Effects of food deprivation on the hypothalamic feeding-regulating peptides gene expressions in serotonin depleted rats.

We examined the effects of serotonin (5-HT) depletion induced by peripheral injection of 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) on the expression of feeding-regulating peptides expressions by using in situ hybridization histochemistry in adult male Wistar rats. PCPA pretreatment had no significant effect on basal levels of oxytocin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), pro-opiomelanocortin (POMC), cocaine and amphetamine-regulated transcript (CART), neuropeptide-Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin in the hypothalamus. Food deprivation for 48 h caused a significant decrease in CRH, TRH, POMC, and CART, and a significant increase in NPY, AgRP and MCH. After PCPA treatment, POMC and CART did not decrease despite food deprivation. NPY was significantly increased by food deprivation with PCPA, but was attenuated compared to food deprivation without PCPA. These results suggest that the serotonergic system in the hypothalamus may be involved in the gene expression of POMC, CART, and NPY related to feeding behavior.

Initial Japanese experience with the LAP-BAND system.

INTRODUCTION: Laparoscopic bariatric surgery has gradually spread in Japan since it was introduced in 2000. In 2005, we introduced laparoscopic adjustable gastric banding (LAGB) with the LAP-BAND system into Japan. Here, we evaluate our intermediate-term results with the LAP-BAND system. METHODS: Between August 2005 and June 2010, 27 Japanese patients with morbid obesity (BMI ≥ 35 kg/m(2) ) underwent LAGB with the LAP-BAND system in our institution. Our patients' average weight was 111 kg and BMI was 41 kg/m(2) . All LAGB procedures were performed through the pars flaccida pathway with band fixation using gastric-to-gastric sutures. The average follow-up period was 48 months. RESULTS: All procedures were completed laparoscopically. One early complication (sudden cardiac arrest due to postoperative bleeding) and three late complications (port trouble, megaesophagus, and band slippage) were experienced, and reoperations were performed in three of the patients. Weight loss and percentage of excess weight loss on average were 26 kg and 53% after 3 years and 22 kg and 53% after 6 years, respectively. In line with this good weight loss, comorbidities, especially those of type 2 diabetes and metabolic syndrome were frequently resolved or improved. CONCLUSION: LAGB with the LAP-BAND system appears to be beneficial in obese Japanese patients.

Cilnidipine regulates glucose metabolism and levels of high-molecular adiponectin in diet-induced obese mice.

The aim of the present study is to examine the effects of the antihypertensive drug cilnidipine on glucose metabolism and adipocytokines, including adiponectin, in diet-induced obese (DIO) mice. The effects of cilnidipine on insulin sensitivity and the levels of adiponectin in DIO mice were examined after the mice had been treated with cilnidipine dissolved in water at a dose of 0.2 g l(-1) for 14 days. As expected, treatment with cilnidipine decreased the systolic and diastolic blood pressures in DIO mice, compared with control mice (P<0.05 for each parameter). Cilnidipine treatment improved glucose and insulin sensitivity in DIO mice. In addition, cilnidipine treatment dramatically increased the level of adiponectin in white adipose tissue (P<0.05) and the circulating levels of total and high-molecular weight (HMW) adiponectin in DIO mice (P<0.01 for each parameter). Furthermore, the secretion of HMW adiponectin and the ratio of HMW adiponectin/total adiponectin were both increased after cilnidipine treatment. Finally, the secretion of adiponectin from adipocytes was increased after cilnidipine treatment. Taken together, these results indicate that cilnidipine improves insulin tolerance and adiponectin levels, especially high-molecular type adiponectin, in DIO mice.

Role of the spleen in the development of steatohepatitis in high-fat-diet-induced obese rats.

Obesity is considered a systemic low-grade inflammatory state. Although the spleen is the main immune organ with a close anatomical relationship with the liver, its role in the progression of fatty liver disease remains uncertain. Therefore, we sought to clarify the functional role of the spleen in the development of steatohepatitis in high-fat (HF)-diet-induced obese rats. Male Sprague-Dawley rats were fed HF food and divided into two groups, a splenectomy (SPX) group and a sham-operation (Sham) group. The liver and abdominal white adipose tissue (WAT) were removed one and six months after surgery, and we evaluated the effects of SPX on WAT and HF-induced fatty liver. SPX rats exhibited worse dyslipidemia and inflammatory changes in WAT one month after surgery. Hepatic steatosis and inflammation were accelerated by SPX, based on the time after surgery. At one month after surgery, the tissue triglyceride content increased in SPX rats, compared with Sham controls (P < 0.05). The liver histology also showed a worsening of steatosis in those rats. At six months after SPX, dramatic inflammatory and fibrotic changes were observed in liver tissue sections. Hepatic carnitine palmitoyltransferase-1 was suppressed at one and six months after SPX (P < 0.05 for each). WAT and liver tissue levels of inflammatory markers such as tumor necrosis factor-α, and the expression of Kupffer cells were all increased at six months in SPX rats, compared with Sham controls (P < 0.05 for each). Our results indicate that the preservation of the spleen contributes to the prevention of the progression of hepatic steatosis to steatohepatitis in obese rats.

Intracerebroventricular administration of urotensin II regulates food intake and sympathetic nerve activity in brown adipose tissue.

To clarify the functional roles of urotensin II in regulating energy balance, we investigated the effects of a central infusion of urotensin II on food intake, uncoupling protein (UCP) 1 mRNA expression, temperature, and sympathetic nervous system activity in brown adipose tissue (BAT), a site that regulates energy expenditure in rodents. A bolus central infusion of urotensin II at a dose of 1 nmol/rat into the third cerebral ventricle decreased food intake (p<0.05). Additionally, urotensin II induced c-Fos-like-immunoreactivity (c-FLI) in the paraventricular nucleus (PVN) as compared with that in the control (phosphate buffered saline [PBS]-treated) group. Furthermore, urotensin II increased BAT UCP 1 mRNA expression (p<0.05). Finally, central infusion of urotensin II significantly increased BAT sympathetic nerve activity, which was accompanied by a significant elevation in BAT temperature (p<0.05) in rats. Taken together, central infusion of urotensin II regulates food intake and BAT sympathetic nerve activity in rats.

Apelin-13 microinjection into the paraventricular nucleus increased sympathetic nerve activity innervating brown adipose tissue in rats.

The aim of present study is to clarify the role of apelin in regulating energy homeostasis in brown adipose tissue (BAT). We examined the central effects of apelin-13 on the brain c-fos like immunoreactivity (c-FLI), BAT temperature and the activity of the sympathetic nerve activity innervating BAT in rats. In the hypothalamus, central infusion into the third cerebral ventricle (i3vt) of apelin-13 caused induction of c-FLI in the paraventricular nucleus (PVN) compared with the controls (PBS-treated) group. In addition, microinjection of apelin-13 into the PVN produced significant increases in BAT temperature. Furthermore, microinjection of apelin-13 treatment increased BAT sympathetic nerve activity compared with controls. We conclude that apelin-13 microinjection into PVN increases sympathetic nerve activity innervating BAT.

Adult-onset Still's disease with macrophage activation syndrome successfully treated with a combination of methotrexate and etanercept.

We report a 16-year-old female case of intractable adult-onset Still's disease accompanied by macrophage activation syndrome, who went into full remission after switching from infliximab to etanercept. Although the disease promptly relapsed when etanercept was discontinued, she again responded fully upon the reintroduction of etanercept. Furthermore, the effect of etanercept was apparently enhanced by combining it with a sufficient dose of methotrexate. This combination therapy should be considered as one of treatment options for the disease.

Involvement of remnant spleen volume on the progression of steatohepatitis in diet-induced obese rats after a splenectomy.

AIM: This study investigated the correlation between remnant spleen volume after splenectomy (SPX) and the degree of hepatic steatosis and/or inflammation. METHODS: Male Sprague-Dawley rats were fed HF food and divided into three groups: sham-operation (Sham) group, a hemisplenectomy (H-SPX) group, and a total-splenectomy (T-SPX) group. Serum was collected and livers removed 12 weeks after surgery. We measured serum lipid markers and evaluated liver changes by comparing the three groups. Additionally, we examined liver changes 24 weeks after SPX. RESULTS: Serum triglyceride and free fatty acid levels after SPX were higher than those of sham controls, and a significant difference was found between T-SPX and the other groups (P < 0.05 for each). Increased intrahepatic fat accumulation was shown in SPX rats along with lower residual spleen volume; this fat accumulation after SPX was accelerated in rats at 24 weeks. Additionally, liver inflammatory changes, including an increase in the Kupffer cell population and pro-inflammatory cytokine production, as well as a high level of oxidative stress, were observed in the liver sections from SPX rats, which correlated significantly with less volume of the residual spleen. Also, an increase in pro-inflammatory cytokine content and a decrease in anti-inflammatory cytokine content were shown in the residual spleen from H-SPX rats, as compared to those of sham controls (P < 0.05 for each). CONCLUSION: These results indicate the importance of preserving splenic tissue. This residual spleen may play an important role in preventing the progression from diet-induced hepatic steatosis to steatohepatitis.

Candesartan restored cardiac Hsp72 expression and tolerance against reperfusion injury in hereditary insulin-resistant rats.

AIMS: We tested the hypothesis that candesartan, an angiotensin II (AII) type 1 receptor antagonist, would restore the depressed phosphatidylinositol 3 (PI3) kinase-dependent Akt phosphorylation, an essential signal to induce heat-shock protein 72 (Hsp72) in response to hyperthermia, in Otsuka Long-Evans Tokushima fatty (OLETF) rats. METHODS AND RESULTS: At 14 weeks of age, male OLETF rats and Long-Evans Tokushima Otsuka (LETO) rats were treated with candesartan (0.25 mg/kg/day) for 2 weeks. Thereafter, hyperthermia (43°C for 20 min) was applied. We observed the following: (i) Candesartan did not improve insulin sensitivity in OLETF rats. (ii) Candesartan restored depressed PI3 kinase-dependent Akt phosphorylation and Hsp72 expression in OLETF rat hearts. (iii) Cardiac ventricular tissue contents of AII were greater in OLETF rats, which were suppressed by candesartan. (iv) Cardiac levels of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphorylation were greater in OLETF rats, which were suppressed by candesartan. In cultured cardiomyocytes, application of AII induced PTEN phosphorylation, which was suppressed by candesartan. (v) In high-fat diet insulin-resistant rats, similar results were observed with respect to Hsp72 expression, Akt phosphorylation and PTEN phosphorylation. (vi) In isolated, perfused heart experiments, reperfusion-induced cardiac functional recovery was suppressed in OLETF rat hearts, which was improved by candesartan. CONCLUSION: Our results suggest that the depression of PI3 kinase-dependent Akt activation in response to hyperthermia in OLETF rats can be restored by candesartan. Substantial activation of the renin-angiotensin system, represented by increased myocardial AII content and subsequent PTEN phosphorylation, may underlie the pathogenesis which is ameliorated by candesartan.

Ghrelin in small intestine, its contribution to regulation of food intake and body weight in cross-intestinal parabiotic rats.

Ghrelin has been shown to be associated with feeding behavior in humans and rodents. It has been suggested that ghrelin may play a role behind the effect of bariatric surgery. Inbred rats were made into parabiotic pairs so that they shared a single abdominal cavity. A further operation is performed later in which the small intestines are transected and re-connected so that one rat continually lost nutrition to its partner. Changes in food intake and body weight were recorded. Seven weeks later, content of ghrelin in the plasma, stomach and upper intestines were measured in the paired rats. Rats which lost nutrients to its counterpart (Loss rats) ingested significantly more food than sham control rats (p<0.001). Rats which gained nutrient (Gain rats) ingested less than controls (p<0.001). There was no significant difference in body weight, blood glucose, insulin, free fatty acids and triglycerides between the paired rats. There was significantly higher levels of ghrelin in the plasma (p<0.008) and the intestine of the Loss rats (p<0.02). There were no difference in ghrelin in the stomach between parabiotic rats and sham operated controls. The ghrelin content of the plasma and intestines were significantly higher in the Loss rats, which ate more, and normal in the Gain rats, which ate less than controls. Because no remarkable changes in the ghrelin content were observed in the stomach, difference in the quality of the chime may affect the local synthesis and release of ghrelin.

Central control of fever and female body temperature by RANKL/RANK.

Receptor-activator of NF-kappaB ligand (TNFSF11, also known as RANKL, OPGL, TRANCE and ODF) and its tumour necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodelling, lymph node organogenesis and formation of a lactating mammary gland. RANKL and RANK are also expressed in the central nervous system. However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Here we report that RANKL and RANK have an essential role in the brain. In both mice and rats, central RANKL injections trigger severe fever. Using tissue-specific Nestin-Cre and GFAP-Cre rank(floxed) deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rank(floxed) deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1beta and TNFalpha. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE(2)/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rank(floxed) mice exhibit increased basal body temperatures, suggesting that RANKL and RANK control thermoregulation during normal female physiology. We also show that two children with RANK mutations exhibit impaired fever during pneumonia. These data identify an entirely novel and unexpected function for the key osteoclast differentiation factors RANKL/RANK in female thermoregulation and the central fever response in inflammation.

Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population.

There is evidence that the obesity phenotype in the Caucasian populations is associated with variations in several genes, including neuronal growth regulator 1 (NEGR1), SEC16 homolog B (SCE16B), transmembrane protein 18 (TMEM18), ets variant 5 (ETV5), glucosamine-6-phosphate deaminase 2 (GNPDA2), prolactin (PRL), brain-derived neurotrophic factor (BDNF), mitochondrial carrier homolog 2 (MTCH2), Fas apoptotic inhibitory molecule 2 (FAIM2), SH2B adaptor protein 1 (SH2B1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF), Niemann-Pick disease, type C1 (NPC1), melanocortin 4 receptor (MC4R) and potassium channel tetramerisation domain containing 15 (KCTD15). To investigate the relationship between obesity and these genes in the Japanese population, we genotyped 27 single-nucleotide polymorphisms (SNPs) in 14 genes from obese subjects (n=1129, body mass index (BMI) > or =30 kg m(-2)) and normal-weight control subjects (n=1736, BMI <25 kg m(-2)). The SNP rs10913469 in SEC16B (P=0.000012) and four SNPs (rs2867125, rs6548238, rs4854344 and rs7561317) in the TMEM18 gene (P=0.00015), all of which were in almost absolute linkage disequilibrium, were significantly associated with obesity in the Japanese population. SNPs in GNPDA2, BDNF, FAIM2 and MC4R genes were marginally associated with obesity (P<0.05). Our data suggest that some SNPs identified by genome-wide association studies in the Caucasians also confer susceptibility to obesity in Japanese subjects.

Hypothalamic neuronal histamine signaling in the estrogen deficiency-induced obesity.

Menopause is one of the triggers that induce obesity. Estradiol (E2), corticotropin-releasing hormone (CRH), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among E2, CRH, and histamine during the regulation of feeding behavior and obesity in rodents. Food intake was measured in rats after the treatment of E2, alpha-fluoromethyl histidine, a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine, or CRH antagonist. We measured food intake and body weight in wild-type mice or mice with targeted disruption of the histamine receptors (H1-R) knockout (H1KO mice). Furthermore, we investigated CRH content and histamine turnover in the hypothalamus after the E2 treatment or ovariectomy (OVX). We used immunohistochemical staining for estrogen receptors (ERs) in the histamine neurons. The E2-induced suppression of feeding was partially attenuated in rats pre-treated with alpha-fluoromethyl histidine or CRH antagonist and in H1KO mice. E2 treatment increased CRH content and histamine turnover in the hypothalamus. OVX increased food intake and body weight, and decreased CRH content and histamine turnover in the hypothalamus. In addition, E2 replacement reversed the OVX-induced changes in food intake and body weight in wild-type mice but not in H1KO mice. Immunohistochemical analysis revealed ERs were expressed on histamine neurons and western blotting analysis and pre-absorption study confirmed the specificity of ER antiserum we used. These results indicate that CRH and hypothalamic neuronal histamine mediate the suppressive effects of E2 on feeding behavior and body weight.

Hyperthermia-induced cardioprotection is potentiated by ischemic postconditioning in rats.

We tested the hypothesis that the protective effects of hyperthermia (HT) could be augmented by ischemic postconditioning (PostC) via enhancement of reperfusion-induced Akt phosphorylation. The role of the mitoKATP channel as an effecter to protect hearts against ischemia/reperfusion injury was also investigated. In isolated perfused heart experiments using a Langendorff apparatus, 30 min of no-flow global ischemia was followed by 120 min of reperfusion. Ischemic PostC, 5 cycles of 10-sec reperfusion/10-sec ischemia, was achieved at the initial moment of reperfusion. Hyperthermia (HT, 43 degrees C for 20 min) was applied 24 hr before ischemia onset. Ischemic PostC alone did not show significant protection, but HT did. The HT-induced protection in terms of infarct size, recovery of left ventricular performance, amount of released creatine kinase and apoptosis were enhanced by ischemic PostC. These protective effects were consistent with the levels of Akt phosphorylation 7 min after reperfusion and were completely blocked by the pretreatment with the phosphatidylinositol 3-kinase inhibitor wortmannin. HT-induced protection was also completely abolished by concomitant perfusion with 5-hydroxydecanoate (5HD, 100 microM), an inhibitor of the mitochondrial ATP-sensitive potassium (mitoKATP) channel. However, the potentiated protection by ischemic PostC remained, even in the presence of 5HD. In conclusion, ischemic PostC could potentiate the protective effects of HT possibly via enhancement of reperfusion-induced Akt phosphorylation. Although the opening of the mitoKATP channel is predominantly involved as an effecter in HT-induced protection, potentiated protection by ischemic PostC may involve mechanisms other than the mitoKATP channel.

Adrenomedullin improves cardiac expression of heat-shock protein 72 and tolerance against ischemia/reperfusion injury in insulin-resistant rats.

We recently reported that long-term treatment with pioglitazone restored cardiac Akt phosphorylation in response to hyperthermia (HT) and subsequent cardiac heat-shock protein 72 (HSP72) expression, in heredity insulin resistance rats via improvement of insulin sensitivity. Because adrenomedullin (AM) promotes Akt phosphorylation and attenuates myocardial ischemia/reperfusion injury, we tested the hypothesis that pretreatment with AM before HT could restore depressed Akt activation and cardiac HSP72 expression, thereby enhancing protection against ischemia/reperfusion injury in this model. At 16 wk of age, male insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats were treated with AM (0.05 microg/kg . /min iv) or vehicle for 60 min. Thereafter, HT (43 C for 20 min) or normothermia (NT; 37 C for 20 min) was applied. The heart was isolated 1 and 24 h after HT. 1) Either AM or HT induced myocardial Akt phosphorylation in a phosphatidylinositol 3-kinase-dependent manner, which was augmented by their combination. 2) Akt phosphorylation induced by HT, or a combination of HT and AM, was attenuated in insulin-resistant OLETF rat hearts. 3) The levels of Akt phosphorylation in response to AM and/or HT correlated with reperfusion-induced left ventricular functional recovery and amount of released creatine kinase during reperfusion. 4) AM protected the hearts of OLETF rats and LETO rats. Our results suggest that AM pretreatment could enhance HT-induced myocardial Akt phosphorylation and subsequent HSP72 expression in a phosphatidylinositol 3-kinase-dependent manner, in association with tolerance against ischemia/reperfusion injury. This intervention was effective even in insulin-resistant hearts.

Initial Japanese experience with intragastric balloon placement.

BACKGROUND: We introduced intragastric balloon placement in Japan and evaluated the initial data. METHODS: Between December 2004 and March 2008, intragastric balloons [BioEnterics Intragastric Balloon (BIB) system] were placed in 21 Japanese patients with obesity [six women, 15 men; mean age 40+/-9 years; mean body mass index (BMI) 40+/-9 kg/m2]. The inclusion criteria were morbid obesity (BMI>or=35 kg/m2), the presence of obesity-related disorders, and failure with conventional treatments for at least 6 months. The balloon was routinely removed under endoscopy after 5 months. RESULTS: No serious complications occurred, but in two of the 21 patients (9.5%), early removal (within 1 week) of the balloon was required due to continuous abdominal discomfort. Two other patients (9.5%) could not control their eating behavior and were considered unresponsive to the treatment, and their balloons were also removed before 5 months. Seventeen of the 21 patients (81%) finished the treatment, and the average weight loss and percent excess weight loss (%EWL) at the time the balloons were removed were 12+/-5 kg and 27+/-9%, respectively. Eight patients were followed for 1 year without intervention of consecutive bariatric surgery, and at that time, four of these patients had kept more than 20% of %EWL. The other patients regained their weight in the first year. CONCLUSIONS: Intragastric balloon placement is a safe and effective procedure in obese Japanese patients, and about half of the patients will maintain their weight loss after the balloon is removed.

Influence of systolic blood pressure and cigarette smoking on endothelial function in young healthy people.

BACKGROUND: Flow-mediated dilatation (FMD) of the brachial artery represents systemic endothelial function, so the relationship between FMD and blood pressure (BP) profile, in relation to the effects of cigarette smoking, was investigated in young healthy subjects. METHODS AND RESULTS: The 62 healthy subjects (14 females, 48 males; mean 29.7+/-5.5 years old), were divided into a smoking group (n=30) and non-smoking group (n=32). FMD was induced by reactive hyperemia. It was lower in the smoking group than in the non-smoking group (P<0.05). In the non-smoking group, there was an inverse correlation (r=-0.59, P<0.0005) between FMD and systolic BP (SBP), which was not recognized in the smoking group. Multiple stepwise regression analysis revealed that FMD was predicted by either the SBP or the brachial artery diameter in the non-smoking group, whereas it was predicted by the brachial artery diameter in the smoking group. Subdivision by cut-off value of SBP =120 mmHg demonstrated that although FMD with SBP <120 mmHg was preserved in subjects in the non-smoking group, it was depressed to a level comparable with SBP >or=120 mmHg in the smoking group. CONCLUSIONS: Highly-preserved FMD in subjects with SBP <120 mmHg appears to be impaired by cigarette smoking, resulting in a loss of association between FMD and SBP.

Lipoprotein (a) as a risk factor for silent cerebral infarction in hemodialysis patients.

In patients with chronic renal failure undergoing hemodialysis (HD), silent cerebral infarctions (SCIs) are associated with high mortality. Levels of lipoprotein (a) (Lp[a]) increase with renal dysfunction and may be a novel predictor for cerebrovascular events. We tested the hypothesis that increased Lp(a) levels correlate with the occurrence of SCI in HD patients. Using cranial magnetic resonance imaging findings, we divided 62 Japanese patients undergoing HD into with-SCI group (61 +/- 7 years, mean +/- SD, n = 34) and without-SCI group (60 +/- 6 years, n = 28). We compared the sex, body mass index, metabolic profiles, Lp(a) levels, and smoking habits between the 2 groups. The following observations were noted: (1) The number of patients with diabetes or hypertension did not differ between the 2 groups. (2) The levels of Lp(a) were higher in the with-SCI group in comparison with the without-SCI group (P < .0001). (3) The proportion of smokers was higher in the with-SCI group than in the without-SCI group (P < .05). (4) Plasma levels of high-density lipoprotein cholesterol were lower, whereas uric acid was higher, in the with-SCI group than in the without-SCI group (P < .001 and P < .05, respectively). (5) Multiple logistic regression analysis identified Lp(a) levels as being significantly associated with the presence of SCI (odds ratio, 1.23; 95% confidence interval, 1.09-1.38; P < .0001). This study indicates that patients with chronic renal failure, who are maintained on HD, exhibit an increased prevalence of SCI and that Lp(a) is significantly associated with the presence of SCI in HD patients.

Role of interleukin-6 levels in cardiovascular autonomic dysfunction in type 2 diabetic patients.

PURPOSE: Increased serum interleukin-6 (IL-6) levels are associated with an increased risk of cardiovascular disease, and cardiovascular autonomic dysfunction is associated with high mortality in type 2 diabetic patients. However, the relationship between IL-6 levels and cardiovascular autonomic dysfunction has not been fully elucidated. The aim of this study was to determine whether serum IL-6 levels are associated with cardiovascular autonomic dysfunction in type 2 diabetic patients. METHODS: Eighty type 2 diabetic patients who did not have organic heart disease were categorized into a high IL-6 group (>2.5 pg/ml, n = 40, age 59 +/- 12 years) or a non-high IL-6 group (<2.5 pg/ml, n = 40, 61 +/- 12 years). Cardiac autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations and (123)I-metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: The body mass index values (BMI), fasting insulin levels and homeostasis model assessment index values were higher in the high IL-6 group than in the non-high IL-6 group (p < 0.01). Early and delayed (123)I-MIBG myocardial uptake values were lower (p < 0.01), and the percent washout rate of (123)I-MIBG was higher (p < 0.05) in the high IL-6 group than in the non-high IL-6 group. Furthermore, multiple regression analysis revealed that the IL-6 level was independently predicted by the BMI and the myocardial uptake of (123)I-MIBG during the delayed phase. CONCLUSIONS: The results indicate that elevated IL-6 levels are associated with depressed cardiovascular autonomic function and obesity in type 2 diabetic patients.

High-sensitivity C-reactive protein level is a significant risk factor for silent cerebral infarction in patients on hemodialysis.

In patients with chronic renal failure on hemodialysis (HD), silent cerebral infarctions (SCIs) are associated with high mortality. The levels of high-sensitivity C-reactive protein (HSCRP), a marker of inflammation and atherosclerosis, elevate with increasing renal dysfunction. We tested the hypothesis that increased HSCRP levels correlate with the occurrence of SCI in HD patients. By brain magnetic resonance imaging findings, we divided 54 patients undergoing HD into a with-SCI group (61 +/- 8 years, n = 30) and a without-SCI group (60 +/- 7 years, n = 24). We compared sex, body mass index, metabolic profiles, HSCRP levels, and smoking habits in Japanese patients on HD with and without SCI. We made the following observations: (1) The number of patients with diabetes or hypertension did not differ between the 2 groups. (2) The levels of HSCRP were higher in the with-SCI group in comparison with the without-SCI group (P < .0001). (3) The proportion of smokers was higher in the with-SCI group than in the without-SCI group (P < .05). (4) Plasma levels of high-density lipoprotein cholesterol were lower, whereas uric acid was higher, in the with-SCI group than in the without-SCI group (P < .05 and P < .0001, respectively). (5) Multivariate logistic analysis identified HSCRP levels as being significantly associated with the presence of SCI (odds ratio, 1.61; 95% confidence interval, 1.17-2.85; P < .001). This study indicates that patients in chronic renal failure who are maintained on HD exhibit an increased prevalence of SCI and that HSCRP is significantly associated with the presence of SCI in HD patients.