Chronic kidney disease is a risk factor for cardiovascular death in a community-based population in Japan: NIPPON DATA90.

BACKGROUND: Chronic kidney disease (CKD) has been identified as a risk factor for cardiovascular disease (CVD). METHODS AND RESULTS: The risk of cardiovascular death was evaluated in a large cohort of participants selected randomly from the overall Japanese population. Participants (mean age, 52.4 years) free of previous CVD were followed up for 10 years. Glomerular filtration rate (GFR) was estimated using the abbreviated equation developed at the Cleveland Clinic laboratory for the Modification of Diet in Renal Disease study. Of the 7,316 participants, 6.7% had CKD with a GFR<60 at baseline. Even after adjustment for other risk factors, the presence of CKD conferred an increased risk of cardiovascular death with a hazard ratio of 1.20 (95% confidence interval, 0.82-1.76). Furthermore, a negative, graded correlation between GFR and risk of cardiovascular death was observed: 1.09 (0.72-1.64) for a 60or=90). The proportion of excess cardiovascular death due to CKD was 1.3%. CONCLUSION: CKD was an independent risk factor for cardiovascular death in a community-dwelling Japanese population.     

Overcoming graft rejection in heavily transfused and allo-immunised patients with bone marrow failure syndromes using fludarabine-based haematopoietic cell transplantation

Allogeneic haematopoietic cell transplantation (HCT) can cure a variety of non-malignant haematological disorders. Although transplant outcomes for selected patients with severe aplastic anaemia (SAA) and paroxysmal nocturnal haemoglobinuria (PNH) have improved, older age, allo-immunisation from transfusions, prior immunosuppressive therapy and a prolonged time from diagnosis to transplantation are associated with worse outcome. Because of its potent immunosuppressive effects, we investigated a fludarabine-based non-myeloablative conditioning regimen in patients with transfusion-dependent non-malignant haematological disorders at increased risk for graft rejection with conventional transplant conditioning. Twenty-six patients with transfusion dependent/anti-thymocyte globulin (ATG)-refractory SAA, PNH or pure red cell aplasia underwent HCT from a human leucocyte antigen (HLA)-compatible relative. Transplant conditioning consisted of cyclophosphamide (120 mg/kg) and fludarabine (125 mg/m2) with or without ATG. Ciclosporine, alone or combined with mycophenolate mofetil or methotrexate, was used as graft-versus-host disease (GVHD) prophylaxis. All patients achieved durable engraftment and transfusion-independence. Twenty-four of 26 patients are alive at a median of 21 months following transplantation. Although a high cumulative incidence of acute (65% grades II-IV, 54% grades III-IV) and chronic GVHD (56%) was observed, only one patient died from transplant-related causes (cumulative incidence 7%). These data show that HCT following fludarabine-based non-myeloablative conditioning results in durable engraftment and excellent survival in SAA and PNH patients at high risk for graft rejection.     

Distinct roles of GSK-3α and GSK-3β phosphorylation in the heart under pressure overload

Glycogen synthase kinase-3 (GSK-3) is a master regulator of growth and death in cardiac myocytes. GSK-3 is inactivated by hypertrophic stimuli through phosphorylation-dependent and -independent mechanisms. Inactivation of GSK-3 removes the negative constraint of GSK-3 on hypertrophy, thereby stimulating cardiac hypertrophy. N-terminal phosphorylation of the GSK-3 isoforms GSK-3α and GSK-3β by upstream kinases (e.g., Akt) is a major mechanism of GSK-3 inhibition. Nonetheless, its role in mediating cardiac hypertrophy and failure remains to be established. Here we evaluated the role of Serine(S)21 and S9 phosphorylation of GSK-3α and GSK-3β in the regulation of cardiac hypertrophy and function during pressure overload (PO), using GSK-3α S21A knock-in (αKI) and GSK-3β S9A knock-in (βKI) mice. Although inhibition of S9 phosphorylation during PO in the βKI mice attenuated hypertrophy and heart failure (HF), inhibition of S21 phosphorylation in the αKI mice unexpectedly promoted hypertrophy and HF. Inhibition of S21 phosphorylation in GSK-3α, but not of S9 phosphorylation in GSK-3β, caused phosphorylation and down-regulation of G1-cyclins, due to preferential localization of GSK-3α in the nucleus, and suppressed E2F and markers of cell proliferation, including phosphorylated histone H3, under PO, thereby contributing to decreases in the total number of myocytes in the heart. Restoration of the E2F activity by injection of adenovirus harboring cyclin D1 with a nuclear localization signal attenuated HF under PO in the αKI mice. Collectively, our results reveal that whereas S9 phosphorylation of GSK-3β mediates pathological hypertrophy, S21 phosphorylation of GSK-3α plays a compensatory role during PO, in part by alleviating the negative constraint on the cell cycle machinery in cardiac myocytes.     

Prognostic value of the Tei index combining systolic and diastolic myocardial performance in patients with acute myocardial infarction treated by successful primary angioplasty

Cardiac systolic (left ventricular ejection fraction) and diastolic (mitral inflow velocity pattern and/or mitral deceleration time) function were reported as predictors of clinical outcome or left ventricular remodeling in patients with acute myocardial infarction (AMI). Recently, a new index (Doppler-derived index combining systolic and diastolic myocardial performance; Tei index) for combined systolic and diastolic ventricular function has been reported to be a useful and convenient method for evaluation of global ventricular function. We therefore investigated the usefulness of the Tei index by echocardiography for evaluation of infarct size and clinical outcome in patients with AMI treated by successful primary angioplasty. We analyzed 10 age-matched control subjects and 43 consecutive patients with first AMI treated by successful primary angioplasty. The Tei index of the AMI patients was significantly greater than that of the control subjects (0.630 ± 0.106 vs 0.375 ± 0.036, P 0.0001). Also, the Tei index showed a significant positive correlation with peak creatine kinase values and ^99mTc-tetrofosmin scores. Moreover, multiple logistic regression analysis showed that the Tei index 0.70 (P = 0.0313, odds ratio = 14.14) was the only significant explanatory factor for cardiac death or developed congestive heart failure. The Tei index combining systolic and diastolic myocardial performance reflects infarct size and might be a predictor of clinical outcome in patients with AMI treated by successful primary angioplasty.     

Green fluorescent protein expression in dendritic cells enhances their immunogenicity and elicits specific cytotoxic T-cell responses in humans

OBJECTIVE: Green fluorescent protein (GFP) has been used to monitor and select cells transduced with vectors encoding other transgenes of interest. We investigated the immunogenic nature of GFP in humans and further explored whether this xenoprotein could be used as a functional adjuvant to enhance T-cell immunity to the melanoma tumor antigen MART1. METHODS: Peripheral blood lymphocytes from healthy donors were stimulated by autologous dendritic cells expressing GFP, then cloned by limiting dilution and tested for antigen specificity following coculture with GFP-expressing or GFP-negative targets. In a parallel experiment, lymphocytes from HLA A 0201+ healthy donors were stimulated with four different Melan-A/MART1(27-35) peptide-pulsed stimulators: 1) MART1 peptide-pulsed DCs, 2) MART1 peptide-pulsed DCs loaded with GFP protein, 3) MART1 peptide-pulsed GFP adenovirus-transduced DCs, and 4) MART1 peptide-pulsed null adenovirus-transduced DCs. The percentage of CD3+/CD8+ MART1 peptide-specific T cells was determined by intracellular cytokine staining for gamma-IFN. RESULTS: Multiple CD4+ and CD8+ T cell clones were expanded which secreted gamma-IFN and demonstrated high levels of cytotoxicity to GFP-expressing targets as assessed by ELISA and Cr51 release respectively. We next investigated the impact of GFP expression on DCs used to stimulate cytotoxic T cells specific for a tumor-associated peptide. The percentage of MART1- specific CD8+ T cells that were generated was higher when MART1-pulsed GFP adenovirus-transduced DCs were used as stimulators (28%) compared to MART1-pulsed DCs alone (11%, p = 0.01), MART1-pulsed null adenovirus-transduced DCs (11.7%, p = 0.02), or MART1-pulsed DCs loaded with GFP protein (12.2%). CONCLUSIONS: These findings further support GFP's immunogenicity and suggest this xenoprotein might further be used to enhance the expansion of tumor-specific T cells.     

Histopathologically-diagnosed splenic metastasis in a hepatocellular carcinoma case with adrenal metastasis

We encountered a patient with hepatocellular carcinoma (HCC), with adrenal gland metastasis, in whom splenic metastasis was diagnosed histopathologically. A 59-year-old man visited our hospital in May 2001 with chief complaints of abdominal distension and pretibial pitting edema. Multiple HCCs associated with HCV-positive liver cirrhosis were detected. Transarterial embolization (TAE) was performed a total of 4 times for HCCs. A left adrenal gland metastatic lesion was detected and it was found to increase in diameter from 3 cm to 6 cm over a four-month period; left adrenalectomy was performed in June 2002. Because of marked splenomegaly and findings of hypersplenism, the spleen was also resected. Although no metastatic lesions were evident on macroscopic examination of the spleen, a small metastatic lesion from moderately differentiated HCC, approximately 0.5 mm in diameter, was detected histopathologically. Splenic metastasis from HCC is rare, usually occurring with metastases involving other organs. Our patient also had adrenal gland metastasis. Therefore, hematogenous metastasis to the congested spleen via the systemic circulation was suspected.     

The patient-based outcome of upper-extremity surgeries using the DASH questionnaire and the effect of disease activity of the patients with rheumatoid arthritis

The Disabilities of the Arm, Shoulder and Hand (DASH) is a standardized patient-based outcome measure, which assesses integrated upper-extremity disorders. The objectives of this study were to investigate subjective outcome after upper-extremity surgeries for the patients with rheumatoid arthritis (RA) using the DASH questionnaire (Japanese version) and to investigate the influence of disease activity on the surgical outcome using the Disease Activity Score (DAS) 28-CRP(4). Approximately 127 surgical procedures for the upper extremities in 127 patients with RA were recruited in this study. Surgeries were performed in 4 shoulders, 35 elbows, 60 wrists and 28 hands. The DASH score (disability/symptom score) was investigated just before surgery and at follow-up. The mean follow-up period after the surgery was 15 months on average (range, 6 to 24 months). The preoperative DASH score (disability/symptom score) 50 +/- 23 (mean +/- SD) decreased significantly to 38 +/- 23 at the follow-up (n = 127, p < 0.01). Standardized response mean and effect size revealed a medium effect of -0.6 and -0.5. Patients with various degrees of disease activity improved and the improvements per se were comparable of preoperative disease activity and postoperative response to medical treatment. A favorable subjective outcome of rheumatoid upper-extremity surgeries can be anticipated under the good control of disease activity.     

Prophylactic intraaortic balloon pumping preserves left ventricular systolic function in acute anterior myocardial infarction without cardiogenic shock

OBJECTIVES: Left ventricular function and prognosis were evaluated in patients with acute myocardial infarction who underwent primary percutaneous coronary intervention supported by intraaortic balloon pumping. METHODS: Fifty-eight consecutive patients with first acute myocardial infarction were treated between July 1999 and April 2006. Twenty-five had cardiogenic shock on admission, whereas 33 did not. Patients with anterior acute myocardial infarction without cardiogenic shock were divided into the prophylactic intraaortic balloon pumping group (Group 1; n=17) and the rescue intraaortic balloon pumping group (Group 2; n=9). RESULTS: Thirty-day in-hospital mortality was 52% in cardiogenic shock patients, and 3% in non-shock patients. Baseline characteristics of non-shock anterior acute myocardial infarction were similar including Thrombolysis in Myocardial Infarction (TIMI) risk scores (5.1 and 5.0) in the two groups. However, average left ventricular ejection fraction in the convalescent stage was superior in Group 1 (48.7% vs. 37.8%, p = 0.03). Thirty-day in-hospital mortality was 0% in Group 1 and 11% in Group 2 (p = 0.34). Cox's hazard ratio in Group 2 to Group 1 was 2.38 (95% confidence intrerval; 0.84-11.1, p = 0.09) in terms of the subsequent major cardiac events. CONCLUSIONS: Prophylactic use of intraaortic balloon pumping starting prior to primary percutaneous coronary intervention preserves the convalescent left ventricular systolic function in patients with high risk for anticipated cardiac events after anterior acute myocardial infarction without cardiogenic shock.     

Effect of conventional risk factors for excess cardiovascular death in men: NIPPON DATA80.

BACKGROUND: The present study examined how sex differences in conventional risk factors for cardiovascular disease (CVD), especially smoking, account for excess male mortality from CVD in Japan. METHODS AND RESULTS: In a 14-year follow-up study, causes of death were ascertained among 10,546 Japanese aged 30 years or older at the baseline. The proportion of the excess male risk of CVD explained by the differences in risk factors was estimated as (HR0-HR1)/(HR0-1), where HR0 is the age-adjusted hazard ratio (men vs women) and HR1 is the age and risk factor-adjusted hazard ratio. The age-adjusted male:female ratios were 1.60 (95% confidence interval (CI), 1.32-1.94) for CVD, 1.75 (95% CI, 1.33-2.30) for stroke, and 1.55 (95% CI, 0.97-2.49) for coronary heart disease. The proportion of excess male risk of CVD explained by smoking was 46% and excess risk explained by all risk factors including smoking was 36%. In men, drinking habits decreased the excess risk of CVD. Except for the association between drinking habits and CVD, the impact of the hazard ratios of conventional risk factors had no sex difference. CONCLUSIONS: Smoking contributes substantially to excess male mortality from CVD when the smoking rates vary substantially by sex.     

Comparison of three-year clinical outcome of the multi-link stent with the Palmaz-Schatz stent in Japanese patients with coronary artery disease: a case control study

Results of trials using the ACS Multi-Link (ML) stent, one of the new generation stents, were similar to or slightly better than those of trials using the Palmaz-Schatz (PS) stent. The purpose of this study was to compare long-term (3-year) clinical outcomes of patients with coronary artery disease treated with the ML stent to those treated with the PS stent. The present study consisted of 52 patients who underwent successful coronary ML stent implantation (ML group) and 52 matched control patients who underwent successful coronary PS stent implantation (PS group) from October 1997 to September 1999. During follow-up periods, cardiac events occurred in 11 patients (21%) in the ML group and 14 patients (27%) in the PS group, respectively (p = NS). Angiographic restenosis rates of American College of Cardiology/American Heart Association (ACC/AHA) lesion type A or B1 were 8.3% in both groups, and ACC/AHA lesion type B2 or C were 39.3% in the ML group and 35.7% in the PS group, respectively (p = NS). In addition, angiographic restenosis rates of ACC/AHA lesion type A or B1 were significantly lower than those of lesion type B2 or C in both groups. The results of the present study suggest that 6-month angiographic and 3-year clinical outcomes in patients with coronary artery disease treated by coronary stenting with the ML stent were comparable to those with the PS stent.