral adiposity was significantly associated with reduced cardiac autonomic and diastolic functions. Higher autonomic functions were significantly associated with a parameter of better cardiac diastolic function (E/A) (SDNN: r = 0.306, p < 0.01; HF: r = 0.341, p < 0.01), with the association independent of diabetes, body mass index, visceral adiposity and insulin resistance index. Thus, reduced autonomic function may be a potential predictor for decreased cardiac diastolic functions in metabolic disorders.

Low circulating endogenous secretory receptor for AGEs predicts cardiovascular mortality in patients with end-stage renal disease.

OBJECTIVE: Receptor for advanced glycation end-products (RAGE) is involved in diabetic vascular complications. We have recently shown that plasma endogenously secretory RAGE (esRAGE), an alternatively spliced form of RAGE, is closely associated with metabolic syndrome and atherosclerosis. Here, we evaluated if plasma esRAGE is a predictor of cardiovascular mortality in a cohort of 206 (171 nondiabetic) patients with end-stage renal diseases (ESRD). METHODS AND RESULTS: The cohort was followed for a median of 111 months, and 74 deaths including 34 cardiovascular deaths were recorded. Plasma esRAGE was measured at baseline. Cumulative incidence of cardiovascular death by Kaplan-Meier estimation was significantly higher in subjects in the lowest tertile of plasma esRAGE than those in the middle or the highest tertile both in all and nondiabetic subjects alone. In all subjects, as compared with the lowest tertile of plasma esRAGE, the hazards ratios for the highest and middle tertile were 0.40 (95% CI, 0.18 to 0.89) and 0.26 (0.10 to 0.66), respectively. The higher risk for lower esRAGE was still significant even after adjusted either with body mass index, hypertension, dyslipidemia and vascular complications, but was confounded by age and diabetes. CONCLUSIONS: Low circulating esRAGE is a predictor for cardiovascular mortality in ESRD patients.

Hypokalemia associated with pseudo-Cushing's syndrome and magnesium deficiency induced by chronic alcohol abuse.

Hypokalemia and hypomagnesemia are frequently observed in patients with chronic alcoholism. However, the involvement of deranged cortisol regulation in patients with those conditions has not been reported. A 63-year-old Japanese male with chronic alcoholism was referred to the Department of Diabetes, Endocrinology and Metabolism for examination and treatment of hypokalemic periodic paralysis. Laboratory findings showed hypokalemia (2.3 mmol/l), as well as a high level of urinary excretion of potassium and hypomagnesemia (1.2 mg/dl), whereas urinary excretion of magnesium was undetectable. Potassium infusion treatment recovered that level in serum to 4.1 mmol/l, though it decreased to 2.2 mmol/l following discontinuation. A dexamethasone suppression test and urinary cortisol level showed corticotropin-dependent hypercortisolemia. However, gadolinium-enhanced MRI revealed no evidence of pituitary adenoma. The patient recovered from hypokalemia following an administration of magnesium in addition to potassium, which was accompanied by potassium over-excretion improvement. After being discharged, serum potassium level was maintained within a normal range with only magnesium infusion treatment. Furthermore, alcohol intake was reduced from 160 to 20 g/day and an endocrinological re-examination after that restriction showed normal cortisol regulation. The patient was diagnosed with pseudo-Cushing's syndrome induced by alcohol abuse. Serum potassium level was maintained within a normal range even after discontinuation of magnesium supplementation. Our findings in this case indicate that pseudo-Cushing's syndrome in conjunction with hypomagnesemia may be involved in development of hypokalemia in patients with chronic alcoholism.

Ectopic adrenocorticotropic hormone syndrome associated with olfactory neuroblastoma: acquirement of adrenocorticotropic hormone expression during disease course as shown by serial immunohistochemistry examinations.

Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a condition of endogenous hypercortisolism sustained by an extrapituitary ACTH-secreting tumor. Olfactory neuroblastoma (ONB) is a rare malignant neoplasm of the sinonasal tract and is derived from the olfactory epithelium. Because the paranasal sinus is not a common site of EAS, the development of ONB in patients with EAS is rare. We herein report the first known case of ONB with acquirement of ACTH production during the clinical course as proven by immunohistochemistry. A 50-year-old man diagnosed with ONB was referred to our department in July 2015 because of hypokalemia, hyperglycemia, decreased eosinophil and granulocyte counts, and elevated serum levels of ACTH and cortisol. Although two previous ONB biopsy specimens (2011 and 2014) showed no ACTH immunoreactivity, a newly obtained specimen in August 2015 clearly showed ACTH immunoreactivity. This is the first case of ectopic ACTH syndrome associated with an ONB that acquired the ability to express ACTH during its clinical course as shown by serial immunohistochemical examinations.

Low sleep quality is associated with progression of arterial stiffness in patients with cardiovascular risk factors: HSCAA study.

BACKGROUND AND AIMS: Improvement in sleep quality is considered to be a viable target for prevention and treatment of cardiovascular diseases. To gain insight into its underlying mechanisms, we evaluated the significance of objectively measured sleep quality in patients with regard to progression of arterial stiffness over a 3-year follow-up period. METHODS: This prospective cohort study included 306 serial patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) study. In addition to classical cardiovascular risk factors (body mass index, current smoking, past history of cardiovascular disease, dyslipidemia, diabetes mellitus), the participants were examined for ambulatory blood pressure (BP), apnea-hypopnea index (AHI), standard deviation of the NN (RR) interval (SDNN) for heart rate variability (HRV), and objective sleep quality using actigraphy findings. Brachial-ankle pulse wave velocity (baPWV) was measured at both baseline and follow-up (36.6 ±â€¯6.8 months) as a parameter of arterial stiffness. RESULTS: Increases in PWV (%) were greater (p = 0.03) in the low sleep quality (LSQ) group (5.75 ±â€¯1.15%) as compared to the normal sleep quality group (2.69 ±â€¯0.85%). Patients with the greatest increase (≥20%) from baseline exhibited a significantly (p < 0.05) larger percentage of LSQ (75% vs. 49.6%) as compared to those without PWV progression (<0%), with the association still significant (odds ratio 3.62, 95% confidence interval 1.04-12.55, p = 0.04) even after adjustment for other clinical risk factors. For all subjects, univariate logistic regression analyses showed that diabetes and LSQ were significantly associated with the greatest increase of PWV. Comparisons of characteristics among specific subgroups showed more prominent associations of LSQ with the greatest increase of PWV in patients with greater age, dyslipidemia, and higher AHI. CONCLUSIONS: LSQ was associated with progression of arterial stiffness over a 3-year period, independent of cardiovascular risk factors such as BP, AHI, and HRV.

Receptor for advanced glycation end products is involved in impaired angiogenic response in diabetes.

Angiogenic response is impaired in diabetes. Here, we examined the involvement of receptor for advanced glycation end products (RAGE) in diabetes-related impairment of angiogenesis in vivo. Angiogenesis was determined in reconstituted basement membrane protein (matrigel) plugs containing vascular endothelial growth factor (VEGF) implanted into nondiabetic or insulin-deficient diabetic wild-type or RAGE(-/-) mice. The total, endothelial, and smooth muscle (or pericytes) cells in the matrigel were significantly decreased in diabetes, with the regulation dependent on RAGE. In the matrigel, proangiogenic VEGF expression was decreased, while antiangiogenic thrombospondin-1 was upregulated in diabetic mice, regardless of the presence of RAGE. In wild-type mice, proliferating cell nuclear antigen (PCNA)-positive cells in the matrigel were significantly less in diabetic than in nondiabetic mice, while the numbers of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells were significantly higher. This alteration in PCNA- and TUNEL-positive cells in diabetes was not observed in RAGE(-/-) mice. Similarly, the percentage of nuclear factor kappaB-activated cells is enhanced in diabetes, with the regulation dependent on the presence of RAGE. Importantly, adenovirus-mediated overexpression of endogenous secretory RAGE, a decoy receptor for RAGE, restores diabetes-associated impairment of angiogenic response in vivo. Thus, RAGE appears to be involved in impairment of angiogenesis in diabetes, and blockade of RAGE might be a potential therapeutic target.

Nonpharmacological Management of Gout and Hyperuricemia: Hints for Better Lifestyle.

We reviewed lifestyle factors that influence serum uric acid levels and risk of gout flare, and how to improve their deleterious effects. Since obesity increases uric acid and weight gain increases gout risk, weight reduction by daily exercise and limiting intake of excess calories is recommended. However, strenuous exercise, which causes adenine nucleotide degradation; starvation, which decreases uric acid excretion; and dehydration may raise the level of uric acid in serum and trigger gout. Increased intake of purine-rich foods, such as meat and seafood, raise the level of uric acid in serum and is associated with increased risk of gout, whereas dairy products, especially low-fat types, are associated with a lower risk of gout. Also, heavy alcohol drinking raises the uric acid level and increases the risk of gout through adenine nucleotide degradation and lactate production. Sweet fruits and soft drinks containing fructose should be moderated, since fructose may raise uric acid and increase gout risk through uric acid production and/or decreased excretion. On the other hand, the Mediterranean diet is recommended for gout patients, since it may also help prevent hyperuricemia. Furthermore, coffee and vitamin C supplementation could be considered as preventive measures, as those can lower serum uric acid levels as well as the risk of gout.

Plasma brain-derived neurotrophic factor concentration is a predictor of chronic kidney disease in patients with cardiovascular risk factors - Hyogo Sleep Cardio-Autonomic Atherosclerosis study.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been shown to have protective effects against cardiovascular diseases and death through neural and non-neural pathways via tropomyosin-related kinase B signaling. However, it is not known whether plasma BDNF concentration is a predictor of chronic kidney disease (CKD). DESIGN: This study was conducted as a prospective cohort study as part of the Hyogo Sleep Cardio-Autonomic Atherosclerosis. METHODS: We measured plasma BDNF concentration in 324 patients without CKD, defined as an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73m2, and with cardiovascular risk factors. As potential confounders, sleep condition, nocturnal hypertension, and autonomic function were quantitatively examined. The patients were followed for a median 37 months (range 2-59 months) and occurrence of CKD was noted. RESULTS: Plasma BDNF concentration was significantly and independently associated with CKD development, which occurred in 38 patients (11.7%). Kaplan-Meier analysis revealed that patients with reduced plasma BDNF concentration exhibited a significantly (p = 0.029) greater number of CKD events as compared to those with a higher concentration. Moreover, comparisons of key subgroups showed that the risk of CKD in association with low plasma BDNF concentration was more prominent in patients with a greater reduction of nocturnal systolic blood pressure, better movement index, higher standard deviations of the NN(RR) interval or average NN(RR) interval for each 5-minute period, and without past cardiovascular disease events, smoking habit, or albuminuria. CONCLUSIONS: Plasma BDNF concentration is an independent predictor for development of CKD in patients with cardiovascular risk factors.

Serum Macro TSH Level is Associated with Sleep Quality in Patients with Cardiovascular Risks - HSCAA Study.

Macro thyroid-stimulating hormone (TSH) has been reported to be associated with seasonality and regulated by changes in day length in rodents, different from free TSH. In the present study, we investigated structural differences between macro TSH and free TSH levels in human serum, as well as the association of macro TSH with sleep quality. We enrolled 314 patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) study. Sleep quality shown by actigraphy, sleep physical activity, and percent sleep in all and TSH closely matched subjects were significantly associated with high macro TSH levels. Macro and free TSH were similarly increased following thyrotropin-releasing hormone (TRH) stimulation, while circadian changes associated with those were distinct. To further analyze the structure of macro TSH, serum samples were separated by gel filtration chromatography. Although treatment with glycosidase did not affect morbidity, the macro TSH fraction had a markedly low affinity to the Con A column as compared with free TSH, indicating a distinct glycosylation structure. In conclusion, an increase in serum macro TSH is associated with low sleep quality and regulated in a manner distinct from free TSH, potentially due to an altered glycosylation structure.