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Nonalcoholic fatty liver disease (NAFLD) is often accompanied by metabolic disorders such as metabolic syndrome and type 2 diabetes (T2DM). Heat shock response (HSR) is one of the most important homeostatic abilities but is deteriorated by chronic metabolic insults. Heat shock (HS) with an appropriate mild electrical stimulation (MES) activates HSR and improves metabolic abnormalities including insulin resistance, hyperglycemia and inflammation in metabolic disorders. To analyze the effects of HS + MES treatment on NAFLD biomarkers, three cohorts including healthy men (two times/week, n = 10), patients with metabolic syndrome (four times/week, n = 40), and patients with T2DM (n = 100; four times/week (n = 40) and two, four, seven times/week (n = 20 each)) treated with HS + MES were retrospectively analyzed. The healthy subjects showed no significant alterations in NAFLD biomarkers after the treatment. In patients with metabolic syndrome, many of the NAFLD steatosis markers, including fatty liver index, NAFLD-liver fat score, liver/spleen ratio and hepatic steatosis index and NAFLD fibrosis marker, aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, were improved upon the treatment. In patients with T2DM, all investigated NAFLD steatosis markers were improved and NAFLD fibrosis markers such as the AST/ALT ratio, fibrosis-4 index and NAFLD-fibrosis score were improved upon the treatment. Thus, HS + MES, a physical intervention, may become a novel treatment strategy for NAFLD as well as metabolic disorders.

Heat shock protein 72 (HSP72) is a major inducible molecule in the heat shock response that enhances intracellular stress tolerance. Decreased expression of HSP72 is observed in type 2 diabetes, which may contribute to the development of insulin resistance and chronic inflammation. We used HSP72 knockout (HSP72-KO) mice to investigate the impact of HSP72 on glucose metabolism and endoplasmic reticulum (ER) stress, particularly in the liver. Under a high-fat diet (HFD) condition, HSP72-KO mice showed glucose intolerance, insulin resistance, impaired insulin secretion, and enhanced hepatic gluconeogenic activity. Furthermore, activity of the c-Jun NH2-terminal kinase (JNK) was increased and insulin signaling suppressed in the liver. Liver-specific expression of HSP72 by lentivirus (lenti) in HFD-fed HSP72-KO mice ameliorated insulin resistance and hepatic gluconeogenic activity. Furthermore, increased adipocyte size and hepatic steatosis induced by the HFD were suppressed in HSP72-KO lenti-HSP72 mice. Increased JNK activity and ER stress upon HFD were suppressed in the liver as well as the white adipose tissue of HSP72-KO lenti-HSP72 mice. Thus, HSP72 KO caused a deterioration in glucose metabolism, hepatic gluconeogenic activity, and β-cell function. Moreover, liver-specific recovery of HSP72 restored glucose homeostasis. Therefore, hepatic HSP72 may play a critical role in the pathogenesis of type 2 diabetes.

The gastrointestinal tract is considered an important endocrine organ for controlling glucose homeostasis via the production of incretins. A 21-year-old man emergently underwent total colectomy due to severe ulcerative colitis, and overt diabetes became evident. Weekly administration of a glucagon-like peptide (GLP)-1 receptor agonist (RA) dramatically improved his glucose control. Levels of GLP-1 or gastric inhibitory polypeptide (GIP) were low at the baseline in the duodenum and serum of the patient. After 11 months of GLP-1RA treatment, his HbA1c worsened again, and intensive insulin therapy was necessary to control his glucose levels. Our report may explain the significance of residual incretin for maintaining the pancreatic β-cell function.

Cell stresses, such as ER stress or oxidative stress are considered to be key mediators in pathophysiology of type 2 diabetes. Heat shock protein (HSP) 72, a major inducible HSP against heat, serves to protect cells from those cellular stresses and works in protein quality control. Induction of HSP72 improves glucose intolerance in type 2 diabetic model mice. In this study, we investigated glucose metabolism in whole body HSP72 deficient (KO) mice. The effects of hepatic HSP72 induction in KO mice were also investigated. KO mice and control mice were subjected to a high-fat diet regimen. Metabolic parameters and pathophysiological examination were performed. HSP72 was overexpressed in mice by lenti-virus to investigate the role of HSP72 in liver. There were no significant differences in body weight and food intake between two groups. Fasting and random-fed blood glucose levels were significantly higher in KO mice than those in control mice. The fasting insulin level was significantly lower in KO mice. Upon glucose challenge, blood glucose levels were higher in KO mice. On insulin tolerance test, KO mice exhibited insulin resistant phenotype. Visceral fat mass was increased and hepatic steatosis was obvious in KO mice with increased SREBP-1c mRNA expression. Upon insulin stimulation, phosphorylation of Akt was decreased in KO liver, with increased activation of JNK. Hepatic gluconeogenesis was not suppressed in KO accompanied by increased gluconeogenic enzymes. When restoring HSP72 expression in liver by lenti-virus on KO mice, blood glucose, hepatic steatosis and gluconeogenesis were ameliorated. Interestingly, visceral fat size and macrophage infiltration were both reversed by hepatic HSP72 induction. Deficiency of HSP72 leads to type 2 diabetic phenotype. As induction of HSP72 in liver is beneficial to improve glucose homeostasis in KO, the abundance of HSP72 in liver is critical in diabetic pathophysiology, and appropriate HSP72 induction may serve as a target in the treatment of type 2 diabetes. Disclosure T. Kondo: None. S. Kitano: None. N. Miyakawa: None. T. Watanabe: None. R. Goto: None. K. Ono: None. M. Igata: None. J. Kawashima: None. H. Motoshima: None. T. Matsumura: None. E. Araki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi. Funding Japan Society for the Promotion of Science

Because the renin-angiotensin-aldosterone system influences glucose homeostasis, the mineralocorticoid receptor (MR) signal in pancreatic islets may regulate insulin response upon glucose load. Glucagon-like peptide-1 (GLP-1) production is stimulated by interleukin-6 (IL-6) in pancreatic &alpha, cells. To determine how glucose homeostasis is regulated by interactions of MR, IL-6 and GLP-1 in islets, we performed glucose tolerance and histological analysis of islets in primary aldosteronism (PA) model rodents and conducted in vitro experiments using &alpha, cell lines. We measured active GLP-1 concentration in primary aldosteronism (PA) patients before and after the administration of MR antagonist eplerenone. In PA model rodents, aldosterone decreased insulin-secretion and the islet/pancreas area ratio and eplerenone added on aldosterone (E+A) restored those with induction of IL-6 in &alpha, cells. In &alpha, cells treated with E+A, IL-6 and GLP-1 concentrations were increased, and anti-apoptotic signals were enhanced. The E+A-treatment also significantly increased MR and IL-6 mRNA and these upregulations were blunted by MR silencing using small interfering RNA (siRNA). Transcriptional activation of the IL-6 gene promoter by E+A-treatment required an intact MR binding element in the promoter. Active GLP-1 concentration was significantly increased in PA patients after eplerenone treatment. MR signal in &alpha, cells may stimulate IL-6 production and increase GLP-1 secretion, thus protecting pancreatic &beta, cells and improving glucose homeostasis.

MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally regulate gene expression and have been shown to participate in almost every cellular process. Several miRNAs have recently been implicated in glucose metabolism, but the roles of miRNAs in insulin-resistant conditions, such as obesity or type 2 diabetes, are largely unknown. Herein, we focused on miR-222, the expression of which was increased in the livers of high fat/high sucrose diet-fed mice injected with gold thioglucose (G+HFHSD). Overexpression of miR-222 in primary mouse hepatocytes attenuated Akt phosphorylation induced by insulin, indicating that miR-222 negatively regulates insulin signaling. As per in silico analysis, miR-222 potentially binds to the 3' untranslated region (3' UTR) of the IRS-1 gene, a key insulin signaling molecule. In fact, IRS-1 protein expression was decreased in the livers of G+HFHSD-fed mice. We further confirmed a direct interaction between miR-222 and the 3' UTR of IRS-1 via luciferase assays. Our findings suggest that up-regulation of miR-222 followed by reduction in IRS-1 expression may be a viable mechanism of insulin resistance in the liver.

Objective Silver-containing carboxymethylcellulose fiber dressing (Aquacel ® -Ag) has been used to treat burns and ulcers with a large amount of exudate. The aim of this investigation was to confirm whether Aquacel ® -Ag has beneficial effects when it is used as nasal packing. Methods We included 44 patients who underwent bilateral endoscopic sinus surgery due to chronic rhino-sinusitis. Beschitin-F ® or Aquacel ® -Ag was packed postoperatively into the bilateral middle meatus. Patient's comfort was recorded using a VAS, as well as wound healing, postoperative bleeding and local infection. Postoperative-specific organisms were also evaluated from the removed packing materials located in the middle meatus when they were removed on the 4th day after surgery. Results The scores for nasal obstruction and pain were not statistically different in each group. Postoperative bacteriologic studies indicated marked differences. Coagulase-negative staphylococci were predominant and potential pathogens were recovered in a few cases in the Aquacel ® -Ag group. In contrast, potential pathogens, including Streptococcus pneumonia , Haemophilus influenza , and Gram-negative rods, were predominant in the Beschitin-F ® group. Conclusion The results indicate that Aquacel ® -Ag might contribute to hemostasis, wound healing, and patient comfort after endonasal surgery, similar to Beschitin-F ® . Additionally, it may have advantages concerning the prevention of postoperative infection.

Aims/Introduction The goal of the study was to examine the effects of sitagliptin dose-up or glimepiride dose-up in Japanese patients with type 2 diabetes who were controlled inadequately by sitagliptin and glimepiride in combination. Materials and Methods A multicenter, prospective, randomized, open-label study was carried out in 50 patients with type 2 diabetes treated with sitagliptin and low-dose glimepiride. The patients were randomly assigned to receive the addition of 50 mg/day sitagliptin or 0.5 mg/day glimepiride. The primary end-point was the percentage change in glycated hemoglobin (HbA1c). Results During a follow-up period, the difference in the percentage changes in HbA1c between the two groups was not significant (P = 0.13). However, HbA1c was significantly decreased by glimepiride dose-up (P

To assess the efficacy and safety of adding sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in subjects with type 2 diabetes inadequately controlled with multiple daily insulin injections therapy (MDI). HbA1c, 1,5-anhydroglucitol (1,5-AG), body mass index (BMI), insulin doses, six-point self-measured plasma glucose (SMPG) profiles were assessed before, after 12 weeks, and after 24 weeks of MDI with 50 mg/day of sitagliptin in 40 subjects with type 2 diabetes. Safety endpoints included hypoglycemia and any adverse events. HbA1c significantly decreased during the first 12 weeks ( -0.64±0.60%), and was sustained over 24 weeks ( -0.69±0.85%). 1,5-AG increased significantly from 7.5±4.5 μg/mL at baseline to 9.6±5.5 μg/mL after 24 weeks. The bolus insulin dose at 12 weeks was decreased, and the mean plasma glucose, the SD of daily glucose, M-value, and the mean amplitude of glycemic excursions (MAGE) also decreased significantly as compared with baseline values. BMI and frequency of hypoglycemia were not changed significantly. Univariate linear regression analyses revealed that % change in HbA1c was significantly associated with BMI, and % changes in the indexes of glycemic instability (SD of daily glucose and MAGE) were significantly associated with age. In conclusion, adding sitagliptin to MDI significantly improved glycemic control and decreased the daily glucose fluctuation in subjects with type 2 diabetes inadequately controlled with MDI, without weight gain or an increase in the incidence of hypoglycemia. This trial was registered with UMIN (no. UMIN000010157).

Activation of heat shock response (HSR) improves accumulated visceral adiposity and metabolic abnormalities in type 2 diabetes. To identify the optimal intervention strategy of the activation of the HSR provided by mild electrical stimulation (MES) with heat shock (HS) in type 2 diabetes. This study was a prospective, frequency-escalating, randomized, open-label, triple-arm trial in Japan. A total of 60 obese type 2 diabetes patients were randomized into three groups receiving two, four, or seven treatments per week for 12 weeks. No adverse events were identified. MES + HS treatment (when all three groups were combined), significantly improved visceral adiposity, glycemic control, insulin resistance, systemic inflammation, renal function, hepatic steatosis and lipid profile compared to baseline. The reduction in HbA1c was significantly greater among those treated four times per week (−0.36%) or seven times per week (−0.65%) than among those treated two times per week (−0.10%). The relative HbA1c levels in seven times per week group was significantly decreased when adjusted by two times per week group (−0.55%. p = 0.001). This research provides the positive impact of MES + HS to treat obese patients with type 2 diabetes mellitus.

Aims/Introduction: Several experimental studies have shown that ezetimibe improves steatosis and insulin resistance in the liver. This suggests that ezetimibe may improve glucose metabolism, as well as lipid metabolism, by inhibiting hepatic lipid accumulation. Therefore, we compared HbA1c levels after 3 months ezetimibe treatment with baseline levels in patients with type 2 diabetes and examined the factors associated with reductions in HbA1c following ezetimibe administration. Materials and Methods: Lipid profiles, hepatic function, and HbA1c were assessed before and after 3 months treatment with 10 mg/day ezetimibe in 96 patients with type 2 diabetes and hypercholesterolemia. Regression analysis was used to investigate associations between metabolite levels and the percentage change in HbA1c. Results: Low-density lipoprotein–cholesterol was significantly lower after 3 months treatment compared with baseline, and HbA1c decreased in approximately 50% of patients. Univariate linear regression analyses showed that changes in HbA1c were significantly associated with serum alanine aminotransferase (ALT), the aspartate aminotransferase (AST)/ALT ratio, and age. Two-tailed chi-square tests revealed that serum ALT ≥35 IU/L and an AST/ALT ratio

Aims/Introduction: Multidetector computed tomography (MDCT) coronary angiography has been applied as a tool for non-invasive evaluation of the coronary arteries. The purpose of the present study was to evaluate the effectiveness of MDCT in screening for coronary artery disease (CAD), and to identify the indications for screening in diabetes patients with CAD. Materials and Methods: The study population consisted of 52 Japanese type 2 diabetes patients who underwent examination with a 64-slice MDCT scanner, electrocardiogram (ECG), echocardiography and ultrasonographic scanning of the carotid arteries. Regression analysis was carried out to assess the correlation between MDCT results and CAD risk factors. Results: Stenosis of the coronary artery was detected in 19/52 patients. Of the 19 patients, 7 patients had no symptoms, including chest pain, and no ischemic changes in ECG. Significant differences between patients with stenosis and those without stenosis were detected by mean IMT (1.21 vs 0.95 mm), and duration of diabetes (20 vs 13 years). Two-tailed χ2-test showed that a duration of diabetes of more than 20 years (odds ratio 6.222) and more than 1.1 mm of mean-IMT (odds ratio 4.600) significantly correlated with the stenosis. Conclusions: It was shown that MDCT is useful in detecting coronary artery stenosis in diabetic patients without symptoms of CAD or ECG abnormality, and the predictors of CAD are mean IMT and duration of diabetes. It is recommended that patients with more than 1.1 mm mean IMT at the carotid artery and/or more than 20 years duration of diabetes should be screened for CAD by carrying out MDCT.

Objective In hypertensive patients, primary aldosteronism (PA) is the most prevalent type of secondary hypertension, and screening for PA has become very important. Calcium channel blockers (CCB) are widely used to treat hypertension, but most CCBs stimulate plasma renin activity (PRA) and increase plasma aldosterone concentration (PAC), both of which are used in the screening for PA. The aim of this study was to determine whether the newly introduced CCB, azelnidipine, affects PRA and PAC. Methods 40 hypertensive patients were treated with 16 mg of azelnidipine for 4 weeks. Results Azelnidipine treatment in drug-naive (DN) cases significantly decreased systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). PRA and PAC in the DN group on azelnidipine treatment were indistinguishable from those in the DN group before treatment. Compared with other CCB treatments such as amlodipine, manidipine and slow-release nifedipine, azelnidipine showed comparable or significant reductions in SBP, DBP and HR. In patients who were switched from other CCBs to azelnidipine, PRA and PAC were decreased, except for PAC on amlodipine treatment. Since the PRA reduction rate exceeded that of PAC, the aldosterone/renin ratio (ARR) was significantly increased in those on azelnidipine treatment who had been switched from manidipine or nifedipine treatment, suggesting the restoration of possibly underestimated ARR values. Conclusion These data indicate that azelnidipine does not affect PRA or PAC, suggesting that azelnidipine could be a useful antihypertensive CCB while undergoing PA screening.

An association between remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome and insulin or dipeptidyl peptidase-4 (DPP4) inhibitor therapy were previously reported. We encountered four cases of RS3PE syndrome with type 2 diabetes mellitus or impaired glucose tolerance (IGT) without insulin or DPP4 inhibitor medication.

Objective Intranasal corticosteroid sprays (INCSs) are commonly used for therapy of allergic rhinitis (AR). Adherence to regular use of INCSs is influenced by patient perception and preferences of products. The study objective was to compare perceived sensory attributes of fluticasone furoate nasal spray (FFNS) and mometasone furoate nasal spray (MFNS) in AR patients. Methods In a multicenter, randomized, crossover, prospective study, 40 seasonal AR patients were administered both FFNS and MFNS for 2 weeks each in a crossover fashion, for a total of 4 weeks. Patients completed questionnaires for each product regarding perceived sensory attributes at the end of each two-week period of product administration. Results FFNS was significantly preferred over MFNS. Significantly, fewer subjects perceived a bitter taste ( p = 0.01), medication running down their throat ( p = 0.033), and medication running out of their nose ( p = 0.002) with FFNS. MFNS was more frequently reported to induce nasal irritation ( p = 0.012), sneezing ( p = 0.017), and rhinorrhea ( p = 0.007) compared to FFNS. Interestingly, these findings were markedly observed in females. Medicine dripping out of the nose and nasal shooting were the most common problems reported for MFNS with a higher proportion of subjects who felt moderate-to-severe discomfort. Overall, 52.5% of patients expressed a preference for FFNS compared with 22.5% for MFNS. Conclusion Several perceived sensory attributes of FFNS were rated significantly superior to MFNS. FFNS may contribute to enhanced treatment outcomes in AR patients due to improved treatment adherence.

Considering possible tumorigenic activity of cyclooxygenase (COX) isozymes in myeloma, we examined expression levels of COX-1 and -2 in seven human myeloma cell lines (ARH-77, IM-9, RPMI-8226, HPC, HS-Sultan, TSPC-1, and U-266). As analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR), all the cell lines constitutively expressed COX-1, while COX-2 levels markedly varied among different cell lines. Induction of COX-2 by phorbol ester was observed in RPMI-8226 and HPC cells. In contrast, COX-2 was constitutively expressed in ARH-77 and IM-9 cells. Moreover, the high expression level of COX-2 protein in ARH-77 cells was verified by Western blotting. Intact cells of ARH-77 converted 14C-labeled arachidonic acid to prostaglandin E2, F2alpha, and D2, and this activity was dose-dependently inhibited by selective COX-2 inhibitors (SC-58125 and NS-398), a non-selective COX inhibitor (indomethacin), and relatively high concentrations of a selective COX-1 inhibitor (SC-560). These COX inhibitors also suppressed the proliferation of ARH-77 cells, but significant suppression was seen only at 100 microM, a much higher concentration than those sufficient for the COX inhibition. Moreover, proliferation of the myeloma cells lacking COX-2 was also suppressed by 100 microM of SC-58125. These results suggested that the anti-proliferative effect of the COX inhibitors is independent of the inhibition of COX-2.

FTY720 has been originally developed as a new immunosuppressive agent, which prolongs graft survival in organ transplantation. Adrenomedullin (AM) participates in the regulation of sodium homeostasis and has renoprotective effects. The possible involvement of renal AM in the pathophysiology of glomerulonephritis (GN) and the effect of FTY720 has been evaluated in rats. HgCl 2 (1 mg/kg body weight) was inoculated subcutaneously 3 times/week for a total of 2 weeks. FTY720 (3 or 10 mg/kg) was inoculated subcutaneously daily. The proteinuria, urinary N -acetyl-beta- d -glucosaminidase (NAG) excretion and serum total cholesterol levels were increased and serum albumin level was reduced in rats with HgCl 2 -induced GN compared with controls. FTY720 reduced proteinuria (3 mg/kg: −25%; 10 mg/kg: −41%), urinary NAG excretion (−11%; −52%) and total cholesterol level (−21%; −55%) in a dose-dependent manner. Renal AM level and its mRNA expression were increased in rats with GN compared with controls (Peptide Cortex: +69%; Medulla: +82%; mRNA Cortex: +25%). Interestingly, FTY720 additionally increased these levels (Peptide Cortex: +38%; Medulla: +39%; mRNA Cortex: +20%). Renal AM levels correlated with urinary NAG excretion and creatinine clearance. These results suggest that FTY720 suppresses the renal damage in rats with GN and renal AM may participate in the pathophysiology of GN and the renoprotective effects of FTY720.

We studied the effects of mycophenolate mofetil, a specific inhibitor of inosine monophosphate dehydrogenase, on the mercuric chloride induced autoimmune glomerulonephritis in Brown Norway rats and also on the renal contents of adrenomedullin. In the rats with autoimmune glomerulonephritis, plasma and renal tissue adrenomedullin levels were increased significantly. Coadministration of mycophenolate mofetil resulted in prevention of autoimmune glomerulonephritis and also in maintaining of plasma and renal tissue adrenomedullin levels at control levels. Adrenomedullin mRNA expressions in the renal cortex were also higher in the rats with autoimmune glomerulonephritis. Significant positive correlations were found between renal cortical adrenomedullin levels and urinary Na+ and N-acetyl-beta-D-glucosaminidase excretion. A significant negative correlation between renal cortical adrenomedullin levels and creatinine clearance was also found. These results suggest that mycophenolate mofetil suppresses the renal damage in rats with autoimmune glomerulonephritis and renal adrenomedullin may participate in the pathophysiology of autoimmune glomerulonephritis.

Summary We previously reported an association between the human leukocyte antigen (HLA) haplotype DRB1*1302-DQB1*0604 in the HLA class II region and non-obstructive azoospermia in Japanese men. To identify possible associations between the HLA-DRB1*1302-DQB1*0604 allele in the HLA class II region and azoospermia factor (AZF) deletion in the Y chromosome, we performed genomic polymerase chain reaction (PCR) analysis of the AZF region. We then determined spermatogenic impairment (Johnsen score) in testicular biopsy specimens from patients with or without the DRB1*1302-DQB1*0604 haplotype. The AZF microdeletion rate in patients with this haplotype was 3.85%, compared with 11.8% in others (no correlation). However, Johnsen scores in patients with the DRB1*1302-DQB1*0604 haplotype were 3.13 ± 1.34 (mean ± SD), compared with 3.70 ± 1.51 in others (p

In order to identify and characterize genetic polymorphism of the swine major histocompatibility complex ( Mhc: SLA) class I genes, RT-PCR products of the second and third exons of the three SLA classical class I genes, SLA-1, SLA-2 and SLA-3 were subjected to nucleotide determination. These analyses allowed the identification of four, eight and seven alleles at the SLA-1, SLA-2 and SLA-3 loci, respectively, from three different breeds of miniature swine and one mixed breed. Among them, 12 alleles were novel. Construction of a phylogenetic tree using the nucleotide sequences of those 19 alleles indicated that the SLA-1 and -2 genes are more closely related to each other than to SLA-3. Selective forces operating at single amino acid sites of the SLA class I molecules were analyzed by the Adaptsite Package program. Ten positive selection sites were found at the putative antigen recognition sites (ARSs). Among the 14 positively selected sites observed in the human MHC ( HLA) classical class I molecules, eight corresponding positions in the SLA class I molecules were inferred as positively selected. On the other hand, four amino acids at the putative ARSs were identified as negatively selected in the SLA class I molecules. These results suggest that selective forces operating in the SLA class I molecules are almost similar to those of the HLA class I molecules, although several functional sites for antigen and cytotoxic T-lymphocyte recognition by the SLA class I molecules may be different from those of the HLA class I molecules.

The clinical results in two patients with glomus tumor recently treated in our department are reported. The first case involved a mixed type of glomus tympanicum tumor and glomus jugulare tumor, while the second case showed glomus jugulotympanicum tumor. These were both classified as class C1 according to Fisch's classification. Both cases were treated surgically by an infratemporal fossa approach. Preoperative embolization diminished bleeding. The first case underwent partial tumor removal with postoperative radiotherapy using a γ-knife. The second case underwent total tumor removal.

誤嚥をきたし，リハビリテーションで改善のみられない難治性嚥下障害の患者に対して，嚥下性肺炎の防止や患者のQOL向上のために誤嚥防止手術を選択することがある。当科ではこれまでに，原疾患が神経難病の患者18例に対して，誤嚥防止目的のために気道食道の分離術を行った。原疾患は筋萎縮性側索硬化症(ALS)が11例，パーキンソン病が3例と多く，術式は，気管食道吻合術7例，喉頭全摘出術9例，喉頭全摘出術＋咽頭弁形成術2例であった。ALSでは唾液や水分でのむせによる苦痛や呼吸困難から手術を選択するものを多く認めた。一方，それ以外の神経難病では嚥下性肺炎の反復により手術を選択するものがほとんどであった。術後は18例中17例で経口摂取が可能（14例で全量経口摂取可能）となったが，原疾患が進行性であるため，経過とともに経口不良となる症例を多く認めた。しかし，本来の目的である誤嚥の防止ははかれており，肺炎の防止，喀痰吸引回数の減少，そしてより長く経口摂取が可能となりQOLが向上するという点から，神経難病においても誤嚥防止手術は有用であると思われた。

Background The induction of heat shock protein (HSP) 72 by mild electrical stimulation with heat shock (MES + HS), which improves visceral adiposity and insulin resistance in mice, may be beneficial in treating metabolic syndrome (MS) or type 2 diabetes mellitus (T2DM). Methods Using open-label crossover trials, 40 subjects with MS or T2DM were randomly assigned using computer-generated random numbers to 12 weeks of therapeutic MES + HS followed by 12 weeks of no treatment, or vice versa. During the intervention period, physical and biochemical markers were measured. Findings Compared to no treatment, MES + HS treatment was associated with a significant decrease in visceral adiposity (− 7.54 cm2 (− 8.61%), 95% CI − 8.55 to − 6.53 (p = 0.037) in MS, − 19.73 cm2 (− 10.89%), 95% CI − 20.97 to − 18.49 (p = 0.003) in T2DM). Fasting plasma glucose levels were decreased by 3.74 mg/dL (− 5.28%: 95% CI − 4.37 to − 3.09 mg/dL, p = 0.029) in MS and by 14.97 mg/dL (10.40%: 95% CI − 15.79 to 14.15 mg/dL, p, Highlights • We report the use of mild electrical stimulation with heat shock (MES + HS) in treating metabolic syndrome or type 2 diabetes. • The treatment improves visceral adiposity, glucose homeostasis, insulin resistance and chronic inflammatory status. • Our findings suggest that MES + HS might be a valuable therapeutic option for patients with these lifestyle-related diseases.

Aims/Introduction: Several experimental studies have shown that ezetimibe improves steatosis and insulin resistance in the liver. This suggests that ezetimibe may improve glucose metabolism, as well as lipid metabolism, by inhibiting hepatic lipid accumulation. Therefore, we compared HbA1c levels after 3 months ezetimibe treatment with baseline levels in patients with type 2 diabetes and examined the factors associated with reductions in HbA1c following ezetimibe administration. Materials and Methods: Lipid profiles, hepatic function, and HbA1c were assessed before and after 3 months treatment with 10 mg/day ezetimibe in 96 patients with type 2 diabetes and hypercholesterolemia. Regression analysis was used to investigate associations between metabolite levels and the percentage change in HbA1c. Results: Low‐density lipoprotein–cholesterol was significantly lower after 3 months treatment compared with baseline, and HbA1c decreased in approximately 50% of patients. Univariate linear regression analyses showed that changes in HbA1c were significantly associated with serum alanine aminotransferase (ALT), the aspartate aminotransferase (AST)/ALT ratio, and age. Two‐tailed chi‐square tests revealed that serum ALT ≥35 IU/L and an AST/ALT ratio

Aims/Introduction: Multidetector computed tomography (MDCT) coronary angiography has been applied as a tool for non‐invasive evaluation of the coronary arteries. The purpose of the present study was to evaluate the effectiveness of MDCT in screening for coronary artery disease (CAD), and to identify the indications for screening in diabetes patients with CAD. Materials and Methods: The study population consisted of 52 Japanese type 2 diabetes patients who underwent examination with a 64‐slice MDCT scanner, electrocardiogram (ECG), echocardiography and ultrasonographic scanning of the carotid arteries. Regression analysis was carried out to assess the correlation between MDCT results and CAD risk factors. Results: Stenosis of the coronary artery was detected in 19/52 patients. Of the 19 patients, 7 patients had no symptoms, including chest pain, and no ischemic changes in ECG. Significant differences between patients with stenosis and those without stenosis were detected by mean IMT (1.21 vs 0.95 mm), and duration of diabetes (20 vs 13 years). Two‐tailed χ2‐test showed that a duration of diabetes of more than 20 years (odds ratio 6.222) and more than 1.1 mm of mean‐IMT (odds ratio 4.600) significantly correlated with the stenosis. Conclusions: It was shown that MDCT is useful in detecting coronary artery stenosis in diabetic patients without symptoms of CAD or ECG abnormality, and the predictors of CAD are mean IMT and duration of diabetes. It is recommended that patients with more than 1.1 mm mean IMT at the carotid artery and/or more than 20 years duration of diabetes should be screened for CAD by carrying out MDCT.

Objectives. To determine whether vesicoureteral reflux is associated with the human leukocyte antigen (HLA) genes. Methods. We evaluated 40 Japanese patients (27 males and 13 females) with reflux. HLA-DR low-resolution genotyping and high-resolution typing of HLA-DRB1 alleles were performed. The frequencies of the HLAs and alleles were calculated and compared with those previously reported in 493 healthy Japanese. Results. Low-resolution typing showed that the frequency of the HLA-DR11 antigen was significantly higher in the patients with reflux than in the control group. High-resolution typing revealed that the frequencies of HLA-DRB1*1101 and 1502 alleles were significantly higher in the patients with reflux than in the control group. In the patients with and without renal scarring, the frequencies of the HLA-DR11 antigens and HLA-DRB1*1101 alleles were significantly lower in those with renal scarring. In the patients with and without the chief complaint of urinary tract infection symptoms, the frequencies of HLA-DR13 antigens and HLA-DRB1*1302 alleles were significantly lower in those with that chief complaint. Conclusions. The susceptibility to reflux is, in part, controlled by HLA genes themselves or an unknown gene or genes, the locus for which is located close to the DRB1 gene. The lack of a HLA-DRB1*1101 allele and DRB1*1302 allele in patients with reflux might be connected with renal scarring and urinary tract infection, respectively.

The use of long-term middle ear ventilation tubes (Paparella type II) was retrospectively analyzed in 66 ears with otitis media with effusion, in children treated at Kagawa Medical University Hospital between January 1990 and March 1998. The average intubation period was 23.9 months. The average pure tone air conduction threshold showed a remarkable improvement of between 32.7dBHL and 16.9dBHL. Otorrhea was observed in 25 ears (37.8%), obstruction in 2 ears (3.0%), granulation in 3 ears (4.5%) and permanent ear drum perforation in 11 ears (19.6%). No cholesteatma or adhesion of the ear drum was seen. Recurrence of otitis media with effusion was found in 9 of 45 ears (20.0%). In conclusion, Paparella type II tube can be placed for a long-term period and have a low rate of reccurence, but have a high rate of otorrhea and permanent ear drum perforation.

Eight patients with malignant melanoma of the head and neck were treated in our department between 1983 and 1998. Their ages ranged from 49 to 84 years, with a mean age of 65. One case showed the amelanotic type histologically. These cases were classified according to the criteria of the National Institute of Health. Five and 3 cases were stage I and stage III, respectively. All cases were treated by combination therapy consisting of surgery, radiation, chemotherapy, immunotherapy and hormonal therapy. Four cases survived for 2 years and 2 cases more than 5 years.

Surgical treatments for aspiration can be classified as either functional or radical. It is necessary to divide the airway from the feeding tract in order to prevent aspiration in patients complaining of severe aspiration. Thacheoesophageal diversion was established as a surgical management technique for severe aspiration by Lindeman in 1975. This technique, which completely separates the airway and feeding tract is less invasive and reversible procedure for reconstruction. We performed tracheoesophageal diversion in six patients from 1991 to 1997. All patients improved aspiration pneumonia. Five patients who had no swallowing disturbance preoperatively, were able to eat orally after the operation.This procedure preserving the larynx can lighten the psychological damage to the patient and his/her family. Although tracheoesophageal diversion leaves the unresolved problem of postoperative phonation, it is a useful surgical procedure for the patient who complains of severe aspiration and can improve quality of life.

The Bacillus sp. SAM1606 alpha-glucosidase with a broad substrate specificity is the only known alpha-glucosidase that can hydrolyze alpha,alpha'-trehalose efficiently. The enzyme exhibits a very high sequence similarity to the oligo-1,6-glucosidases (O16G) of Bacillus thermoglucosidasius and Bacillus cereus which cannot act on trehalose. These three enzymes share 80% identical residues within the conserved regions (CR), which have been suggested to be located near or at the active site of the alpha-amylase family enzymes. To identify by site-specific mutagenesis the critical residues that determine the broad substrate specificity of the SAM1606 enzyme we compared the CR sequences of these three glucosidases and selected five targets to be mutagenized in SAM1606 alpha-glucosidase, Met76, Arg81, Ala116, Gly273, and Thr342. These residues have been specifically replaced by in vitro mutagenesis with Asn, Ser, Val, Pro, and Asn, respectively, as in the Bacillus O16G. The 12 mutant enzymes with single and multiple substitutions were expressed and characterized kinetically. The results showed that the 5-fold mutation virtually abolished the affinity of the enzyme for alpha, alpha'-trehalose, whereas the specificity constant for the hydrolysis of isomaltose, a good substrate for both the SAM1606 enzyme and O16G, remained essentially unchanged upon the mutation. This loss in affinity for trehalose was critically governed by a Gly273 --> Pro substitution, whose effect was specifically enhanced by the Thr342 --> Asn substitution in the 5-fold and quadruple mutants. These results provide evidence for the differential roles of the amino acid residues in the CR in determining the substrate specificity of the alpha-glucosidase.

A 65-year-old man with a history of rectal cancer surgery presented to the emergency department, with fever and arthralgia in the neck, radiating to the shoulder, since the previous day. Although the origin of the fever was unknown, he was eventually admitted to the hospital because of disability and then treated with broad antibiotics. On day 3, his symptoms became concentrated at the back of his throat. He experienced laboured breathing and respiratory distress. He was also drooling and his voice was muffled. Acute epiglottitis was suspected, and a lateral soft-tissue radiograph (figure 1A) and CT (figure 1B) showed a swollen epiglottis, which is termed as the ‘thumb sign’ (figure 1A, B; arrow), and narrowed vallecula (figure 1A, B; arrow head), consistent with …

Objective Several studies have assessed the efficacy of angiotensin receptor blockers (ARBs) on peripheral insulin sensitivity using the euglycemic hyperinsulinemic clamp technique in hypertensive subjects. However, these subjects were mostly non-diabetic, and some studies showed that ARB treatment did not improve insulin sensitivity. Thus, it is still uncertain whether ARBs could improve insulin sensitivity in subjects with hypertension and diabetes. Therefore, we evaluated the effect of olmesartan on peripheral insulin sensitivity in subjects with type 2 diabetes and hypertension using M/I value during the euglycemic-hyperinsulinemic clamp technique. Methods We enrolled 10 Japanese subjects with type 2 diabetes and hypertension who had never taken antihypertensive agents. Their blood pressure, fasting plasma glucose level, HbA1c and glucose utilization rate during euglycemic-hyperinsulinemic clamp (M/I value) were examined before and after 6 months of treatment with 10-20 mg/day olmesartan (mean: 13.0 mg/day). Results Blood pressure decreased significantly from 156/88 mmHg before starting olmesartan to 135/76 mmHg after 6 months of olmesartan treatment. The mean M/I value increased significantly from 6.33 ± 3.19 (mg/kg/min/mU/L) × 100 to 8.11 ± 4.20 (mg/kg/min/mU/L) × 100. Peripheral insulin sensitivity improved in eight out of ten subjects. Fasting glucose levels and HbA1c levels also decreased significantly. Conclusion These results indicate that olmesartan improves glucose metabolism by improving the peripheral insulin sensitivity in subjects with type 2 diabetes.

We report a case of bilateral infraorbital nerve enlargement (IONE) associated with immunoglobulin (Ig)G4-related ophthalmic disease and describe the associated histopathologic findings. An otherwise healthy 59-year-old man presented with bilateral exophthalmos and right visual disturbance. Orbital magnetic resonance imaging showed bilateral IONE and a soft tissue mass in the right orbit. Excisional biopsy in the left infraorbital canal was performed. Histopathologic assessment revealed IgG4-related disease involving the epineurium of the infraorbital nerve. The patient received systemic steroid therapy, to which he responded well. IONE in IgG4-related ophthalmic disease is due to IgG4-related disease involving the epineurium.

Thermal burns of the larynx after swallowing hot beverages are extremely rare among adults. Most reported cases have occurred among young children. We report the case of a male adult who, upon swallowing hot milk from a bottle, experienced a burn of the larynx affecting the epiglottis and surrounding supraglottic structures. Since dyspnea usually occurs within hours of a burn of the larynx, the importance of airway management in this case is emphasized.