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To date, almost all case reports of insulin‐derived amyloidosis described the presence of a subcutaneous mass that was observable on physical examination. This report presents two cases of insulin‐derived amyloidosis without palpable masses at insulin injection sites. In both cases, blood glucose concentrations improved, and the insulin dose could be reduced by an average of 45% after changing the insulin injection sites. The insulin absorption at the site was reduced to at most 40% of that at a normal site in one case. Magnetic resonance imaging and ultrasonography were useful to screen and differentiate insulin‐derived amyloidosis without a palpable mass. This report showed that insulin‐derived amyloidosis without a palpable mass can be present at the insulin injection site, and has similar clinical effects to insulin‐derived amyloidosis with palpable masses., This report showed that insulin‐derived amyloidosis without a palpable mass can be present at the insulin injection site and has similar clinical effects to insulin‐derived amyloidosis with palpable masses. Magnetic resonance imaging and ultrasonography were useful to screen and differentiate insulin‐derived amyloidosis without a palpable mass.

Background We designed a prospective and randomized trial of mizoribine (MZR) therapy combined with prednisolone (PSL) for idiopathic membranous nephropathy (IMN) with steroid-resistant nephrotic syndrome (SRNS). Methods Patients with IMN were divided into 2 groups, and MZR combined with PSL was administered for 2 years. PSL was initially prescribed at 40 mg/day and tapered. MZR was given once-a-day at 150 mg and 3-times-a-day at 50 mg each to groups 1 and 2. Serum MZR concentrations from 0 to 4 h after administration were examined within one month of treatment. The concentration curve and peak serum level (C max) of MZR were estimated by the population pharmacokinetic (PPK) parameters of MZR. Results At 2 years, 10 of 19 patients (52.6 %) in group 1 and 7 of 18 patients (38.9 %) in group 2 achieved complete remission (CR). The time-to-remission curve using the Kaplan–Meier technique revealed an increase in the cumulative CR rate in group 1, but no significant difference between the groups. Meanwhile, there was a significant difference in C max between groups 1 and 2 (mean ± SD: 1.20 ± 0.52 vs. 0.76 ± 0.39 μg/mL, p = 0.04), and C max levels in CR cases were significantly higher than those in non-CR cases. Receiver operating characteristic analysis showed that C max more than 1.1 µg/mL was necessary for CR in once-a-day administration. Conclusion Administration of MZR once a day is useful when combined with PSL for treatment of IMN with SRNS. In addition, it is important to assay the serum concentration of MZR and to determine C max, and more than 1.1 µg/mL of C max is necessary for CR.

Background: The value of faecal biomarkers for screening small bowel inflammation in patients with Crohn’s disease (CD) remains to be elucidated. This prospective study was to evaluate the utility of faecal biomarkers for detecting small intestinal inflammation. Methods: A total of 122 consecutive patients with a diagnosis of CD in the small intestine were screened for eligibility. Computed tomography enterography (CTE) was undertaken to evaluate small bowel inflammation followed by colonoscopy to confirm no large bowel involvement. Seventy eligible patients with inflammation confined to the small intestine were included. Faecal samples were collected for assaying calprotectin, lactoferrin and haemoglobin. For assessing the degree of small bowel inflammation, a semi-quantitative scoring system (CTE0, normal; CTE1, mild; CTE2, moderate; CTE3, severe) was applied. Results: The median calprotectin, lactoferrin and haemoglobin levels were significantly higher in patients with small bowel inflammation, CTE scores 1–3 ( n = 42) versus 0 ( n = 28): calprotectin, 330 versus 40 ng/ml, p < 0.0001; lactoferrin, 14 versus 3 ng/ml, p < 0.0001; haemoglobin, 29.5 versus 6.5 ng/ml, p = 0.005. There was a strong positive relationship between the faecal biomarkers and CTE score: calprotectin, p < 0.0001; lactoferrin, p < 0.0001; haemoglobin, p = 0.0004. A cutoff value of 140 ng/ml for calprotectin had a sensitivity of 69% and a specificity of 82% with an area under the receiver operating characteristic curve (AUC) of 0.82 to detect small bowel inflammation (CTE scores 1–3), while lactoferrin 6 ng/ml had a sensitivity of 69% and a specificity of 79% with an AUC of 0.83, and haemoglobin 9 ng/ml showed a sensitivity of 71% and a specificity of 39% with an AUC of 0.70. Conclusions: Faecal calprotectin, lactoferrin, and to a lesser degree haemoglobin are relevant biomarkers for screening small bowel inflammation in CD patients without large bowel involvement. Further well-designed large-scale studies in this clinical setting should strengthen our findings.

Introduction Neonatal hemochromatosis (NH) is a rare neonatal disorder that results in liver cirrhosis with hemosiderin deposition in the liver and other organs, similarly to hereditary hemochromatosis. Excess iron is transferred from the mother to fetus through the placenta in NH. We examined the expression of iron metabolism-related substances in placental syncytiotrophoblasts (STB) by immunostaining to clarify how the transfer of iron through STB increases in NH. Methods Immunostaining was performed using formalin-fixed, paraffin-embedded sections of placentae from three NH cases, four gestational age-matched controls, and, depending on the antibody examined, five to seven full-term controls. The reactivity of immunostaining was assessed by averages of scores assigned by 3 researchers. Results On the microvillar surface of STB, the reactions of the antibodies against transferrin receptor 1 (TFR1), transferrin, ferritin, hepcidin, ferroportin, divalent metal transporter-1 (DMT1), hephaestin, and HFE were stronger in NH than in controls. In the cytoplasm, the reactions of antibodies against TFR1, transferrin, ferritin, hepcidin, DMT1, hephaestin, HFE, and ZIP 14 were stronger in NH than in gestational age-matched controls. Among these reactions, those of anti-TFR1 antibody on the surface of STB in NH was especially marked. Discussion In the placenta of NH, increases in expressions of TFR1, transferrin, and ferritin of which those of TFR1 were especially marked, reflect increased iron influx from the mother to fetus. The hepcidin observed on the surface and in the cytoplasm of STB of NH is suggested to be from the mother, possibly to compensate for the decreased fetal liver-derived hepcidin.

Their aim was to examine whether microvascular leakage of endogenous albumin, a representative marker for blood-brain barrier (BBB) damage, was induced in the periventricular area of diabetic db/db mice because periventricular white matter hyperintensity formation in magnetic resonance images was accelerating in elderly patients with diabetes mellitus. Using light and electron microscopes, and semi-quantitative analysis techniques, immunoreactivity of endogenous albumin, indicating vascular permeability, was examined in the periventricular area and spinal cord of db/db mice and db/+m control mice. Greater immunoreactivity of albumin was observed in the vessel wall of the periventricular area of db/db mice than in controls. Additionally, weak immunoreactivity was observed in the spinal cord of both db/db mice and controls. The number of gold particles, indicating immunoreactivity of albumin, in the perivascular area of db/db mice was significantly higher than that of control mice, but there was no significant difference in the number of particles in the spinal cord between db/db mice and controls. These findings suggest that albumin microvascular leakage, or BBB breakdown, is induced in the periventricular area of diabetic mice. Microsc. Res. Tech. 79:833-837, 2016. © 2016 Wiley Periodicals, Inc.

Background: It is recommended that ileocolonoscopy is performed within 1 year after resection for Crohn’s disease (CD). Nevertheless, optimal monitoring strategies for recurrence after the ileocolonoscopy remain to be elucidated. This prospective study was to evaluate the value of serial monitoring of faecal calprotectin (FC) after ileocolonoscopy for the assessment of endoscopic recurrence in asymptomatic patients. Methods: Patients in clinical remission who had no endoscopic recurrence at ileocolonoscopy 6–12 months after ileocolonic resection were studied. FC levels were measured every 2 months up to 24 months after the ileocolonoscopy. When the FC level was elevated (⩾140 µg/g), a second ileocolonoscopy was immediately undertaken. In contrast, patients who maintained low FC levels (Results: A total of 30 patients were studied. In eight patients, the FC level was raised during the 24-month follow up. Six of the eight patients (75%) had endoscopic recurrence. Of 22 patients who maintained low FC levels, 20 (91%) had no endoscopic recurrence, whereas two showed endoscopic recurrence at the end of the follow up. The incidence of endoscopic recurrence was significantly higher in patients with elevation of FC levels versus those with maintained low FC levels (75% versus 9%). A cut-off value of 140 µg/g for FC had a sensitivity of 75%, a specificity of 91%, a positive predictive value of 75%, a negative predictive value of 91% and a diagnostic accuracy of 87% to detect endoscopic recurrence. Conclusions: Consecutive monitoring of FC is useful for the assessment of endoscopic recurrence after the initial ileocolonoscopy. Increased FC levels indicate a need for repeat ileocolonoscopy, while sustained low FC levels predict a low risk of endoscopic recurrence. In patients maintaining low FC levels, unnecessary invasive endoscopic examinations can be avoided.

Objectives Achieving endoscopic remission or decreasing the level of fecal biomarkers as an ideal therapeutic goal in ulcerative colitis has not been determined. This prospective study was to compare the clinical relevance of endoscopic score with fecal biomarkers for predicting relapse after clinical remission and mucosal healing (MH). Methods One hundred and sixty-four patients who achieved clinical remission and MH (Mayo endoscopic subscore (MES) 0 or 1) were included. At entry, fecal samples were collected for the measurement of calprotectin, lactoferrin, and hemoglobin. Thereafter patients received masalamine maintenance therapy, and were followed for 12 months. Results During 12-month study, 46 patients (28%) relapsed. The relapse rate was not significantly higher in 27/80 patients (34%) with MES 1 than in 19/84 patients (23%) with MES 0 (P = 0.16). The median fecal calprotectin, lactoferrin, and hemoglobin were significantly higher in patients with relapse than those in remission (calprotectin, 182 vs. 94 μg/g; lactoferrin, 185.5 vs. 111 μg/g; hemoglobin, 168 vs. 104 ng/mL; all P

This prospective study was to evaluate the significance of fecal calprotectin and lactoferrin for the prediction of ulcerative colitis (UC) relapse. Eighty UC patients in remission for ≥3 months on mesalamine as maintenance therapy were included. At entry, stool samples were collected for the measurement of calprotectin and lactoferrin. All patients were followed up for the following 12 months. To identify predictive factors for relapse, time-dependent analyses using the Kaplan-Meier graphs and Cox's proportional hazard model were applied. During the 12 months, 21 patients relapsed. Mean calprotectin and lactoferrin levels were significantly higher in patients with relapse than those in remission (calprotectin—173.7 vs 135.5 μg/g, P = 0.02; lactoferrin—165.1 vs 130.7 μg/g, P = 0.03). A cutoff value of 170 μg/g for calprotectin had a sensitivity of 76 % and a specificity of 76 % to predict relapse, while a cutoff value of 140 μg/g for lactoferrin had a sensitivity of 67 % and a specificity of 68 %. In a multivariate analysis, calprotectin (≥170 μg/g) was a predictor of relapse (hazard ratio, 7.23; P = 0.002). None of the following parameters were significantly associated with relapse: age, gender, duration of UC, number of UC episode, severity of the previous episode, extent of UC, extraintestinal manifestation, and lactoferrin level. Fecal calprotectin showed a higher sensitivity and specificity than fecal lactoferrin for predicting UC relapse. Fecal calprotectin level appeared to be a significant predictor of relapse in patients with quiescent UC on mesalamine as maintenance therapy.

High fructose intake is known to be associated with increased plasma triglyceride concentration, impaired glucose tolerance, insulin resistance, and high blood pressure. In addition, excess fructose intake is also thought to be a risk factor for dementia. Previous immunohistochemical studies have shown the presence of glucose transporter 5 (GLUT5), a major transporter of fructose, in the epithelial cells of the choroid plexus and ependymal cells in the brains of humans, rats, and mice, while GLUT2, a minor transporter of fructose, was localized in the ependymal cells of rat brain. In this study, immunoreactivity for the fructose transporter GLUT8 was observed in the cytoplasm of the epithelial cells in the choroid plexus and in the ependymal cells of the brains of humans and mice. These structures were not immunoreactive for GLUT7, GLUT11, and GLUT12. Our findings support the hypothesis of the transport of intravascular fructose through the epithelial cells of the choroid plexus and the ependymal cells.

Smoothelin is a specific type of cytoskeletal protein found in smooth muscle cells (SMCs). Several previous research studies have examined the relationship between smoothelin and atherosclerotic plaque. The aim of the present study was to further assess the association between the human SMTN gene and cerebral infarction (CI) using a haplotype-based case–control study. A total of 168 CI patients and 259 supercontrols were genotyped for the five single-nucleotide polymorphisms (SNPs) used as genetic markers for the human SMTN gene (rs2074738, rs5997872, rs56095120, rs9621187 and rs10304). Data were analyzed for three separate groups that included total subjects, men and women. The genotypic distribution of rs10304 for men showed a significant difference between the control and CI groups. In addition, the frequency of the C-T-T-A haplotype (established by rs5997872, rs56095120, rs9621187 and rs10304) was significantly higher in the CI versus the control group ( p = 0.013), while the frequency of the C-A-T-G haplotype (established by rs5997872, rs56095120, rs9621187 and rs10304) in the CI group was significantly lower than that seen in the controls ( p = 0.021). In conclusion, we confirmed that the haplotype constructed using rs5997872, rs56095120, rs9621187 and rs10304 was a useful genetic marker of CI in Japanese men.

Objectives: Smoothelin is a specific kind of cytoskeletal protein present in smooth muscle cells. Some researchers have shown the relationship between smoothelin and atherosclerotic plaque. The human SMTN gene encodes smoothelin-A and smoothelin-B. The aim of the present study was to assess the association between the human SMTN gene and myocardial infarction (MI) using a haplotype-based case–control study. Methods: A total of 227 MI patients and 257 supercontrols were genotyped for five single-nucleotide polymorphisms used as genetic markers of the human smoothelin gene. Data were analyzed for three separate groups: total subjects, men, and women. Results: For the women, the frequency of the C-T-T-G haplotype (established by rs5997872, rs56095120, rs9621187, and rs10304) was significantly higher in the MI group than in the control group (p=0.012). Conclusions: We confirmed that the haplotype constructed using rs5997872, rs56095120, rs9621187, and rs10304 is a useful genetic marker of MI in Japanese females.

We investigated alterations between serum interleukin 18 (IL-18) and IL-18 binding protein (18BP) in T2DM patients. 18 BP began to increase after IL-18 increased and reached a threshold, in which case kidney dysfunction would have developed. These data indicate that 18BP might express glomerular dysfunction more closely than IL-18.

Background Mesalazine is often used to maintain remission in patients with ulcerative colitis. Aim To investigate if increasing the dose of mesalazine is safe and effective for patients with ulcerative colitis who relapse under low-dose maintenance therapy. Methods Ninety consecutive patients who relapsed during maintenance therapy with oral mesalazine at 1.5–2.25 g/day were included. All patients had mildly or moderately active ulcerative colitis at entry, and were treated with oral mesalazine at 4.0 g/day for the following 8 weeks. At entry and week 8, endoscopic examinations were carried out to assess the severity of endoscopic inflammation. The primary as well as the secondary endpoints were clinical and endoscopic improvements at week 8. Results No patient experienced any serious side effect, and the treatment with 4.0 g/day mesalazine over the 8 week period was well tolerated by all patients. Fifty-nine patients (66%) achieved clinical improvement in stool frequency and/or rectal bleeding including 40 (44%) with clinical remission (normal stool frequency and no rectal bleeding). Forty-three patients (48%) showed endoscopic improvement including 25 (28%) with endoscopic remission. Conclusions Increasing the dose of mesalazine up to 4.0 g/day appeared to be safe and effective for patients who relapsed under low-dose, 1.5–2.25 g/day maintenance therapy.

Although it has been reported that plasma insulin is removed by hemodialysis (HD), the mechanism for this has not been elucidated. We investigated the mechanism of insulin removal during HD treatment and the characteristics of insulin removal with three high-flux membranes. In our in vivo study, 20 stable diabetic patients on HD were randomly selected for three HD sessions with three different membranes: polysulfone (PS), cellulose triacetate (CTA), and polyester polymer alloy (PEPA). Blood samples were obtained from the blood tubing at the arterial (A) site at the beginning and end of the sixth HD session to investigate insulin reduction in patients. At 1 h after the initiation of dialysis, blood samples were obtained from both the A and venous sites of the dialyzer to investigate the insulin clearance with the different membranes. There was a significant reduction in patients' plasma insulin at each time point with each of the three membranes. The insulin clearance with the PS membrane was significantly higher than that with the CTA and PEPA membranes. Although no difference was observed in the plasma insulin reduction rate between the three membranes in the total subject group, there was a significantly higher reduction rate with the PS membrane in insulin-dependent diabetes mellitus subjects. The clearance of insulin in in vitro tests was significantly higher with the PS and PEPA membranes than with the CTA membrane in both new and clinically used dialyzers. Insulin was not detected in the dialysate or ultrafiltration fluids in either the in vivo or in vitro studies. The mechanism of plasma insulin clearance by HD is mainly by adsorption, and the amount of insulin adsorbed differed depending on the dialyzer membrane used.

Pyrrole–imidazole (PI) polyamides are small synthetic molecules that recognize and attach to the minor groove of DNA, thereby inhibiting gene transcription by blocking transcription factor binding. These derivatives can act as gene silencers inhibiting target gene expression under stimulatory conditions such as disease. To evaluate PI polyamides as treatments for the progression of renal diseases, we examined morphological effects, pharmacological properties, and the specificity of PI polyamides targeted to the transforming growth factor (TGF)-β1 promoter during salt-induced hypertensive nephrosclerosis in Dahl salt-sensitive rats. The targeted PI polyamide markedly reduced glomerulosclerosis and interstitial fibrosis without side effects. PI polyamide significantly decreased expression of TGF-β1 and extracellular matrix in the renal cortex. Microarray analysis found that only 3% of the transcripts were affected by PI polyamide, but this included decreased expression of extracellular matrix, TGF-β1-related cytokines, angiogenic, and cell stabilizing factors, proteinases, and renal injury-related factors. Thus, targeted PI polyamides are potential gene silencers for diseases not treatable by current remedies.

Statins exert pleiotropic effects, including antioxidative and cellular protective effects. Endogenous adrenomedullin (AM) induces anti-inflammatory, anti-fibrotic and proangiogenic effects. We examined the effects of simvastatin on cardiac fibrosis and apoptosis in AM heterozygous knockout (AM(+/-)) mice treated with angiotensin (Ang) II and high salt loading. Seven-week-old AM(+/-) mice were infused with Ang II while on a high-salt diet with or without simvastatin for 2 weeks. Hearts were stained by hematoxylin-eosin or Masson's trichrome, and were immunostained with isolectin B(4) and α-smooth muscle actin antibodies. Expression of c-Kit and Sca-1 messenger RNA (mRNA) was evaluated by real-time PCR analysis. Apoptotic cells in hearts were identified by terminal deoxynucleotidyl transferase-mediated UTP end labeling (TUNEL) staining. Hearts from Ang II/salt loading AM(+/-) mice showed marked perivascular fibrosis around coronary arteries. Treatment with simvastatin significantly inhibited the fibrosis around coronary arteries in Ang II/salt-loading AM(+/-) mice. Expression of c-Kit and Sca-1 mRNAs in hearts from Ang II/salt-loading AM(+/-) mice was significantly lower than in hearts from wild-type mice. Treatment with simvastatin significantly increased the suppressed expression of c-Kit and Sca-1 mRNAs. In addition, treatment with simvastatin significantly increased the number of isolectin B(4)-positive capillary arteries in hearts from Ang II/salt-loading AM(+/-) mice. Ang II/high salt significantly increased apoptotic cells in hearts from AM(+/-) mice; this trend was reversed by treatment with simvastatin. Thus, statins have potent cardioprotective effects that may be associated with anti-fibrotic, proangiogenic and anti-apoptotic effects in Ang II/salt-loading AM(+/-) mice.

Background: During active ulcerative colitis (UC), vast numbers of granulocytes, monocytes/macrophages (GM) infiltrate the mucosal tissue and can potentially exacerbate inflammation and injury. Accordingly, we were interested to see if selective depletion of GM by adsorption (GMA) impacts mucosal healing (MH) in UC patients. Methods: In all, 124 patients with clinically and endoscopically active UC received 5 or 10 GMA sessions at one or two sessions/week. The endoscopic severity of mucosal inflammation at entry and 1 week after the last GMA session were scored as follows: 0 = normal mucosa and inactive disease; 1 = mild inflammation; 2 = moderate inflammation; 3 = severe inflammation. Likewise, a score 0 or 1 at post-GMA course was defined as MH. Results: At entry the endoscopic severity of the mucosal inflammation was 2 in 100 patients (81%) and 3 in 24 patients (19%). Following the course of GMA, 56 patients (45%) achieved clinical remission (normal stool frequency and no rectal bleeding). Thirty-four of these 56 responders achieved MH; 32 (94%) of the 34 patients with MH had an endoscopic score of 2 (moderate inflammation) at entry. The maintained clinical remission rate was significantly higher in the 34 patients who achieved MH as compared with 22 patients who achieved clinical remission without MH (P = 0.0005). Conclusions: MH is achieved more frequently in patients with moderate than with severe endoscopic severity at entry. Further, patients with MH have a reduced risk of future clinical relapse as compared with patients who achieve remission without MH. (Inflamm Bowel Dis 2010)

During adult life, the insulin/insulin-like growth factor1 (IGF1) signaling pathway plays an important role in cardiovascular function. Several reports have suggested that low baseline levels of IGF1 increase the risk of fatal ischemic heart disease. Thus, IGF1 may be involved in cardiovascular disease. The aim of the present study was to investigate the relationship between the human IGF1 gene and myocardial infarction (MI) in the Japanese population via the use of single nucleotide polymorphisms (SNPs). After selecting six SNPs in the human IGF1 gene (rs2162679, rs7956547, rs2288378, rs2072592, rs978458 and rs6218), we performed a case-control study using each of the SNPs and haplotypes in 320 MI patients and 307 non-MI controls. Multiple logistic regression analysis demonstrated that the GG+GA variant of rs2162679 (p=0.009) and the AA+GA variant of rs2072592 (p=0.026) exhibited a resistant effect for MI. The haplotype-based case-control study revealed that the frequency of the A-T-G-G haplotype for rs2162679-rs7956547-rs2072592-rs978458 was significantly higher in the MI group (47.3%) as compared to the non-MI group (41.4%) (p=0.037, odds ratio=1.270). The frequency of the A-T-G-T haplotype for rs2162679-rs7956547-rs978458-rs6218 was also significantly higher in the MI group (47.3%) as compared to the non-MI group (41.3%) (p=0.033, odds ratio=1.276). The current results suggest that specific SNPs and haplotypes can be utilized as genetic markers for MI risk or MI resistance. In addition, IGF1 or a neighboring gene might be associated with increased or decreased susceptibility to MI.

BACKGROUND Elastin microfibril interfacer 1 (EMILIN-1) is a negative regulator of the transforming growth factor-beta (TGF-beta) signaling, which is involved in blood pressure (BP) homeostasis. Emilin1 knockout mice display elevated BP. The aim of the present study was to assess the association between the human EMILIN1 gene and essential hypertension (EH) using a haplotype-based case-control study. METHODS A total of 287 EH patients and 253 age-matched controls were genotyped for the five single-nucleotide polymorphisms (SNPs) used as genetic markers for the human EMILIN1 gene (rs2289408, rs2289360, rs2011616, rs2304682, and rs4665947). Data were analyzed for three separate groups: the total subjects, men, and women. RESULTS For the total, the genotypic distribution of rs2289360, rs2011616, and rs2304682 differed significantly between control and EH (P = 0.010, P = 0.009, and P = 0.008, respectively). For the total and men, there were significant differences noted between the controls and the EH patients for both the dominant model (GG vs. AA+AG) (P = 0.006, P = 0.021, respectively), and the recessive model (AA vs. AG+GG) (P = 0.028, P = 0.038, respectively) of rs2011616. For the total and the men, logistic regression analysis indicated that the AG+GG genotype of rs2011616 was significantly higher in EH patients (P = 0.033, P = 0.043, respectively). The frequency of the G-G-T haplotype (established by rs2536512, rs2016116, rs17881426) was significantly higher in EH men (P = 0.007), and the G-A-T haplotype (established by rs2536512, rs2016116, rs17881426) was significantly higher in control men (P < 0.001). CONCLUSIONS We confirmed that rs2289360, rs2011616, and rs2304682 in the human EMILIN1 gene, as well as the haplotype constructed using rs2536512, rs2011616, and rs17881426 are useful genetic markers of EH in Japanese men.

Insulin resistance plays a central role in the pathophysiology of diabetes complications. Angiotensin II receptor blockers (ARBs) regulate angiotensin II receptor-mediated inhibition of intracellular glucose transporter 4 translocation. Telmisartan, one of the known ARBs, was reported to improve insulin resistance via the increase of peroxisome proliferator-activated receptor gamma activity in the model animal. This study examined whether this effect was observed in diabetes patients under the usual antihypertensive dosage of telmisartan treatment.Twenty-seven diabetes patients were chosen for this prospective study. Patient blood pressures were successfully controlled for the most recent 6 months by ARBs other than telmisartan. After informed consent was obtained, we changed to telmisartan from the other ARBs. The parameters of hypertension, hyperlipidemia, glycemic control, and renal function were examined.The values of the homeostasis model assessment of insulin resistance (HOMA-IR) improved from 7.1 +/- 1.5 to 3.8 +/- 3.6 after 3 months. The serum level of adiponectin significantly increased after 6 months. The distributions of other parameters were correlated with that of HOMA-IR or adiponectin.The data indicate that the usual antihypertensive dosage of telmisartan improves insulin resistance and changes adiponectin effect in patients with diabetes mellitus. Adipokine-related insulin resistance and angiotensin II receptor 1-mediated insulin resistance are improved by telmisartan.

Aim: To evaluate the dose-response effects of granulocyte-colony stimulating factor (G-CSF) on atherosclerosis, we examined how G-CSF treatment at different concentrations affects atherosclerotic plaque formation in the aorta of cholesterol-fed rabbits.Methods: Japanese White rabbits (n=8 each) fed on a 1.5% cholesterol diet were subcutaneously injected with G-CSF at 50 (GL), 100 (GM), or 300 µg/kg/day (GH) for five days, or with 3 cycles of G-CSF at 100 µg/kg/day at 3-week intervals (GM3), or human serum albumin (Control). The extent and composition of atherosclerosis was evaluated 14 weeks after cholesterol feeding.Results: Although G-CSF treatment did not affect plasma lipid levels, the percentage of aortic surface involvement in the GM3 group was significantly decreased (p

ANCA関連血管炎において，単純血漿交換（PEX）や二重濾過血漿交換法（DFPP）は重症例で施行され，その有効例が報告されている．一方，PEXによるアレルギー反応やDFPPによる出血傾向，感染症の増悪などの重篤な副作用をひき起こす場合があり，その施行には十分な検討が必要と考えられる．症例1は75歳，男性，MPO-ANCA関連血管炎に急速進行性糸球体腎炎（RPGN）および肺胞出血を併発したため，ステロイドパルス療法とPEXを2クール施行した．症例2は43歳，女性，非常に急速な腎機能障害の進行を認めたためステロイドパルス療法とDFPPを施行した．DFPP例において一時的にIgGおよびフィブリノゲンの低下を認めたが，いずれの症例もplasmapheresisによる明らかな副作用はなく，MPO-ANCA titerの著明な低下と肺胞出血やRPGNを含む重篤な症候の速やかな改善を認め，良好な経過を得た．今回提示したMPO-ANCA関連血管炎の2症例では免疫抑制療法に加えてplasmapheresisが病態改善に有効であったと考えられる．本疾患におけるPEXおよびDFPPの選択には肺胞出血を含む出血傾向や全身の状態を検討し判断する必要がある．

Mitiglinide, a rapid- and short-acting insulinotropic sulfonylurea receptor ligand, exhibits hypoglycemic action unlike other sulfonylureas. The efficacy of the combination of mitiglinide and alpha-glucosidase inhibitors for diabetic patients on hemodialysis (HD) has not been prospectively evaluated; therefore, we evaluated the efficacy and safety of mitiglinide in these patients.We performed an open-label randomized study with 36 type 2 diabetics with poor glycemic control on HD and receiving daily doses of voglibose (0.9 mg). The patients were randomly assigned to two groups: a combination-therapy group (mitiglinide group), mitiglinide initial dose 7.5 - 15 mg titrated to 30 mg daily and constant daily dose 0.9 mg of voglibose, and a monotherapy group (control group), constant daily dose 0.9 mg of voglibose alone. The efficacy of the treatment was determined by monitoring plasma glucose, hemoglobin A1c (Hb(A1c)), and glycated albumin (GA) levels and using homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerance were determined by monitoring clinical and laboratory parameters.The final dose of mitiglinide was 22.9 +/- 8.9 (mean +/- s.d.) mg (0.41 mg/kg) daily. Mitiglinide reduced fasting plasma glucose and GA levels after 4 weeks and Hb(A1c) levels after 8 weeks. Triglyceride levels and HOMA-IR values also decreased significantly after mitiglinide treatment. No significant changes in blood pressure levels or serious adverse effects such as hypoglycemia or liver impairment were observed.This study suggests a combination therapy of mitiglinide and voglibose may have potential for the treatment of diabetics on HD. Due to the small sample size used, further studies should be performed, particularly to assess the safety of mitiglinide treatment.

Background: The efficacy of infliximab for endoscopic recurrence after resection of Crohn's disease (CD) has not yet been reported. The aim of this prospective study was to investigate the impact of infliximab on early endoscopic lesions after resection for CD. Methods: Twenty-six patients maintaining clinical remission (CD activity index [CDAI] score

Cilnidipine, a dual calcium channel antagonist, is assumed to regulate hypertension via N- and L-type calcium channel. The N-type calcium channel is associated with sympathetic nerve activation. This effect may improve the glome- rular hemodynamics in the injured nephron, and may mitigate the progression of renal injury. To clarify the effect of cil- nidipine in instances of already existing decreased renal blood flow, we examined the alteration of renal hemodynamics before and after cilnidipine therapy in patients with advanced chronic kidney disease (CKD). Cilnidipine was adminis- trated daily to 17 CKD patients with hypertension for 12 months. Another 16 patients were similarly administered am- lodipine during this study, a long-acting L-type calcium channel antagonist has also been shown to be renoprotective. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and protein excretion in 24-hour accumulated urine were measured at the start and end of the study. The parameters of renal hemodynamics were calculated by Gomez's es- timation equation. Systolic blood pressure decreased to 80 % of the level at the beginning of the study, and ERPF in- creased to 127 % of the level at baseline. Glomerular capillary pressure on single nephron was reduced to 90 %, although total GFR decreased within the non-statistical change. Especially, renal vascular resistance ratio (RA/RE) on single neph- ron improved to 120 %. Cilnidipine improves ERPF and glomerular hypertension without worsening total renal function. N- and L-type calcium channel antagonist is effective and safe for patients with advanced CKD as a result of improve- ment of glomerular capillary resistance.

Recent studies on dendritic cells (DCs) and macrophages have greatly advanced our knowledge of glomerular immunopathology. This rapidly developing field most likely has considerable impact on our understanding of the major mediators of tissue injury and repair in kidney disease. The pivotal role of cytokine in the initiation, differentiation, and amplification of local immune response production by antigen-presenting cells (APC; DCs, macrophages, and so forth) has been well documented, but the precise biological role of the numerous APC-derived products as effectors in both renal inflammation and repair remains a topic of intense research. This review focuses on the activated DCs and macrophages for the development and resolution of kidney disease, and discusses mechanistic information on the inflammatory process, including tissue injury and healing. A multi-dimensional study may contribute to further clarification of the role of their cellular activation in the progression of human kidney disease.

AIM We previously identified a quantitative trait locus (QTL) on rat chromosome 5 that appeared to be primarily controlled by the sympathetic nervous system. Because sympathetic overactivity is related to hypertension, solute carrier family 6, member 9 (SLC6A9) is a candidate gene for the connection of this QTL with blood pressure regulation. In the present study, we therefore explored the role of SLC6A9 genetic variations in human essential hypertension (EH). METHODS We evaluated three single nucleotide polymorphisms (SNPs) (rs2286245, rs3791124 and rs2486001) in 758 essential hypertension patients and 726 controls. Polymorphism-related genotypes were determined with TaqMan assays. RESULTS The allelic frequency of rs2286245 (C versus T, p=0.032) showed significant differences between EH and normotensive controls (NT) groups. The genotypic distribution of rs3791124 in its dominant model (AA+GA versus GG, p=0.027) also showed significant differences between EH and NT groups. The genotype and allele distributions of rs2486001 did not exhibit any significant differences. CONCLUSION We found an association between SLC6A9 gene polymorphisms and essential hypertension in a Japanese population, suggesting that SLC6A9 is a susceptibility locus for essential hypertension.

Background: Atherosclerosis leads to myocardial infarction (MI) and P2RY2 plays an important role in this process. The aim of the present study was to investigate the association between human P2RY2 and MI via a haplotype-based case-control study that additionally analyzed the group by sex. Methods and Results: The 310 MI patients and 254 controls were genotyped for 5 single-nucleotide polymorphisms (SNPs) of the human P2RY2 gene (rs4944831, rs1783596, rs4944832, rs4382936, rs10898909). Data were separately analyzed for the total, male, and female subjects. For men, the GA+AA genotype of rs10898909 was significantly higher in MI patients as compared with controls (P=0.040). Logistic regression analysis found a significant difference for the genotype (P=0.016). As compared with controls, the frequencies of the C-A and T-C-A haplotypes were significantly higher (P=0.016, and P=0.045, respectively) in men, whereas the frequencies of the C-G and T-A-A haplotypes were significantly lower (P=0.023, and P=0.025, respectively) in MI patients. Conclusions: The GA+AA genotype, as well as the C-A and T-C-A haplotypes, of human P2RY2 could be genetic markers for MI in Japanese men. (Circ J 2009; 73: 2322-2329)

BACKGROUND CYP4F2, a member of the cytochrome P450 family, acts mainly as an enzyme and is involved not only in the metabolism of leukotriene B4, but also in that of arachidonic acid. It converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the regulation of the vascular tone in the brain. The aim of this study was to assess the association between the human CYP4F2 gene and cerebral infarction (CI), using a haplotype-based case-control study with separate analyses of data from the gender groups. METHODS A total of 175 CI patients and 246 control subjects were genotyped for five single-nucleotide polymorphisms (SNPs) of the human CYP4F2 gene (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). For data analysis, three separate groups were assessed: all subjects, men, and women. RESULTS In the male subjects, the G allele frequency for rs2108622 was significantly higher in CI patients as compared to control subjects (P = 0.025). The overall distribution of the haplotypes in the men was significantly different between the CI patients and the control subjects (P = 0.027). Additionally, the frequency of the T-C-G haplotype for men was significantly higher in the CI patients than in the control subjects (P = 0.008). Multiple logistic regression analysis also revealed the significance of the T-C-G haplotype in men, even after adjustment for confounding factors. CONCLUSIONS The results of this study indicate that, in Japanese men, CI is associated with the G allele of rs2108622 and, in addition, that the T-C-G haplotype appears to be a useful genetic marker for CI.

Background/Aims: We established dedifferentiated fat (DFAT) cells from mature adipocytes that differentiate to multiple lineages and have characteristics similar to those of mesenchymal stem cells. In this study, we evaluated the effect of implantation of DFAT cells on habu snake venom (HSV)-induced renal dysfunction in tenascin-C knockout (TC-KO) mice. Methods: Cultured DFAT cells were incubated with PDGF-BB and immunostained with anti-desmin antibody to determine mesenchymal differentiation. HSV was injected, and DFAT cells from GFP mice were implanted in TC-KO mice via the tail vein. Expression of tenascin-C, transforming growth factor-β1 (TGF-β1), and fibronectin mRNAs in the renal cortex were evaluated by RT-PCR analysis. Results: Cultured DFAT cells showed desmin immunostaining in response to PDGF-BB.HSV injection induced glomerulosclerosis, which was significantly improved by implantation of DFAT cells. Serum BUN increased after HSV injection and was significantly decreased by implantation of DFAT cells. Tenascin-C mRNA was detected in the renal cortex in implanted mice. Expression of TGF-β1 and fibronectin mRNAs increased in the renal cortex after HSV injection, and was significantly decreased by implantation of DFAT cells. Conclusion: DFAT cells may provide a source for cell therapy for severe progressive renal disease.

BACKGROUND Endothelial progenitor cells (EPCs) derived from bone marrow migrate to areas of endothelial damage and repair them. EPC function is impaired by oxidative stress. We examined the effects of an antioxidative beta1-adrenoceptor blocker on the number and function of EPCs in hypertensive rats. METHODS Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were fed diets loaded with high salt. The SHRs were treated with celiprolol or atenolol for 2 weeks. Peripheral blood mononuclear cells (MNCs) were separated, subjected to flow cytometric analysis to determine the number of circulating EPCs, and cultured to quantify EPC colony formation. EPC migration was evaluated in migration assay chambers. EPC senescence was evaluated using beta-galactosidase assay. Oxidative stress of EPCs was evaluated using thiobarbituric acid-reactive substance (TBARS) assay. The expression of nicotinamine adenine dinucleotide phosphate (NAD(P)H) oxidase component mRNAs in the renal cortex, aorta, and heart were evaluated by real-time PCR. RESULTS The number, colony formation, and migration of EPCs in SHRs were significantly lower than those in WKY rats. TBARS scores in EPCs from SHRs were significantly higher than those from WKY rats. Celiprolol increased the number of circulating EPCs and stimulated EPC colony formation and migration, while decreasing EPC senescence. Celiprolol inhibited oxidation in EPCs from SHRs, and decreased the expression of NAD(P)H oxidase component mRNAs in the renal cortex, aorta, and heart. CONCLUSION EPCs are impaired in SHRs in response to oxidative stress. Celiprolol decreases oxidative stress in hypertension in vivo and improves EPC numbers and function. It appears, therefore, that celiprolol may exert beneficial cardiovascular effects through its antioxidative properties.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a membrane protein that can support the binding, internalization, and proteolytic degradation of oxidized low-density lipoprotein. The LOX-1 expression increases in the neointima after balloon injury. To develop an efficient compound to inhibit LOX-1, we designed and synthesized a novel gene silencer pyrrole-imidazole (PI) polyamide targeting the rat LOX-1 gene promoter (PI polyamide to LOX-1) to the activator protein-1 binding site. We examined the effects of PI polyamide to LOX-1 on the LOX-1 promoter activity, the expression of LOX-1 mRNA and protein, and neointimal hyperplasia of the rat carotid artery after balloon injury. PI polyamide to LOX-1 significantly inhibited the rat LOX-1 promoter activity and decreased the expression of LOX-1 mRNA and protein. After balloon injury of the arteries, PI polyamide to LOX-1 was incubated for 10 minutes. Fluorescein isothiocyanate–labeled PI polyamide was distributed to almost all of the nuclei in the injured artery. PI polyamide to LOX-1 (100 μg) significantly inhibited the neointimal thickening by 58%. PI polyamide preserved the re-endothelialization in the injured artery. PI polyamide significantly inhibited the expression of LOX-1, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, and matrix metalloproteinase-9 mRNAs in the injured artery. The synthetic PI polyamide to LOX-1 decreased the expression of LOX-1 and inhibited neointimal hyperplasia after arterial injury. This novel gene silencer PI polyamide to LOX-1 is, therefore, considered to be a feasible agent for the treatment of in-stent restenosis.

BACKGROUND We have earlier identified a quantitative trait locus (QTL) on rat chromosome 5 that appears to be primarily under the control of the sympathetic nervous system. Because sympathetic overactivity is related to both hypertension and insulin resistance, FABP3 is a candidate gene for the link between this QTL and blood pressure regulation. In this study, therefore, we explored the role of FABP3 genetic variations in essential hypertension (EH) in humans. METHODS We evaluated two single-nucleotide polymorphisms (SNPs) (rs2279885 and rs2271072) in 758 patients with EH and 726 controls. Polymorphism-related genotypes were determined using TaqMan assays, while haplotypes were estimated from the genotype data. RESULTS The frequencies of occurrence of the G allele of rs2279885 and the C allele of rs2271072 were significantly higher in subjects with EH than in normotensive (NT) subjects (P = 0.0339, P = 0.0209, respectively). However, the genotype distributions did not exhibit any significant differences. CONCLUSION We found an association between FABP3 gene polymorphisms and EH in a Japanese population, thereby suggesting that FABP3 is a susceptibility locus for EH.

Although the “gold standard” for diagnosis of tuberculous meningitis (TBM) is bacterial isolation of Mycobacterium tuberculosis , there are still several complex issues. Recently, we developed an internally controlled novel wide-range quantitative nested real-time PCR (WR-QNRT-PCR) assay for M. tuberculosis DNA in order to rapidly diagnose TBM. For use as an internal control calibrator to measure the copy number of M. tuberculosis DNA, an original new-mutation plasmid (NM-plasmid) was developed. Due to the development of the NM-plasmid, the WR-QNRT-PCR assay demonstrated statistically significant accuracy over a wide detection range (1 to 10 5 copies). In clinical applications, the WR-QNRT-PCR assay revealed sufficiently high sensitivity (95.8%) and specificity (100%) for 24 clinically suspected TBM patients. In conditional logistic regression analysis, a copy number of M. tuberculosis DNA (per 1 ml of cerebrospinal fluid) of >8,000 was an independent risk factor for poor prognosis for TBM (i.e., death) (odds ratio, 16.142; 95% confidence interval, 1.191 to 218.79; P value, 0.0365). In addition, the copy numbers demonstrated by analysis of variance statistically significant alterations ( P < 0.01) during the clinical treatment course for 10 suspected TBM patients. In simple regression analysis, the significant correlation ( R 2 = 0.597; P < 0.0001) was demonstrated between copy number and clinical stage of TBM. We consider the WR-QNRT-PCR assay to be a useful and advanced assay technique for assessing the clinical treatment course of TBM.

This study aims to evaluate the clinical features, diagnosis, and treatment efficacy in patients with pneumonia-associated rhabdomyolysis and acute renal failure. The subjects included six patients who had presented with rhabdomyolysis and acute renal failure due to bacterial or viral pneumonia on admission to our university hospital and the Yokohama Social Insurance Central Hospital between 2004 and 2005. The causative organisms were identified as Legionella pneumophila (N = 1), Staphylococcus epidermidis (N = 2), Staphylococcus aureus (N = 1), and Unknown (N = 2). For anuric or oliguric patients (N = 4), a blood purification therapy was performed, while conservative therapy was administered to those with a normal urine volume (N = 2). The patient suffering from L. pneumophila pneumonia did not survive, while the other patients regained full kidney function. It is important to identify, evaluate, and treat patients with bacterial or viral pneumonia-associated rhabdomyolysis and acute renal failure.

Currently, published reports of mucosal inflammation in the terminal ileum of ulcerative colitis (UC) before colectomy are scarce.To investigate inflammation in the terminal ileum of UC patients by endoscopic examinations and measurement of mucosal cytokine profiles.Fifty consecutive patients with active UC were studied. At ileocolonoscopy, mucosal biopsies were taken from the terminal ileum. As control, mucosal biopsies from 20 patients without inflammation were examined.Thirty-eight patients showed endoscopically normal terminal ileum, four showed backwash ileitis, and eight showed non-backwash ileitis (ileitis with normal caecum). Pancolitis was observed in all of four patients with backwash ileitis, in 4 of 8 (50%) with non-backwash ileitis, and in 4 of 38 (11%) without ileal inflammation (P=0.0002). Extraintestinal manifestations were observed in none of 4 patients with backwash ileitis, in 6 of 8 (75%) with non-backwash ileitis, and in 3 of 38 (8%) without ileal inflammation (P0.0001). In patients with backwash ileitis and non-backwash ileitis, ileal interleukin [IL]-1beta, IL-6, IL-8 and tumour necrosis factor-alpha levels were significantly elevated compared with the control group. Only extraintestinal manifestation was associated with higher ileal cytokine levels, whereas age, sex, and duration, extent and severity of UC did not show any apparent association.In patients with backwash ileitis, elevated ileal cytokines might reflect a reaction to regurgitation of colonic content into the ileum, but in patients without backwash ileitis, alternative factors are expected to contribute to the aetiology of ileal inflammation. Patients with extraintestinal manifestations had elevated ileal cytokine levels.

Objective CYP4A11 is an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid, which is involved in regulation of vascular tone in the brain. Recent evidence indicates that the polymorphism of the CYP genes is associated with cerebral infarction (CI). The aim of the present study was to assess the association between the human CYP4A11 gene and CI using a haplotype-based case-control study divided by gender. Methods Three SNPs of the human CYP4A11 gene (rs2269231, rs1126742, and rs9333025) were selected and genotyped for 174 CI patients and 293 controls. The data were assessed for three separate groups: total subjects, men and women. Results In men, the genotype distribution of rs9333025 significantly differed between the CI patients and control subjects (P = 0.047). The distribution of the dominant model of rs9333025 (GG vs. GA + AA) significantly differed between both the total and the men groups (P = 0.033, P = 0.028, respectively). Logistic regression analysis adjusted for the history of hypertension and diabetes mellitus also showed that the GG genotype was significantly more frequent in the CI patients than in the controls, both for the total and men groups (P < 0.001, P = 0.008, respectively). The overall distribution of the haplotypes constructed with the 3 SNPs showed significant differences between the CI and the control in total group (P = 0.049). The T-C-G haplotype was significantly more frequent in control subjects than in the CI patients in the total group (P = 0.020). Conclusions The GG genotype of rs9333025 could be a genetic marker for CI in Japanese men. In addition, the T-C-G haplotype might also be a protective marker for CI in Japanese.

Background Angiotensin II (Ang II) receptor blocker (ARB) has been reported to have protective effects on the cardiovascular system independent of blood pressure reduction. Endothelial progenitor cells (EPCs) play a significant role in neovascularization of ischemic tissue. The average lifespan of EPCs was recently reported to be shortened by oxidative stress and regulated by anti-oxidative mechanisms. It has been reported that EPCs are present in peripheral blood and have the ability to repair cardiovascular damage. We investigated the effects of an ARB, candesartan, on EPC function and cardiovascular oxidation in salt-loaded, stroke-prone, spontaneously hypertensive rats (SHR-SP) in vivo. Methods Salt-loaded SHR-SP were treated with candesartan (1 mg/kg/day), a diuretic (trichlormethiazide, TCM, 1.6 mg/kg/day), or an antioxidant (tempol, 5 mg/kg/day) for 2 weeks. Peripheral blood mononuclear cells (MNCs) were isolated and cultured to assay EPC colony formation and migration. Oxidative stress in EPCs was evaluated by thiobarbituric acid reactive substance (TBARS) assay. We evaluated messenger RNA (mRNA) expression of c-kit in the heart, the renin-angiotensin system (RAS) in EPC colonies, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit in cardiovascular organs. Results Candesartan and tempol, but not TCM, markedly increased EPC colony number in SHR-SP and reduced TBARS. Candesartan also significantly decreased mRNA expression of NADPH oxidase subunits in cardiovascular organs and increased cardiac c-kit mRNA expression. EPCs expressed mRNAs of renin, cathepsin D, chymase, and Ang II type 1 and type 2 receptors. Conclusions Candesartan, an ARB, improves EPC dysfunction and increases cardiac c-kit expression through the anti-oxidative mechanism in hypertension. The local RAS induces oxidative stress and regulates the EPC functions.

Long-term enteral nutrition may maintain clinical and endoscopic remission in patients with Crohn's disease (CD). The aim of this prospective study was to investigate the impacts of long-term enteral nutrition on clinical and endoscopic disease activities and mucosal tissue cytokines in patients with quiescent CD.Forty patients with CD who achieved clinical remission were included. Of these, 20 received continuous elemental diet (Elental) infusion during the nighttime and a low-fat diet during the daytime (EN group) and 20 received neither nutritional therapy nor food restriction (non-EN group). With these regimens, all 40 patients were monitored for 1 year. Further, ileocolonoscopy was performed at entry, at 6 and 12 months, and mucosal biopsies were taken for cytokine assays.On an intention-to-treat basis, 5 patients (25%) in the EN group and 13 (65%) in the non-EN group had a clinical relapse during the 1-year observation (P = 0.03). The mean endoscopic inflammation (EI) scores were not significantly different between the groups at both entry and 6 months, but at 12 months EI scores were significantly higher in the non-EN group than in the EN group (P = 0.04). Additionally, the mucosal tissue interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha levels significantly increased with time in the non-EN group (entry versus 12 months, IL-1beta, P = 0.02; IL-6, P = 0.002; TNF-alpha, P = 0.001). In the EN group these cytokines did not show a significant increase.Long-term enteral nutrition in patients with quiescent CD has a clear suppressive effect on clinical and endoscopic disease activities and the mucosal inflammatory cytokine levels.

Background A major mechanism of hypertension in many postmenopausal women is deficiency of female gonadal steroids. A long postmenopausal period may thus represent one factor that influences the prevalence of hypertension because of long periods of estrogen loss. Methods When we conducted a medical survey in northwestern China, we also asked 150 postmenopausal female subjects to provide age at menopause in a questionnaire. Age at menopause ranged from 37 to 57 years for all subjects. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) in all subjects were obtained from 24-h ambulatory blood-pressure monitoring. Results An inverse correlation was identified between age at menopause and SBP and DBP, and a positive correlation was found between postmenopausal period and either SBP or DBP. Blood pressure, age at menopause, and postmenopausal period were not significantly related to body mass index, plasma renin activity, glomerular filtration rate, or urinary excretion values of sodium and potassium. Conclusions Our results clearly demonstrated that higher blood-pressure levels in postmenopausal women depend on age at menopause and postmenopausal period, but not subjects’ age, suggesting that a longer absence of female gonadal steroids represents a major factor contributing to increased blood pressure in elderly women.

The aim of the present study was to evaluate the alteration in plasma immunoreactive insulin (IRI) and glucose concentrations due to hemodialysis (HD) treatment by using a dialysate with or without glucose in HD patients. We divided the patients into three groups: non-diabetic patients (n-DM group), well-controlled diabetic patients (HbA(1c)7.0% [w-DM group]), and poorly-controlled diabetic patients (HbA(1c)or = 7.0% [p-DM group]). Using a dialysate with a glucose concentration of 100 mg/dL (glu(+)-dialysate) and a glucose-free dialysate (glu(-)-dialysate), we studied the daily profiles of plasma glucose in the three groups. We measured the levels of plasma glucose and IRI at three time points (predialysis and 2 h and 4 h after the initiation of dialysis) at pre(A) and postdialyzer (V) sites in HD patients. There was a significant increase in the daily profiles of the plasma glucose level from the time before dinner until bedtime in both the w-DM and p-DM groups, when comparing the values on an HD day with those on a non-HD day. In the p-DM group, the use of the glu(-)-dialysate resulted in a significant hyperglycemia in the evening hours when compared with the use of the glu(+)-dialysate. In the DM group, the use of the glu(+)-dialysate resulted in a significant decrease in the plasma glucose and IRI levels during HD. However, in the n-DM group, there was no difference in the plasma glucose levels during HD. On the other hand, the use of a glucose-free dialysate led to a significant decrease in the plasma glucose and IRI levels during HD in all groups. The plasma IRI levels decreased significantly between the A and V sites at each point in all groups irrespective of the glucose concentration of the dialysate. The present study confirmed that the concentration of not only glucose but also IRI had decreased during the passage of the plasma through the dialyzer. In HD patients with diabetes, the glucose content of the hemodialysis solution plays an important role in preventing acute hypoglycemia and hyperglycemia on HD days.

Often, well-controlled plasma glucose levels but high hemoglobin A(1c) levels have been observed at prehemodialysis in diabetic patients. The present study aimed to evaluate this difference between fasting glucose and hemoglobin A(1c) levels. We investigated hemodialysis-induced alterations in the plasma glucose and insulin levels. Based on their glycemic control level at inclusion, subjects were divided into poor control (hemoglobin A(1c)> or =7.0%; n = 8) and good control groups (hemoglobin A(1c)

Background. Granulocyte, monocyte/macrophage adsorptive apheresis is a novel treatment for active ulcerative colitis. However, as yet no study has reported on a subset of patients who might respond well to granulocyte, monocyte/macrophage adsorptive apheresis therapy. Aim. To identify factors affecting clinical and endoscopic efficacies of granulocyte, monocyte/macrophage in patients with ulcerative colitis. Methods. Fifty consecutive patients with active ulcerative colitis initially received five granulocyte, monocyte/macrophage adsorptive apheresis sessions with the Adacolumn over five consecutive weeks. Patients who improved without achieving remission received five additional granulocyte, monocyte/macrophage adsorptive apheresis sessions. Results. One week after the last granulocyte, monocyte/macrophage adsorptive apheresis session, 26 (52%) and 17 patients (34%) achieved clinical and endoscopic remission, respectively. In the multivariate analysis, the dose of prednisolone administered at entry and the cumulative dose of prednisolone administered before entry were independent significant factors for both clinical and endoscopic remission, negatively impacted the efficacy of granulocyte, monocyte/macrophage adsorptive apheresis. Age, gender, duration of ulcerative colitis, number of prior relapses, duration of current exacerbation, extent and severity of ulcerative colitis, extra-intestinal manifestations, entry haematology values and C-reactive protein did not affect the outcome. Conclusions. Based on the outcomes of this study, it appears that steroid-na¨ ove patients and patients on low dose steroid and short duration of exposure respond to granulocyte, monocyte/macrophage adsorptive apheresis. Further studies in larger cohorts of patients should strengthen our findings. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

We report the case of a patient who developed eosinophilia during hemodialysis and became intolerant to dialysis therapy. The patient, a 40-year-old woman, was initiated on hemodialysis for end-stage renal failure caused by chronic glomerulonephritis. After starting on dialysis, her eosinophil count gradually increased. During the ninth session, she developed abdominal pain of an unknown cause after approximately 1 h of dialysis. The symptom, which persisted in the following sessions, was considered to be a dialysis-related complication. We attempted different dialyzers and anticoagulants, but without improvement. The dialysis therapy was discontinued and steroid treatment was given. The hypereosinophilic condition improved rapidly and dialysis therapy was restarted successfully without causing abdominal pain. To investigate the cause of this problem, we measured the leukocyte count and anaphylatoxin C3a level in peripheral blood during dialysis, and compared the results before and after steroid treatment. The results showed that the significant decrease in the leukocyte count observed before steroid treatment was reduced to a mild decrease after steroid treatment. In contrast, C3a did not show a significant difference between the values obtained before and after steroid treatment. These findings suggest that eosinophilia played an important role in the etiology of dialysis intolerance and that C3a was not involved in the decrease in leukocytes under the conditions experienced by the present patient.

We investigated whether or not uremic serum has an influence on IL-1beta and IL-1Ra production by normal peripheral blood mononuclear cells (PBMC). Four groups of subjects were divided into healthy controls and non-dialyzed patients with chronic renal failure (CRF), patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) patients. We examined cytokine concentrations and cytokine production by PBMC from a normal subject at the density of 2.5 x 10(6) cells/mL incubated with 25% serum in the medium and serum containing polymyxin-B or lipopolysaccharides (LPS). IL-1Ra concentrations in the serum of the uremic groups were significantly higher than those of the controls. In IL-1beta production by PBMC in medium with both serum and serum containing polymyxin-B, these values in the uremic groups were significantly higher than in the controls. In IL-1Ra production with serum containing polymyxin-B, these values in the uremic groups were significantly higher than in the controls. In contrast, in IL-1Ra production by PBMC in medium with serum containing LPS, these values in the uremic groups were significantly lower than in the controls. It was concluded that uremic serum not only contains nonendotoxemic cytokine-inducing substances, but also shows impaired cytokine production by PBMC in response to LPS.

We report a rare case of ACTH-independent macronodular adrenal hyperplasia (AIMAH) with primary hyperparathyroidism (PHPT). A 57-year-old woman was admitted to our hospital for further examination of secondary hypertension and bilateral adrenal macrotumors. Midnight serum cortisol elevation with undetectable plasma ACTH, increased 24-hour urinary free cortisol excretion, and loss of the normal circadian rhythm in cortisol secretion established the diagnosis of Cushing's syndrome. Total resection of the enlarged left adrenal gland was performed with subsequent steroid replacement. Her general condition improved but serum calcium level increased 3 weeks after surgery. PHPT was diagnosed on the basis of endocrinological examination, although imaging studies failed to detect parathyroid lesion. In summary, we believe this to be the first report of a case of AIMAH with PHPT.

Background/Aims: Mannose-binding lectin (MBL) is characteristic of an acute-phase-reacting protein like C-reactive protein (CRP). However, the prognostic value of the serum MBL level has not been examined. The aim of this study was to evaluate whether the serum MBL level can predict all-cause mortality in hemodialysis (HD) patients. Methods: A total of 131 patients without active infection, who had been on maintenance HD for at least 2 years, were included in this study. The serum MBL, high-sensitivity CRP (hs-CRP) level, nutrition markers, and biochemical parameters were measured in June 1999. The cohort was then followed prospectively for 36 months, and clinical data were recorded. Results: The MBL level of the 131 HD patients was 9.054 ± 5.115 µg/ml (mean ± SD). During the follow-up period, 18 patients (9 males and 9 females) died and 113 (64 males and 49 females) survived. The two leading causes of death were cardiovascular events (n = 6, 33.3%) and infection (n = 4, 22.2%). The serum MBL level was significantly lower among the nonsurvivors (6.596 ± 4.990 µg/ml) than among the survivors (9.445 ± 5.046 µg/ml; p < 0.05). There was a significant, although very weak, correlation between the MBL level and albumin level (p < 0.05), but there was no correlationbetween the MBL level and the hs-CRP level. The patients were divided into two groups according to the serum MBL level (5 µg/ml). Multivariate analysis of factors predicting all-cause mortality in multivariate logistic regression analysis identified a serum MBL level Conclusions: Our findings suggest that the serum MBL level is a significant predictor of outcome in HD patients. HD patients with a low level of serum MBL should be carefully monitored.

Background: The main aim of this prospective study was to examine whether systemic (plasma) and local (mucosal) cytokine production is a predictor of future relapse in patients with quiescent ulcerative colitis (UC). The impact of other clinical and laboratory parameters on relapse was also studied. Methods: Fifty consecutive patients with quiescent UC were included. At enrollment, blood and mucosal (rectal biopsies) samples were collected. All patients were followed up regularly for 1 year after enrollment. Plasma and mucosal cytokine levels were measured by enzyme-linked immunosorbent assay. To identify independent significant predictive factors for relapse, time-dependent analyses using the Kaplan-Meier method and the Cox proportional hazard model were performed. Results: Thirty-four patients remained in remission, and 16 patients relapsed during the 1-year follow-up. Higher interleukin (IL)-8 levels in the rectal mucosa were significantly associated with relapse. In contrast, IL-1β, IL-6, and tumor necrosis factor-α levels in the rectal mucosa were not associated with relapse. Conventional blood markers and plasma cytokines (IL-1β, IL-6, IL-8, and tumor necrosis factor-α) did not correlate with relapse. Among clinical factors, age and number of prior relapses were significantly associated with relapse. In multivariate analysis, a higher rectal mucosal IL-8 level (≥160 pg/mg of tissue; hazard ratio, 4.7), younger age (

Background: Uremic toxins have been shown to promote glomerular hypertrophy. The present study was performed to elucidate the relation between uremic toxins and tubulointerstitial changes. Methods: Sixty male Sprague-Dawley rats underwent 2/3 nephrectomy (Nx; n = 30) and 4/5 Nx (n = 30). Experiments were initiated 2 weeks after surgery, and were performed over an 8-week period. Half of each group (Nx-A) was administered 1 g/day of an oral carbonaceous adsorbent, AST-120, with pair-feeding, and the other half (Nx-C) served as controls. All rats were sacrificed at week 8 after a clearance study. Results: The shortest diameter of proximal tubules (PTD) and interstitial fibrosis area (IFA) at week 8 in 2/3 Nx-A rats was significantly decreased compared to that in 2/3 Nx-C rats (similar body weights, systolic blood pressures, glomerular filtration rates, and urinary protein excretion levels). The values of PTD and IFA, glomerular filtration rate and urinary protein excretion level at week 8 in 4/5 Nx-A rats were significantly decreased compared to those in 4/5 Nx-C rats (similar body weights and systolic blood pressures). Conclusion: Administration of AST-120 minimized the appearance of proximal tubular hypertrophy and interstitial fibrosis, and subsequently prevented the occurrence of proteinuria and decreased renal function. The present study indicates that uremic toxins adsorbed by AST-120 promote tubular hypertrophy and interstitial fibrosis in nephrectomized rats.