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Background Although neuroendocrine tumors (NETs) are rare, the number of patients with NET is increasing. However, in Japan, there have been no epidemiological studies on NET since 2005; thus, the prevalence of NET remains unknown. Methods We reported the epidemiology of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [pancreatic neuroendocrine tumors (PNETs) and gastrointestinal neuroendocrine tumors (GI-NETs)] in Japan in 2005. Here, we conducted the second nationwide survey on patients with GEP-NETs who received treatment in 2010. Results A total of 3,379 patients received treatment for PNETs in 2010, representing a 1.2-fold increase in the number of patients from 2005 to 2010. The prevalence was estimated to be 2.69/100,000, with an annual onset incidence of 1.27/100,000 in 2010. Non-functioning tumor (NF)-PNETs comprised 65.5 % of cases followed by insulinoma (20.9 %) and gastrinoma (8.2 %). Interestingly, the number of patients with NF-PNETs increased ~1.8 fold since 2005. A total of 19.9 % of patients exhibited distant metastasis at initial diagnosis; 4.3 % had complications with multiple endocrine neoplasia type 1 (MEN-1), and only 4.0 % had NF-PNETs associated with MEN-1. Meanwhile, an estimated 8,088 patients received treatment for GI-NETs, representing a ~1.8-fold increase since 2005. The prevalence was estimated to be 6.42/100,000, with an annual onset incidence of 3.51/100,000. The locations of GI-NETs varied: foregut, 26.1 %; midgut, 3.6 %; and hindgut, 70.3 %. Distant metastasis and complications with MEN-1 were observed in 6.0 and 0.42 % at initial diagnosis, respectively. The frequency of carcinoid syndrome in patients with GI-NETs was 3.2 %. Conclusion We clarified the epidemiological changes in GEP-NETs from 2005 to 2010 in Japan.

Cerebral amyloid angiopathy (CAA) results from amyloid-β deposition in the cerebrovasculature. It is frequently accompanied by Alzheimer’s disease and causes dementia. We recently demonstrated that in a mouse model of CAA, taxifolin improved cerebral blood flow, promoted amyloid-β removal from the brain, and prevented cognitive dysfunction when administered orally. Here we showed that taxifolin inhibited the intracerebral production of amyloid-β through suppressing the ApoE–ERK1/2–amyloid-β precursor protein axis, despite the low permeability of the blood–brain barrier to taxifolin. Higher expression levels of triggering receptor expressed on myeloid cell 2 (TREM2) were associated with the exacerbation of inflammation in the brain. Taxifolin suppressed inflammation, alleviating the accumulation of TREM2-expressing cells in the brain. It also mitigated glutamate levels and oxidative tissue damage and reduced brain levels of active caspases, indicative of apoptotic cell death. Thus, the oral administration of taxifolin had intracerebral pleiotropic neuroprotective effects on CAA through suppressing amyloid-β production and beneficially modulating proinflammatory microglial phenotypes.

Background There have been few epidemiological studies on gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Japan. Methods We examined the epidemiology of GEP-NETs [pancreatic endocrine tumors (PETs) and gastrointestinal neuroendocrine tumors (GI-NETs)] in Japan in 2005 using a nationwide stratified random sampling method. Results A total of 2,845 individuals received treatment for PETs. Prevalence was estimated as 2.23/100,000 with an annual onset incidence of 1.01/100,000. Non-functioning tumor (NF)-PET constituted 47.4%, followed by insulinoma (38.2%) and gastrinoma (7.9%). Distant metastases were reported in 21% patients with NF-PETs and occurred more frequently as tumor size increased (>2 cm). Multiple endocrine neoplasia type 1 (MEN-1) was detected in 10% of PETs but only in 6.1% of NF-PETs. NF-PETs were detected incidentally by physical examination in 24% patients. In 2005, an estimated 4,406 patients received treatment for GI-NETs. Prevalence was estimated as 3.45/100,000, with an annual onset incidence of 2.10/100,000. The locations of GI-NETs varied: foregut, 30.4%; midgut, 9.6%; and hindgut, 60.0%. Distant metastases were observed in 6%. Lymph node metastases occurred more frequently as tumor size increased (>1 cm). The frequency of MEN-1 complications was 1%. Physical examination revealed GI-NETs in 44% patients. The frequency of symptomatic GI-NETs was 3.4%. Interestingly, 77.1% of patients with foregut GI-NETs had type A gastritis. Conclusion Our results show there are large differences in GEP-NETs between Japan and Western nations, primarily due to differences in the presence of MEN-1 in NF-PETs and the location, symptomatic status, and prevalence of malignancy in GI-NETs.

Microglia maintain brain homeostasis and modulate neuroinflammation and are implicated in the pathogenesis of various neurological diseases such as Alzheimer’s disease. In this study, we found that in lipopolysaccharide (LPS)-stimulated microglia, the endoplasmic reticulum (ER) stress-related eIF-2α–ATF4 pathway plays significant roles in TNF-α and IL-6 production, as well as in the inflammasome-mediated production of IL-1β. Furthermore, our analysis revealed that oxytocin (OT), a nonapeptide synthesized in the hypothalamus, suppressed the production of these proinflammatory cytokines by inhibiting activation of the eIF-2α–ATF4 pathway. Our findings therefore suggest a novel anti-inflammatory axis of OT in activated microglia, which would be helpful for developing the novel effective strategies for regulating microglia-associated neuroinflammation.

Hemodynamic overload in the heart can trigger maladaptive hypertrophy of cardiomyocytes. A key signaling event in this process is nuclear acetylation by histone deacetylases and p300, an intrinsic histone acetyltransferase (HAT). It has been previously shown that curcumin, a polyphenol responsible for the yellow color of the spice turmeric, possesses HAT inhibitory activity with specificity for the p300/CREB-binding protein. We found that curcumin inhibited the hypertrophy-induced acetylation and DNA-binding abilities of GATA4, a hypertrophy-responsive transcription factor, in rat cardiomyocytes. Curcumin also disrupted the p300/GATA4 complex and repressed agonist- and p300-induced hypertrophic responses in these cells. Both the acetylated form of GATA4 and the relative levels of the p300/GATA4 complex markedly increased in rat hypertensive hearts in vivo. The effects of curcumin were examined in vivo in 2 different heart failure models: hypertensive heart disease in salt-sensitive Dahl rats and surgically induced myocardial infarction in rats. In both models, curcumin prevented deterioration of systolic function and heart failure-induced increases in both myocardial wall thickness and diameter. From these results, we conclude that inhibition of p300 HAT activity by the nontoxic dietary compound curcumin may provide a novel therapeutic strategy for heart failure in humans.

We report case details of a morbidly obese patient with type 2 diabetes mellitus (T2DM) who became a failure of diabetes remission after laparoscopic sleeve gastrectomy (LSG). He had a marked improvement of hyperglycemia after the revision surgery using Roux‐en‐Y gastric bypass (RYGB), where passage failure of a solid food intake at the gastric angle portion disappeared after the revision surgery. Interestingly, he showed improvements of insulin and a marked glicentin secretions with minor changes in glucagon related peptide 1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) secretions in the oral glucose tolerance test OGTT after the RYGB surgery compared with post‐LSG. Although a marked increase in glucose‐induced glicentin secretion after RYGB surgery with increased insulin secretion, further studies are needed to confirm if the increased glicentin secretion after RYGB surgery is linked to stimulation of insulin secretion. Glucose‐induced hypersecretion of glicentin was found in patients undergone RY‐GB surgery. Glicentin stimulated glucose‐induced insulin secretion. Glicentin hypersecretion is related to diabetes remission after RY‐GB surgery.

Objective The expression level of monocyte chemoattractant protein-1 (MCP-1) is increased in atherosclerotic regions, inducing monocyte migration to the blood vessel wall. Although the serum MCP-1 concentration is higher in patients with than without cardiovascular disease, the precise correlations between the serum MCP-1 concentration and factors associated with smoking and atherosclerosis are unknown. Methods The serum MCP-1 concentration was measured using an enzyme-linked immunosorbent assay in 207 consecutive smokers who visited our smoking cessation clinic. Results Sex-adjusted analysis of smokers revealed that the MCP-1 concentration was positively correlated with age (β = 0.311), smoking duration (β = 0.342), systolic blood pressure (β = 0.225), and diastolic blood pressure (β = 0.137) but not with the body mass index. Multivariate regression analysis showed that smoking duration and systolic blood pressure were independent determinants of the MCP-1 concentration. Conclusions The MCP-1 concentration was positively correlated with blood pressure among smokers. Long-term smokers with high blood pressure may be more susceptible to plaque rupture at atherosclerotic lesion sites.

The blood levels of Adiponectin, anti-inflammatory and anti-arteriosclerotic adipocytokine, decrease due to smoking and obesity. Cigarette smokers are generally known to gain weight after smoking cessation (SC). Nevertheless, precise changes in serum adiponectin levels after SC and specific effects of abdominal obesity on those changes remain unknown. The objective of this study was to elucidate the changes in serum adiponectin levels after SC and the effects of abdominal obesity on those changes. In 86 patients (56 males and 30 females) who had successfully quit smoking, serum adiponectin levels were measured using an enzyme-linked immunosorbent assay at baseline and 1 year after beginning SC. Body mass index and waist circumference (WC) were significantly increased 1 year after beginning SC. Adiponectin levels, however, did not change after SC. Using the median ΔWC (+2.8%) as the cutoff point, patients were then divided into two groups. The percent change in adiponectin levels from baseline to 1 year was significantly greater in the ΔWC < median group (-1.1%) than in the ΔWC ≥ median group (+8.1%) (p = 0.011). Despite weight gain and increased abdominal obesity, serum adiponectin levels did not decrease after SC. Therefore, the beneficial effect of SC may eliminate the adverse effects of subsequent weight gain. Conversely, patients with less abdominal obesity had increased adiponectin levels 1 year after SC. Therefore, in such patients, the beneficial effect of SC on adiponectin levels is apparent.

Antiatherogenic Effect of Pioglitazone in Type 2 Diabetic Patients Irrespective of the Responsiveness to Its Antidiabetic Effect Noriko Satoh , MD, PHD 1 , Yoshihiro Ogawa , MD, PHD 2 , Takeshi Usui , MD, PHD 1 , Tetsuya Tagami , MD, PHD 1 , Shigeo Kono , MD, PHD 1 , Hiroko Uesugi , MD, PHD 3 , Hiroyuki Sugiyama , MD, PHD 3 , Akira Sugawara , MD, PHD 1 , Kazunori Yamada , MD, PHD 1 , Akira Shimatsu , MD, PHD 1 , Hideshi Kuzuya , MD, PHD 1 and Kazuwa Nakao , MD, PHD 2 1 Diabetes Center and Clinical Research Institute of Kyoto National Hospital, Kyoto, Japan 2 Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan 3 Department of Internal Medicine, Saiseikai Noe Hospital, Osaka, Japan Address correspondence and reprint requests to Yoshihiro Ogawa, MD, PhD, Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. E-mail: ogawa.mmm{at}mri.tmd.ac.jp Abstract OBJECTIVE —Thiazolidinediones (TZDs), a class of insulin-sensitizing agents used clinically to treat type 2 diabetes, are also antiatherogenic. This study was designed to elucidate the relationship between the antiatherogenic and antidiabetic effects of pioglitazone, a TZD, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS —A total of 136 Japanese type 2 diabetic patients were included and divided into two groups: the pioglitazone-treated group (30 mg daily for 3 months) ( n = 70) and the untreated control group ( n = 66). The changes in glycolipid metabolism as well as plasma high-sensitivity C-reactive protein (CRP), leptin, adiponectin, and pulse wave velocity (PWV) were monitored to analyze the relationship between the antiatherogenic and antidiabetic effects of pioglitazone. RESULTS —The pioglitazone treatment significantly reduced hyperglycemia, hyperinsulinemia, and HbA 1c levels and increased plasma adiponectin concentrations relative to the control group ( P < 0.01). It also significantly decreased CRP and PWV ( P < 0.01). The antiatherogenic effect was observed in both the nonresponders showing <1% of reduction in HbA 1c ( n = 30) and responders showing >1% of reduction ( n = 40). ANCOVA revealed that treatment with pioglitazone was associated with a low CRP and PWV, independent of the changes in parameters related to glucose metabolism. CONCLUSIONS —This study represents the first demonstration of the antiatherogenic effect of pioglitazone in both nonresponders and responders with respect to its antidiabetic effect and suggests that pioglitazone can exert its antiatherogenic effect independently of its antidiabetic effect. CRP, C-reactive protein DBP, diastolic blood pressure FPG, fasting plasma glucose HOMA-IR, homeostasis model assessment for insulin resistance IMT, intima-media wall thickness IRI, immunoreactive insulin PPAR-γ, peroxisome proliferator-activated receptor-γ PWV, pulse-wave velocity SBP, systolic blood pressure TZD, thiazolidinedione VSMC, vascular smooth muscle cell Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted June 1, 2003. Received February 23, 2003. DIABETES CARE

A recent clinical trial revealed that highly purified eicosapentaenoic acid (EPA), an n-3 polyunsaturated fatty acid, reduces the incidence of cardiovascular diseases. However, the detailed mechanism underlying the anti-atherogenic effect of EPA is still poorly understood. In this study, we examined the effect of EPA on cardio-ankle vascular index (CAVI), a new index of arterial stiffness that is less influenced by blood pressure (BP), as well as on serum amyloid A-low-density lipoprotein (SAA–LDL), an oxidized LDL (oxLDL), in the metabolic syndrome. Ninety-two obese Japanese subjects with metabolic syndromes were randomly divided into two groups ( n =46): the EPA-treated group (1.8 g administered daily for 3 months) and the control group. Measurements were taken to assess the changes in glucose-lipid metabolism, SAA–LDL, C-reactive protein (CRP), leptin, adiponectin and pulse wave velocity (PWV), and CAVI. EPA treatment significantly reduced the levels of immunoreactive insulin, triglycerides, SAA–LDL, CRP, PWV and CAVI and increased the levels of adiponectin relative to the control group for 3 months ( P <0.05). Stepwise multivariate linear regression analysis revealed that the only significant determinant for a decrease in CAVI by EPA is a reduction in SAA–LDL ( P <0.05). Moreover, the EPA-induced reduction of SAA–LDL was only significantly correlated with a decrease in total cholesterol and an increase in adiponectin ( P <0.05). This study is the first demonstration that EPA improves arterial stiffness and is less influenced by BP, possibly through the suppression of SAA–LDL, thereby leading to a reduction in the frequency of cardiovascular disease development in metabolic syndrome.