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Earlobe creases are surrogate markers for high risk of cardiovascular disease. There is no data concerning earlobe creases among hemodialysis patients, who have an increased risk of cardiovascular disease. A cross-sectional study was conducted to determine the prevalence of earlobe creases and their association with prevalent cardiovascular disease among hemodialysis patients. Patients undergoing hemodialysis were recruited from five outpatient hemodialysis centers. Both earlobes were photographed during a dialysis session with the patient in a supine position and the photos evaluated independently by two experienced nephrologists blinded to the participants' clinical characteristics. Prevalent cardiovascular diseases were defined as a history of myocardial infarction, cerebrovascular accident, or peripheral vascular disease. Sensitivity, specificity, and positive and negative predictive values for detection of prevalent cardiovascular disease were calculated. Logistic analysis was used to examine the association between earlobe creases and prevalent cardiovascular disease. Earlobe creases were identified in 24.5% of 330 hemodialysis patients (200 men; mean age, 67.8 years). The prevalence of earlobe creases increased with age for men (P for trend

Earlobe creases are surrogate markers for high risk of cardiovascular disease. There is no data concerning earlobe creases among hemodialysis patients, who have an increased risk of cardiovascular disease. A cross-sectional study was conducted to determine the prevalence of earlobe creases and their association with prevalent cardiovascular disease among hemodialysis patients. Patients undergoing hemodialysis were recruited from five outpatient hemodialysis centers. Both earlobes were photographed during a dialysis session with the patient in a supine position and the photos evaluated independently by two experienced nephrologists blinded to the participants' clinical characteristics. Prevalent cardiovascular diseases were defined as a history of myocardial infarction, cerebrovascular accident, or peripheral vascular disease. Sensitivity, specificity, and positive and negative predictive values for detection of prevalent cardiovascular disease were calculated. Logistic analysis was used to examine the association between earlobe creases and prevalent cardiovascular disease. Earlobe creases were identified in 24.5% of 330 hemodialysis patients (200 men; mean age, 67.8 years). The prevalence of earlobe creases increased with age for men (P for trend0.0001), but not for women (P for trend = 0.07). Sensitivity, specificity, and positive and negative predictive values were 30.9% (95% confidence interval, 21.9-41.6), 77.5% (71.9-82.3), 30.9% (21.9-41.6), and 77.5% (71.9-82.3), respectively. Multivariate logistic analyses indicated the prevalence of earlobe crease was not associated with prevalent cardiovascular diseases. The prevalence is similar to that previously reported for Japanese individuals not undergoing dialysis. No association between earlobe creases and prevalent cardiovascular diseases was identified.

Background The parathyroid gland secretes 1-84 and 7-84 parathyroid hormone (PTH) fragments, and its regulation is dependent on stimulation of the extracellular calcium-sensing receptor. While the intact PTH system detects both PTH fragments, the whole PTH system detects the 1-84PTH but not the 7-84PTH. Cinacalcet hydrochloride (CH) binds to calcium-sensing receptor as a calcimimetic. Here we investigated the role of CH treatment in the assessment of parathyroid gland function. Methods Stable adult dialysis patients for whom CH therapy was planned were included. Patients for whom CH therapy was not planned were simultaneously included as the control group. Results The CH group (n = 44) showed significantly higher circulating levels of Ca, intact PTH, and whole PTH, before the CH treatment than the control group (n = 112). The Ca, intact PTH, and whole PTH levels decreased along with the CH therapy, and the Ca levels became comparable in the 8th week of treatment and thereafter. The CH group in the 8th week and thereafter showed significantly lower whole/intact PTH ratios than the control group, while the whole/intact PTH ratio was not significantly different between before and during the CH therapy. A multiple regression analysis revealed that the whole/intact PTH ratio was almost constant, but both the serum Ca level and a CH therapy could potentially modify the fixed number. When the whole PTH levels were estimated by intact PTH levels using the relationship between them in the control group, the levels were clearly overestimated in the CH group. Conclusions Although the direct effect of CH on the whole/intact PTH ratio is masked by its hypocalcemic action, we could successfully demonstrate that the ratio in CH users is lower than that in the non-users with comparable levels of serum Ca. Evaluating parathyroid function with intact PTH according to the clinical practice guidelines in patients being treated with CH may lead to significant overestimation and subsequent overtreatment.

A combination of healthy lifestyle factors is associated with lower risks of coronary heart disease, diabetes, and stroke, but little is known about its association with chronic kidney disease. This study analyzed the effect of a combination of healthy lifestyle factors on the incidence of proteinuria among participants without chronic kidney disease. Of the 7565 persons aged 40-79 years who participated in the Specific Health Checkups and Guidance System in Sado Island, Japan in 2008, 4902 participants (2015 males) without chronic kidney disease were included. The healthy lifestyle score was calculated by summing the total number of lifestyle factors for which the participants were at low risk. Low risk was defined as (1) nonsmoker, (2) body mass index

Despite significant therapeutic advances, mortality of dialysis patients remains unacceptably high. The aim of this study is to compare mortality and its causes in dialysis patients with those in the general Japanese population. We used data for 2008 and 2009 from the Japanese Society for Dialysis Therapy registry and a national Vital Statistics survey. Cardiovascular mortality was defined as death attributed to heart failure, cerebrovascular disorders, myocardial infarction, hyperkalemia/sudden death, and pulmonary thromboembolism. Non-cardiovascular mortality was defined as death attributed to infection, malignancies, cachexia/uremia, chronic hepatitis/cirrhosis, ileus, bleeding, suicide/refusal of treatment, and miscellaneous. We calculated standardized mortality ratios and age-adjusted mortality differences between dialysis patients and the general population for all-cause, cardiovascular versus non-cardiovascular, and cause-specific mortality. During the 2-year study period, there were 2,284,272 and 51,432 deaths out of 126 million people and 273,237 dialysis patients, respectively. The standardized mortality ratio for all-cause mortality was 4.6 (95% confidence interval, 4.6-4.7) for the dialysis patients compared to the general population. Age-adjusted mortality differences for cardiovascular and non-cardiovascular disease were 33.1 and 30.0 per 1000 person-years, respectively. The standardized mortality rate ratios were significant for all cause-specific mortality rates except accidental death. Our study revealed that excess mortality in dialysis patients compared to the general population in Japan is large, and differs according to age and cause of death. Cause-specific mortality studies should be planned to improve life expectancies of dialysis patients.

Infectious disease is the second leading cause of death among dialysis patients, and it is generally assumed that the mortality rate of infectious disease is considerably higher in dialysis patients than in the general population. There are no comprehensive studies on this issue and on the contribution of each category of infectious disease to excess mortality in dialysis patients in Japan. We used mortality data reported to the Japanese Society for Dialysis Therapy and national Vital Statistics data for 2008 and 2009. We calculated standardized mortality ratios and compared the mortality rates for each category of infectious disease. During the 2-year study period, 274,683 and 10,435 deaths from infectious diseases were recorded in 126 million people and 273,237 dialysis patients, respectively. The standardized mortality ratio for all infectious diseases was 7.5 (95% confidence interval, 7.3-7.6) in dialysis patients with respect to the general population in Japan. The categories of infectious disease with a significantly higher standardized mortality ratio among the dialysis patients were sepsis, peritonitis, influenza, tuberculosis, and pneumonia and in that order. In particular, the mortality rate of sepsis contributed to 69.5% of the difference in infectious disease mortality between dialysis patients and the general population. This study underlines markedly increased mortality from infectious diseases, particularly from sepsis, in dialysis patients compared with the general population.

Although the lung is a defining feature of air-breathing animals, the pathway controlling the formation of type I pneumocytes, the cells that mediate gas exchange, is poorly understood. In contrast, the glucocorticoid receptor and its cognate ligand have long been known to promote type II pneumocyte maturation; prenatal administration of glucocorticoids is commonly used to attenuate the severity of infant respiratory distress syndrome (RDS). Here we show that knock-in mutations of the nuclear co-repressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) in C57BL/6 mice (SMRTmRID) produces a previously unidentified respiratory distress syndrome caused by prematurity of the type I pneumocyte. Though unresponsive to glucocorticoids, treatment with anti-thyroid hormone drugs (propylthiouracil or methimazole) completely rescues SMRT-induced RDS, suggesting an unrecognized and essential role for the thyroid hormone receptor (TR) in lung development. We show that TR and SMRT control type I pneumocyte differentiation through Klf2, which, in turn, seems to directly activate the type I pneumocyte gene program. Conversely, mice without lung Klf2 lack mature type I pneumocytes and die shortly after birth, closely recapitulating the SMRTmRID phenotype. These results identify TR as a second nuclear receptor involved in lung development, specifically type I pneumocyte differentiation, and suggest a possible new type of therapeutic option in the treatment of RDS that is unresponsive to glucocorticoids.

We compare the direct homogeneous low-density lipoprotein cholesterol (LDL-C) assay with the Friedewald formula (FF) for determination of LDL-C in a large community-dwelling population.A total of 21,194 apparently healthy subjects aged 40 to 79 years with triglyceride (TG) concentrations4.52 mmol/l were enrolled. LDL-C were directly measured by the enzymatic homogeneous assay (LDL-C (D)) and also estimated by the FF (LDL-C (F)). Paired t-test, Pearson's correlation coefficient and linear regression analysis were performed and the concordances of the National Cholesterol Education Program (NCEP) risk category were estimated.Both in fasting (n=3270) and nonfasting samples (n=17,924), LDL-C (D) highly correlated with LDL-C (F): r=0.971 and 0.955, respectively. Concordant results for NCEP categories were 84.8% for fasting samples and 80.1% for nonfasting samples. However, the bias between the 2 measurements increased in samples with TG concentrations1.69 mmol/l, especially in nonfasting samples.The results showing less variability of the direct LDL-C assay than that of the FF in nonfasting samples suggest that epidemiological studies can use LDL-C measured by the direct assay both in fasting and nonfasting samples.

Elevated plasma B-type natriuretic peptide (BNP) levels suggest a high risk for future onset of cardiovascular events including congestive heart failure (CHF) and mortality. In the general population, although median plasma BNP levels have been reported to be higher in women than in men, the incidence of CHF and mortality are lower in women. However, no studies have examined gender-specific risk stratification of plasma BNP levels for future onset of CHF and mortality.Subjects of this study were recruited from our general population. Baseline data including plasma BNP were determined in 13,466 subjects (men 4527, women 8939; median age = 64 yrs). A multivariate Cox regression analysis was performed to examine the predictive ability of plasma BNP for new onset of CHF and mortality.The mean follow-up duration was 2.9 years. After adjustment for traditional cardiovascular risk factors including atrial fibrillation, hazard ratios for CHF development for values above the 75th percentile of BNP were 13.4 (p0.001) in men and 8.5 (p0.001) in women. Similarly, each increment of 1SD in log BNP levels increased the hazard ratio by 8.8 (p0.001) in men, and 6.7 (p0.001) in women. The area under the receiver operating characteristic curve was significant for prediction of the onset of CHF (men; 0.853, women; 0.838). In addition, increased plasma BNP levels implied high risk of any-cause mortality in men (above the 75th percentile; hazard ratio = 1.8, p=0.005: increment of 1SD; hazard ratio = 1.4, p=0.024), but this relationship was suboptimal in women.Measurements of plasma BNP provides strong predictive information about future onset of CHF in both sexes, with predictive ability for death being effective especially in men.

Background: Plasma B-type natriuretic peptide (BNP) levels are confounded by renal dysfunction, so this study examined whether plasma BNP might be a reliable biomarker of the onset of cardiovascular (CV) events in a population-based cohort with impaired renal function. Methods and Results: Baseline data, including plasma BNP, serum creatinine, and urinary protein levels, were determined in participants from a community-based population. Estimated glomerular filtration rate (eGFR) was calculated, and chronic kidney disease (CKD) was defined as either: eGFR

Background: Many studies have estimated the prevalence of anti-hepatitis C virus (HCV) antibody among hemodialysis (HD) patients; however, the prevalence of HCV core antigen—which indicates the presence of chronic HCV infection—is not known.Methods: Standardized prevalence ratios (SPRs) for anti-HCV antibody and HCV core antigen among HD patients (n = 1214) were calculated on the basis of data from the general population (n = 22 472) living in the same area.Results: The prevalences of anti-HCV antibody and HCV core antigen were 12.5% and 7.8%, respectively, in male hemodialysis patients, and 8.5% and 4.1% in female hemodialysis patients. The SPRs (95% confidence interval) for anti-HCV antibody and HCV core antigen were 8.39 (6.72–10.1) and 12.9 (9.66–16.1), respectively, in males, and 5.42 (3.67–7.17) and 8.77 (4.72–12.8) in females.Conclusions: The prevalences of chronic HCV infection among male and female HD patients were 13-fold and 9-fold, respectively, those of the population-based controls. Further studies should therefore be conducted to determine the extent of chronic HCV infection among HD patients in other populations and to determine whether chronic HCV infection contributes to increased mortality in HD patients.

Background People living in the northeastern part of Japan have high prevalences of hypertension and stroke. The current status of cardiovascular risk factors in them should be elucidated. Methods The survey was carried out from 2002 to 2004 in the northeastern part of the main island of Japan. A total of 26,472 Japanese men and women were enrolled (acceptance rate: 84.5%). Sex- and age-specific prevalences of cardiovascular risk factors were determined. Mean values of predictive markers (high-sensitivity C reactive protein (hsCRP), brain natriuretic peptide (BNP) and microalbuminuria) were also determined in each group. Risk factor-related variables in non-hypertensive subjects and hypertensive subjects were compared. Results Proportions of subjects with hypertension, diabetes and dyslipidemia were 46.0%, 7.6%, and 30.3%, respectively, in males and 38.6%, 4.0%, and 38.5%, respectively, in females. Mean values of hsCRP and BNP were 1.41 mg/L and 26.5 pg/mL, respectively, in males and 1.01 mg/L and 23.7 pg/mL, respectively, in females. Proportions of male and female subjects with microalbuminuria were 22.0% and 23.4%, respectively. These markers become higher with advance of age. Prevalence of atrial fibrillation was 1.56%, and it increased with advance of age in both men and women. High prevalences of cardiovascular risk factors in this area were found. Hypertensive subjects who did not take anti-hypertension medication accounted for about 20% of total subjects and their blood pressure remained poorly controlled. Conclusion Attention should be given to cardiovascular risk factors in the Japanese northeastern rural population.

We present here a male patient who had developed nephrotic syndrome 11 yr after kidney transplantation. Nephrotic syndrome suddenly occurred after severe sunburn he got in Hawaii. Such a clinical course seemed very rare in kidney transplantation, and multifactorial etiology was suspected. The histological findings of graft biopsy were intricate. On light microscopy, there were mesangial expansion and endocapillary proliferation with duplication of GBM and crescent formation. Deposits of IgM in mesangium were the most prominent finding on immunofluorescence microscopy, but IgA and C3 deposits were also detected. Electron microscopy revealed paramesangial and a few subepithelial dense deposits. Additionally, small organized deposits were found in the subepithelial space. Based on these findings, a provisional diagnosis of IgA nephropathy superimposed on chronic transplant glomerulopathy was made. However, hepatitis C virus related nephropathy could not be excluded.

In cancer immunotherapy with dendritic cells (DCs), which are the most potent antigen-presenting cells, it is important that DCs present peptides derived from tumor-associated antigens on major histocompatibility complex (MHC) class I molecules and activate tumor-specific cytotoxic T lymphocytes. However, exogenous antigens are generally presented on MHC class II but not class I molecules. To develop effective immunotherapy for cancer, an antigen delivery carrier that can induce MHC class I presentation of exogenous antigens is necessary. Several strategies to induce DCs to present exogenous antigens on MHC class I molecules have been reported. First, DCs that phagocytosed a particulate form of antigens present peptides derived from the antigens on MHC class I molecules. Second, DCs that incorporated antigens via certain endocytic receptors such as Fc receptors efficiently present peptides on MHC class I molecules. We combined these two strategies and prepared antigen-containing IgG-conjugated liposomes (IgG-liposomes). In this study, we investigated the feasibility of IgG-liposomes as antigen delivery carriers in cancer immunotherapy with DCs. Immunization of mice with DCs that endocytosed ovalbumin (OVA)-containing IgG-liposomes, but not OVA-containing bare liposomes or soluble OVA, completely prevented the growth of OVA-expressing lymphoma cells. These results suggest that IgG-liposomes represent an efficient antigen delivery carrier for DCs in cancer immunotherapy.

Accumulation of protein-bound uraemic toxins (PBUTs) is one of the reasons for the development of uraemia-related complications including cardiovascular disease; however, conventional haemodialysis is limited in its ability to remove PBUTs. We aimed to examine whether the oral charcoal adsorbent AST-120 has an additive effect on PBUT removal in haemodialysis patients. During the 4-week study, anuric patients undergoing haemodialysis received AST-120 (6 g/day) in the last 2 weeks (n = 10) or the first 2 weeks (n = 10). Serum levels of total and free PBUTs such as indoxyl sulfate, p-cresyl sulfate and phenyl sulfate at the pre- and postdialysis sessions were measured before and after AST-120 use and after discontinuation. Levels of the oxidative stress markers oxidized albumin and 8-isoprostane were also measured. AST-120 use induced dramatic reduction of indoxyl sulfate (total, 45.7% [33.2–50.5%]; free, 70.4% [44.8–79.8%]), p-cresyl sulfate (total, 31.1% [25.0–48.0%]; free, 63.5% [49.3–70.9%]) and phenyl sulfate (free, 50.6% [32.3–71.2%]) levels; however, this effect disappeared after the discontinuation of AST-120. AST-120 use also induced substantial reduction of the oxidized albumin and 8-isoprostane levels. In conclusion, oral administration of AST-120 had additive effects on the continuous reduction of some PBUTs in anuric patients undergoing haemodialysis.

One of the possible causes of enhanced atherosclerosis in patients with chronic kidney disease (CKD) is the accumulation of uremic toxins. Since macrophage foam cell formation is a hallmark of atherosclerosis, we examined the direct effect of indoxyl sulfate (IS), a representative uremic toxin, on macrophage function. Macrophages differentiated from THP-1 cells were exposed to IS in vitro. IS decreased the cell viability of THP-1 derived macrophages but promoted the production of inflammatory cytokines (IL-1β, IS 1.0 mM: 101.8 ± 21.8 pg/mL vs. 0 mM: 7.0 ± 0.3 pg/mL, TNF-α, IS 1.0 mM: 96.6 ± 11.0 pg/mL vs. 0 mM: 15.1 ± 3.1 pg/mL) and reactive oxygen species. IS reduced macrophage cholesterol efflux (IS 0.5 mM: 30.3% ± 7.3% vs. 0 mM: 43.5% ± 1.6%) and decreased ATP-binding cassette transporter G1 expression. However, lipid uptake into cells was not enhanced. A liver X receptor (LXR) agonist, T0901317, improved IS-induced production of inflammatory cytokines as well as reduced cholesterol efflux. In conclusion, IS induced inflammatory reactions and reduced cholesterol efflux in macrophages. Both effects of IS were improved with activation of LXR. Direct interactions of uremic toxins with macrophages may be a major cause of atherosclerosis acceleration in patients with CKD.

Liposomes represent a promising vehicle to deliver exogenous antigens to dendritic cells (DCs) for tumor immunotherapy. Targeting exogenous antigens to Fcgamma receptors on DCs has been shown to result in efficient presentation of antigen-derived peptides on major histocompatibility complex (MHC) class I and class II molecules. In this study, it was investigated whether DCs that endocytosed physicochemically optimized antigen-containing liposomes conjugated with IgG efficiently present antigens on MHC class I and class II molecules, and consequently induce strong antitumor immune responses. IgG-conjugated liposomes that were 200 nm in diameter without attaching polyethylene glycol were most efficiently endocytosed by DCs. Human monocyte-derived DCs that endocytosed tetanus toxoid (TT)-containing IgG liposomes via CD32 stimulated CD4(+) T cells more strongly than DCs pulsed with TT-containing bare liposomes or with soluble TT. Immunization of mice with DCs that endocytosed ovalbumin (OVA)-containing IgG liposomes but not OVA-containing bare liposomes or soluble OVA completely prevented the growth of OVA-expressing lymphoma cells. Importantly, administration of DCs that endocytosed OVA-containing IgG liposomes to the mice with established OVA-expressing tumors strongly suppressed tumor growth. This study demonstrates an IgG liposome with physicochemical properties suitable for delivering antigens to DCs and paves the way to the application of IgG liposomes for tumor immunotherapy using DCs.

It is not clear whether there is a dose-response relationship between the number of cigarettes smoked per day and CRP level and whether there is a relationship between the length of smoking cessation and CRP level.Geometric mean levels of CRP were compared in smoking status groups for 1926 men aged 40 to 69 years using analysis of covariance.After adjusting for several confounding factors, geometric mean levels of CRP (mg/L) were significantly different among the three smoking status groups (0.41 in non-smokers, 0.57 in current smokers, 0.48 in past smokers, P0.05). A linear trend was not found in the relationship between CRP level and number of cigarettes smoked per day. The mean CRP level in the long cessation (or =5 years) group was significantly lower than that in the short cessation (5 years) group (0.45 vs. 0.58, P0.05) and similar to that in the non-smokers group (0.45 vs. 0.41, NS).CRP levels in current smokers are elevated but unrelated to the number of cigarettes smoked per day. In past smokers, long-term smoking cessation may contribute to the reduction in risk of development of cardiovascular diseases through inflammatory mechanisms.

Bone marrow cells contribute to regeneration of damaged glomerular endothelial cells. Background There is accumulating evidence that adult bone marrow (BM) cells show unexpected plasticity, and can differentiate into a wide range of specialized cells. In the case of intrinsic renal glomerular cells, BM-derived cells have been reported to differentiate into both mesangial cells and podocytes. However, there is controversy on recruitment of glomerular endothelial cells, although endothelial cells in other tissues are known to be recruited from the BM. Methods Sprague-Dawley (SD) rats and SD rats made chimeric by transplantation of bone marrow cells from enhanced green fluorescent protein (EGFP) transgenic littermate rats, were injected with anti-Thy-1.1 antibody, followed by unilateral nephrectomy (1-kidney model). Chimeric rats used in 1-kidney model were sacrificed for histologic examination at weeks 2, 4, 8, and 11. We examined isolated glomeruli and frozen sections of kidneys from rats of each group at weeks 2 and 11 by confocal laser scan microsopy (CLSM), both immunohistologically and three dimensionally. Results In the 1-kidney group, using chimeric rats transplanted with EGFP(+) bone marrow cells, most rats died, presumably of uremia, after 8 to 11 weeks. A CLSM study using isolated glomeruli and frozen sections of kidneys revealed that bone marrow-derived PECAM-1(+), RECA-1(+) cells, and OX-7(+) cells contributed to the structural support for the glomerular capillaries during the chronic course. Global glomerular sclerotic lesions and diffuse tubular atrophic changes, with interstitial cell infiltration, were remarkable at weeks 8 and 11. Conclusion Bone marrow–derived endothelial progenitor cells participated in glomerular endothelial cell turnover after severe damage. Treatment that could target bone marrow–derived endothelial progenitor cells and promote angiogenesis in regions of progressive glomerular lesions may be a promising therapeutic approach for preventing end-stage renal disease.

今回, われわれは電解質分析装置STAX-3の日常の管理方法およびその問題点を, 標準血清およびコントロール血清を用いて検討した. STAX-3におけるNa+, K+およびCl-測定の日差再現性は, 変動係数が標準血清では0.8%以内, コントロール血清では1.1%以内であり, 良好な結果であったが, コントロール血清は標準血清と比較し, やや安定性が低かった. これらの結果より, 日常の管理には標準血清より価格の安いコントロール血清を用い, 装置の保守点検後およびコントロール血清を用いた日常管理で異常を示した場合, その確認のために, 理論値が表示されており, より安定である標準血清を用いることが適切と思われた. また, データ保証のためにはコントロール血清の選択と取扱い, および装置の設置環境に留意し, 管理を行うことが必要である.

Despite significant therapeutic advances, mortality of dialysis patients remains unacceptably high. The aim of this study is to compare mortality and its causes in dialysis patients with those in the general Japanese population. We used data for 2008 and 2009 from the Japanese Society for Dialysis Therapy registry and a national Vital Statistics survey. Cardiovascular mortality was defined as death attributed to heart failure, cerebrovascular disorders, myocardial infarction, hyperkalemia/sudden death, and pulmonary thromboembolism. Non-cardiovascular mortality was defined as death attributed to infection, malignancies, cachexia/uremia, chronic hepatitis/cirrhosis, ileus, bleeding, suicide/refusal of treatment, and miscellaneous. We calculated standardized mortality ratios and age-adjusted mortality differences between dialysis patients and the general population for all-cause, cardiovascular versus non-cardiovascular, and cause-specific mortality. During the 2-year study period, there were 2,284,272 and 51,432 deaths out of 126 million people and 273,237 dialysis patients, respectively. The standardized mortality ratio for all-cause mortality was 4.6 (95% confidence interval, 4.6-4.7) for the dialysis patients compared to the general population. Age-adjusted mortality differences for cardiovascular and non-cardiovascular disease were 33.1 and 30.0 per 1000 person-years, respectively. The standardized mortality rate ratios were significant for all cause-specific mortality rates except accidental death. Our study revealed that excess mortality in dialysis patients compared to the general population in Japan is large, and differs according to age and cause of death. Cause-specific mortality studies should be planned to improve life expectancies of dialysis patients.

Infectious disease is the second leading cause of death among dialysis patients, and it is generally assumed that the mortality rate of infectious disease is considerably higher in dialysis patients than in the general population. There are no comprehensive studies on this issue and on the contribution of each category of infectious disease to excess mortality in dialysis patients in Japan. We used mortality data reported to the Japanese Society for Dialysis Therapy and national Vital Statistics data for 2008 and 2009. We calculated standardized mortality ratios and compared the mortality rates for each category of infectious disease. During the 2-year study period, 274,683 and 10,435 deaths from infectious diseases were recorded in 126 million people and 273,237 dialysis patients, respectively. The standardized mortality ratio for all infectious diseases was 7.5 (95% confidence interval, 7.3-7.6) in dialysis patients with respect to the general population in Japan. The categories of infectious disease with a significantly higher standardized mortality ratio among the dialysis patients were sepsis, peritonitis, influenza, tuberculosis, and pneumonia and in that order. In particular, the mortality rate of sepsis contributed to 69.5% of the difference in infectious disease mortality between dialysis patients and the general population. This study underlines markedly increased mortality from infectious diseases, particularly from sepsis, in dialysis patients compared with the general population.

Background: It is not known whether chronic or past hepatitis C virus (HCV) infection contributes to the high mortality rate in hemodialysis patients.Methods: This prospective study of 1077 adult hemodialysis patients without hepatitis B virus infection used Poisson regression analysis to estimate crude and sex- and age-adjusted rates (per 1000 patient-years) of all-cause, cardiovascular, infectious disease-related and liver disease-related mortality in patients negative for HCV antibody (group A), patients positive for HCV antibody and negative for anti-HCV core antigen (group B), and patients positive for anti-HCV core antigen (group C). The relative risks (RRs) for each cause of death in group B vs group C as compared with those in group A were also estimated by Poisson regression analysis after multivariate adjustment.Results: A total of 407 patients died during the 5-year observation period. The sex- and age-adjusted mortality rate was 71.9 in group A, 80.4 in group B, and 156 in group C. The RRs (95% CI) for death in group B vs group C were 1.23 (0.72 to 2.12) vs 1.60 (1.13 to 2.28) for all-cause death, 0.75 (0.28 to 2.02) vs 1.64 (0.98 to 2.73) for cardiovascular death, 1.64 (0.65 to 4.15) vs 1.58 (0.81 to 3.07) for infectious disease-related death, and 15.3 (1.26 to 186) vs 28.8 (3.75 to 221) for liver disease-related death, respectively.Conclusions: Anti-HCV core antigen seropositivity independently contributes to elevated risks of all-cause and cause-specific death. Chronic HCV infection, but not past HCV infection, is a risk for death among hemodialysis patients.

Aim: To examine and compare the predictive value of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TC/HDL-C and LDL-C/HDL-C ratios for future cardiovascular outcomes in the general Japanese population.Methods: A total of 24,566 eligible participants aged 18 years or older, without cardiovascular disease, were enrolled through multiphase health screening and divided into quartile groups based on lipoprotein levels or ratios. Primary endpoints of the study were definitive acute myocardial infarction (AMI) and ischemic stroke, and cases of sudden death with unknown causes were not included. We used Cox proportional hazard models to examine the relationships between the quartiles and incidences of AMI or ischemic stroke, adjusting for traditional risk factors.Results: Mean age was 63.7 years for males and 60.7 years for females. Mean follow-up period was 2.7 years, and 40 cases of AMI and 182 cases of ischemic stroke were recorded. The hazard ratio (HR) for AMI was significantly higher in the top quartile of the LDL-C/HDL-C ratio and LDL-C levels, and third quartile of TC among male participants. The HR of male participants with a LDL-C/HDL-C ratio of 2.6 or higher was significantly higher than other quartiles. No association between lipoprotein levels or their ratio quartiles and ischemic stroke was seen for either sex after adjusting for risk factors.Conclusions: Our results indicated that the LDL-C/HDL-C ratio is an independent predictor for AMI, and the importance of better management of cardiovascular risks among people with high LDLC/HDLC ratios for the prevention of future cardiovascular disease.

Objective The purpose of this study was to evaluate the association between homebound status and newly certified need of care among elderly in a rural community and to clarify the characteristics of those in homebound status. Methods The Iwate-KENpoku COhort (Iwate-KENCO) study (26,469 participants) spanned the period from 2002 to 2004 and was conducted in northern Iwate Prefecture, Japan. In the present study, 12,056 elderly (men, 4,751; women, 7,305) participated after being screened for eligibility (> or =65 years of age; without certification for need of care; and without a history of stroke, cardiac heart failure, or ischemic heart disease). Being homebound was operationally defined as walking outdoors for less than 5 minutes per day. Cox's proportional hazard model was used to estimate the hazard risk (HR) for newly certified need of care and the 95% confidence interval (95% CI) after controlling for confounding factors by gender. Results After a mean follow-up period of 2.65 years, 200 men (4.2%) and 412 women (5.6%) obtained certification for need of care. Homebound status was significantly associated with newly certified need of care in women (HR=1.64, 95%CI=1.29-2.09), but not in men (HR=1.07, 95%CI=0.76-1.52). Homebound status among elderly women was associated with nutritional status, missing teeth, and irregular daily rhythms. Conclusion These findings suggest that being homebound is a risk factor for elderly women receiving certification for need of care.

Objective Structural heart diseases including atrial fibrillation are precursors for ischemic stroke. Plasma B-type natriuretic peptide (BNP) has been reported to be increased in patients with several types of structural heart diseases. However, the predictive value of plasma BNP for ischemic stroke remains unknown. We have studied the predictive ability of plasma BNP for future development of stroke in community dwelling adults. Methods Subjects of this community-based study were recruited from the general population (n = 13,466). Plasma BNP levels and cardiovascular risk factors were determined at baseline. The incidence of ischemic stroke in the cohort was identified from regional stroke registry data. A multivariate Cox regression analysis was performed to analyze the relationship between plasma BNP levels and the risk of stroke. Results During a mean follow-up period of 2.8 years, 102 participants (65 males, 37 females) experienced a first ischemic stroke. In men, after adjustment for classical cardiovascular risk factors and atrial fibrillation, the hazard ratio (HR) for ischemic stroke was significantly elevated in the highest plasma BNP quartile (HR = 2.38; 95% CI = 1.07–5.29). In women, the relationship between plasma BNP levels and risk of ischemic stroke was of marginal significance after adjusting for the presence or absence of atrial fibrillation (HR = 3.03; 95% CI = 0.84–10.92, P = 0.09). Conclusion Elevated plasma BNP levels predict the risk of ischemic stroke within men from the general population.

Elevated plasma B-type natriuretic peptide (BNP) levels have been reported to be a marker for risk of cardiovascular events (CVE) including heart failure, coronary artery disease and stroke in the general population. However, plasma BNP is increased by renal dysfunction, and it is therefore not known whether plasma BNP might be a reliable biomarker for predicting onset of CVE in the cohort with impaired renal function as represented by chronic kidney disease (CKD). Baseline data including plasma BNP, serum creatinine, and urine protein were determined in 14265 participants from a community-based population. Estimated glomerular filtration rate (eGFR) was calculated using a modified MDRD equation, and CKD was defined by the following two methods (Def 1 = eGFR2 and/or proteinuria; Def 2 = eGFR2 ). Numbers of CKD subjects were 1927 according to Def 1 and 1604 according to Def 2. CVE endpoint was surveyed prospectively. The mean follow-up duration was 2.9 years. After adjustment for traditional cardiovascular risk factors and atrial fibrillation, relative risk (RR) for CVE was significantly higher in the highest BNP quartile compared to the lowest BNP quartile according to both definitions (Def 1, RR=3.51, p ). Furthermore, the RR for a composite endpoint of CVE and death was also significantly higher in the highest BNP quartile, again by both definitions (Def1, RR=2.71, p

Background High C-reactive protein (CRP) levels have been reported to be associated with an increased risk of atherosclerotic cardiovascular events. The relationship of CRP levels to the risk of cerebrovascular events in the Japanese population, which has a lower prevalence of coronary artery disease and a lower CRP level than Western populations, has not been fully clarified. The present study examined the predictive value of serum high sensitivity CRP (hs-CRP) levels for future cerebrovascular events and mortality in the general Japanese population. Methods The subjects for this community-based, prospective cohort study were recruited from the general population (n = 7901, male only, mean age = 64.0 years). Serum hs-CRP levels and cardiovascular risk factors were determined at baseline. The mean follow-up period was 2.7 years. After excluding subjects with a cardiovascular history, the relationships between hs-CRP levels and cerebrovascular events and mortality were assessed. Results During follow-up, 130 participants had a first stroke (95 ischemic strokes), and 161 participants died. The hs-CRP tertile level was a significant predictor for a first ischemic stroke (3rd tertile, HR = 1.77: 95% Cl, 1.04–3.03, compared with the 1st tertile), after adjustment for age and classical cardiovascular risk factors. Similar trends were observed for the prediction of all-cause mortality (3rd tertile, HR = 2.26: 95% Cl, 1.49–3.42, compared with the 1st tertile). Conclusion CRP levels can be used to predict future ischemic stroke and mortality in Japanese men from the general population, independently from traditional cardiovascular risk factors.

To examine whether dietary intake of n-3 polyunsaturated fatty acid (n-3PUFA) is associated with serum C-reactive protein (CRP) levels with regard to smoking status in the Japanese general population in a cross-sectional study.A total of 14,191 participants aged 40-69 years were enrolled and divided into quartile groups according to their intake of n-3PUFA. Multivariate-adjusted logarithm-transformed CRP levels were compared between the quartile groups with regard to smoking status after adjusting for traditional risk factors and intake of saturated fatty acids. Adjusted CRP levels were inversely associated with dietary intake of n-3PUFA for both the male subjects and female subjects (p0.05 for trend). A linear trend was not seen between intake of n-3PUFA and adjusted CRP levels in male nonsmokers. Adjusted CRP level in the lowest quartile group of n-3PUFA was significantly higher than the levels in other groups in male smokers.Sufficient dietary intake of n-3PUFA may attenuate inflammatory reaction and this effect is more evident among high-risk populations such as male smokers although the small numbers of female ex-smokers and nonsmokers limited statistical power to draw strong conclusions about these groups.

There is increasing evidence that changes of glomerular hemodynamics or glomerular growth responses may promote the development of glomerulosclerosis. Major problems retarding research progress include lack of suitable experimental animal models, with the exception of the ablation model, and the need for in vivo real-time analysis of glomerular hemodynamics. This study examined the sequence of pathological changes from the viewpoints of microcirculation and histopathology, from the acute stage to the chronic course and the final stage of glomerulosclerosis, using the confocal laser scanning microscope system. There is a marked difference in prognosis between sham-operated (two-kidney) and nephrectomized (one-kidney) rats after injection with anti-Thy-1 antibody. The former reversibly returns to normal and the latter irreversibly go to progressive sclerosis, respectively. The turning point determining the progression of glomerulosclerosis in both groups seemed to be the period from 7 to 14 days after disease induction, when disturbance of local intraglomerular blood flow continued in the one-kidney groups. In conclusion, this study provides the first hemodynamic-based evidence showing that disturbance of intraglomerular microcirculation is a critical marker for progressive glomerulosclerosis.

Immune responses to pathogens need to be maintained within appropriate levels to minimize tissue damage, whereas such controlled immunity may allow persistent infection of certain types of pathogens. Interleukin 10 (IL-10) plays an important role in such immune regulation. We previously showed that HSV-stimulated human plasmacytoid dendritic cells (pDCs) induced naive CD4+ T cells to differentiate into interferon γ (IFN-γ)/IL-10–producing T cells. Here we show that HSV-stimulated pDCs induce allogeneic naive CD4+ T cells to differentiate into cytotoxic regulatory T cells that poorly proliferate on restimulation and inhibit proliferation of coexisting naive CD4+ T cells. IL-3–stimulated pDCs or myeloid DCs did not induce such regulatory T cells. Both IFN-α and IL-10 were responsible for the induction of anergic and regulatory properties. High percentages of CD4+ T cells cocultured with HSV-stimulated pDCs, and to a lesser extent those cocultured with IL-3–stimulated pDCs, expressed granzyme B and perforin in an IL-10–dependent manner. CD4+ T cells cocultured with HSV-stimulated pDCs accordingly exhibited cytotoxic activity. The finding that virus-stimulated pDCs are capable of inducing CD4+ cytotoxic regulatory T cells suggests that this DC subset may play an important role in suppressing excessive inflammatory responses and also in inducing persistent viral infection.

Real-time observation of glomerular hemodynamic changes in diabetic rats: Effects of insulin and ARB. Background The progression of diabetic nephropathy is closely related to disturbances in glomerular hemodynamics, such as glomerular hypertension and/or hyperperfusion. The aim of this study was to observe and to analyze glomerular hemodynamics in rats with diabetes mellitus (DM) in vivo using confocal laser scan microscopy (CLSM). We also examined the effects of candesartan cilexetil (TCV-116), a selective angiotensin II type 1 receptor blocker (ARB), on glomerular hemodynamics in DM. Methods Munich-Wistar rats were divided into six groups: (1) four-day control; (2) four-day DM; (3) 28-day control; (4) 28-day DM; (5) DM treated with insulin; (6) DM treated with TCV-116. The kidney-to-body weight ratio, glomerular volume, and proteinuria were estimated. Glomerular hemodynamic changes were observed using CLSM and renal expression of endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) was evaluated by immunofluorescence. Results The kidney-to-body weight ratio, glomerular volume, the diameters of afferent arterioles (AA) and efferent arterioles (EA), erythrocyte velocities within glomeruli, and volume flow in glomerular capillary loops in four-day DM were significantly higher than in control rats, and increases were even more pronounced in the 28-day DM. TCV-116 treatment ameliorated all these findings and significantly decreased proteinuria, but there was no effect on the blood glucose level. On the other hand, insulin treatment was followed by normalization of all these changes induced in DM. Enhanced renal expression of eNOS in DM was suppressed when treated with either TCV-116 or insulin, while expression of nNOS was unaltered among the four groups. Conclusion This imaging procedure allowed us to evaluate glomerular microcirculation in vivo, including the diameters of AA and EA, erythrocyte velocity, and volume flow. DM significantly induced glomerular hemodynamic alteration and renalhypertrophy. DM treated with either insulin or ARB ameliorated these changes. This study shows that progress in imaging technology promises to make major contributions to revealing the involvement of hemodynamic changes in glomerular diseases, aiding prognosis and the monitoring of therapeutic effects, as well. hypertrophy. DM treated with either insulin or ARB ameliorated these changes. This study shows that progress in imaging technology promises to make major contributions to revealing the involvement of hemodynamic changes in glomerular diseases, aiding prognosis and the monitoring of therapeutic effects, as well.

Amyloid light-chain (AL)-type amyloidosis is a plasma cell disorder with a poor prognosis for survival. Although prognostic factors, such as the number of organs involved and heart function or failure in respond to therapy have been clarified based on studies including a large series of patients, there are large interindividual differences in the prognosis of patients with primary AL-type renal amyloidosis.To clarify the prognostic factors of AL-type renal amyloidosis, we retrospectively investigated the clinical manifestations, histopathological data, and prognosis of 21 patients with amyloidosis, who had been diagnosed by renal biopsy.Eleven patients died, at a mean observational time of 21.7 months after renal biopsy, whereas the mean observational time was 51.0 months for the 10 patients who survived. The creatinine clearance rate was significantly higher, and the serum creatinine concentration and the grade of interstitial damage were significantly lower in surviving patients (P0.05). The presence of amyloid fibrils in organs other than the kidney did not influence prognosis for survival. However, the intraventricular septum was thinner in surviving patients (P0.1). Thirteen patients had undergone melphalan-prednisolone therapy, but it did not affect prognosis for survival. Cox proportional hazard regression analysis revealed that the renal function at the time of diagnosis was a significant and independent prognostic factor for survival.Our study demonstrated that renal function at the time of biopsy and renal interstitial damage are the best predictors of survival in AL-type renal amyloidosis.

A change in intracellular Ca 2+ is considered to be the common final signaling pathway through which renin secretion is governed. Therefore, information relating to the generation, control, and processing of Ca 2+ signaling in juxtaglomerular cells (JG) will be critical for understanding JG cell behavior. In this study, we investigated the means by which JG cells harmonize their intracellular Ca 2+ signals and explored the potential role of these mechanisms in renin secretion. Mechanical stimulation of a single JG cell initiated propagation of an intercellular Ca 2+ wave to up to 11.9±4.1 surrounding cells, and this was prevented in the presence of the ATP-degrading enzyme, apyrase (1.7±0.7 cells), or by desensitization of purinergic receptors via pretreatment of cells with ATP (1.8±0.9 cells), thus implicating ATP as a mediator responsible for the propagation of intercellular Ca 2+ signaling. Consistent with this, JG cells were demonstrated not to express the gap junction protein connexin43, and neither did they possess functional gap junction communication. Furthermore, massive mechanical stretching of JG cells elicited a 3-fold increase in ATP release. Administration of ATP into isolated perfused rat kidneys induced a rapid, potent, and persistent inhibition of renin secretion, together with a transient elevation of renal vascular resistance. ATP (1 mmol/L) caused up to 79% reduction of the renin secretion activated by lowering the renal perfusion flow ( P 2+ signals.

We performed simultaneous angioscopy and intravascular ultrasound imaging (IVUS) to evaluate the luminal changes of cardiac chambers, valves and vessels in patients with various categories of cardiovascular disease. We observed cardiac chambers in 7, coronary arteries in 3, aortic valve in 6, aorta in 10, vena cava in 2, pulmonary arteries in 3 and femoral arteries in 5 pts. The angioscopy was suitable for detection of the changes in color and for 3D evaluation of small changes. The IVUS was suitable for detection of calcified tissues and for evaluation of cardiac and vessel wall structures. Furthermore, we could observe dynamic motion of the cardiac valves by the IVUS. The results indicate that simultaneous observation by IVUS and angioscopy gives us much more information on the cardiovascular changes.

Percutaneous transluminal coronary angioplasty (PTCA) was performed on 12 patients with angina pectoris. PTCA reduced the percentage of stenosis of the coronary artery from 75.6 +/- 10.1 (means +/- SD) to 32.6 +/- 19.5. In addition, anginal attacks per week was reduced from 8.4 +/- 3.2 to 2.5 +/- 0.7. No life-threatening complications were produced by PTCA. The results indicates the effectiveness of PTCA as a treatment for angina pectoris.

第I報に記載したように,日本で分離された仮性結核菌は,血清学的に5型に分類されるほか,どの菌型にも属さない菌株が3株存在する.この菌株は,越智らによりI型に分類されたものである.また,越智らの分類によるV型は,VおよびV′型の2亜型に細分されているが,外国では,V型がさらに亜型に細分をされるという報告はない.本試験は,型別不能の3株の性状と,V型に属する菌株の亜型について,検討するために行なわれた.1.型別不能株の性状a.マウスに対し,1株(#l)は弱い病原性を示したが,他の2株(#3および#14)は,ほとんど病原性を示さなかった.モルモットに対しては,3株とも,1mgの腹腔内接種で病原性を示さなかった.b.生物学的性状およびファージ感受性については,3株とも仮性結核菌の性状を有し,Yersiniaenterocoliticaとは区別される.c.血清学的に,既知の菌型に知られていない〇一抗原を保有した.この抗原をO-13とし,新しい菌型としてVI型に分類した.2.V型菌の細分a.V型菌は,AおよびBの亜型に細分された.両者はそれぞれ共通の〇一抗原と,亜型特異抗原を有する.共通抗原を,従来v型に知られているO-10とし,VA型の特異抗原を,0-14,およびVB型の特異抗原をO-15とした.b.この分類に従えば,フランスから送られたV型菌は,VA型に属する.本試験の結果,仮性結核菌はIA,IB,IIA,IIB,III,IVA,IVB,VA,VBおよびVI型の10型に分けられ,〇一抗原には,O-2からO-15までの14因子が明らかになった.

Coronary luminal changes induced by percutaneous balloon or laser coronary angioplasty were examined angioscopically in 10 patients with ischemic heart disease. A fiberscope (2.6F to 5.3F) was introduced into the coronary artery with the use of a guiding catheter with or without a balloon at the tip. Angioscopy was successful before angioplasty in nine and after angioplasty in 10 of 11 coronary segments. Before angioplasty, the stenotic segments were composed of yellowish or whitish atheromatous plaques with smooth surfaces or spiral folds in patients with stable angina pectoris. In one patient with unstable angina pectoris, the stenotic segment was scalloped angiographically and showed an irregular and whitish plaque angioscopically. After angioplasty, endothelial exfoliation with scattered thrombi (10 segments), bellows-like folds (two), longitudinal cleft (one), plaque rupture (two), and intimal dissection (two) could be identified angioscopically. These changes, with the exception of dissection, could not be identified angiographically. In one patient who underwent thermal argon laser angioplasty, the dilated segment appeared brownish, which indicated carbonization. In one patient with acute myocardial infarction, the occlusive thrombi were vaporized by thermal laser angioplasty. The results demonstrate the clinical feasibility of percutaneous angioscopy for pathologic documentation of coronary luminal changes before and after angioplasty.

欧州では,各種動物における仮性結核菌の感染が多い.人においても,いわゆるチフス型の症例は減少したが,それに代って,腸間膜リンパ節炎(虫垂炎型)が増加している.日本をはじめ欧州諸国以外の国では,本菌の感染については,あまり注目されていない.著者らは,日本における本菌の分布を,文献に従って調査するとともに,血清学的分類を行なった.成績を要約すれば,以下の通りである.1. これまでに公表されたものと,未公表の分離成績によれば,人1,サル5,ブタ3,ヤギ2,ウサギ23,およびモルモット14株,計48株が分離されている.これは欧州各国の分離成績より著しく少数である.一方,由来においても,欧州に多く見られる鳥類からの検出については,報告がない.2.40株について血清学的型別を行なった結果,I型9株(22.5%),11型1株(2.5%),I1型3株(7.5%),Iv型9株(22.5%),V型15株(37.5%)および型別不能3株(7.5%)に分類された.I,IIおよびIv型の亜型は,すべてB型であった.3. ウサギおよびモルモット由来菌は,それぞれ5および4菌型が検出された.IおよびIV型菌は,宿主間に広く分布している.4.越智らにより分類されている菌型と,既知の菌型との関係を明らかにしたくTable4).