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Deterioration of adipocyte function due to increased oxidative stress predisposes patients to metabolic disorders in advanced age. However, the roles of tumor suppressors in such conditions remain largely unknown. Therefore, we aimed to address their dynamics in aged adipocytes using a long-term culture model. We compared 3T3-L1 adipocytes at 17–19 days (long-term) with those at 8–10 days (short-term) after initiation of adipogenic induction for mimicking ‘aged’ and ‘young’ adipocytes, respectively. H2O2 release and dihydroethidium (DHE) staining was increased, while superoxide dismutase (SOD) activity was reduced in long-term cultured adipocytes, which is suggestive of enhanced oxidative stress in this group. Moreover, qRT-PCR revealed increased mRNAs of Nox4 (a subunit of NADPH oxidase complex), Ccl2 (a proinflammatory chemokine) and Il6 [a marker of senescence-associated secretory phenotype (SASP)] along with decreased levels of Pparγ, Adipoq and Slc2a4 (genes related to glucose metabolism). These alterations were associated with increased expression of the tumor suppressors alternate-reading-frame protein p19Arf (Arf) and p16Ink4a. However, silencing of Arf reduced mRNAs of Adipoq and Slc2a4 and enhanced release of Il6. The effect was opposite in Arf overexpressing adipocytes, which showed reduced superoxide production as assessed with DHE staining and SOD activity. Western blots showed that Arf negatively regulates the phosphorylation of Akt. Luciferase assay in Hela cells additionally suggested that Arf negatively regulates Il6 transcriptional activity through a PI3 K/Akt mediated pathway. These findings strongly suggest that the enhanced Arf expression in oxidative stress plays compensatory protective roles against aging-related dysregulation of gene expression in adipocytes.

Background: Many elderly patients are admitted to hospitals for pneumonia, and the mortality rate for such cases is high. However, few studies have analyzed in detail the causes of death in the elderly hospitalized due to pneumonia. Purpose: The study aimed to investigate the prognosis of elderly individuals hospitalized due to pneumonia from the viewpoints of mortality risk factors and causes of death. Methods: The subjects were patients aged 70 years or older who were admitted to our hospital for pneumonia from January 2015 to June 2017. A total of 442 cases (mean age; 83.1 years) were targeted for analysis after excluding patients with hospital-acquired pneumonia, patients who were transferred to another facility. A total of 58 patients died in the hospital. In addition to analyzing their causes of death, the following factors were compared with cases that showed improvement: altered mental status; blood pressure; saturation of oxygen (SpO2); age; length of hospital stay; body mass index (BMI); serum albumin (ALB) levels; serum urea nitrogen (UN) levels; serum C-reactive protein (CRP) levels. Results: The causes of death in the 58 patients were as follows: pneumonia (15 cases; 26%), frailty (12 cases; 21%), heart failure (7 cases; 12%), sepsis (5 cases; 9%), lung cancer (6 cases; 10%), non-lung cancers (4 cases), and other causes (9 cases). A logistic regression analysis revealed that BMI (OR 0.88; 95% CI: 0.8-0.97), altered mental status (2.23, 1.16–4.30), SpO2≤90% (2.16, 1.08–4.33), and ALB levels (0.34, 0.19–0.61) were independent mortality risk factors. Conclusions: It is insufficient to categorize pneumonia in elderly patients as simply an infectious disease.

Background The impact of nicorandil as adjunctive therapy for percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) is controversial. We performed 15O-labeled water positron emission tomography (PET) to quantify regional myocardial perfusion in patients with STEMI who received nicorandil or no adjunctive therapy during PCI. Methods PCI was performed within 8 h after STEMI onset in 33 patients. 14 patients received intracoronary nicorandil 2 mg immediately after recanalization of the culprit lesion (Nico group). After 3–4 weeks, PET was performed in which myocardial blood flow (MBF) was measured at baseline and during adenosine triphosphate (ATP)-induced hyperemia. Myocardial vascular resistance (MVR) was calculated for all segments. Data were obtained from the reperfused (Rep) and normal segments (Cont) in each patient. Results In patients not given nicorandil (No-Nico group), the MBF was significantly lower in Rep than that in Cont at baseline and during hyperemia (Cont vs. Rep: 0.82 ± 0.14 vs. 0.68 ± 0.11, P = 0.001, ATP-Cont vs. ATP-Rep: 2.00 ± 0.72 vs. 1.52 ± 0.61, P = 0.017), which was restored in the Nico group (Cont vs. Rep: 0.79 ± 0.17 vs. 0.78 ± 0.20; ATP-Cont vs. ATP-Rep: 2.02 ± 0.84 vs. 1.84 ± 0.62). MVR was elevated in Rep at baseline and during hyperemia in the No-Nico group. MVR elevation in Rep was prevented in the Nico group. Conclusions 15O-labeled water PET was feasible for segmental analysis of MBF during the subacute phase of STEMI. It revealed that intracoronary administration of nicorandil to STEMI patients who underwent PCI prevented MVR elevation and thus restored MBF in the reperfused segments to a level similar to that in the normal segments., Highlights • 15O-labeled water positron emission tomography (PET) is a tool to compare directly reperfused segments with normal segments simultaneously in each patient's hearts. • 15O-labeled water PET permits noninvasive quantitative measurement of myocardial blood flow during the subacute phase of myocardial infarction. • 15O-labeled water PET detects restoration of myocardial blood flow after intracoronary administration of nicorandil in STEMI patients.

Vascular endothelial growth factor-A (VEGF-A) released from adipocytes promotes angiogenesis; and thereby ameliorates the local hypoxia-induced adipose inflammation and insulin resistance. Here, we newly found that eicosapentaenoic acid (EPA) upregulated both mRNA expression and release of VEGF-A in mature 3T3-L1 adipocytes. Silencing mRNA of G-protein coupled receptor 120 (GPR120) and specific inhibition of peroxisome proliferator-activated receptor γ (PPARγ) by GW9662 respectively attenuated the EPA-induced augmentation of VEGF-A release by adipocytes. Furthermore, transfection of GPR120 gene alone and PPARγ gene alone to HEK293 cells respectively increased the promoter activity of VEGF-A as assessed by luciferase reporter assay, which was further augmented when both genes were co-transfected. Promoter deletion analysis and chromatin immunoprecipitation assay revealed that co-transfection of GPR120 enhanced EPA-induced PPARγ binding to PPAR-response element in VEGF-A promoter region. Thus, by the synchronized activation of a membrane receptor GRP120 and a nuclear receptor PPARγ, EPA enhances VEGF-A production in adipocytes.

Background Post-transplantation de novo and recurrent immunoglobulin A (IgA) deposition (IgAD) in the allograft is commonly observed. However, the association between post-transplantation IgAD and reduced allograft function has not been determined. We therefore investigated the association between reduced allograft function and post-transplantation IgAD using serial allograft biopsies. Methods IgAD was retrospectively analyzed in 45 adults who underwent kidney transplantation for chronic glomerulonephritis, including IgA nephropathy, at Kagawa University Hospital. Allograft biopsy samples were obtained from per protocol biopsies obtained 1 and 3 years after transplantation, as well as from episode biopsies. Factors contributing to post-transplantation IgAD were assessed by calculating adjusted odds ratios (AORs) using logistic regression analysis. Results Of the 45 recipients, 18 had post-transplantation allograft IgAD. The estimated glomerular filtration rates (eGFR) 1, 2, and 3 years after transplantation were lower in the recipients with than without IgAD. Urinalysis was normal in 61% of recipients with IgAD. Reduced allograft function (eGFR 2 ) 1 year after transplantation was significantly associated with post-transplantation IgAD (AOR = 34.4 [95% CI = 2.35–502], P = .01). Conversely, blood concentrations of mycophenolic acid and latent IgAD from donor kidneys were not significantly associated with post-transplantation IgAD. Conclusion Reduced allograft function may be associated with post-transplantation IgAD in the allograft.

How nutritional excess leads to inflammatory responses in metabolic syndrome is not well characterized. Here, we evaluated the effects of ω-3 polyunsaturated fatty acid specific G-protein coupled receptor 120 (GPR120) activation on inflammatory pathways in adipocytes, and the influence of this process on macrophage migration. Using 3T3-L1 adipocytes, we found that agonizing GPR120 using its synthetic ligand, GSK137647, attenuated both basal and lipopolysaccharide-induced production of interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2). Moreover, the intervention reduced the phosphorylation of nuclear factor kappa B inhibitor alpha (IκBα) and nuclear translocation of nuclear factor kappa-B p65 subunit (p65). Furthermore, the silencing of GPR120 itself reduced IL-6 and CCL2 mRNA expression. Inhibition of protein kinase C (PKC) augmented the down-regulatory effect of GSK137647 on IL-6 and CCL2 mRNA. Using a luciferase assay to measure promoter activity of the IL-6 gene in mouse embryonic fibroblasts, we demonstrated that exogenous transfection of GPR120 alone reduced the promoter activity, which was augmented by GSK137647. Inhibition of PKC further reduced the promoter activity. Nevertheless, RAW 264.7 macrophages grown in conditioned medium collected from GSK137647-treated adipocytes attenuated the expressions of matrix metalloproteinases-9 and -3, and tissue inhibitor of metalloproteinase-1. Conditioned medium also inhibited the lipopolysaccharide-induced migration of these macrophages. Taken together, these findings provide critical evidence that although GPR120 is associated with a PKC-mediated pro-inflammatory pathway, the direct inhibitory effects of GPR120 on the nuclear factor kappa B pathway are anti-inflammatory. Moreover, GPR120 activity can attenuate the adipocyte-mediated enhanced production of extracellular matrix-modulating factors in macrophages and can reduce their migration by a paracrine mechanism.

The urinary angiotensinogen (AGT) excretion rate could be a novel biomarker for the intrarenal activity of the renin-angiotensin system. Little is known about the circadian rhythm of AGT levels in plasma or urine. In this short article, making use of data in plasma and urine of healthy volunteers and patients with chronic kidney diseases, we first report that we were unable to find evidence for a circadian rhythm of AGT under any condition. Next we critically discuss to what degree elevated urinary AGT levels might be considered an independent biomarker that is not simply the non-specific consequence of proteinuria.

The cyclin-dependent kinase inhibitor p21 plays important roles in chronic renal disorders; however, its roles in response to acute renal stress are unclear. Here we evaluated p21 in acute kidney injury and ischemic preconditioning using wild-type and p21 knockout mice that underwent renal ischemia followed by reperfusion. The decline in renal function and histological changes were worse in the knockout than in wild-type mice. Ischemia/reperfusion increased p21 expression in the kidney of wild-type mice compared with sham surgery, suggesting p21 may confer tolerance to ischemia/reperfusion injury. We next tested whether p21 is associated with the protective effect of ischemic preconditioning, an established method to reduce ischemia/reperfusion injury. Ischemic preconditioning attenuated ischemia/reperfusion injury in wild-type but not p21-knockout mice. This preconditioning decreased the number of proliferating tubular cells before but increased them at 24 h after ischemia/reperfusion in the kidneys of wild-type mice. In p21-knockout mice, ischemic preconditioning did not change the number of proliferating cells before but decreased them after ischemia/reperfusion. Ischemic preconditioning increased renal p21 expression and the number of cells in the G1 phase of the cell cycle before ischemia/reperfusion compared with sham surgery. Thus, renal p21 is essential for the beneficial effects of renal ischemic preconditioning. Transient cell cycle arrest induced by ischemic preconditioning by a p21-dependent pathway seems to be important for subsequent tubular cell proliferation after ischemia/reperfusion.

Background. High-normal albuminuria (HNA) is an independent predictor of cardiovascular risk in the generalpopulation. Although hypertensive donor (HTD) candidates with HNA were considered acceptable donors by theAmsterdam Forum 2004, the transplant prognosis of HTDs with HNA has not been determined. Therefore, weinvestigated the transplant prognosis of HTDs with HNA.Methods. We retrospectively analyzed 52 adult living-donor kidney transplants performed at Kagawa UniversityHospital. HNA was defined as albuminuria of 15 to 30 mg/g Cr. Changes in kidney function of donors and recipientswere assessed up to 2 years after transplantation.Results. Overall, 38 donors were normotensive and 14 were hypertensive. Nine of 14 HTDs exhibited HNA beforedonation. More HTDs with HNA had arteriosclerotic vasculopathy or glomerulosclerosis than did normotensivedonors (NTDs). Hypertension and the degree of albuminuria did not affect the donors’ posttransplantation kidneyfunction. The risk of discompensatory changes in kidney function after donation was significantly higher in HTDswith HNA than in NTDs (odds ratio, 10.5; 95% confidence interval, 1.51Y72.9; P=0.02). In multivariate analysis, thecoexistence of hypertension and HNA was not significantly associated with discompensatory changes after donation(adjusted odds ratio, 6.04; 95% confidence interval, 0.19Y192; P=0.31). Recipients of HTDs with HNA had similarallograft survival rates but lower allograft function compared with recipients of NTDs.Conclusions. Although further studies are needed to confirm our results, the short-term prognosis of living-donorkidney transplantation was similar between HTDs with HNA and NTDs.Keywords: High-normal albuminuria, Hypertension, Living-donor kidney transplantation, Marginal donor,Preimplantation kidney biopsy.(Transplantation 2013;00: 00Y00)

Alpha2-macroglobulin is a protease inhibitor that enhances procoagulant properties via the neutralization of plasmin, plasminogen activators and metalloproteinases. Additionally, alpha2-macroglobulin is thought to be involved in inflammatory reactions as a carrier protein for interleukin-6 (IL-6). The objective of this study was to evaluate the usefulness of alpha2-macroglobulin as a biomarker for cerebrovascular diseases. Patients with acute ischemic stroke (n = 159; 93 male and 66 female, 71.6 ± 10.3 years) and patients with no previous history of stroke (n = 77; 38 male and 39 female, 70.7 ± 9.5 years) were consecutively enrolled in this study. White matter lesions were assessed via the fluid-attenuated inversion recovery image of magnetic resonance images using the Fazekas classification. The serum alpha2-macroglobulin levels were measured by nephelometry. The serum alpha2-macroglobulin levels at admission in patients with acute ischemic stroke were higher than those in the control patients (230.2 ± 73.7 vs. 205.0 ± 55.8 mg/dl, p = 0.009). The serum alpha2-macroglobulin levels were positively correlated with age and the severity of the white matter lesions (R (2) = 0.048, p < 0.001 and R (2) = 0.058, p < 0.001, respectively), although there was no significant association between serum alpha2-macroglobulin levels and IL-6 levels. In addition, multivariate analysis showed that increased serum alpha2-macroglobulin levels were independently associated with the severity of white matter lesions [standardized partial regression coefficient (β) 0.102, p = 0.026]. Increased serum alpha2-macroglobulin levels might be involved in the pathophysiology of acute ischemic stroke. Furthermore, serum alpha2-macroglobulin levels, which were associated with high-grade white matter lesions, may reflect the chronic pathophysiological condition of cerebral small vessel disease.

Excess fluid distribution is a common disorder in peritoneal dialysis (PD) patients. Tacrolimus malabsorption may also occur in PD patients, and may lead to acute allograft rejection after transplantation. The purpose of this study was to evaluate the relationship between tacrolimus pharmacokinetics and excess fluid distribution according to pre-transplant dialysis modality.We retrospectively analyzed 41 adult living-donor kidney transplantations, including nine PD patients and 32 hemodialysis (HD) patients. We examined tacrolimus pharmacokinetics in the peri-operative period and determined the association between the tacrolimus absorption rate and body weight reduction. The absorption efficacy of tacrolimus was evaluated as the dose-normalized tacrolimus absorption rate. Tacrolimus concentrations in PD effluent were measured by high-performance liquid chromatography.The tacrolimus absorption rate on the day before kidney transplantation tended to be lower in PD patients than in HD patients; however, the rate improved after kidney transplantation and was similar in both groups of patients. The peak tacrolimus concentration time was later in PD patients than in HD patients. The body weight reduction after kidney transplantation was greater in PD patients than in HD patients, and was significantly associated with the change in tacrolimus absorption rate (p=0.04, r=0.32). Only 0.002% of the oral tacrolimus dose was removed by PD itself.Excess fluid distribution in PD patients appears to contribute to tacrolimus malabsorption rather than PD itself. We should consider the risk of tacrolimus malabsorption in patients with possible excess fluid distribution, particularly in PD patients.

Vascular and cardiac valve calcification is associated with cardiovascular mortality in the general population. Increasing clinical and experimental evidence suggests that inflammation accelerates the progression of calcification, which has molecules in common with bone metabolism. For example, osteopontin (OPN), osteoprotegerin (OPG), receptor activator of the nuclear factor κB ligand (RANKL), and alkaline phosphatase (ALP) are proposed to play central roles in the calcification or demineralization of atherosclerotic lesions and the calcification of cardiac valves. Abnormalities in the balance of these proteins may lead to perturbations in vascular/valve calcification. "How to prevent calcification" is a common task based on conventional data; however, several pathological findings indicate that heavily calcified plaques are stable, which may not lead to coronary events. Vulnerable plaques tend to be either noncalcified or only mildly or moderately calcified. "How to treat calcification," which depends on the details of the specific patient, thus remains a difficult challenge. In addition to the detection of calcification, characterization as well as quantification of it is necessary for optimal treatment of this pathology in the future.

Morning hypertension is an independent risk factor for cardiovascular diseases, particularly stroke. However, the optimal time at which to take antihypertensive medication to treat morning hypertension remains unclear. We prospectively enrolled elderly patients (over 65 years old) with morning hypertension who had suffered an ischemic stroke (or strokes). Additional treatments (one of six arms) were randomly administered for 10 weeks in the morning, in the evening or at bedtime (n=15 for each time point/medication). The patients measured their blood pressure and heart rate at home for 14 days prior to the intervention and for the final 14 days, and recorded the data in a blood pressure diary. The patients' urinary albumin/creatinine ratios were evaluated before and after the 10-week intervention. A total of 270 patients were enrolled in this study (mean age: 75.6±5.8 years; female/male ratio: 125/145). Their morning and evening systolic blood pressures were significantly decreased after following any of the study medication dosing schedules (P

Background: Donor shortage is a serious problem worldwide and it is now debated whether kidneys from marginal donors are suitable for renal transplantation. Recent studies have shown that the findings of preimplantation kidney biopsy are useful to evaluate vasculopathy in the donated kidney, and may predict transplant outcomes in deceased- donor kidney transplantation. However, few studies have focused on the pathological findings of preimplantation biopsy in living-donor kidney transplantation. Therefore, we investigated whether arteriosclerotic vasculopathy in living-donor kidneys at the time of transplantation predicts the recipient’s kidney function (allograft function) later in life. Methods: We retrospectively analyzed 75 consecutive adult living-donor kidney transplants performed at Kagawa University Hospital. Renal arteriosclerotic vasculopathy was defined according to the presence of fibrous intimal thickening in the interlobular artery. Results: Forty-one kidneys exhibited mild arteriosclerotic vasculopathy on preimplantation kidney biopsies. The decreases in estimated glomerular filtration rate after donation were similar in donors with or without renal arteriosclerotic vasculopathy. Pre-existing arteriosclerotic vasculopathy did not affect graft survival rate, patient survival rate or the incidence of complications. Recipients of kidneys with arteriosclerotic vasculopathy had lower allograft function at 1 and 3 years after transplantation than the recipients of arteriosclerosis-free kidneys with or without donor hypertension. In multivariate analysis, fibrous intimal thickening on preimplantation biopsy was predictive of reduced allograft function at 1 year after transplantation. Conclusions: The present study demonstrated that mild arteriosclerotic vasculopathy in the donated kidney is an important pathological factor that reflects future impaired function of renal allografts from marginal donors.

Highlights: {yields} Mechanisms for preadipocyte hyperplasia by pioglitazone, a PPAR{gamma} agonist, are shown. {yields} Pioglitazone promotes cell-cycle of 3T3-L1 preadipocytes and increases their number. {yields} Pioglitazone downregulates a cyclin dependent kinase inhibitor, p16{sup Ink4a}. {yields} PPAR{gamma} transrepresses p16{sup Ink4a} gene in preadipocytes, which pioglitazone enhances. -- Abstract: Pioglitazone, a synthetic ligand of peroxisome proliferator-activated receptor (PPAR){gamma}, causes preadipocyte proliferation through a mechanism which still remains elusive. Here, to address the mechanism, we investigated the effects of PPAR{gamma} and pioglitazone on the kinetics of cyclin-dependent kinase inhibitors, especially with p16{sup Ink4a} (p16) centered, by employing 3T3-L1 preadipocytes. Pioglitazone promoted preadipocyte proliferation by increasing S and G{sub 2}/M cell-cycle entry, which was accompanied by decreased p16 mRNA expression. PPAR{gamma} overexpression along with the luciferase reporter assay confirmed that PPAR{gamma} was crucial for the downregulation of p16 mRNA transcription, and that the action was augmented by pioglitazone. Thus, pioglitazone exerted cell-cycle dependent promoting effect on preadipocyte proliferation, of which mechanisms include p16-downregulation through PPAR{gamma}.

Left ventricular (LV) hypertrophy (LVH) may be eccentric or concentric (2 × LV posterior wall thickness relative to LV end-diastolic dimension ≤ 0.42 or > 0.42, respectively). The LV diastolic function between age-matched hypertensive patients with eccentric and concentric LVH was compared in the present study. Echocardiography was used to measure LV mass index (LV mass/body surface area; LVMI) as an index of LVH. LV diastolic function was assessed by measurements of peak early transmitral flow velocity ( E)/peak late transmitral flow velocity ( A) (the E/A ratio), peak early diastolic mitral annular velocity ( e′) and the E/e′ ratio. Although LVMI, E/A and e′ did not differ between the two groups, E/e′ was significantly higher (worse) in patients with concentric LVH (13.4 ± 5.4) than in those with eccentric LVH (11.1 ± 3.6). Among hypertensive patients with LVH, those with concentric LVH may, therefore, have more severe LV diastolic dysfunction than those with eccentric LVH even if their LVMIs, which reflect the degree of LVH, are similar.

Although visit-to-visit variability in systolic blood pressure (SBP) has recently been demonstrated to be a strong predictor of stroke, there are no data about relationships between SBP variability and cardiac damage in hypertensive patients. We compared relationships between visit-to-visit variability in SBP and left ventricular (LV) diastolic dysfunction with the relationships between the mean SBP value and cardiac parameters in treated patients. Forty treated hypertensive patients (69 ± 9 years of age) had their blood pressure measured at outpatient clinics every 1 or 2 months over a 1-year period. The standard deviation (s.d.) of SBP and the difference between the maximum and minimum SBPs during this year were calculated to assess visit-to-visit variability. The mean SBP during the year was also calculated. LV diastolic function was assessed by the ratio (E/A) of early (E) and late (A) diastolic transmitral flows, early diastolic mitral annular velocity (e') and the ratio (E/e') of E to e' using Doppler echocardiography. E/A only correlated with the s.d. of SBP (r=-0.327, P=0.040), whereas e' correlated with s.d. of SBP (r=-0.496, P=0.001) and maximum-minimum SBP difference (r=-0.490, P=0.001). E/e' correlated with s.d. of SBP (r=0.384, P=0.014), maximum-minimum SBP difference (r=0.410, P=0.009), and the mean value of SBP (r=0.349, P=0.028). Multiple regression analysis demonstrated only the maximum-minimum SBP difference independently associated with E/e' (β=0.410, P=0.009). Thus, the visit-to-visit variability of SBP showed better correlation with LV diastolic dysfunction than mean values of SBP. High visit-to-visit variability of SBP was associated with LV diastolic dysfunction and may constitute a high risk for diastolic heart failure in hypertensive patients.

Although myocardial flow reserve (MFR) in congestive heart failure (CHF) has been reported to be impaired, the mechanism has not been fully shown in humans. Therefore, we performed positron emission tomography to measure myocardial blood flow (MBF) in patients with CHF and compared it with hemodynamic parameters. Sixteen normal coronary patients with CHF and ten normal controls were enrolled. 15O-labeled water positron emission tomography was performed at rest and during peak hyperemia induced by adenosine triphosphate. MFR was calculated as the ratio of peak hyperemic to baseline MBF. All CHF patients underwent cardiac catheterization. Baseline MBF was similar between CHF patients and normal controls (0.73 ± 0.25 vs. 0.80 ± 0.12 mL/min/g, p = NS). Hyperemic MBF was significantly reduced in CHF patients than in controls (1.68 ± 1.09 vs. 3.21 ± 0.69 mL/min/g, p < 0.05). therefore, MFR was significantly reduced in CHF patients than in controls (2.30 ± 1.30 vs. 4.03 ± 0.90, p < 0.05). There was no significant correlation between baseline MBF and either pulmonary capillary wedge pressure or left ventricular end-diastolic pressure, while both hyperemic MBF and MFR significantly correlated with both pulmonary capillary wedge pressure (r = −0.67 and r = −0.75, respectively) and left ventricular end-diastolic pressure (r = −0.51 and r = −0.60, respectively). Despite elevated preload, MBF at rest in CHF patients was compensated to the similar level as that in controls. However, this compensation may exhaust vasodilatory reserve in the failing human heart. Thus, preload at rest is a determinant of myocardial vasodilator reserve and preload reduction may ameliorate coronary vasodilator response in CHF patients.

We examined which echocardiographic parameter correlated best with plasma brain natriuteric peptide (BNP) levels in treated hypertensive patients. Enrolled in the study were 122 treated hypertensive patients (70 ± 9 y). The left ventricular mass index and left atrial dimension (LAD) were measured using echocardiography as indexes of left ventricular hypertrophy and left atrial enlargement, respectively. Among all the echocardiographic parameters, LAD correlated best with BNP (r = 0.343, p < 0.001). Stepwise regression analysis showed that LAD (β coefficient = 0.513, p < 0.001) was independently associated with BNP. Left atrial enlargement, rather than left ventricular hypertrophy, may be clinically useful for predicting elevated BNP levels in treated hypertensive patients.

Although increased blood–brain barrier (BBB) permeability is observed as a result of cerebral ischemia,1,2 disruption of the BBB has also been identified in other pathological conditions, such as multiple sclerosis.3 Furthermore, cerebrovascular abnormalities have been observed in cognitive disorders.4 BBB permeability increases with normal aging, and further increases in patients with vascular dementia,5 suggesting that BBB dysfunction is present from an early stage in patients exhibiting mild symptoms of cognitive impairment and minor cerebral microvascular diseases, such as lacunar stroke. Accumulating evidence has suggested a potential relationship between hypertension and the risk of cognitive impairment.6–8 For instance, the Honolulu-Asia Aging Study and other clinical studies have shown that high midlife systolic blood pressure is a significant predictor of reduced cognitive function in later life, as well as a risk factor for vascular dementia.6–8 Additionally, a strong relationship between average dietary sodium intake and mortality due to stroke and cardiovascular diseases risk has been determined.9,10 In spontaneously hypertensive rats and stroke-prone spontaneously hypertensive rats, a disturbed fence function of tight junctions (TJs) has been demonstrated in BBB endothelial cells.11,12 However, it remains unclear whether BBB disruption and cognitive impairment occur during development of salt-dependent hypertension. The brain renin–angiotensin system (RAS) plays an important role in the pathogenesis of cognitive impairment. Increased angiotensin II (AngII) levels result in impaired cognitive function in renin/angiotensinogen transgenic mice.13 Furthermore, treatment with an angiotensin receptor blocker (ARB) ameliorates the cognitive impairment in mice fed a high-salt and cholesterol diet, or type-2 diabetic mice.14,15 In addition, ARB treatment decreases BBB permeability in diabetic rats,16 which suggests that activation of the brain RAS is involved in the pathogenesis of cognitive impairment and BBB permeability in certain pathophysiological conditions. However, Hirawa et al.17 reported that long-term inhibition of RAS improves memory function in aged, low-salt treated, normotensive, Dahl salt-sensitive (DSS) rats. However, it has not been determined whether increased BBB permeability induced by inappropriate activation of brain RAS contributes to cognitive deficits observed during development of salt-dependent hypertension. Therefore, the present study tested the hypothesis that augmentation of BBB permeability and cognitive impairment are associated with inappropriate activation of the brain RAS during development of salt-dependent hypertension. To test this, BBB permeability was analyzed, as well as TJ expression, cognitive function, and the effects of an ARB at a subpressor dose, in DSS hypertensive rats.

Obesity is known to be associated with a number of effects on skin physiology. KKA(y) obese mouse is a model of type 2 diabetes characterized by systemic oxidative stress because of severe obesity, hypertriglyceridaemia, hyperglycaemia and hyperinsulinaemia. We investigated lipid peroxidation and vascular endothelial growth factor (VEGF) expression in the skin of KKA(y) obese mice. We also investigated the effect of lipid peroxidation derivatives on VEGF production and proliferation in human epidermal keratinocyte cell line (HaCaT). The lipid peroxidation level in the mouse skin tissue was determined by measuring the levels of thiobarbituric acid-reactive substances. The levels of VEGF expression, p44/p42 mitogen-activated protein kinase (MAPK) activation and CD36 expression were analysed by Western blot. Their localization was examined by immunofluorescence. For the in vitro experiments, an enzyme-linked immunosorbent assay was utilized to measure VEGF secretion in the medium. In vitro experiments demonstrated that lipid peroxidation derivatives increased VEGF production in HaCaT cells, which was blocked by a p44/p42 MAPK inhibitor and anti-CD36 antibody. We observed increased levels of lipid peroxidation derivatives, p44/p42 MAPK activation and VEGF expression in the skin of KKA(y) obese mice. Notably, pitavastatin, an inhibitor of competitive 3-hydroxy-3-methylglutaryl coenzyme A reductase, suppressed all of these processes. Our results suggest that lipid peroxidation induces VEGF expression via CD36 and p44/p42 MAPK pathway in the skin of obese mice.

Recent studies demonstrated a possible role of aldosterone in mediating cell senescence. Thus, the aim of this study was to investigate whether aldosterone induces cell senescence in the kidney and whether aldosterone-induced renal senescence affects the development of renal injury. Aldosterone infusion (0.75 μg/h) into rats for 5 weeks caused hypertension and increased urinary excretion rates of proteins and N-acetyl-β-D-glucosaminidase. Aldosterone induced senescence-like changes in the kidney, exhibited by increased expression of the senescence-associated β-galactosidase, overexpression of p53 and cyclin-dependent kinase inhibitor (p21), and decreased expression of SIRT1. These changes were abolished by eplerenone (100 mg/kg/d), a mineralocorticoid receptor (MR) antagonist, but unaffected by hydralazine (80 mg/liter in drinking water). Furthermore, aldosterone induced similar changes in senescence-associated β-galactosidase, p21, and SIRT1 expression in cultured human proximal tubular cells, which were normalized by an antioxidant, N-acetyl L-cysteine, or gene silencing of MR. Aldosterone significantly delayed wound healing and reduced the number of proliferating human proximal tubular cells, while gene silencing of p21 diminished the effects, suggesting impaired recovery from tubular damage. These findings indicate that aldosterone induces renal senescence in proximal tubular cells via the MR and p21-dependent pathway, which may be involved in aldosterone-induced renal injury.

Prevention of cardiovascular complications in obese patients frequently includes statin administration for coexisting dyslipidemia. Herein, we investigated the impacts of pitavastatin at clinically relevant doses on adipose dysfunction and insulin resistance.We treated 3T3-L1 preadipocytes with 10-100 ng/ml pitavastatin from initiation of differentiation (Day 0) to Day 8 (differentiation/maturation phase) or from Day 8 to Day 16 (post-maturation phase). Subsequently, we administered pitavastatin (6.2mg/day/kg) to 7-week-old female KKAy mice for 6 weeks; untreated KKAy mice served as obese controls.Pitavastatin impaired neither lipogenesis nor adiponectin expression during the differentiation/maturation phase. During the post-maturation phase, pitavastatin prevented excessive triglyceride accumulation, which was associated with attenuated glucose transporter-4 expression, and dose-dependently upregulated hormone-sensitive lipase expression. Decrements in the adiponectin/plasminogen activator-1 ratio were also dose-dependently inhibited. In KKAy mice, Coulter counter analyses revealed that pitavastatin treatment significantly decreased (by 16.8%) the frequency of hypertrophic adipocytes (150 microm in diameter) in parametrial adipose pads, of which total weight remained unaltered. Correspondingly, plasma adiponectin was significantly higher in pitavastatin-treated KKAy mice than in the untreated KKAy mice (12.5+/-3.8 microg/ml vs. 8.3+/-1.5 microg/ml, p0.05). Moreover, the area under the time-glucose curve after intraperitoneal insulin was decreased by 16% in pitavastatin-treated KKAy mice (p0.05 vs. untreated controls).Pitavastatin did not impair differentiation/maturation of preadipocytes and prevented their deterioration with hypertrophy after maturation at clinical concentrations in vitro. These effects likely contributed to improved insulin sensitivity, in an obese model, via prevention of adipocyte hypertrophy and adipocytokine dysregulation.

Although left ventricular (LV) hypertrophy and diastolic function assessed by echocardiography and chronic kidney disease (CKD) have been established as predictors of cardiovascular events in hypertensive patients, the relationships between the echocardiographic parameters and renal function have not been fully examined. We examined which echocardiographic parameter correlates best with estimated glomerular filtration rate (eGFR) in patients with cardiovascular risk factors. Enrolled in the study were 309 patients (mean age 67 +/- 13 y) with cardiovascular risk factors. Echocardiography was performed to measure left ventricular mass index (LVMI) as an index of LV hypertrophy. Transmitral early to atrial velocity (E/A) ratio and peak early diastolic mitral annular velocity (E') were measured as indexes of LV diastolic function. E/E' was calculated as a parameter of LV preload. eGFR was measured using the equation proposed by the Japanese Society of Nephrology. The correlations of LVMI (r = -0.333, p0.001) and hypertension (r = -0.326, p0.001) to eGFR were closer than those of E' (r = 0.276, p0.001) and E/A (r = 0.224, p0.001) to eGFR. Stepwise regression analysis showed that hypertension (beta coefficient = -0.211, p0.001) and LVMI (beta coefficient = -0.206, p0.001) were independently associated with eGFR. The E/E' increased with a decrease in eGFR, and E/E' in CKD stage 5 (16.0 +/- 6.8) was significantly higher than that in patients in whom eGFRor = 90 mL/min/1.73 m(2) (10.5 +/- 4.5) (p0.001). Left ventricular diastolic function may be influenced by the increase in LV preload due to progression of CKD stage. Therefore, LV hypertrophy may be superior to LV diastolic dysfunction in predicting low eGFR in patients with CKD using echocardiography.

Although mitral annular velocity assessed by tissue Doppler echocardiography has been established as a parameter of left ventricular (LV) diastolic function, aortic annular velocity has never been investigated as a parameter of cardiovascular function. We investigated whether aortic annular velocity can be measured using the same tissue Doppler echocardiographic method that is used for measuring mitral annular velocity, as well as the correlation between the aortic annular velocity thus measured and arterial stiffness that was assessed by the cardio-ankle vascular index (CAVI). Sixty-three patients (69 +/- 13 years) with hypertension, diabetes, or dyslipidemia, who had no overt heart disease, were enrolled. The mitral and aortic annular velocities were measured at the mitral and aortic annuluses, respectively, using tissue Doppler echocardiography. Aortic annular velocity was successfully obtained in all patients. The correlation between the peak early diastolic aortic annular velocity (r = -0.803, p0.001) and CAVI as an index of arterial stiffness was greater than that of the peak early diastolic mitral velocity and CAVI (r = -0.649, p0.001). Stepwise regression analysis showed that the age (beta coefficient = 0.488, p = 0.002) and the peak early diastolic aortic annular velocity (beta coefficient = -0.405, p = 0.008) were independent determinants of the CAVI. The strong inter-relationship was found between left ventricular diastolic function assessed by the aortic annular velocity and arterial stiffness assessed by CAVI. In conclusion, the aortic annular velocity may be helpful for assessing arterial stiffness in patients with cardiovascular risk factors.

The diameter of the inferior vena cava (IVC) measured with echocardiography is clinically used as a parameter to estimate right atrial pressure, which reflects dehydration or overhydration. Because elderly patients fall easily into dehydration, normal values for IVC diameters in elderly patients may be helpful for geriatric medicine. However, normal values of IVC diameter in relation to age have not been investigated. The purpose of this study was to elucidate age-related changes in IVC diameter using echocardiography. Enrolled in the study were 200 patients (67 ± 15 yrs: range 17-94 yrs) with cardiovascular risk factors but no overt cardiac diseases. IVC diameters throughout the respiratory cycle were measured as maximum and minimum IVC diameters (IVC(max), IVC(min)) using M-mode echocardiography. To assess IVC collapsibility, the respirophasic variation of IVC diameter was calculated as (IVC(max) - IVC(min))/(IVC(max)) ×100. Maximum IVC diameter was decreased with advancing age (r = -0.221, p = 0.002). The respirophasic variation of the IVC diameter was increased with advancing age (r = 0.244, p = 0.001). Stepwise multiple regression analysis showed that age was an independent determinant for both maximum IVC diameter (s coefficient = -0.249, p < 0.001) and respirophasic variation of the IVC diameter (s coefficient = 0.268, p < 0.001). Age-related decrease in maximum IVC diameter and increase in the respirophasic IVC collapsibility may indicate the decrease in right atrial pressure in some elderly patients. Therefore, elderly patients with decreased maximum IVC and increased respirophasic IVC collapsibility may need prevention for dehydration.

Aortitis syndrome is a chronic vasculitis that leads to arterial wall thickening and stiffening in large elastic arteries. However, there are no established markers for assessing arterial stiffening in aortitis syndrome. The cardio-ankle vascular index (CAVI) has recently been utilized to assess arterial stiffening that is associated with atherosclerosis-related diseases. We hypothesized that CAVI can be applicable for assessing alterations in arterial stiffness during immunosuppressive therapy for aortitis syndrome. A 69-year-old woman with a 2-month history of recurrent fever, fatigue, and malaise, showed intense 18F-fluorodeoxyglucose (18F-FDG) uptake in the thoracic aorta and common carotid arteries in 18F-FDG-positron emission tomography. These clinical and imaging findings resulted in the diagnosis of aortitis syndrome. The patient also showed the elevated CAVIs on both sides (right, 10.3; left, 10.4) (normal value for her age, 9.1 +/- 0.8), indicating the arterial stiffness due to aortitis syndrome. The patient was treated for 34 weeks with immunosuppressive therapy, which included oral prednisolone and methotrexate. C-reactive protein (from 4.24 to 0.49 mg/dL) and immunoglobulin G (from 2,627 to 1,524 mg/dL) were decreased by 7 weeks after initiation of the treatment. The decrease in these inflammatory parameters suggests the effectiveness of the immunosuppressive therapy. In addition, after the 34-week treatment, the CAVIs on both sides (right, 9.3; left, 9.2) were within the normal range. These data indicate that the immunosuppressive therapy ameliorates the degree of arterial stiffness. In conclusion, CAVI may be a promising marker for evaluating the effectiveness of immunosuppressive therapy in patients with aortitis syndrome.

The purpose of this study was to examine the usefulness of 11C-acetate positron emission tomography (PET) for assessing the efficacy of cardiac resynchronization therapy (CRT). Enrolled in this study were 20 patients with severe heart failure. All patients underwent 11C-acetate PET within 1 week after CRT. The oxygen consumption was measured by the monoexponential clearance rate of 11C-acetate (Kmono) for both CRT-off and -on. Cardiac efficiency (CE) was determined using the concept of the work metabolic index (WMI). WMI was calculated as WMI = (stroke volume index) × (systolic blood pressure) × (heart rate)/Kmono. The patients were divided into two groups: 14 patients with improved CE (from 5.27 ± 0.91 to 6.77 ± 1.12) and 6 patients with deteriorated CE (from 5.35 ± 0.92 to 4.86 ± 0.84) by CRT-on. Kmono decreased from 0.053 ± 0.006 to 0.046 ± 0.003 by CRT-on in the improved CE group (p = 0.028), but increased from 0.049 ± 0.006 to 0.050 ± 0.006 in the deteriorated-CE group (p = 0.036). Stroke volume index, systolic blood pressure, and heart rate did not change by CRT-on for either group. At the one-year follow-up, there were significantly higher rates of major cardiac adverse events in the deteriorated-CE group than in the improved-CE group (p = 0.032). Therefore, the improvement of CE, as assessed by 11C-acetate PET in the early period after CRT, is produced by the decrease in oxygen consumption in patients showing good responses to CRT. The decrease in oxygen consumption in the early period after CRT is thus a useful marker for predicting a good clinical outcome after CRT.

Recent studies have shown that blocking non-proteolytically activated prorenin with a decoy peptide for the handle region of the prorenin prosegment (HRP) inhibits the development of microvascular complications in diabetic animals. In the present study, we investigated whether non-proteolytic activation of prorenin contributes to the development of fructose-induced insulin resistance. Rats were fed a standard diet (n = 10), a 60% high fructose diet (n = 16), or a high fructose diet + HRP (0.1 mg kg(-1) day(-1), n = 16) for 10 weeks. Fructose-fed rats showed higher systolic blood pressure (SBP), fasting plasma triglycerides, total cholesterol and insulin levels; which, except for SBP, were suppressed by HRP. The responses of plasma glucose and insulin levels to oral glucose loading were significantly greater in fructose-fed rats than in standard diet-fed rats. The HRP normalized the enhanced responses of plasma glucose and insulin levels that were observed in fructose-fed rats. Moreover, HRP suppressed the enhanced prorenin activation and angiotensin II formation in the soleus muscle of fructose-fed rats. These data suggest that local angiotensin II generation in skeletal muscle, induced by non-proteolytic activation of prorenin, contributes to the development of insulin resistance induced by a high fructose diet.

Background Peripheral arterial disease (PAD) is a major complication of haemodialysis (HD), especially in patients with diabetes mellitus. Although previous reports have indicated that low-density lipoprotein apheresis (LDL-A) improves arteriosclerosis in PAD patients, the mechanism by which LDL-A affects PAD is still unclear. In this study, we tested the hypothesis that LDL-A attenuates reactive oxygen species (ROS) production in HD patients with PAD. Methods Twenty HD patients with PAD were investigated in this study. Clinical effects were evaluated by thermography and angiography. Oxidative stress in serum was evaluated by thiobarbituric acid reactive substances (TBARS) and expression of p22phox mRNA. Results Ischaemic symptoms due to PAD were gradually improved in 13 patients (65%) after LDL-A. One session of LDL-A removed approximately 75% of LDL from serum. Some patients exhibited dramatic improvement of severe symptoms of PAD such as skin ulcers after serial performance of LDL-A. The levels of LDL cholesterol, malondialdehyde-modified LDL, high-sensitivity C-reactive protein, vascular endothelial growth factor, international normalized ratio of pro-thrombin time and bradykinin were decreased after a single session of LDL-A, although there were no additional changes after 10 sessions of LDL-A. The levels of fibrinogen and p22phox mRNA were decreased by a single session of LDL-A, and these decreases continued over the entire period of treatment. TBARS was decreased after a course of LDL-A. Conclusions LDL-A improved ischaemic symptoms in HD patients with PAD by reducing ROS production in leucocytes. We conclude that LDL-A is an effective therapy for patients with HD complicated by PAD.

Aluminum polyphosphate was prepared from aluminum nitrate solution and sodium polyphosphate solution with cation exchange resin in the molar ratio of Al/P = 1/3. Urea and hexamethylenetetramine were added in this preparation process. The thermal behavior of the obtained phosphates was analyzed by differential thermal analyses, X‐ray diffraction, and Fourier transform infrared spectroscopy. Furthermore, these materials and their thermal products were estimated by specific surface area, pore size distribution, particle size distribution, acid strength, amount of acidic sites, and adsorption of trimethylamine.

There are no data regarding changes in plasma brain natriuretic peptide (BNP) levels in patients with Fabry's diseases during enzyme replacement therapy (ERT). We describe a patient with Fabry's disease who demonstrated the improvement in plasma brain BNP levels in response to ERT. Fabry's disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A, which results in progressive intracellular accumulation of globotriaosylceramide (Gb3) in various organs including the heart. Cardiac involvement is frequent in Fabry's disease, resulting in cardiac dysfunction due to hypertrophic changes of the myocardium and thickening of the valves. Although ERT has been reported to improve cardiac function, no consensus has been reached regarding the effectiveness of ERT in female patients with heterozygous Fabry's disease. We report a 44-year-old woman having heterozygous Fabry's disease, who showed mitral valve thickening and regurgitation on echocardiogram. ERT was performed by intravenous infusion of recombinant alpha-galactosidase A every 2 weeks. We assessed the influences of ERT on cardiac function by measuring echocardiograhic parameters and monitoring BNP levels, which show treatment-induced drop in patients with heart failure. Although her cardiac function and mitral regurgitation assessed by echocardiography had not improved 18 months after the beginning of ERT, the plasma BNP level, which was 91.5 pg/ml before ERT, fell to 18.9 pg/ml. In conclusion, plasma BNP levels may be useful for evaluating the effectiveness of ERT for heterozygous Fabry's disease, even in patients who demonstrate no improvement in echocardiographic parameters of cardiac structure and function.

Recent studies indicate a role of chymase in the regulation of angiotensin II (AngII) formation in cardiovascular and renal tissues. We investigated a possible contribution of chymase to AngII formation and to renal fibrosis in unilateral ureteral obstruction (UUO). Eight-week-old Syrian hamsters were subjected to UUO and treated with vehicle, the specific chymase inhibitor (CI) 4-[1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1H-benzimidazol-2-ylsulfanyl]-butyric acid (50 mg/kg, twice a day, p.o.), or the selective AT1-receptor blocker olmesartan (10 mg/kg per day, p.o.) for 14 days. UUO-induced renal interstitial fibrosis was associated with increases in renal mRNA levels of α-smooth muscle actin (SMA), type I collagen, and transforming growth factor (TGF)-β. The UUO hamsters showed markedly higher AngII contents and increased AT1-receptor mRNA level in the obstructed kidney than sham-operated ones. In contrast, angiotensin-converting enzyme (ACE) protein expression was significantly lower in UUO hamsters. In UUO hamsters, treatment with CI or olmesartan significantly decreased AngII levels in renal tissue and mRNA levels of α-SMA, type I collagen, and TGF-β and ameliorated tubulointerstitial injury. On the other hand, neither CI nor olmesartan changed systolic blood pressure, renal ACE, and AT1-receptor protein levels. These data suggest that chymase-dependent intrarenal AngII formation contributes to the pathogenesis of interstitial fibrosis in obstructed kidneys of hamsters. Keywords:: chymase, angiotensin II, angiotensin-converting enzyme, unilateral ureteral obstruction

Cardio-ankle vascular index (CAVI) has been established as a marker of arterial stiffness, which is increased in hypertensive patients. CAVI reflects the stiffness of the aorta, femoral artery, and tibial artery. Sunitinib, multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-tumor activities, has been proved effective in patients with gastrointestinal stromal tumors. However, the treatment with sunitinib is often complicated by side effects such as hypertension. We describe an 84-year-old woman with gastrointestinal stromal tumor, who showed changes in arterial stiffness preceding the appearance of hypertension in the early phase after sunitinib initiation. The patient received sunitinib (50 mg given daily) for gastrointestinal stromal tumor. We assessed the influence of sunitinib on arterial stiffness every 7 days by measuring CAVI. The CAVI, which reflects arterial stiffness, was increased from 9.95 at baseline to 11.65 at 7 days after the initiation of sunitinib, whereas the blood pressure remained unchanged (117/72 and 119/76 mmHg). At 14 days after sunitinib initiation, the blood pressure was increased to 159/89 mmHg, indicating the occurrence of hypertension, while the CAVI was 11.90, the similar level detected at 7 days. Subsequently, sunitinib treatment was discontinued, because of the marked decrease in blood platelets. Both blood pressure and CAVI, together with blood platelets, were restored to the baseline values at 12 days after cessation of sunitinib. In conclusion, the increase in the CAVI preceded the appearance of sunitinib-induced hypertension. Arterial stiffness assessed by CAVI may be useful for early detection of sunitinib-induced hypertension.

Objective: The aim of this investigation was to determine the factors influencing acute intracerebral hemorrhage severity on admission and clinical outcomes at discharge. Methods: Sixty acute stroke hospitals throughout Japan participated in the Japan Standard Stroke Registry Study (JSSRS), documenting the in-hospital course of 16,630 consecutive patients with acute stroke from January 2001 to March 2004. We identified 2,840 adult patients from the JSSRS who had intracerebral hemorrhage. Results: Intracerebral hemorrhage severity on admission was strongly related to age, previous stroke history, and hemorrhage size in a monotone fashion [χ2(9) = 374.5, p < 0.0001]. Drinking history was also predictive of intracerebral hemorrhage severity on admission, but the association was not monotone. Interestingly, intracerebral hemorrhage severity on admission was increased in nondrinking and heavy drinking compared to mild drinking (p < 0.05). Unsuccessful outcome (modified Rankin scale score = 3–6) was related to age, previous stroke history, hemorrhage size, and intracerebral hemorrhage severity on admission [χ2(9) = 830.4, p < 0.0001]. Mortality was related to hemorrhage size, intraventricular hemorrhage, intracerebral hemorrhage severity on admission, and surgical operation [χ2(7) = 540.4, p < 0.0001]. Conclusion: We could find four varied factors associated with intracerebral hemorrhage severity and its outcomes. Interestingly, intracerebral hemorrhage severity tended to be greater in nondrinking and heavy drinking than mild drinking. Additionally, surgical operation decreased intracerebral hemorrhage mortality.

Background Peritoneal mesothelial cells play an important role in peritoneal dialysis and are often exposed to dialysis fluid containing high glucose levels. Loss of peritoneal function is a major complication associated with long-term peritoneal dialysis. In this study, we hypothesized that high glucose levels induce apoptosis, and that insulin attenuates this apoptosis in peritoneal mesothelial cells. To clarify this hypothesis, we examined the effects of insulin on the phosphatidylinositol 3-kinase/Akt signaling pathway and apoptosis in rat peritoneal mesothelial cells. Methods Phosphorylated insulin receptor and Akt were detected by western blot analysis. Apoptosis was evaluated by measuring caspase 3 activity and by TUNNEL staining. Results Insulin (100 nmol/L) increased tyrosine phosphorylation of insulin receptor in peritoneal mesothelial cells. Furthermore, insulin (1-100 nmol/L) dose-dependently stimulated Akt phosphorylation. Treatment with the phosphatidylinositol 3-kinase inhibitors wortmannin (100 nmol/L) and LY294002 (10 micromol/L) attenuated insulin-induced Akt phosphorylation, indicating that insulin phosphorylates Akt via a phosphatidylinositol 3-kinase-dependent pathway. Insulin attenuated caspase 3 activity and decreased the number of TUNNEL-positive cells. The phosphatidylinositol 3-kinase inhibitors and overexpression of a dominant-negative mutant of Akt inhibited the effect of insulin on apoptosis. Conclusions The present data indicate that insulin attenuates high glucose-induced apoptosis via the phosphatidylinositol 3-kinase/Akt signaling pathway in peritoneal mesothelial cells. Therefore, the insulin signaling pathway may play a protective role in peritoneal function.

Although patients with type 2 diabetes demonstrate cardiac diastolic dysfunction, it is well known that cardiac diastolic dysfunction is produced by hypertension and aging. The purpose of the present study was to elucidate the cardiac structure and function in normotensive patients with type 2 diabetes in various age strata in order to assess the effect of diabetes mellitus itself on cardiac function. Echocardiographic examination was performed in 77 normotensive patients with type 2 diabetes (age: 63+/-11 years) and 76 healthy control subjects (age: 60+/-11 years) who were in their forties, fifties, sixties, and seventies. The left ventricular (LV) wall thickness and dimension were measured by M-mode echocardiography. The relative wall thickness, LV mass index, and LV ejection fraction (LVEF) were calculated. LV diastolic function was assessed by the peak velocity of early rapid filling (E velocity) and the peak velocity of atrial filling (A velocity), and the ratio of E to A (E/A) using the transmitral flow velocity, which were obtained by Doppler echocardiography. No difference was observed in the relative wall thickness, LV mass index, or LVEF between the diabetic patients and control subjects in any of the age strata. The E/A ratio in the patients with type 2 diabetes was not different from that in the control subjects in their 40s (1.17+/-0.35 versus 1.20+/-0.36). However, E/A was significantly lower in the diabetic patients than in the control subjects in their 50s (0.87+/-0.28 versus 1.14+/-0.24), 60s (0.78+/-0.22 versus 0.97+/-0.27), and 70s (0.66+/-0.19 versus 0.84+/-0.21) (p0.05). The duration of type 2 diabetes was significantly longer in patients in their 50s (7.0+/-2.5 years), 60s (8.0+/-3.2 years), and 70s (10.4+/-3.2 years) than in patients in their 40s (3.3+/-1.9 years) (p0.001). The value of E/A in the diabetic patients correlated with the duration of type 2 diabetes (r=-0.62, p0.001). These results indicate that cardiac diastolic dysfunction without LV systolic dysfunction in patients with well-controlled type 2 diabetes is related neither to hypertension nor LV hypertrophy, but rather to aging and the duration of type 2 diabetes.

Argatroban, which is a thrombin inhibitor, has an indication as a treatment in the acute phase on atherosclerotic ischemic stroke in Japan. Howeve, in cardioembolic stroke, argatroban is considered to be contraindicated with the side effect of hemorrhage, though there is no clear clinical evidence to show that argatroban increases hemorrhagic compared with heparin. The efficacy of anticoagulant treatment with argatroban on cardioembolic stroke was evaluated retrospectively in this study. We identified 3,113 patients from the Japan Standard Stroke Registry Study who had had a cardioembolic ischemic stroke. We excluded patients with the anti-platelet treatment or the combination therapy of anticoagulation. Our analyses are therefore based on a cohort of 2,529 patients who were treated either with heparin, and argatroban, or with no anti-coagulation treatment. With multivariable regression, hemorrhagic it was shown that hemorrhage was significantly reduced in heparin and argatroban treatments in the patients with mild severity. There was no significant difference in the recurrence of ischemic stroke between the treatments. Both argatroban and heparin showed dramatic improvement compared with the no treatment standard, but only heparin achieved statistical significance for mortality and change in NIHSS score (admission to discharge) in the moderate stroke subgroup [NIHSS 11-22]. Both heparin and argatroban [more so than heparin alone] have a significantly reduced mortality risk. From the present study, it is suggested that argatroban may be useful on cardioembolic stroke, increasing the improvement of recovery of stroke severity without increasing the risk of hemorrhage. Further prospective studies are awaited for evaluating better the efficacy of argatroban on cardioembolic stroke.

The aim of this study was to elucidate the cardiac function in bed-bound patients following cerebrovascular accidents. In accord with the criteria for activities of daily living (ADL) of the Japanese Ministry of Health, Labour and Welfare, 51 age-matched poststroke patients without heart disease were classified into 3 groups: rank A (house-bound) (n = 16, age, 85 +/- 6 years), rank B (chair-bound) (n = 16, age, 84 +/- 8 years), and rank C (bed-bound) (n = 19, age, 85 +/- 9 years). Using echocardiography, the left ventricular (LV) diastolic function was assessed by the ratio of early filling (E) and atrial contraction (A) transmitral flow velocities (E/A) of LV inflow. LV systolic function was assessed by LV ejection fraction (LVEF), and the Tei index was also measured to assess both LV systolic and diastolic function. No difference was observed in the E/A and LVEF among the 3 groups. The Tei index was higher in rank C (0.56 +/- 0.17) than in rank A (0.39 +/- 0.06) and rank B (0.48 +/- 0.17), and a statistically significant difference was observed between rank A and rank C (P < 0.05). Serum albumin and blood hemoglobin were significantly lower in rank C (3.1 +/- 0.4 and 10.6 +/- 1.8 g/dL) than in rank A (4.1 +/- 0.3 and 12.4 +/- 1.2 g/dL) (P < 0.001 and P < 0.05, respectively). These results indicate that latent cardiac dysfunction and poor nutritional status may exist in bed-bound patients (rank C) following cerebrovascular accidents. The Tei index may be a useful index of cardiac dysfunction in bed-bound patients because it is independent of the cardiac loading condition.