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Objective There is no definite consensus regarding the treatment and guidance for individuals with high-normal fasting plasma glucose levels (FPG;100-109 mg/dL). The present study aimed to determine the risk factors for future diabetes in Japanese people with high-normal FPG. Methods Retrospective cohort studies were conducted from 2008 to 2012, including 15,097 individuals who underwent medical examinations. First, the participants were divided into normal FPG (n=13,065) and high-normal FPG (n=2,032) groups to compare the diabetes incidence. Second, the high FPG group was divided into diabetes onset (n=133) and non-diabetes onset (n=1,899) groups to compare the baseline values. Third, to determine the risk factors for future diabetes in the high-normal FPG group, multivariate analyses were conducted. Results The cumulative incidence during the mean follow-up of 4 years was 94/13,065 (0.72%) and 133/2,032 (6.55%) in the normal FPG and high-normal FPG groups, respectively. Within the high-normal FPG group, the baseline body mass index, waist circumference, triglycerides, FPG, alanine aminotransferase (ALT), and gamma-glutamyl transferase were significantly higher and high-density lipoprotein cholesterol (HDL-C) was significantly lower in the diabetes onset group than in the non-diabetes onset group. Obesity, abdominal obesity, hypertriglyceridemia, low HDL-C, and high ALT were significant risk factors for diabetes according to a multivariate analysis. Conclusion The high-normal FPG group had a higher risk of diabetes than the normal FPG group, particularly when accompanied with obesity, abdominal obesity, hypertriglyceridemia, low HDL-C, and high ALT. Thus, this high risk group should receive appropriate guidance for lifestyle changes to avoid developing diabetes at an early stage.

In this prospective, randomized, open-label, blinded end point study, we aimed to establish whether strict blood pressure control (P =0.38). In summary, blood pressure targets of

BACKGROUND Vascular calcification is an independent determinant of cardiovascular events in maintenance haemodialysis (HD) patients. It is not known whether acute changes of the serum calcium concentration before and after HD (DeltaCa) are associated with the development of aortic calcification. METHODS We enrolled 71 patients dialysed with a dialysate with 3.0 mEq/l calcium and determined their aortic calcification index (ACI) by abdominal computed tomography twice at an interval of 3 years. To identify the factors contributing to the rate of progression of aortic calcification, we analysed the average values for clinical and laboratory data obtained between the first and second evaluations of ACI. RESULTS The second ACI (mean+/-SD: 80.2+/-63.9) was significantly greater than the first ACI (61.0+/-61.0) after an interval of 35.8+/-4.2 months. The annualized change of ACI (DeltaACI/year) was significantly and directly associated with the DeltaCa and C-reactive protein (CRP) (both P

Adrenomedullin (AM) is a bioactive peptide having a wide range of biological actions such as vasodilatation, natriuresis, diuresis and inhibition of aldosterone secretion. Various organs and tissues, including the myocardium, vascular wall and kidneys, produce AM, and AM is also present in the bloodstream. Plasma levels of AM were elevated in patients with essential or secondary hypertension as compared with normotensive controls. When infused in a relatively short period of time, AM reduced blood pressure in humans and experimental animals largely through vasodilatation. The blood pressure of transgenic mice overexpressing AM was lower than that of their wild-type littermates; while heterozygotes of AM knockout mice showed higher blood pressure, suggesting a role for endogenous AM in the regulation of blood pressure. Studies with cultured cardiac cells suggest a role for AM in inhibiting hypertrophy or fibrosis of the heart as an autocrine or paracrine factor. Animal experiment studies showed that either prolonged infusion or virally mediated overexpression of AM ameliorated the cardiovascular and renal damage associated with hypertension. Thus, a body of evidence accumulated in this field suggests that AM functions to counteract the elevation in blood pressure and progression of hypertensive organ damage.

It is unknown whether long-term pharmacological stimulation of soluble guanylate cyclase (sGC), elevating intracellular cGMP levels, has a beneficial effect on hypertension. The purpose of this study is to investigate the effects of BAY41-2272, an orally available sGC stimulator, on cardiovascular remodeling in hypertensive rats. Eight-week-old male Wistar rats with hypertension induced by angiotensin II infused subcutaneously at 250 ng/kg per minute were treated orally with a low ([L] 2 mg/kg per day) or high ([H] 10 mg/kg per day) dose of BAY41-2272 for 14 days. BAY41-2272-H partially suppressed the rise in blood pressure and reduced the heart weight (4.20±0.34 versus 3.68±0.20 mg/g; P P P P P P P P P P

Background/Aims: Adrenomedullin (AM) has anti-proliferative and apoptotic effects on mesangial cells (MCs). Both effects play an important role in the progression of glomerulonephritis (GN). Glucocorticoids are widely used for the treatment of GN; however, the relationship between AM regulation in MCs or glomeruli and glucocorticoid treatment has not been clarified. Methods: Using the cultured rat MCs, AM secretion induced by methylprednisolone (m-PSL), and MC proliferation and apoptosis caused by AM were examined. In addition, the role of AM receptor antagonist, AM(22-52), was also investigated. Then, we made an anti-glomerular basement membrane (GBM) GN rat model and compared the AM expression and production in each glomeruli obtained from the control or m-PSL-treated anti-GBM GN rats. Results: In the cultured rat MCs, AM secretion was increased by m-PSL. MC proliferation was inhibited, while MC apoptosis was increased by AM. MC apoptosis was inhibited by the addition of AM(22-52). M-PSL therapy ameliorated the progression of anti-GBM GN rats. AM expression and production were increased in the glomeruli from m-PSL-treated rats compared to the controls. Conclusion: Considering the anti-proliferative and apoptotic effects of AM on MCs, increased AM in the glomeruli might participate in the improvement of glomerular lesions in anti-GBM GN rats treated with m-PSL.

Receptor activity-modifying proteins (RAMPs) enable calcitonin receptor-like receptor (CRLR) to function as a calcitonin gene-related peptide receptor (CRLR/RAMP1) or an adrenomedullin (AM) receptor (CRLR/RAMP2 or -3). Here we investigated the functions of the cytoplasmic C-terminal tails (C-tails) of human RAMP1, -2, and -3 (hRAMP1, -2, and -3) by cotransfecting their C-terminal deletion or progressive truncation mutants into HEK-293 cells stably expressing hCRLR. Deletion of the C-tail from hRAMP1 had little effect on the surface expression, function, or intracellular trafficking of the mutant heterodimers. By contrast, deletion of the C-tail from hRAMP2 disrupted transport of hCRLR to the cell surface, resulting in significant reductions in (125)I-hAM binding and evoked cAMP accumulation. The transfection efficiency for the hRAMP2 mutant was comparable with that for wild-type hRAMP2; moreover, immunocytochemical analysis showed that the mutant hRAMP2 remained within the endoplasmic reticulum. FACS analysis revealed that deleting the C-tail from hRAMP3 markedly enhances AM-evoked internalization of the mutant heterodimers, although there was no change in agonist affinity. Truncating the C-tails by removing the six C-terminal amino acids of hRAMP2 and -3 or exchanging their C-tails with one another had no effect on surface expression, agonist affinity, or internalization of hCRLR, which suggests that the highly conserved Ser-Lys sequence within hRAMP C-tails is involved in cellular trafficking of the two AM receptors. Notably, deleting the respective C-tails from hRAMPs had no effect on lysosomal sorting of hCRLR. Thus, the respective C-tails of hRAMP2 and -3 differentially affect hCRLR surface delivery and internalization.

Leukocytapheresis (LCAP) is a therapeutic strategy for extra corporeal immunomodulation that has been used to treat several immunological disorders, including ulcerative colitis (UC), with encouraging results, inducing remission in steroid-resistant patients. However, we have experienced some complications during or after LCAP therapy. Common adverse effects include fever, chills, nausea, vomiting, and hypotension. One of the reasons for these adverse effects might be the use of nafamostat mesilate (NM) as an anticoagulant. In the present study, 75 patients with UC were divided into two groups, an NM group and a dalteparin sodium (DS) group. The clinical efficacy of these treatments, improvement after treatment, changes in leukocyte differential count, and adverse effects after LCAP therapy were then compared. The clinical efficacy, improvement after treatment, and changes in leukocyte classification were not significantly different between the two groups, while some adverse effects were observed in the NM group but not in the DS group. In conclusion, LCAP therapy is a useful therapy for patients with moderate to severe UC who fail to respond to glucocorticoid therapy, however, a safe anticoagulant should be used to avoid its related adverse effects.

As the numbers of aging patients with manifestations of renal disease increase, the elderly must frequently undergo renal biopsies. This study examined the characteristics of clinicopathological correlations in elderly patients. Medical and clinical records from renal biopsies registered in two hospitals between January 2000 and December 2004 were reviewed. Among 406 patients (female: male 224/182; age 43.9 +/- 18.8 years, mean +/- SD) who underwent renal biopsies, 61 (15.1%) who were aged 65 years and older (female: male, 29/32; age 72.8 +/- 5.2 years) were selected. The elderly usually underwent percutaneous renal biopsies for renal diseases such as nephrotic syndrome (43%) and acute or rapidly progressive renal failure (A/RPRF, 39%). Focal/segmental glomerulosclerosis (23%), minimal change disease (19%), and membranous nephropathy (15%) are frequently diagnosed based on biopsy specimens from patients with nephrotic syndrome. Among patients presenting with A/RPRF, 17 (71%) and 4 (17%) had pauci-immune, MPO-ANCA positive, crescentic glomerulonephritis and interstitial nephritis, respectively, and benefited from therapeutic intervention. Histopathological and pre-biopsy clinical diagnoses differed in nine (15%) patients. The complication rate after biopsy was low (3%). Primary glomerular diseases presenting with nephrotic syndrome and primary crescentic glomerulonephritis associated with rapidly progressive renal failure were the most frequently diagnosed among the elderly who underwent renal biopsy. Percutaneous renal biopsy provides clinically useful information about the elderly because clinical presentation and the predicted diagnosis sometimes vary.

Summary. Background: Thrombus propagation on disrupted plaque is a major cause of acute coronary events and serious complication after coronary intervention. 5-hydroxytryptamine (5-HT) is a potent vasoactive and platelet-aggregating substance that is predominantly mediated by 5-HT2A receptor. However, the roles of 5-HT2A receptor in occlusive thrombus formation on disrupted plaque remain obscure. Objective: We investigated the role of 5-HT2A receptor in thrombus formation using a rabbit model of repeated balloon-injury. Methods: Three weeks after a first balloon-injury of the femoral arteries, luminal diameter, neointimal growth, and vasoconstriction by 5-HT in vitro were examined. Thrombus propagation and the role of 5-HT2A receptor after a second balloon-injury were evaluated using sarpogrelate, a selective 5-HT2A receptor antagonist. Results: Three weeks after the first balloon-injury, luminal stenosis was evident in the femoral arteries, where the neointima expressed tissue factor and 5-HT2A receptor. The hypercontractile response of the stenotic arteries to 5-HT was significantly reduced by sarpogrelate. Balloon-injury of the neointima with substantially reduced blood flow promoted the formation of occlusive thrombus that was immunoreactive against glycoprotein IIb-IIIa, 5-HT2A receptor and fibrin. Intravenous injection of sarpogrelate significantly inhibited ex vivo platelet aggregation induced by adenosine 5′-diphosphate, thrombin and collagen alone as well as with 5-HT, and significantly prevented occlusive thrombus formation in vivo. Conclusions: The 5-HT2A receptor appears to play a crucial role in occlusive thrombus formation in diseased arteries via platelet aggregation and vasoconstriction. Inhibition of 5-HT2A receptor might help reduce the onset of acute coronary events and of acute coronary occlusion after the intervention.

Adrenomedullin (AM) administered intracolonically ameliorated the severity of acetic acid-induced colonic ulceration in rats. Ulcers were induced by subserosal injection of acetic acid into the colon. AM-treated group was administered 0.25-1.0 microg of AM in 0.5 ml of saline intracolonically once a day; the control group received only saline. AM administration dose-dependently and significantly reduced the size of the ulcerative lesions, the associated edema, and the infiltration of the affected area by inflammatory cells. AM also reduced tissue levels of interleukin-6, but not interferon-gamma. AM reduces the severity of acetic acid-induced colitis in rats, probably by inhibiting the production and/or release of Th-2 cell-derived factors such as interleukin-6.

Adrenomedullin (AM) is a vasodilator peptide having a wide range of biological actions such as reduction of oxidative stress and inhibition of endothelial cell apoptosis. The AM gene is expressed in vascular walls, and AM was found to be secreted from cultured vascular endothelial cells, smooth muscle cells, and adventitial fibroblasts. Plasma AM levels in patients with arteriosclerotic vascular diseases are elevated in possible association with the severity of the disease. When administered over a relatively short period, AM dilates blood vessels via an endothelium-dependent or independent mechanism. Experiments in vitro have shown that AM exerts multiple actions on cultured vascular cells, which are mostly protective or inhibitory against vascular damage and progression of arteriosclerosis. Either prolonged infusion or overexpression of AM suppressed intimal thickening, fatty streak formation, and perivascular hyperplasia in rodent models for vascular remodeling or atherosclerosis. Intimal thickening induced by periarterial cuff was more severe in AM gene-knockout mice than their littermates, suggesting a protective role for endogenous AM. Moreover, AM has recently been suggested to possess angiogenetic properties. Collectively, a body of evidence suggests that AM participates in the mechanism against progression of vascular damage and remodeling, thereby alleviating the ischemia of tissues and organs.

Based on observations of the clinical course in patients with IgA nephropathy (IgAN), D'Amico et al proposed the concept of the "point of no return (PNR)", after which progression to end-stage renal disease (ESRD) becomes inevitable. They reported that the approximate PNR is serum creatinine (sCr) 3.0 mg/dL.To confirm the PNR and to clarify the factors affecting renal function deterioration in IgAN patients, we analyzed the sequential data of those with 1.2or= sCr2.0 mg/dL at renal biopsy. Forty-seven patients with moderate to severe histological lesions and whose 36-month follow-up did not require renal replacement therapy were enrolled in this study.None of the patients who once exceeded sCr 2.0 mg/dL could return to2.0 mg/dL during the observation period (103.3 +/- 54.3 (36-237) months). Kaplan-Meier analysis revealed that the renal outcome of patients with average mean blood pressure (MBP)or= 102 mmHg and/or urinary protein (UP) scoreor= 2.0 with sCr up to 2.0 mg/dL was significantly poor. Multivariate analysis using the Cox's proportional hazards model, identified only MBP and UP during the course until sCr reached 2.0 mg/dl as independent prognostic factors for ESRD, having hazard ratios of 2.56 (per 10 mmHg; 95% confidence interval (95% CI) 1.08-6.05) and 4.37 (per 0.5 point; 95% CI 1.36-14.1), respectively.We confirmed PNR as a sCr level of 2.0 mg/dL (equivalent to estimated glomerular filtration rate (GFR) of 30-35 mL/min/1.73m2) during the course of IgAN in Japan. Proper management of both BP and UP until sCr has reached PNR is essential to arrest the progression to ESRD in IgAN.

Adrenomedullin (AM) is a potent vasodilator peptide whose major source is the vascular wall. In the present study, the mechanism of release of AM was investigated in the rat mesenteric resistance artery. The isolated mesenteric vascular bed was perfused with Krebs solution at a constant flow rate (5 ml/min) and AM in the perfusate was measured by a highly sensitive enzyme immunoassay (Immunoenzymometric assay; IEMA) method. In preparations without endothelium, spontaneous release of AM was detected in the perfusate (68.7 ± 5.8 fmol/ml, n = 45). Periarterial nerve stimulation (PNS, 4 and 8 Hz) caused 11.4 ± 3.9% (4 Hz) and 9.1 ± 3.5% (8 Hz) decreases in the spontaneous release of AM. Removal of Ca 2+ from the medium did not affect the spontaneous AM release, but abolished the PNS-induced inhibition of spontaneous AM release. Perfusion of 10 nM calcitonin gene-related peptide (CGRP) or 0.1 μM capsaicin (inducer of CGRP release) inhibited significantly the spontaneous AM release. PNS (8 Hz)-induced inhibition of spontaneous AM release was antagonized by CGRP(8–37) (CGRP receptor antagonist). These results suggest that AM is mainly released from vascular smooth muscle cells of the rat mesenteric artery and endogenous or exogenous CGRP inhibits AM release.

Hemodialysis (HD) patients often experience cardiovascular events, that might be related to altered calcium-phosphate metabolism, dyslipidemia, and chronic inflammation in addition to hypertension. Sevelamer, a non-calcium-containing phosphate binder, may improve the lipid profile of HD patients. However, the influence of sevelamer on chronic inflammation has not been clarified.We enrolled 36 maintenance HD patients with a serum calcium (Ca) or phosphate (P) level constantly greater than 9.5 mg/dL and 5.5 mg/dL, respectively. The dose of sevelamer was titrated to achieve a serum Ca and P in the target ranges. The study period was 24 weeks. Patients underwent the following measurements: bone mineral markers, lipids, and a high-sensitivity C-reactive protein (hs-CRP).In the 28 patients who completed the study, sevelamer significantly reduced the mean non-high-density lipoprotein cholesterol (non-HDL-C) level by 15% and 20% (p0.0001) after 12 and 24 weeks, respectively, in addition to reducing the serum P level and Ca x P product. Similarly, there was a significant reduction of the serum hs-CRP level after 12 and 24 weeks [median at baseline: 1.03 mg/dL (interquartile range 0.26-3.98 mg/dL) versus 0.57 (0.17-1.47) and 0.38 (0.16-1.03), respectively, p = 0.0259]. The reduction rate of hs-CRP was significantly correlated with those of non-HDL-C (r = 0.451, p0.0401) and P (r = 0.453, p0.0008)Hs-CRP levels were reduced by sevelamer administration, as well as non-HDL-C, P, and the Ca x P product. Sevelamer may have an anti-inflammatory effect, in addition to lowering phosphate and lipid levels in HD patients.

Adrenomedullin is a potent hypotensive peptide that may act on myocytes to inhibit hypertrophy and on fibroblasts to inhibit growth in vitro induced by mechanical stretching and angiotensin II. Adrenomedullin is processed from the inactive intermediate adrenomedullin precursor with a glycine extension, which is subsequently converted to biologically active mature adrenomedullin by enzymatic amidation. Total adrenomedullin is the sum of intermediate and mature adrenomedullin. We examined the effect of a subpressor dose of angiotensin II on the production of left ventricular adrenomedullin and on protein levels of mature adrenomedullin in the left ventricle in vivo. We also investigated whether the effect is mediated by the angiotensin II type 1 receptor. Concentrations of total and mature adrenomedullin in the left ventricle and mature adrenomedullin-to-intermediate adrenomedullin ratio were significantly increased by angiotensin II infusion, regardless of pressure overload. Total and mature adrenomedullin concentrations significantly correlated with the weight of the left ventricle. Furthermore, increased adrenomedullin gene expression and protein levels were completely suppressed by a subdepressor dose of angiotensin II type 1 receptor blocker. In conclusion, angiotensin II stimulates the production of cardiac adrenomedullin and accumulates mature adrenomedullin in the left ventricle independently of hemodynamic stress. These processes are partially regulated through the angiotensin II type 1 receptor in vivo.

We measured plasma levels of interleukin-6 and C-reactive protein at the orifice of the left coronary artery and at the great cardiac vein in patients who had coronary artery disease and those who had angiographically normal coronary arteries (controls). We also measured coronary microvascular resistance in the control group. We found increased levels of interleukin-6 in the coronary circulation of patients who had coronary artery disease compared with controls. This increase correlated with C-reactive protein production in the coronary circulation and coronary microvascular resistance. These findings suggest that a localized cytokine/inflammatory pathway functions in the coronary circulation and that interleukin-6 is involved in modulating coronary vascular tone.

To determine whether the expression of CD39 in coronary atherosclerotic lesions is related to plaque instability and thrombus formation, we assessed directional coronary atherectomy (DCA) specimens from patients with stable and unstable angina pectoris. CD39 immunoreactivity was decreased in culprit lesions in patients with unstable angina pectoris compared with those with stable angina pectoris, and was reduced in DCA specimens with thrombus formation. These results suggest that CD39 expressed in atheromatous plaque plays an important role in preventing acute coronary syndromes.

Producing components of the extracellular matrix, the vascular adventitia has been recognized as an important modulator of the vascular remodeling process, which determines the vessel architecture. In this study, we examined the effect of the vasodilator peptide adrenomedullin on vascular remodeling induced by balloon injury of rat carotid arteries. Endothelial denudation with wall stretch by ballooning not only induced neointimal formation accompanied with a reduced ratio of the lumen to vessel area, but also increased the fibroblast number and collagen deposition in the adventitial layer. When compared with the saline infusion, intravenous adrenomedullin infusion at 200 ng/h for 14 days suppressed the neointimal formation (-33%, P=0.033), reversing the ratio of lumen to vessel ratio (P=0.030), without affecting systolic blood pressure. Moreover, the adrenomedullin infusion decreased the number of adventitial fibroblasts (-41%, P

Pulse wave velocity (PWV) reflects arterial stiffness and is an independent predictor of cardiovascular mortality and morbidity. However, because it is closely related to blood pressure (BP), PWV is an imperfect measure for evaluating the effects of anti-hypertensive drugs on arterial wall properties. To clarify the effect of benidipine on arterial properties, we first derived the regression line between BP and PWV changes in a short-term experiment. Using this line, we evaluated the long-term effect of benidipine on PWV changes. In the short-term experiment, 29 participants were intravenously administered nicardipine for 90 min. Maximum decreases of brachial-ankle PWV (baPWV) were plotted against the corresponding decreases in BP. In the long-term experiment, 9 hypertensive patients were treated with benidipine for 1 year, during which BP and baPWV were monitored. After 1 year, benidipine was suspended for 2 weeks, and BP and baPWV were reevaluated. In the short-term experiment, PWV was dependent on BP only, and the equation of the regression line was deltaPWV (cm/s) =10.114 x deltaMBP (mmHg) (r=0.913) or deltaPWV (%) =0.719 x deltaMBP (%) (r=0.926). In the long-term therapy, benidipine treatment achieved stable BP control within 3 months; the real PWV decreases (r-PWV) were almost identical to the PWV decrease estimated (e-PWV) from BP lowering at 3 months. However, r-PWV exceeded e-PWV after 6 months. Relative BP and PWV improvements compared to the control were maintained 2 weeks after suspension of benidipine. In conclusion, long-term benidipine administration improves arterial wall properties beyond what can be accounted for by changes in BP.

Background: Although the clinical and histological prognostic factors of IgA nephropathy have been investigated in detail, the value of treatment in terms of renal outcome is not well understood.Methods: We examined data from 237 patients with IgA nephropathy (age 31.4±13.5 years, mean ± SD) who had been followed-up for at least six months (follow-up periods, 62.3±45.5 months). We initially tested the significance of prognostic factors (age, sex, systolic blood pressure, proteinuria, serum creatinine, and histological severity) and treatment strategies (steroid therapy, renin-angiotensin system inhibitors and tonsillectomy) on renal outcome with univariate analysis, then evaluated the findings using the Cox proportional hazards model.Results: Univariate and multivariate analyses showed that among the prognostic variables, a high level of serum creatinine at renal biopsy, large amounts of proteinuria, and extensive histological injury were significant risk factors for end-stage renal failure. Kaplan-Meier analysis showed that the renal survival rates associated with these factors were significantly poorer depending on their severity. Univariate analysis revealed that tonsillectomy was the only significant treatment that contributes to the maintenance of renal survival. Moreover, urinary abnormalities disappeared at a significantly higher frequency when patients were treated by tonsillectomy. The Cox proportional hazards model showed that steroid therapy independently contributed to improve renal prognosis in addition to tonsillectomy, and the hazard ratios were 0.26 (95% CI, 0.07 to 0.93) and 0.37 (95% CI, 0.14 to 0.99), respectively.Conclusion: Steroid therapy and tonsillectomy can independently improve renal outcome in patients with IgA nephropathy., This is an electronic version of an article published in Renal failure,27(1)pp.45-52,2005. Renal failure is available online at:http://www.informaworld.com/smpp/title~db=all~content=t713597293

Adrenomedullin (AM) has antiproliferative and proapoptotic effects on mesangial cells in culture, but the regulation of AM and its receptors in glomeruli with glomerulonephritis have not been clarified.We examined sequential changes in the mRNA expression of AM and its receptors (receptor-activity-modifying proteins; RAMPs), and AM production in the glomeruli of Thy.1 glomerulonephritis, using quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunoradiometric assay (IRMA).Both the mRNA and the protein levels of AM in glomeruli isolated from rats 7 days after injection with anti-thymocyte serum (ATS), when mesangial cell proliferation peaked, were unchanged compared with those in control rats. However, on day 14, when almost all glomeruli had appeared to return to normal, AM mRNA expression was significantly increased (day 14 vs control: 51.2 +/- 9.1 vs 28.4 +/- 7.1 (mmol/mol glyceraldehyde-3-phosphate dehydrogenase; GAPDH); P0.05), as was the AM concentration (12.0 +/- 0.8 vs 8.4 +/- 0.4 fmol/10(4) glomeruli; P0.01). Subsequently, by 28 days after ATS injection, both levels decreased to the control ones. The mRNA expression of AM and RAMP2, in the glomeruli of Thy.1 glomerulonephritis changed similarly over time. Immunohistochemical staining revealed that AM production in mesangial cells was increased predominantly on day 14.AM and RAMP increased during the reso-lution phase of increased mesangial proliferation in Thy.1 glomerulonephritis, but not during the mesangial proliferative phase. Considering the antiproliferative and proapoptotic effects of AM, its action on mesangial cells may be related to the amelioration of glomerulonephritis.

Background: Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide present in the precursor of adrenomedullin (AM), a vasodilative and natriuretic peptide. However, the profile of PAMP in hemodialyzed (HD) patients has not been determined. Methods: We measured plasma levels of PAMP, total AM (tAM) and a mature form of AM (mAM, the biologically active form) in HD patients (n = 31) and in normal controls (n = 21). Results: Plasma concentrations of PAMP before HD were significantly higher than those in controls (4.02 ± 0.24 vs. 1.64 ± 0.12 fmol/ml, p < 0.001) and decreased to the control level after HD (2.17 ± 0.18 vs. 1.64 ± 0.12 fmol/ml; NS). The plasma PAMP level before HD significantly correlated with weight gain during HD sessions (r = 0.41, p < 0.05), but not with predialysis blood pressure. The concentrations of mAM before and after HD were significantly higher than those in controls. The plasma mAM level before HD significantly correlated with weight gain during HD sessions, but not with predialysis blood pressure. The plasma level of PAMP did not correlate with that of mAM in HD patients. Conclusion: PAMP and AM may be involved in the regulation of blood volume in patients undergoing HD.

Objective: The serum IgA/C3 ratio might be considered to serve as a diagnostic marker for patients with IgA nephropathy (IgAN), but its value as a marker of the severity of histological lesions or prognosis is unknown., Methods: We studied the serum IgA/C3 ratio, using standardized reference material, in 86 patients with IgAN and in 32 with non-IgAN. The patients with IgAN were divided according to the severity of histological lesions (mild IgAN, n=29 and severe IgAN, n=57) based on Japanese clinical guidelines., Results: The serum IgA level was significantly higher, while its C3 level was lower in patients with severe IgAN compared to those with non-IgAN. However, these levels were not different between patients with mild IgAN and non-IgAN. In contrast, the serum IgA/C3 ratio obviously differed among the three groups (2.47+/-0.96 vs. 3.63+/-1.44 vs. 4.72+/-1.86; p, Conclusion: The serum IgA/C3 ratio appears to reflect the histological severity of IgAN and could serve as a marker of the progression of IgAN.

Three receptor activity modifying proteins (RAMPs) chaperone calcitonin-like receptor (CLR) to the cell surface. RAMP2 enables CLR to form an adrenomedullin (AM)-specific receptor that is sensitive to AM-(22-52) (AM(1) receptor). RAMP3 enables CLR to form an AM receptor sensitive to both calcitonin gene-related peptide (CGRP)-(8-37) and AM-(22-52) (AM(2) receptor), though rat and mouse AM(2) receptors show a clear preference for CGRP alpha-(8-37) over AM-(22-52). RAMP1 enables CRL to form the CGRP-(8-37)-sensitive CGRP(1) receptor, which can also be activated by higher concentrations of AM. Here we review the available information on the pharmacological features and possible pathophysiological roles of the aforementioned AM receptors.

Objective: To examine the expression and localisation of adrenomedullin in human coronary atherosclerotic lesions from patients with unstable angina (UAP) and stable angina (SAP), and to study the relation between adrenomedullin expression and plaque instability. Design: A retrospective observational study. Patients: Directional coronary atherectomy samples were obtained from 15 patients with UAP and 12 with SAP. Methods: The localisation of adrenomedullin was examined by immunohistochemistry, and adreno-medullin mRNA expression was measured by quantitative polymerase chain reaction. Results: Adrenomedullin immunoreactivity was preferentially localised in macrophages, intimal smooth muscle cells, and proliferated microvessels. The mean number of adrenomedullin positive cells in five high power fields (× 400) per specimen was higher in patients with UAP than in those with SAP (mean (SEM), 110 (13) v 76 (7); p < 0.05); and the ratio of adrenomedullin positive to total cells was higher in patients with UAP (43.0 (2.2)% v 34.2 (2.0)%; p < 0.01). More adrenomedullin mRNA was expressed in the plaque of patients with UAP than in those with SAP (60.4 (16.9)% v 9.7 (3.3)%; p < 0.01). Conclusions: The findings suggest that adrenomedullin is involved in the development of atherosclerosis and plaque instability in human coronary arteries, in an autocrine or paracrine manner.

Plasma adrenomedullin (AM) levels are elevated in various pathological states including cardiovascular and inflammatory diseases. The present study investigated whether an increased AM level is a marker of vascular complications in patients with atherosclerotic risks. In 114 patients with cardiovascular risks and/or diseases including ischemic heart disease (IHD) and peripheral arterial disease (PAD), plasma AM concentration and other inflammatory markers such as high sensitive C-reactive protein (CRP) and interleukin (IL)-6 were examined. The plasma AM level was not altered by the absence or presence of each of four major risk factors, i.e., hypertension, diabetes mellitus, hyperlipidemia, and smoking and its level was not significantly correlated with blood pressure, plasma glucose, or serum lipid levels. The patients with IHD had a significantly higher concentration of plasma AM than those without IHD. The AM level in subjects with PAD was also increased significantly compared with those without PAD. The plasma AM was strongly correlated with inflammatory parameters such as CRP and IL-6. Among AM, CRP, and IL-6, however, only AM was an independent predictor for both IHD and PAD by multiple logistic regression analysis. Our findings suggest the possibility that plasma AM is a novel sensitive marker for the presence of vascular lesions in patients with atherosclerotic risks.

To determine whether the inflammatory response is equally involved in the pathogenesis of restenosis after coronary stenting and directional coronary atherectomy, we assessed restenotic lesions with immunohistochemical methods. Levels of C-reactive protein and macrophages were greater in patients with in-stent restenosis than in those with restenosis after directional coronary atherectomy. This suggests that the inflammatory response is more involved in the pathogenesis of in-stent restenosis than in restenosis after directional coronary atherectomy.

C-reactive protein (CRP) mRNA was detected in coronary plaque. Plasma CRP levels across the coronary circulation were increased much more in patients with unstable angina pectoris and somewhat more in those with stable angina pectoris compared with controls whose coronary arteries were angiographically normal. Thus, CRP within coronary plaque might contribute to increased plasma CRP levels across coronary circulation, particularly among patients with unstable angina pectoris.

We examined the effects of recombinant human C-reactive protein (rhCRP) on atherosclerosis-related factors in cultured human coronary artery endothelial and smooth muscle cells (HCAECs and HCASMCs). After removing endotoxin from commercial rhCRP preparations using the appropriate column, the purified (P)-rhCRP retained the ability to Ca 2+ -dependently bind to phosphorylcholine, but did not augment the secretion of interleukin-6 and MCP-1 from HCAECs, as non-purified (NP)-rhCRP did. By contrast, P-rhCRP elicited 2- to 3-fold increases in the secretion of both hormones from HCASMCs, though the effect was smaller than that obtained with NP-rhCRP. Production of PAI-1 and endothelin-1 was little affected by either rhCRP preparation in either cell type. In addition, P-rhCRP dose-dependently diminished adrenomedullin release from both cell types, but did not affect adrenomedullin receptor expression or function. Our findings highlight the importance of removing endotoxin from commercial rCRP preparations and show that hCRP elicits atherogenic responses from HCASMCs, but not HCAECs.

We describe a 24-year-old man who developed minimal change nephrotic syndrome after allogenic hematopoietic stem cell transplantation (HSCT). One year after undergoing allogenic peripheral blood stem cell transplantation (PBSCT), this patient presented with proteinuria. He also presented with skin and lip lesions considered to be chronic graft-versus host disease. Observation of renal biopsy specimens by light microscopy revealed minor glomerular abnormalities. However, electron microscopy disclosed focal mesangial interposition, irregular thickening of the glomerular basement membrane and subendothelial loosening. Two years after HSCT, the patient developed nephrotic syndrome. Long use of cyclosporine improved the proteinuria and hypoalbuminemia within 12 months.

維持血液透析患者に発症した結核症について, その患者背景・診断根拠・治療法を中心に検討した. 対象は導入期を含む維持血液透析患者8例で, 年齢は59.6±4.9歳 (28-72歳), 男女比は男性3例, 女性5例. 病巣部位は肺結核が2例, 肺外結核が6例 (胸膜炎2例, 頸部リンパ節炎1例, 心外膜炎1例, 脊椎炎1例, 腸結核1例) で, 肺外結核の4例では陳旧性の肺結核病変を認めた. 培養や核酸検査 (PCR) 法で結核菌を証明できたのは1例のみであり, その他の症例では主に生検組織像や画像所見を根拠として抗結核薬による治療的診断が行われていた. 透析導入から結核発症までの期間は, 糖尿病群4例で6.5±4.0か月 (1-10か月), 非糖尿病群4例で108±67.1か月 (4-17年) と糖尿病群で有意に短期であった. 初期治療は, 肺結核の2例でisoniazid (INH), rifampicin (RFP) とstreptomycin (SM) の3剤, 肺外結核の6例でINH, RFPの2剤が併用されており, 全例で治療反応性は良好であった. 透析患者の結核症は肺外結核の割合が高く, 結核菌の証明は困難であり, 積極的な治療的診断が必要であると考えられた. また, 糖尿病合併透析患者では, 特に透析導入早期の結核症発病に注意すべきであることが示唆された.

Human adrenomedullin (hAM) is an endogenous peptide that has potent vasodilator activity. Mature AM is biosynthesized from its intermediate form, glycine-extended AM (AM-gly), by carboxy-terminal amidation. AM-gly is generally considered to be biologically inactive but is a major molecular form in human and rat plasma. The present study demonstrated that recombinant human AM-gly (hAM-gly) elicits potent vasodilator effect on isolated rat aorta. In aortic rings, hAM-gly produced dose-dependent (0.1-100 nM) relaxation in phenylephrine-precontracted strips (pD(2) 8.4+/-0.5). The vasorelaxant potency of hAM-gly was comparable to that of hAM (pD(2) 8.6+/-0.2) but hAM-gly took a significantly (P0.01) longer time to reach the maximal relaxation compared with hAM (T(max) 23+/-4 vs. 5+/-2 min). Vasorelaxant responses to hAM-gly were abolished by endothelial removal. N(omega)-nitro-L-arginine (L-NNA) and AM(22-52) significantly (P0.01) reduced the vasodilator effect of hAM-gly. Furthermore, 4-phenyl-3-butenoic acid (PBA), an alpha-amidation enzyme inhibitor, significantly (P0.05) inhibited the vasorelaxant responses to hAM-gly without any effect on the hAM-induced relaxation, suggesting the possible process of amidation in the rat aorta. We further clarified that the aorta has the ability to convert exogenous hAM-gly to mature hAM and the conversion is inhibited by PBA. These results suggest that the circulating AM-gly may play a role in regulating vascular tone and increased plasma AM-gly may be involved in the pathophysiology of cardiovascular diseases.

Adrenomedullin (AM) has multi-functional properties, of which the vasodilatory hypotensive effect is the most characteristic. AM and its gene are ubiquitous in a variety of tissues and organs, in the cardiovascular system, as well as the adrenal medulla. AM secretion, especially in cardiovascular tissues, is regulated mainly by mechanical stressors such as shear stress, inflammatory cytokines such as interleukin (IL)-1, tumor necrosis factor (TNF), and lipopolysaccharide (LPS), hormones such as angiotensin (Ang) II and endothelin (ET)-1, and metabolic factors such as hypoxia, ischemia, or hyperglycemia. Elevation of plasma AM due to overproduction in response to one or more of these stimuli in pathological conditions may explain the raised plasma AM levels present in cardiovascular and renal diseases such as congestive heart failure, myocardial infarction, hypertension, chronic renal failure, stroke, diabetes mellitus, and septic shock. In addition to shear stress, stretching of cardiomyocytes may be another mechanical stimulus for AM synthesis and secretion. Our recent studies have shown the importance of aldosterone and additional hormonal factor on AM secretion in vascular wall.

We tested whether heterodimers comprised of calcitonin (CT) receptor lacking the 16-amino acid insert in intracellular domain 1 (CTR(I1-)) and receptor activity-modifying protein (RAMP) can function not only as calcitonin gene-related peptide (CGRP) receptors but also as adrenomedullin (AM) receptors. Whether transfected alone or together with RAMP, human (h)CTR(I1-) appeared mainly at the surface of HEK-293 cells. Expression of CTR(I1-) alone led to significant increases in cAMP in response to hCGRP or hAM, though both peptides remained about 100-fold less potent than hCT. However, the apparent potency of AM, like that of CGRP, approached that of CT when CTR(I1-) was co-expressed with RAMP. CGRP- or AM-evoked cAMP production was strongly inhibited by salmon CT-(8-32), a selective amylin receptor antagonist, but not by hCGRP-(8-37) or hAM-(22-52), antagonists of CGRP and AM receptors, respectively. Moreover, the inhibitory effects of CT-(8-32) were much stronger in cells co-expressing CTR(I1-) and RAMP than in cells expressing CTR(I1-) alone. Co-expression of CTR(I1-) with RAMP thus appears to produce functional CT-(8-32)-sensitive AM receptors.

When co-expressed with receptor activity-modifying protein (RAMP) 2, calcitonin receptor-like receptor (CRLR) functions as an adrenomedullin (AM) receptor (CRLR/RAMP2). In the present study, we examined the function of the cysteine (C) residues in the extracellular loops of human (h)CRLR (C212, C225 and C282) and in the extracellular domain of hRAMP2 (C68, C84, C99 and C131). Using site-directed mutagenesis, the cysteine residues were substituted, one at a time, with alanine (A). Co-expression in HEK293 cells of hRAMP2 with the hCRLR C212A or C282A mutant significantly reduced the 50% of effective concentration (EC50) for AM-evoked cyclic adenosine monophosphate (cAMP) production, despite full cell surface expression of the receptor heterodimer. Co-expression of the C225A mutant had no effect on [125I]AM binding or receptor signaling. These results suggest that the cysteine residues in the first (C212) and the second (C282) extracellular loops form a disulfide bond that is important for stabilizing the receptor in the correct conformation for ligand binding and activation. Cells expressing hCRLR with an hRAMP2 mutant (C68A, C84A, C99A or C131A) showed no specific AM binding or AM-stimulated cAMP accumulation. Though abundant in the intracellular compartment, these receptors were not detected at the cell surface, suggesting that all four cysteine residues are essential for efficient transport to the plasma membrane. Cysteine residues in the extracellular loops of hCRLR and in the extracellular domain of hRAMP2 thus appear to play distinct roles in the cell surface expression and function of the receptor heterodimer. (Hypertens Res 2003; 26 (Suppl): S25-S31)

A 40-year-old man presented with initial symptoms of syncope caused by restrictive cardiomyopathy and autonomic nervous system impairment, but it was confirmed that he had a novel transthyretin (TTR) variant, aspartic acid-18 glutamic acid (Glu), and a de novo gene mutation. A polymerase chain reaction-induced mutation restriction analysis with a mismatched sense primer demonstrated that he was heterozygous for TTR Glu 18. Liver transplantation was not performed because of profound weakness and severe postural hypotension. Right-sided heart failure predominated in association with low output syndrome and a gradual decrease in total QRS voltage on electrocardiogram over 5 years of follow-up. Autonomic neuropathy developed and he eventually died of both-sided heart failure at the age of 45 years. Immunohistochemical and DNA studies are important to diagnose and treat TTR-related cardiac amyloidosis.

We report two cases of pheochromocytoma combined with tetralogy of Fallot who showed different clinical courses. Case 1 was a 45-year-old woman with a history of radical operation for tetralogy of Fallot at 20 years of age. She presented with sudden hypertensive attack, and was diagnosed with pheochromocytoma of the left adrenal gland. She was treated surgically, and her high plasma noradrenaline level normalized. Case 2 was a 41-year-old woman who had been suffering from severe cyanosis due to tetralogy of Fallot throughout her life. A palliative operation had been performed at 7 years of age, but a radical operation had not been performed. She has had resistant hypertension since 38 years of age. She was diagnosed as having pheochromocytoma of the left adrenal gland at 41 years of age, but surgery was not performed. She was pharmacologically treated with doxazosin, followed by bisoprolol. Her symptoms somewhat improved, although she continued to have high plasma levels of noradrenaline and adrenomedullin. The combination of pheochromocytoma with tetralogy of Fallot or cyanotic congenital heart disease is rare; however, pheochromocytoma and congenital heart disease might be related through chronic hypoxia and/or gene abnormalities. The presence of pheochromocytoma worsens the hemodynamic state in patients with congenital heart disease regardless of whether radical surgery for congenital heart disease had been performed. Differential diagnosis of pheochromocytoma could be paramount in congenital heart disease patients who show unexpected or unusual symptoms.

L鎖沈着症 (LCDD; light chain deposition disease) は, 単クローン性に産生増加した免疫グロブリンL鎖が全身諸臓器に沈着し, 臓器障害をもたらす比較的稀な疾患である. 今回われわれは, 多発性骨髄腫を伴わないLCDDの1症例を経験した. 患者は44歳の女性で, 急速に進行する腎機能障害と貧血のため, 入院した. 血液および尿中にIgG κ型のM蛋白を認め, 腎生検組織の蛍光抗体法検査によりκ light chainの沈着を糸球体係蹄, ボウマン嚢壁, 尿細管基底膜, 血管壁に認め, LCDDと診断した. 2クールの化学療法 (メルファランとプレドニゾロンの併用療法) を発症初期に施行した結果, 血中IgGおよびM蛋白は減少し, 腎機能障害の進展を一時的に食い止めることができた. 患者の同意がなかったため, 本症例への3度目以降の化学療法を継続できず, 約2年後に血液透析に導入となった. 発症早期のLCDD症例では, 化学療法が腎機能保護に効果的であると考えられ, 間歇的に化学療法を継続することが長期間の腎機能保持には重要であると考えられた.

Objective Both adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP), processed from the same precursor of prepro-adrenomedullin (preproAM), have differential biological properties; AM dilates blood vessels and presumably affects the vascular remodeling, while PAMP inhibits catecholamine secretion. Since aldosterone has been shown to be involved in vascular remodeling, we examined the effects of aldosterone on AM and PAMP secretion and preproAM gene expression in human aortic vascular smooth muscle cells (VSMC). Methods AM and PAMP secreted from human VSMC incubated with aldosterone were measured by radioimmunoassay, and preproAM gene expression was evaluated by quantitative polymerase chain reaction. Results Cultured human VSMC secreted both AM and PAMP into the media, while the secretion rate of AM was much higher than that of PAMP. Aldosterone increased preproAM gene expression in the cultured VSMC in a dose-dependent fashion following incubation for 48 h, with a concomitant increase in AM secretion from the cells, but PAMP secretion remained unchanged. Aldosterone-stimulated AM secretion was significantly reduced by spironolactone. Reverse-phase high-performance liquid chromatography analyses showed that immunoreactive AM secreted from the VSMC untreated or treated with aldosterone emerged at the point of human AM(1-52)-NH 2 . Conclusions AM production was stimulated by aldosterone in cultured human VSMC without an increase in PAMP secretion, suggesting a possible role of AM in modulating vascular remodeling by aldosterone.

Using a novel method employing a V8 protease digestion coupled with ethyl acetate extraction, we have purified a peptide with C-terminal amide structure from porcine cardiac atrium. The peptide was determined to be Ala-Val-Leu-Gly-Leu-CONH2. According to the sequence, we have raised an antibody and established the radioimmunoassay. Using this radioimmunoassay, we have isolated a novel 14 amino acid peptide where C-terminus was amidated. This peptide was termed amidicin. Amidicin is widely distributed in porcine tissue and is especially abundant in pituitary gland, cardiac ventricle, and spleen.

We discovered adrenomedullin (AM) from human pheochromocytoma tissue by monitoring the elevating activity of intracellular cyclic AMP (cAMP) in rat platelets in 1993. Since the discovery of AM, it has attracted intense interest from cardiovascular researchers because AM elicits multiple biological activities, including a potent and powerful hypotensive activity caused by dilatation of resistance vessels. AM is biosynthesized and secreted from tissues, including cardiovascular organs. In addition to AM, "proadrenomedullin N-terminal 20 peptide (PAMP)," another biologically active peptide, was found to be processed from the AM precursor. Plasma AM levels are increased in various cardiovascular and renal diseases. AM, therefore, seems to function as a novel system that controls circulation and body fluid, and may be involved in pathophysiological changes in cardiovascular diseases. Therefore, in this review we will focus on the structure of AM and its gene, distribution, receptor, and the physiological and pathological roles of AM in cardiovascular disease.

Adrenomedullin (AM) and atrial and brain natriuretic peptides (ANP and BNP) exert vasodilator and natriuretic actions and are thought to share roles in counteracting the progression of hypertension or heart failure as circulating or locally-acting hormones. However, little data is available with regard to their roles in subjects who have no apparent cardiovascular diseases. The present study was carried out to identify the factors that affect plasma levels of AM, ANP and BNP in the general population. We measured the plasma levels of AM, ANP and BNP in 184 local residents who had a scheduled regular health checkup, and compared the findings with those for other clinical parameters. Univariate analyses showed that the plasma levels of AM, ANP and BNP were significantly correlated with age. The plasma levels of ANP and BNP were also significantly correlated with systolic blood pressure (SBP) and with pulse pressure (PP), an indicator of the stiffness of the great vessels. Multivariate analyses conducted using a stepwise method revealed that age was a significant, independent variable for the plasma levels of AM, ANP and BNP. In addition, PP was a significant factor for the plasma levels of ANP and BNP, while the plasma AM was significantly associated with body mass index (BMI). Thus, the plasma levels of AM, ANP and BNP all increased in association with aging, and those of ANP and BNP increased in association with PP, suggesting possible relationships between the plasma levels and age-related changes in the cardiovascular system. (Hypertens Res 2002; 25: 887-892)

A 67-year-old female non-smoker, who had been diagnosed with familial hypercholesterolemia associated with severe atherosclerosis of the coronary, carotid and vertebral arteries, developed interstitial pneumonia 4 months after initiating ticlopidine to inhibit platelet aggregation. The lymphocyte stimulation test by ticlopidine was positive and bronchoalveolar lavage fluid showed an increase in lymphocytes and a decrease in the CD4+/8 + ratio, suggesting potentially undesirable side effects of ticlopidine. Two months after ticlopidine therapy was discontinued and prednisolone therapy started, the interstitial pneumonia had almost completely resolved. Two patients, one with ticlopidine-associated bronchiolitis obliterans organizing pneumonia and the other with pneumonia with multiple nodules, have been reported to date and the present patient is the third reported case of ticlopidine-induced pneumonia. The incidence of this side effect may not be so high because approximately 20 years have passed since ticlopidine was first marketed in Japan, but because the drug is now widely prescribed, this serious clinical side effect should be considered. (Circ J 2002; 66: 773 - 776)

To determine whether acute pressure overload (POL) can stimulate adrenomedullin (AM) production, the response of ventricular AM gene expression and plasma AM concentration to aortic banding was investigated in the rat. Furthermore, any link between AM expression and the renin-angiotensin system (RAS) enhanced by acute POL was examined using: a Ca channel blocker (manidipine), an angiotensin II type 1 receptor antagonist (candesartan), and an angiotensin-converting enzyme inhibitor (quinapril). Rats with acute POL produced by suprarenal aortic banding were studied 1, 5 and 14 days after surgery. Plasma AM concentrations in banded rats at day 1 increased 1.49-fold (p