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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

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

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.

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) 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.

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.

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

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.

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.

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.

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.

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

Mutations in the ATP-binding cassette transporter 1 (ABCA1) gene have been recently identified as the molecular defect in Tangier disease (TD) and familial high density lipoprotein deficiency (FHA). We here report novel mutations in the ABCA1 gene in two sisters from a Japanese family with TD who have been described previously (S. Ohtaki, H. Nakagawa, N. Kida, H. Nakamura, K. Tsuda, S. Yokoyama, T. Yamamura, S. Tajima, A. Yamamoto, Atherosclerosis 49 (1983)) and a family with FHA. Both probands of TD and FHA developed coronary heart disease. Sequence analysis of the ABCA1 gene from the patients with TD revealed a homozygous G to A transition at nucleotide 3805 of the cDNA resulting in the substitution of Asp 1229 with Asn in exon 27, and a C to T at nucleotide 6181 resulting in the substitution of Arg 2021 with Trp in exon 47. Sequence analysis of the ABCA1 gene from the FHA patient revealed a homozygous 4 bp CGCC deletion from nucleotide 3787 to 3790 resulting in premature termination by frameshift at codon 1224. These mutations were confirmed by restriction digestion analysis, and were not found in 141 control subjects. Our findings indicate that mutations in the ABCA1 gene are associated with TD as well as FHA.

A 17-year-old male who had been diagnosed with ulcerative colitis was prescribed 80 mg prednisolone and 1,500 mg 5-aminosalicylic acid (5-ASA) per day. Two weeks after initiating therapy, he was referred to our hospital for evaluation of chest pain and high fever. Electrocardiography (ECG) showed ST elevation in limb and precordial leads. Chest pain with high fever and ECG changes were resolved after 5-ASA was discontinued. Three weeks later, the administration of a low dose of 5-ASA was associated with the immediate recurrence of pericarditis associated with chest pain, suggesting a hypersensitive reaction to 5-ASA in this patient.

Expression of the calcitonin receptor-like receptor (CRLR) and its receptor activity modifying proteins (RAMPs) can produce calcitonin gene-related peptide (CGRP) receptors (CRLR/RAMP1) and adrenomedullin (AM) receptors (CRLR/RAMP2 or -3). A chimera of the CRLR and green fluorescent protein (CRLR-GFP) was used to study receptor localization and trafficking in stably transduced HEK 293 cells, with or without co-transfection of RAMPs. CRLR-GFP failed to generate responses to CGRP or AM without RAMPs. Furthermore, CRLR-GFP was not found in the plasma membrane and its localization was unchanged after agonist exposure. When stably coexpressed with RAMPs, CRLR-GFP appeared on the cell surface and was fully active in intracellular cAMP production and calcium mobilization. Agonist-mediated internalization of CRLR-GFP was observed in RAMP1/CGRP or AM, RAMP2/AM, and RAMP3/AM, which occurred with similar kinetics, indicating the existence of ligand-specific regulation of CRLR internalization by RAMPs. This internalization was strongly inhibited by hypertonic medium (0.45 m sucrose) and paralleled localization of rhodamine-labeled transferrin, suggesting that CRLR endocytosis occurred predominantly through a clathrin-dependent pathway. A significant proportion of CRLR was targeted to lysosomes upon binding of the ligands, and recycling of the internalized CRLR was not efficient. In HEK 293 cells stably expressing CRLR-GFP and Myc-RAMPs, these rhodamine-labeled RAMPs were co-localized with CRLR-GFP in the presence and absence of the ligands. Thus, the CRLR is endocytosed together with RAMPs via clathrin-coated vesicles, and both the internalized molecules are targeted to the degradative pathway.

Abstract —Adrenomedullin (AM) is secreted from cultured cardiac myocytes. In this study, we examined whether mechanical stretching stimulates AM production in cardiac myocytes, and if so, whether angiotensin II (Ang II) is involved in that mechanism. Neonatal rat cardiac myocytes cultured in serum-free medium were stretched 10% or 20% on flexible silicone rubber culture dishes, and AM mRNA expression was examined by quantitative polymerase chain reaction. The AM mRNA levels in the myocytes stretched 10% and 20% for 24 hours significantly increased by 56% ( P P P P −6 mol/L Ang II for 24 hours, AM mRNA and secretion increased by 86% ( P P −6 mol/L CV-11974, an Ang II type I (AT 1 ) receptor antagonist, but not by 10 −6 mol/L PD-123319, an Ang II type II antagonist. Stretch-induced increases of AM gene expression and secretion were significantly inhibited ( P −6 mol/L CV-11974 by 46% and 52%, respectively; however, they were not affected by 10 −6 mol/L PD-123319. These findings indicate that AM production from cardiac myocytes is augmented by mechanical stretching, partially through the AT 1 receptors, which suggests a local interaction between AM and the renin-angiotensin system in stretched cardiac myocytes.

Objective: The aim of the present study was to determine the role of adrenomedullin (AM) in cardiac fibroblasts. Methods: The production and secretion of AM were examined in cultured neonatal rat cardiac fibroblasts, and the effects of AM on proliferation and protein synthesis of these cells were assessed by [3H]thymidine and [3H]phenylalanine incorporation, respectively. Results: Cultured cardiac fibroblasts secreted AM into the medium time-dependently at a rate of 20.3±3.0 fmol/5×104 cells/48 h, mean±S.D. Northern blot analysis showed expression of preproAM mRNA of 1.6 kb in these cells. In addition, 10−6 mol/l of angiotensin II (Ang II) and endothelin-1 (ET-1) significantly increased the AM secretion by 55 and 48%, respectively. Synthetic AM significantly reduced 10−6 mol/l Ang II- or 10−7 mol/l ET-1-stimulated [3H]thymidine and [3H]phenylalanine incorporation in a dose-dependent manner, and these effects were attenuated by a calcitonin gene-related peptide (CGRP) type 1 receptor antagonist, CGRP(8-37). Synthetic AM also had a dose-dependent stimulatory effect on cAMP accumulation in these cells, which was significantly attenuated by CGRP(8-37). A cAMP analogue, 8-bromo-cAMP, mimicked the AM effects, inhibiting the Ang II-stimulated [3H]thymidine and [3H]phenylalanine incorporation. Blockage of the effect of endogenous AM by anti-AM monoclonal antibody not only significantly reduced the basal level of intracellular cAMP, but also enhanced the [3H]thymidine and [3H]phenylalanine incorporation into the cells. Conclusions: Cultured neonatal rat cardiac fibroblasts produce and secrete AM, and the secreted AM may inhibit proliferation and protein synthesis of these cells. AM may exert these inhibitory effects partly by elevating intracellular cAMP. It is suggested that AM has an important role in modulating the growth of cardiac fibroblasts in an autocrine or a paracrine manner.

In the biosynthesis of adrenomedullin (AM), an intermediate form, AM(1-52)-glycine-COOH (iAM), is cleaved from proAM and subsequently processed to a biologically active mature form, AM(1-52)-NH2 (mAM), by enzymatic amidation. We recently reported that immunoreactive AM in human plasma consists of mAM and iAM. To clarify the pathophysiological roles of mAM and iAM in heart failure, we established an assay method to specifically detect mAM, and we determined the plasma concentrations of mAM and iAM in 68 patients with congestive heart failure (CHF). The plasma mAM concentrations of the CHF patients classified as being class I or II of New York Heart Association (NYHA) functional classification were significantly greater than those of the 28 healthy controls, and a further increase was noted in the class III or IV patients. Similar increases in plasma iAM were also observed in these patients compared with controls. The increased plasma mAM and iAM in 12 patients with exacerbated CHF were significantly reduced by treatment of their CHF for 7 days. In addition, the plasma concentrations of both mAM and iAM were significantly correlated with pulmonary capillary wedge pressure, pulmonary artery pressure, right atrial pressure, cardiothoracic ratio, heart rate, and the plasma concentrations of atrial and brain natriuretic peptides in the CHF patients. Thus the plasma concentrations of both mAM and iAM were increased progressively in proportion to the severity of CHF. These results suggest that, though the role of iAM remains to be clarified, mAM acts against the further deterioration of heart failure in patients with CHF.

A 66-year-old man whose renal function had progressively deteriorated had an elevated blood pressure and also was found to have an inflammatory abdominal aortic aneurysm (AAA). Blood examination revealed that he had eosinophilia. Livedo reticularis of the toes developed, and a skin biopsy specimen showed embolization of atheromatous plaques in the arterioles of the subcutaneous tissue. Progressive enlargement of inflammatory AAA may have dislodged the atheromatous plaques, resulting in cholesterol embolism.

症例はいずれも閉塞性動脈硬化症 (ASO) を合併した70歳代男性. 症例1は冠動脈造影 (CAG) 後13日目に肺梗塞と急性腎不全を合併した. alteplaseとheparinを投与されたが, 末梢循環不全によると思われる足趾のチアノーゼと動脈の触知不良が出現し, 術後18日目に多臓器不全で死亡した. 剖検所見にて両腎を含む多臓器にコレステリン結晶による塞栓性梗塞を確認した. 症例2は急性心筋梗塞後の経皮的冠動脈形成術 (PTCA) 中に脳梗塞を合併した. aspirinとwarfarinの投与を受けていたが, 徐々に腎機能悪化と両足底のチアノーゼが進行し, PTCA後78日目に血液透析に導入した. 症例3は腹部大動脈瘤に対するYグラフト置換術中に左下肢急性動脈閉塞をきたし, 塞栓除去術を施行した. 約3か月後に, 足趾にチアノーゼと網状皮斑を伴う疼痛が出現し, 歩行困難となった. lipo PGE1の静注とticlopidineの投与を継続していたが, 腎障害が徐々に進行し, 術後144日目に血液透析に導入した. 症例2と3は組織学的診断はなされていないが, 経過中に著しいLDHの上昇と好酸球増多を伴い, atheromatous embolismが強く示唆された. 3例とも動脈内への機械的操作の直後あるいは数日以内に急性動脈塞栓症を発症し, 強力な線溶療法や抗凝固療法, lipo PGE1製剤や抗血小板薬の投与がなされていたことから, 動脈壁粥腫潰瘍表面の防御血栓がはがれてコレステロール結晶の飛散を助長したものと考えられた. 腎不全は確実に進行したが, その原因としてコレステロール塞栓による腎梗塞と高レニン性高血圧による進行性糸球体内皮障害が考えられた. ASO患者では一次性にコレステロール塞栓症をきたすこともあり, ASOの症状悪化時にはコレステロール塞栓症を念頭におき, 抗凝固療法の適応に配慮し, 慎重に腎機能を経過観察する必要がある.

Adrenomedullin (AM) is a novel hypotensive peptide isolated from the human pheochromocytoma. In the present study, 125I-AM was intravenously administered to rats and its distribution was examined by autoradiographic (ARG) techniques using wholebody, light microscopic (LM) and electron microscopic (EM) methods. Whole-body-ARG after administration of 125I-AM showed the highest radioactivity in the lung (parenchyma), followed by the renal cortex and the liver. When localization of 125I-AM in the lung was examined by LM-ARG, silver grains were localized over the arteries, capillaries and venules. In the arteries, the endothelial cells of the small arteries (lumen diameter 20-50 μm) were preferentially labelled and there was little labelling on the large arteries. There were few silver grains on the smooth muscle cells along the entire pulmonary vasculature system. EM-ARG showed many silver grains on the endothelial cells of capillaries and venules. Very few silver grains were observed on the lung when an excess amount of unlabelled AM was administered with 125I-AM.These results indicated that 125I-AM specific binding sites are most abundant in the lung, and the major binding sites are on the endothelial cells of small arteries, alveolar capillaries and venules.

Adrenomedullin (AM) is a peptide with potent vasodilatory and hypotensive properties. Plasma AM levels in rats with experimentally induced hypertension, such as Dahl salt-sensitive rats and two-kidney, one-clip hypertensive rats, are higher than those in normotensive rats. We previously noted, however, that plasma AM levels in spontaneously hypertensive rats (SHR) are similar to those in Wistar-Kyoto rats. To define the role of AM in rats with severe hypertension, we investigated changes in circulating and tissue AM levels in stroke-prone spontaneously hypertensive rats (SHRSP/Izm). The immunoreactive rat AM levels in plasma, urine, and tissue measured with a sensitive radioimmunoassay, and the AM mRNA levels in various tissues in 15-wk-old SHRSP/Izm were compared with those in age-matched Wistar-Kyoto rats (WKY/Izm). The plasma and urinary AM levels in SHRSP/Izm were significantly lower than those in WKY/Izm [plasma AM, 2.14±0.06 (SE) vs. 3.24±0.16fmol/ml, p

Adrenomedullin (AM), a potent vasodilator peptide, exists in the cardiac ventricle; however, the role of AM in the ventricular tissue remains unknown. In the present study, we investigated the production and secretion of AM in cultured neonatal rat cardiomyocytes, and we examined the effect of AM on de novo protein synthesis in these cells by measuring [ 14 C]phenylalanine incorporation. The cardiomyocytes cultured with serum-free media secreted AM into the media in a time-dependent manner at the rate of 12.2±0.5 fmol/10 5 cells/48 hours (mean±SEM). Angiotensin II (1μmol/L) or 10% fetal bovine serum significantly ( P −6 mol/L angiotensin II-and 10% fetal bovine serum-stimulated [ 14 C]phenylalanine incorporation into the cells, by 16% ( P P 14 C]phenylalanine incorporation was abolished dose-dependently by a calcitonin gene-related peptide receptor antagonist, CGRP(8–37). Furthermore, blockade of the action of endogenous AM by either 10 −6 mol/L CGRP(8–37) or anti-AM monoclonal antibody significantly enhanced the basal and 10 −6 mol/L angiotensin II-stimulated [ 14 C]phenylalanine incorporation. In summary, cultured neonatal rat cardiomyocytes produce and secrete AM, and the secreted AM inhibits the protein synthesis of these cells. Thus, AM may act on cardiomyocytes as an autocrine or a paracrine factor modulating the cardiac growth.

The present study was undertaken to determine plasma adrenomedullin levels in patients with non-insulin dependent diabetes mellitus (NIDDM) to elucidate the potential involvement in the pathogenesis of diabetic complications. The patients were 24 males and 21 females with ages of 55 +/- 2.1 years (mean +/- SEM). Plasma adrenomedullin levels were 5.94 +/- 0.44 pmol/l in patients with NIDDM, and were not affected by plasma glucose concentration. The plasma adrenomedullin increased dependent on the severity of diabetic nephropathy and retinopathy. Plasma levels of adrenomedullin positively correlated with various parameters, including serum creatinine levels, urinary excretion of protein, and systolic blood pressure. In contrast, there were negative correlations between the coefficient variation (CV) of RR intervals and plasma adrenomedullin, and between the conduction velocity of ulnar nerves and plasma adrenomedullin levels. These results indicate that the increase in plasma adrenomedullin was closely related to diabetic complications, which may be dependent on the development of microangiopathy.

Urine and plasma levels of uroguanylin and its molecular forms in renal diseases. Uroguanylin activates the intestinal and possibly the renal guanylate cyclase C receptor, and stimulates Cl− secretion. We developed a sensitive radioimmunoassay (RIA) for human uroguanylin and measured its concentration in the urine and plasma. Twenty-four-hour urinary excretion of immunoreactive (ir-) uroguanylin for persons with a high-salt diet (10 g/day) was 137.8 ± 14.4 pmol/day, significantly higher than that for persons with a low-salt diet (7 g/day, 95.1 ± 16.3 pmol/day, P < 0.05). There were significantly positive correlations between the urinary excretion of ir-uroguanylin and Na+, Cl−, K+ or cyclic GMP (cGMP). We demonstrated the presence of messenger RNA of guanylate cyclase C in the medulla of human kidney. The concentration of plasma ir-uroguanylin significantly correlated with that of serum creatinine (r = 0.71, P < 0.001). Biologically active uroguanylin-16 accounted for 99% of the endogenous uroguanylin molecules in normal urine and 60% in plasma, the remainder being the 10kDa precursor. The precursor content increased in the urine and plasma as the severity of renal impairment increased. These findings suggest that bioactive uroguanylin-16 is involved in the regulation of electrolyte homeostasis and that the kidney participates in the metabolism and excretion of uroguanylin.

Proadrenomedullin N-terminal 20 peptide (PAMP-20) is a potent hypotensive peptide processed from the adrenomedullin (AM) precursor. We developed a specific radioimmunoassay which recognizes the C-terminal region of PAMP-20. Using this radioimmunoassay, the distribution of immunoreactive (ir-) PAMP was determined in porcine tissues. High concentrations of ir-PAMP were observed in the adrenal medulla and in the atrium, and these values were comparable to the corresponding concentrations of ir-AM. The concentration of ir-PAMP was almost the same as that of ir-AM in the kidney, while ir-PAMP was significantly lower than ir-AM in the ventricle, lung, and aorta. Reversed-phase high performance liquid chromatography in each porcine tissue sample revealed that two major peaks of ir-PAMP existed: one emerged at a position identical to that of authentic porcine PAMP-20; the other unknown peak was eluted earlier. The unknown peptide was purified to homogeneity from porcine adrenal medulla, and its complete amino acid sequence was determined. This peptide was found to be PAMP[9–20] with a C-terminal amide structure, and was named PAMP-12. Intravenous injections of PAMP-12 in anesthetized rats showed a significant hypotensive effect in a dose-dependent fashion, and the effect was comparable to that of PAMP-20. These data indicate that PAMP-12, a major component of ir-PAMP, is processed from the AM precursor, as is PAMP-20, and may participate in cardiovascular control.

Cardiopulmonary bypass (CPB) can evoke a systemic inflammatory response, which is accompanied by an increase in plasma cytokines that may stimulate the production of adrenomedullin (AM), a potent vasodilator peptide.This study was undertaken to investigate whether CPB influenced plasma AM concentration in 10 patients undergoing cardiac surgical procedures. We found that the plasma AM concentration increased significantly after the commencement of CPB, with the greatest increase observed at weaning from bypass (P < 0.01). After CPB, plasma AM concentration declined but still exceeded baseline significantly 24 h postoperatively. The increase in the plasma AM concentration at weaning from CPB correlated significantly with aortic cross-clamp time (r = 0.74, P < 0.05). The authors conclude that the secretion of AM into circulation is augmented by CPB in patients undergoing cardiac surgery, which suggests a possible role of AM in cardiovascular regulation during and after surgery with CPB. (Anesth Analg 1997;84:1193-7)

SUMMARY 1. The hypotensive effect of chronically infused human adrenomedullin (hAM), a potent vasodilator peptide that has been reported to have a natriuretic action, was examined in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Conscious WKY rats and SHR were infused with 200 ng/h synthetic hAM for 14 days by means of osmotic minipumps. Control groups were infused at the same schedule with 0.9% saline. Systolic blood pressure (SBP) and daily urinary excretion of Na+ and K+ were measured before and during the infusion period. In addition, plasma renin activity (PRA), aldosterone and hAM concentrations were measured on day 14 of infusion. 3. A significant reduction in SBP was observed in hAM-treated SHR at day 2 and SBP remained significantly lower throughout the experiment compared with control SHR. Similarly, SBP in the hAM-treated WKY rats was found to be significantly lower than in control WKY rats during infusion. However, the hypotensive effect was not accompanied by any significant increase in urinary volume or Na+ excretion in hAM-treated rats of either strain. Chronic infusion with hAM significantly suppressed PRA and lowered the concentration of plasma aldosterone in WKY rats but not in SHR. The plasma hAM levels in treated WKY rats and SHR were 0.0 ± 9.4 and 0.6 ± 0.2 fmol/mL, respectively. 4. These findings demonstrate that chronically infused hAM has a hypotensive effect in both WKY rats and SHR without an increase in urinary volume or Na+ excretion at a plasma AM concentration within the physiological limit.

症例は27歳, 女性. IgA腎症による慢性腎不全のため'94年12月に血液透析に導入となった. '94年7月から特発性血小板減少性紫斑病のためプレドニゾロン (PSL) の大量経口投与を受けていたが, 同薬減量中に血小板減少に伴う紫斑が出現し, 当科へ入院した. PSLを増量 (60mg/日) したが効果は持続せず, 6週間目より漸減を開始した. 9月中旬より38℃台の発熱, 乾性咳が出現した. 各種培養は陰性で抗生剤も無効であった. 胸写にて明らかな異常を認めなかったが, 軽度の低酸素血症があり, 胸部CTにて全肺野に不均一な間質性陰影を認めた. 気管支鏡下に採取されたBAL液よりPneumocystis cariniiの胞体を検出し, カリニ肺炎と診断した. 9月26日よりpentamidine 300mg/日の吸入とsulfamethoxazole-trimethoprim合剤2400mg/日の経口投与を開始し, さらに真菌とcytomegalovirusの混合感染を想定してfluconazole 50mg/日とganciclovir 100mg/隔日の経静脈投与を行った. カリニ肺炎の経過は良好であったが, 10月5日に突然強い嘔吐と両下肢の振戦および夜間不穏が出現した. ganciclovir中止後これらの症状は消失したためganciclovir脳症と考えた. 同薬の血中濃度を測定したが非透析日の半減期は著しく延長し, 投与53時間後も2.91μg/lの高濃度を維持していた. 文献的にganciclovirは血液脳関門を通過することが知られており, 同薬の脳内蓄積が脳症の原因と考えられた. カリニ肺炎は進行が早く致死的疾患であり, しばしば真菌やcytomegalovirusの混合感染が見られる. 本症例ではカリニ肺炎を早期診断し, 治癒しえた意義は大変大きいと思われる. しかし, ganciclovir脳症をきたし, 透析患者におけるganciclovirの投与方法の確立が望まれる.

A 70-year-old woman with type IIb therapy-refractory hyperlipidemia was diagnosed as having IgA kappa type multiple myeloma. She had neither a family history nor any other disease known to accompany hyperlipidemia. The serum IgA concentration fell from 3.42 g/dl to 1.24 g/dl following chemotherapy with melphalan and prednisolone, and a concomitant decrease in both the serum cholesterol and triglyceride levels was observed. These serum lipids were positively correlated with the serum IgA concentration (p < 0.001) during the three cycles of chemotherapy. These findings suggest the involvement of the monoclonal protein of IgA in the development of hyperlipidemia in the present case.