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Develops a diffraction method in which the intensity of Bragg reflections is measured while changing continually the wavelength of the radiation over a range in the vicinity of the absorption edge of an atom contained in the crystal. Approaches to the determination of the phase of the structure factor in crystal structure analysis; Ways to measure the intensity gradient for many Bragg reflections.

Aims: Hemodialysis patients have high COVID-19 severity and mortality rates. For this high-risk group of hemodialysis patients with SARS-CoV-2 infection, early SARS-CoV-2 vaccination is recommended to prevent infection and severe disease. Thus far, few reports have evaluated COVID-19 antibody titers in hemodialysis patients. In this study, we investigated the time course of antibody titers acquired by vaccination in patients on dialysis., Materials and Methods: The anti-SARS-CoV-2 spike protein S1 IgG (anti-SP-IgG) antibody titers were compared between 33 outpatient maintenance hemodialysis patients and 32 age- and sex-matched healthy subjects. Antibody tests were performed at five time points: 6 months after the 2 nd vaccination, immediately before the 3 rd vaccination (8 months after the 2 nd vaccination), and 2 weeks, 1 month, and 3 months after the 3 rd vaccination., Results: The dialysis patient group had significantly lower values of anti-SP-IgG antibody titers than the control group 6 months after the 2 nd vaccination (433.7 ± 36.24 vs. 650.2 (427.2 - 759.4) (AU/mL), p = 0.006) and immediately before the 3 rd vaccination (219.3 (129.4 - 423.4) vs. 443.3 (267.1 - 600.4) (AU/mL), p = 0.034), but no significant differences were observed after the 3 rd vaccination (19,000.0 (11,000.0 - 3,6000.0) vs. 23,500.0 (20,250.0 - 29,000.0) (AU/mL), p = 0.538)., Conclusion: This study confirmed that patients undergoing hemodialysis were proven to have acquired sufficient antibody titers after the vaccination.

Objective: Measures of fat distribution and visceral fat accumulation maintain a direct association with mortality in the general population. However, among patients undergoing hemodialysis (HD), there are few reports of this association. This study aimed to investigate the impact of computed tomography (CT)-measured abdominal fat levels, including the visceral fat area (VFA) and subcutaneous fat area (SFA), on all-cause mortality in patients undergoing HD and investigate whether there are sex-specific particularities regarding the associations between the abovementioned parameters., Methods: A total of 258 participants were selected from the population of patients undergoing stable HD. The baseline characteristics were collected by records and interviews. The following variables were assessed at baseline and every year: body mass index, abdominal circumference, VFA, and SFA. Abdominal circumference and body fat distribution were assessed at the level of the umbilicus via CT. All CT scans were performed on a nondialysis day with the subject in a supine position. The primary end point was the 5-year all-cause mortality., Results: This prospective cohort study revealed that age, cardiothoracic ratio, %VFA (VFA/[VFA + SFA]), and albumin were independent predictors of death via multivariable analyses. Regarding the %VFA, its area under the curve (0.599), which did not suffice to predict mortality, was higher than that of VFA, SFA, and body mass index. Also, the effect was recognized mainly in male patients. The %VFA of patients who survived for 60 months increased over time., Conclusion: These data suggest that patients (especially men) with a high VFA-to-abdominal fat ratio have a high risk of death. Thus, more attention should be paid to such patients., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Poor prognosis in hemodialysis (HD) patients is due to the increased prevalence of cardiovascular diseases among them. We previously reported that higher visit-by-visit blood pressure variability is associated with increased cardiovascular mortality in HD patients. This present study aimed to investigate the characteristics of month-by-month blood pressure variability (MMBPV) in these patients., Methods: A total of 324 maintenance HD patients, who could be followed up for 60 months, were recruited. We used standard deviation (SD), coefficient of variation (CV), and variation independent of the mean (VIM) in pre- and post-dialysis systolic blood pressure (pre- and post-SD, pre- and post-CV, and pre- and post-VIM) as an index of MMBPV. We investigated (1) the reproducibility of MMBPV, (2) relationship between these values and background factors, and (3) association between these values and mortality., Results: MMBPV (pre- and post-SD, pre- and post-CV, and pre- and post-VIM) showed significant reproducibility (intraclass correlation, 0.483 [p < 0.001], 0.553 [p < 0.001], 0.450 [p < 0.001], 0.518 [p < 0.001], 0.456 [p < 0.001], and 0.522 [p < 0.001], respectively). High pre-VIM was associated with high interdialytic weight gain and poor nutritional status. High post-VIM was associated with glucose intolerance, high interdialytic weight gain, and poor nutritional status and associated with high rate of cardiovascular deaths independent of other factors (hazard ratio: 1.104, 95% confidence interval: 1.011-1.207, p = 0.028)., Conclusion: These data suggested that pre- and post-VIM in HD patients are reproducible and associated with various background factors, and especially post-VIM is independently correlated with cardiovascular mortality. Further studies are necessary to confirm the mechanism of increased post-VIM and clarify whether reducing post-VIM can improve the prognosis of HD patients., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The (pro)renin receptor [(P)RR)] is a multifunctional protein that is cleaved to generate the soluble (P)RR [s(P)RR], reflecting the status of the tissue renin-angiotensin system and/or activity of the (P)RR. The serum s(P)RR level is associated with arteriosclerosis, independent of other risk factors, in patients undergoing hemodialysis (HD). This study was conducted to investigate whether the s(P)RR level was associated with new-onset cardiovascular events or malignant diseases and poor prognosis in patients undergoing HD. Overall, 258 patients [70 (61-76) years, 146 males] undergoing maintenance HD were prospectively followed up for 60 months. We investigated the relationships between s(P)RR levels and new-onset cardiovascular events/ malignant diseases and mortality during the follow-up period using Cox proportional hazard analyses. The cumulative incidence of new-onset cardiovascular events (P = 0.009) and deaths (P < 0.001), but not of malignant diseases, was significantly greater in patients with higher serum s(P)RR level (≥ 29.8 ng/ml) than in those with lower s(P)RR level (< 29.8 ng/ml). A high serum s(P)RR level was independently correlated with cardiovascular mortality (95% CI 1.001-1.083, P = 0.046). The serum s(P)RR level was associated with cardiovascular events and mortality, thus qualifying as a biomarker for identifying patients requiring intensive care., (© 2021. The Author(s).)

The (pro)renin receptor ((P)RR) is cleaved to generate soluble (P)RR (s(P)RR), which reflects the status of the tissue renin-angiotensin system. Hemodialysis (HD) patients have a poor prognosis due to the increased prevalence of cardiovascular diseases. The present study aimed to investigate whether serum s(P)RR level is associated with the worsening of cardiac function in HD patients. A total of 258 maintenance HD patients were recruited and serum s(P)RR concentration was measured. Background factors in patients who survived (S group) and patients who died (D group) during the 12-month follow-up period and relationships between serum s(P)RR level and changes in cardiac function during the follow-up period in the S group were investigated. The median serum s(P)RR value at baseline was 29.8 ng/ml. Twenty-four patients died during the follow-up period. Cardiothoracic ratio, human atrial natriuretic peptide (hANP), brain natriuretic peptide (BNP), and E over e-prime were significantly higher in the D group. In the S group, changes in hANP or BNP were significantly greater in the higher serum s(P)RR group than in the lower serum s(P)RR group. High serum s(P)RR level was significantly correlated with changes in BNP, independent of other factors. High serum s(P)RR level was associated with increases in BNP, independent of other risk factors, suggesting that an increased expression of (P)RR may be associated with a progression of heart failure in HD patients and that serum s(P)RR concentration could be used as a biomarker for selecting patients requiring intensive care., Competing Interests: The authors have declared that no competing interests exist.

Visit-to-visit blood pressure variability (VVBPV) is an independent risk factor for cardiovascular morbidity and mortality in the general population. Hemodialysis (HD) patients have a poor prognosis due to an increased prevalence of cardiovascular disease. Intradialytic hypotension is associated with excess mortality, but whether VVBPV influences mortality is still unclear in HD patients. The present study aimed to investigate the characteristics of VVBPV in these patients. A total of 324 maintenance HD patients, who could be followed for 60 months, were recruited. We used variation independent of the mean (VIM) in pre-dialysis systolic blood pressure (pre-VIM-SBP) as an index of VVBPV. We investigated (1) the reproducibility of pre-VIM-SBP, (2) the relationship between pre-VIM-SBP and background factors, and (3) the association between pre-VIM-SBP and mortality. Pre-VIM-SBP showed significant reproducibility [intraclass correlation, 0.45 (P < 0.001)]. Higher pre-VIM-SBP was associated with less physical activity and worse left ventricular diastolic function. Higher pre-VIM-SBP was associated with a higher rate of cardiovascular deaths independent of other factors. These data suggest that VVBPV in HD patients is reproducible and associated with various background factors. VVBPV is independently correlated with cardiovascular mortality (hazard ratio: 1.166, 95% confidence interval: 1.030-1.320, P = 0.015). Further studies are necessary to confirm the mechanism of increased VVBPV and to clarify whether reducing VVBPV will improve the prognosis for HD patients.

Introduction: Although gastrointestinal hemorrhage is an important complication for dialysis patients, the details of many points remain unclear with regard to small intestinal lesions., Methods: Capsule endoscopy was performed in fecal occult blood-positive dialysis (n =16) and non-dialysis (n = 20) patients after upper and lower gastrointestinal endoscopies failed to reveal hemorrhagic lesions., Findings: Erosive lesions were observed in 50.0% (8/16) and 25.0% (5/20) of the dialysis and non-dialysis groups, respectively. Vascular lesions were observed in 62.5% (10/16) and 25.0% (5/20), respectively. Vascular lesions were observed at a significantly higher rate in the dialysis patients (P = 0.041), but no significant difference was noted in erosive lesions (P = 0.188). Of patients taking proton pump inhibitor (PPI), Non-Steroidal Anti-Inflammatory Drugs, and antiplatelet drugs, only oral PPI administration was associated with vascular lesions (P = 0.02)., Discussion: In dialysis patients, vascular lesions are the most common among small intestinal lesions, suggesting that they may have caused previously unexplained gastrointestinal hemorrhage in dialysis patients. It was also suggested that the frequent use of PPI may be a cause of small intestinal lesions., (© 2018 International Society for Hemodialysis.)

Primary hepatic leiomyosarcoma is an extremely rare tumor. The diagnosis is difficult, and its etiologic factors have not been clarified. A 63-year-old woman with numerous cysts in her kidneys and liver was diagnosed with autosomal dominant polycystic kidney disease (ADPKD). Several members of her family also had ADPKD. She underwent treatment with tolvaptan to inhibit cyst growth and slow the decline in kidney function. Eight months after the start of the therapy, she was hospitalized with fatigue and fever of unknown origin. Diagnostic imaging showed a very large hepatic tumor, and histologic examination of a fine-needle biopsy specimen revealed the tumor to be malignant. Differentiation between carcinoma and sarcoma was difficult based on the histological findings. The tumor was thought to be excisable; therefore, hepatic resection was attempted. At the time of surgery, as the tumor had grown larger than when imaged, complete resection was impossible. However, a part of the tumor was resected. Histopathological and immunohistological examinations of the surgical specimen confirmed a primary hepatic leiomyosarcoma. Whether the tumor was associated with the presence of ADPKD remains unclear, however, this is the first report of the combination of these two diseases in a patient.

Anion exchanger 1 (AE1), also known as band 3 or SLC4A1, plays a key role in the removal of carbon dioxide from tissues by facilitating the exchange of chloride and bicarbonate across the plasma membrane of erythrocytes. An isoform of AE1 is also present in the kidney. Specific mutations in human AE1 cause several types of hereditary hemolytic anemias and/or distal renal tubular acidosis. Here we report the crystal structure of the band 3 anion exchanger domain (AE1(CTD)) at 3.5 angstroms. The structure is locked in an outward-facing open conformation by an inhibitor. Comparing this structure with a substrate-bound structure of the uracil transporter UraA in an inward-facing conformation allowed us to identify the anion-binding position in the AE1(CTD), and to propose a possible transport mechanism that could explain why selected mutations lead to disease., (Copyright © 2015, American Association for the Advancement of Science.)

There is a close relationship between sleep disordered breathing (SDB) and heart failure. We performed home oxygen therapy (HOT) in patients with SAS undergoing dialysis, and investigated its effects on the heart function. The subjects were 10 SDB patients on dialysis. On retiring at night, oxygen was transnasally administered at 1.0 L/min. The human atrial natriuretic peptide (hANP), brain natriuretic peptide (BNP), total protein, Alb, cholesterol and phosphorus levels were measured before the start of oxygen therapy and after 6 weeks. The mean SpO2 increased from 93.5% [91.5, 97.0] to 96.3% [94.8, 97.4] (median [interquartile range]) (p = 0.015). The hANP (p = 0.0039), BNP (p = 0.0098) and serum Alb (p = 0.015) levels significantly improved. There were no significant changes in the cholesterol, phosphorus or total protein levels. These results suggest that nocturnal oxygen therapy improves indices of heart failure, contributing to the prevention and treatment of heart failure in dialysis patients with SDB.

We report here a case of a 64-year-old woman with myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) -associated glomerulonephritis who developed acute pancreatitis. The patient was admitted to our hospital because of abnormal urinalysis findings, edema, and progressive renal failure. Laboratory studies showed a high white blood cell count (11,570/μL), anemia (hemoglobin 7.8 g/dL), and elevated serum creatinine (2.36 mg/dL) and C-reactive protein (12.20 mg/dL) levels. Furthermore, the MPO-ANCA titer was very high (1,625 U/mL, normal range < 10 U/mL). Histopathological findings of the renal biopsy were consistent with microscopic polyangiitis. Accordingly, we diagnosed MPO-ANCA-associated glomerulonephritis. On the day after the renal biopsy, the patient complained of low back pain. Computed tomography (CT) revealed postbiopsy hemorrhage. Thereafter, the patient's symptoms and laboratory studies gradually worsened. A repeat CT performed a few days later revealed no changes in the perirenal hematoma; however, an enlarged pancreas head was incidentally observed. There was no obvious cause of acute pancreatitis, and MPO-ANCA-associated vasculitis, although rare, was suspected as the cause. We initiated prednisolone pulse therapy for vasculitis along with the administration of nafamostat mesilate and ulinastatin for acute pancreatitis. Subsequently, the levels of pancreatic enzymes gradually increased, but several days later, abdominal magnetic resonance imaging showed improvement in the pancreas head. The pancreatitis gradually resolved over time. Acute pancreatitis occurring concurrently with MPO-ANCA-associated glomerulonephritis is extremely rare. To our knowledge, only a few such cases have been reported and have suggested that steroid therapy may play a role in triggering pancreatic involvement. In our case, however, an enlarged pancreas head was observed before steroid therapy was initiated. Therefore, we consider our case to be very rare.

Objective: The prevalence of thrombotic cerebral infarction is higher in dialysis than in general patients. Changes in cerebral blood flow (CBF) during low-density lipoprotein cholesterol-apheresis (LDL-A) in dialysis patients with arteriosclerosis obliterans (ASO) were evaluated employing xenon-CT (Xe-CT) to investigate the possibility of CBF improvement., Subjects and Methods: Xe-CT was performed before LDL-A in 4 dialysis patients with ASO (3 males and 1 female). LDL-A was then performed once a week 10 times. After the completion of LDL-A treatment, Xe-CT was performed again to observe changes in CBF., Results: Before treatment, CBF in the 4 patients was lower than that in the general population in the same age group. After LDL-A treatment, CBF was improved. The improvement was observed in the cerebral cortex rather than the basal ganglia. The grade of improvement and improved cerebral region varied among the patients., Conclusion: It was suggested that LDL-A may improve not only lower limb blood flow but also CBF. However, further investigation is necessary with regard to the influence of CBF improvement on the brain function and clinical application. The reported results need to be confirmed in larger studies.

Background: In hemodialysis (HD) patients, obesity has been recognized as a serious risk factor for mortality and morbidity for cardiovascular diseases. In addition, abnormalities of lipid profiles exist in these patients., Methods: In patients undergoing maintenance HD, incidences of abnormality of lipid profiles and visceral obesity determined by computed tomography scans were compared. In addition, the relationship between visceral fat area (VFA) and brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, or carotid intima-media thickness (IMT), an index of atherosis, was examined., Results: The incidence of high VFA (27.0%) was significantly greater than that of high body mass index (BMI) (9.7%), high low-density-lipoprotein cholesterol (LDL-C) (4.8%), and high triglyceride (12.7%). In patients with diabetes mellitus (DM), waist circumference and VFA showed a significant positive relationship with baPWV. baPWV was significantly higher in patients with high VFA and DM than in patients with low VFA without DM, those with high VFA without DM, and those with low VFA and DM. Carotid IMT was significantly greater in patients with high VFA and DM than in those with low VFA without DM and those with low VFA and DM., Conclusions: The incidence of high VFA was much greater than that of high BMI, high LDL-C, or high triglyceride. Visceral fat accumulation may be related to both arterial stiffness and atherosis in diabetic patients on maintenance HD.

A 74-year-old male without recent medical treatment visited our hospital complaining of fever and lack of appetite. Upon examination severe azotemia, proteinuria, and urinary occult blood were noted, and the patient was admitted. Results of a blood test showed that his proteinase 3 antineutrophil cytoplasmic autoantibody (PR3-ANCA) level was high. A transthoracic echocardiogram indicated normal cardiac function and no valvular regurgitation or stenosis. Necrotizing glomerulonephritis accompanied by cellular crescentic bodies, but not granuloma, was noted on renal biopsy. An immunofluorescence study demonstrated no immunofluorescence staining in the glomerulus or in the tubulointerstitial or vascular compartments. No lesion was present in the lung or upper respiratory tract. The patient was diagnosed with PR3-ANCA-associated pauci-immune-type crescentic glomerulonephritis and treated with steroids. This treatment resulted in rapid normalization of C-reactive protein, and the PR3-ANCA level slowly decreased and converted to negative. The renal function, however, did not improve, and maintenance dialysis was introduced. No pulmonary or upper airway lesion has developed during 18 months of follow-up. PR3-ANCA-positive crescentic glomerulonephritis accompanied by valvular endocarditis has been described by several reports in Japan; however, this case was not complicated by valvular endocarditis. To our knowledge, this is the 4th case report describing PR3-ANCA-associated crescentic glomerulonephritis in Japan.

Difficulties in gaining vascular access have become one of the major problems in long-term hemodialysis patients. We report a case with an extreme vascular access problem, which was solved by the placement of a permanent central vein catheter after successful angioplasty to the right subclavian and inominate vein stenosis. A 78-year-old woman with end-stage renal disease due to diabetic nephropathy had been on hemodialysis since 1982. She had a history of four procedures that created an arteriovenous fistula during the first four years. In 1986 she was switched to peritoneal dialysis. However, hemodialysis was restarted with a regular arteriovenous fistula in 1991 because of repeated peritonitis, and from 1993 a superficialized brachial artery was used until the artery was exhausted. Since 1997, a permanent central vein catheter was utilized and reinsertion was required four times due to catheter infection during a 6-year period. In 2004, difficulty was experienced in reinserting a new central venous catheter because of multiple stenotic and occlusive lesions of the central veins. Percutaneous transluminal angioplasty was carried out in the stenotic right subclavian and inominate veins, and after successful angioplasty, a permanent central vein catheter could be placed into the right subclavian vein as a vascular access for hemodialysis. Pretreatment with percutaneous transluminal angioplasty of the stenotic central veins before inserting a permanent catheter may be a useful strategy in patients that experience difficulty in the insertion of a catheter.

The prevalence of peripheral arterial occlusive disease is high in patients with terminal renal failure, and it is a major problem in those on dialysis. A low ankle-brachial index (ABI) suggests the presence of arterial stenotic lesions between the aorta and the ankle joint, while a low toe-brachial index (TBI) suggests stenotic lesions between the aorta and the toes. Therefore, a normal ABI (> or =0.9) and a low TBI (<0.6) may indicate the presence of stenotic lesions located only on the peripheral side of the ankle joint. In the present study, risk factors of normal ABI/low TBI were investigated. In 115 patients on maintenance dialysis, the ABI and TBI were simultaneously measured, and the background factors and laboratory data of patients with normal ABI/low TBI (L group) and those with normal ABI/normal TBI (> or =0.6) (N group) were compared. Low ankle-brachial and toe-brachial indices were detected in 13% and 22% of the patients, respectively. Comparison of the background factors and laboratory data between the N and L groups showed that the ratio of diabetes mellitus, interdialytic body weight gain, and Hb(A1c) values were significantly higher in the L group than in the N group. It was clarified that diabetes and excess body weight gain are involved as risk factors in dialysis patients with normal ABI/low TBI.

Background: Identifying patients at high risk of cardiovascular disease is important in managing patients undergoing hemodialysis., Methods: We evaluated a series of prognostic values: flow-mediated dilation (FMD) and nitrogen-mediated dilation (NMD), an index of endothelium-dependent and endothelium-independent function, respectively, ankle-brachial index (ABI), and brachial-ankle pulse wave velocity (baPWV) in patients undergoing chronic hemodialysis., Results: A cohort of 199 patients was studied. At entry, these values were examined and the prognostic significances were investigated. In estimating the significance of baPWV, patients with ABI <0.9 were excluded. During the follow-up period, 24 deaths occurred including 14 cardiovascular and 10 noncardiovascular fatal events. Overall, the survival rates were significantly lower in the low ABI than in the high ABI group, but the survival rates were not significantly different between the high and low FMD, NMD, or baPWV groups. Cardiovascular survival rates were significantly lower in the low ABI than in the high ABI group, and in the high baPWV than in the low baPWV group. The survival rates were not significantly different between the high and low FMD or NMD groups., Conclusions: Screening hemodialysis patients by means of ABI and baPWV but not FMD or NMD provides complementary information in identifying a high-risk population in these patients.

Shear stress is known to dilate blood vessels and exert an antiproliferative effect on vascular walls. These effects have partly been ascribed to shear stress-induced regulation of the secretion of endothelium-derived vasoactive substances. In this study, to elucidate the role of shear stress in endothelin production by endothelial cells, we examined the effect of physiological shear stress on the mRNA expression of endothelin-converting enzyme-1 (ECE-1) as well as endothelin-1 (ET-1) in cultured bovine carotid artery endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs), using a parallel plate-type flow chamber. ECE-1 mRNA expression was significantly down-regulated by shear stress in an intensity- and time-dependent manner within the physiological range (1.5 to 15 dyn/cm(2)). ET-1 mRNA expression decreased together with ECE-1 mRNA expression. Shear stress at 15 dyn/cm(2) for 30 min induced a significant increase in the intracellular peroxide concentration, and the down-regulation of ECE-1 and ET-1 mRNA expression by shear stress was attenuated almost completely on treatment with N-acetyl cysteine (NAC), an antioxidant (20 mM). Furthermore, when H(2)O(2) (0.5 to 2 mM) was added to BAECs in static culture, the ECE-1 as well as ET-1 mRNA expression was attenuated in proportion to the concentration of H(2)O(2). It is suggested that endothelial cells sense shear stress as oxidative stress and transduce signal for the regulation of the gene expression of ECE as well as ET to attenuate vascular tone and inhibit the proliferation of vascular smooth muscle cells., (Copyright 2003 Elsevier Science B.V.)

Adrenomedullin (AM) is a vasoactive hormone which exerts its action through cyclic adenosine monophosphate(cAMP) /cAMP-dependent protein kinase (PKA) cascade and intracellular Ca2+ mobilization. Recently, evidence has accumulated that AM plays a critical role in the regulation of vascular tone, remodeling and morphogenesis. And although numerous reports have examined the action of AM on cultured vascular cells, the results have not been consistent and have depended on the experimental conditions used. Accordingly, the purpose of this study was to clarify the effect of AM on the proliferation and migration of cultured endothelial cells. Our results revealed that AM promoted the growth and migration of endothelial cells (ECs). AM significantly promoted the proliferation of human umbilical vein endothelial cells (HUVECs) (56.0 +/- 8.7% over the controls at 10(-9) mol/l) and this stimulative effect was inhibited by two AM antagonists, AM(22-52) and calcitonin gene-related peptide (CGRP) (8-37). The number of HUVECs migrated to the lower surface of the transwell apparatus was also increased dose-dependently in the AM group (30.4 +/- 4.2% over the controls at 10(-7) mol/l), and this increase was suppressed by the two AM antagonists and by two PKA antagonists, adenosine 3'5'-cyclic monophosphorothioate Rp-isomer and myristoylated protein kinase A inhibitor amide 14-22. The promoting action of AM on endothelial migration was also suppressed by LY294002, an inhibitor for phosphatidylinositol 3-kinase, but not by N(G)-nitro-L-arginine-methyl ester (L-NAME), an antagonist for nitric oxide synthase (NOS). These results indicate that AM promotes proliferation and migration of ECs via a cAMP/PKA dependent pathway and lend support to the idea that AM exerts beneficial effects on vascular regeneration and might be used as a novel therapeutic strategy for patients with vascular disease.

Background: Vein graft disease limits the late results of coronary revascularization. C-type natriuretic peptide (CNP) inhibits the growth of vascular smooth muscle cells. Given the effects of CNP on cGMP cascade, we hypothesized that transfected CNP genes modulate endothelial repair and thrombogenicity in the vein graft., Methods and Results: Autologous rabbit jugular vein grafts were incubated ex vivo in a solution of adenovirus vectors containing CNP gene (Ad.CNP) or Escherichia coli lac Z gene (Ad.LacZ) and then interposed in the carotid artery. Reendothelialization, mural thrombi formation, and intima/media ratio were evaluated on the 14th and 28th postoperative days. More reendothelialization was seen in Ad.CNP-infected grafts than in Ad.LacZ-infected grafts both at 14 days (0.81+/-0.05 versus 0.30+/-0.14, P<0.01) and at 28 days (0.96+/-0.01 versus 0.45+/-0.08, P<0.001). The mural thrombus area was smaller in Ad.CNP-infected grafts than in Ad.LacZ-infected grafts. Neointimal thickening was significantly suppressed in the Ad.CNP group. The in vitro wound assay with human coronary artery endothelial cells revealed significant potentiation of the wound repair process by CNP and atrial natriuretic peptide administration., Conclusions: Infected Ad.CNP accelerated reendothelialization and suppressed thrombosis and neointimal hyperplasia. The method may potentially prevent vein graft disease in patients undergoing coronary artery revascularization.

Formerly, the incidence of primary aldosteronism (PA) among patients with hypertension was believed to be less than 1%. However, recent studies have suggested a much higher incidence of 6.59%-14.4% among such patients. These findings suggest that many cases of PA caused by small aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA) have not been properly diagnosed. To make a more accurate diagnosis in such cases, we developed a new diagnostic procedure for localization of PA, namely, adrenal venous sampling under continuous infusion of adrenocorticotropic hormone (ACTH) and administration of angiotensin II receptor blocker (AVS with ACTH and ARB). Here, we confirm the efficacy of this procedure in the case of a 37-year-old male suspected of having PA. The anticipated diagnosis of PA was based on the presence of hypokalemia, low plasma renin activity (PRA), elevated plasma aldosterone concentration (PAC) and left adrenal mass. However, AVS with ACTH and ARB revealed the presence of bilateral multiple adrenal microadenomas. In the new AVS method, neither ACTH nor the renin-angiotensin system (RAS) exert any influence on the plasma aldosterone level, and a more accurate aldosterone secretary state and a more accurate assessment of the aldosterone secretion of both adrenal glands can be recognized than by conventional AVS. Use of this new method should enable identification of additional cases of APA among patients diagnosed with essential hypertension.

Vascular endothelial growth factor (VEGF) has been recognized as an angiogenic factor that induces endothelial proliferation and vascular permeability. Recent studies have also suggested that VEGF can promote macrophage migration, which is critical for atherosclerosis. We have reported that VEGF is remarkably expressed in activated macrophages, endothelial cells, and smooth muscle cells within human coronary atherosclerotic lesions, and we have proposed the significance of VEGF in the progression of atherosclerosis. To clarify the mechanism of VEGF expression in atherosclerotic lesions, we examined the regulation of VEGF expression by oxidized low density lipoprotein (Ox-LDL), which is abundant in atherosclerotic arterial walls. A recent report has revealed that peroxisome proliferator-activated receptor-gamma (PPARgamma) is expressed not only in adipocytes but also in monocytes/macrophages and has suggested that PPARgamma may have a role in the differentiation of monocytes/macrophages. Furthermore, 9- and 13-hydroxy-(S)-10,12-octadecadienoic acid (9- and 13-HODE, respectively), the components of Ox-LDL, may be PPARgamma ligands. Therefore, we investigated the involvement of PPARgamma in the regulation of VEGF by Ox-LDL. PPARgamma expression was detected in human monocyte/macrophage cell lines, human acute monocytic leukemia (THP-1) cells, and human coronary artery endothelial cells (HCAECs). Ox-LDL (10 to 50 microg/mL) upregulated VEGF secretion from THP-1 dose-dependently. VEGF mRNA expression in HCAECs was also upregulated by Ox-LDL. The mRNA expression of VEGF in THP-1 cells and HCAECs was also augmented by PPARgamma activators, troglitazone (TRO), and 15-deoxy-(12,14)-prostaglandin J(2) (PGJ2). In contrast, VEGF expression in another monocyte/macrophage cell line, human histiocytic lymphoma cells (U937), which lacks PPARgamma expression, was not augmented by TRO or PGJ2. We established the U937 cell line, which permanently expresses PPARgamma (U937T). TRO and Ox-LDL augmented VEGF expression in U937T. In addition, VEGF production by THP-1 cells was significantly increased by exposure to 9-HODE and 13-HODE. In conclusion, Ox-LDL upregulates VEGF expression in macrophages and endothelial cells, at least in part, through the activation of PPARgamma.

Small GTPase Rho and cGMP/cGMP-dependent protein kinase (cGK) pathways exert opposing effects in specific systems such as vascular contraction and growth. However, the direct interaction between these pathways has remained elusive. We demonstrate that cGK phosphorylates RhoA in vitro at Ser188, the same residue phosphorylated by cAMP-dependent protein kinase. In HeLa cells transfected with constitutively active cGK (C-cGK), stress fiber formation induced by lysophosphatidic acid or V14RhoA was blocked. By contrast, C-cGK failed to inhibit stress fiber formation in cells transfected with mutant RhoA with substitution of Ser188 to Ala. C-cGK did not affect actin reorganization induced by Rac1 or Rho-associated kinase, one of the effectors for RhoA. Furthermore, C-cGK expression inhibited the membrane translocation of RhoA. Collectively, our findings suggest that cGK phosphorylates RhoA at Ser188 and inactivates RhoA signaling. The physiological relevance of the direct interaction between RhoA and cGK awaits further investigation., (Copyright 2001 Academic Press.)

Interaction between endothelial cells and mural cells (pericytes and vascular smooth muscle) is essential for vascular development and maintenance. Endothelial cells arise from Flk1-expressing (Flk1+) mesoderm cells, whereas mural cells are believed to derive from mesoderm, neural crest or epicardial cells and migrate to form the vessel wall. Difficulty in preparing pure populations of these lineages has hampered dissection of the mechanisms underlying vascular formation. Here we show that Flk1+ cells derived from embryonic stem cells can differentiate into both endothelial and mural cells and can reproduce the vascular organization process. Vascular endothelial growth factor promotes endothelial cell differentiation, whereas mural cells are induced by platelet-derived growth factor-BB. Vascular cells derived from Flk1+ cells can organize into vessel-like structures consisting of endothelial tubes supported by mural cells in three-dimensional culture. Injection of Flk1+ cells into chick embryos showed that they can incorporate as endothelial and mural cells and contribute to the developing vasculature in vivo. Our findings indicate that Flk1+ cells can act as 'vascular progenitor cells' to form mature vessels and thus offer potential for tissue engineering of the vascular system.

The i.r. spectra of D-glucose and cellulose oligosaccharides up to cellopentaose have been compared with those of cellulose at various temperatures between that of liguid nitrogen and approximately 250 degrees. Significant changes in frequency and intensity of the bands at approximately 3400 cm -1 were observed. The a 1372 cm -1/a2900 cm -1 ratio for each carbohydrate studied decreased gradually as the temperature was increased above ambient. The change of the band intensities at 1429 and 893 cm -1 with temperature was also investigated. The observed spectral changes are assumed to be associated with changes of hydrogen bonding.