Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure.

Heart failure (HF) is a leading cause of death and repeated hospitalizations and often involves cardiac mitochondrial dysfunction. However, the underlying mechanisms largely remain elusive. Here, using a mouse model in which myocardial infarction (MI) was induced by coronary artery ligation, we show the metabolic basis of mitochondrial dysfunction in chronic HF. Four weeks after ligation, MI mice showed a significant decrease in myocardial succinyl-CoA levels, and this decrease impaired the mitochondrial oxidative phosphorylation (OXPHOS) capacity. Heme synthesis and ketolysis, and protein levels of several enzymes consuming succinyl-CoA in these events, were increased in MI mice, while enzymes synthesizing succinyl-CoA from α-ketoglutarate and glutamate were also increased. Furthermore, the ADP-specific subunit of succinyl-CoA synthase was reduced, while its GDP-specific subunit was almost unchanged. Administration of 5-aminolevulinic acid, an intermediate in the pathway from succinyl-CoA to heme synthesis, appreciably restored succinyl-CoA levels and OXPHOS capacity and prevented HF progression in MI mice. Previous reports also suggested the presence of succinyl-CoA metabolism abnormalities in cardiac muscles of HF patients. Our results identified that changes in succinyl-CoA usage in different metabolisms of the mitochondrial energy production system is characteristic to chronic HF, and although similar alterations are known to occur in healthy conditions, such as during strenuous exercise, they may often occur irreversibly in chronic HF leading to a decrease in succinyl-CoA. Consequently, nutritional interventions compensating the succinyl-CoA consumption are expected to be promising strategies to treat HF.

Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild-type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.

Incidence, Predictors, and Outcome Associated With Ventricular Tachycardia or Fibrillation in Patients Undergoing Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction.

BACKGROUND: The characteristics and clinical outcomes associated with sustained ventricular tachycardia and fibrillation (VT/VF) in Japanese acute myocardial infarction (AMI) patients remain unknown.Methods and Results: Consecutive AMI patients (n=1,941) transferred to the Hirosaki University Hospital and treated with primary percutaneous coronary intervention (PCI) within 12 h of onset were retrospectively studied. The incidence of VT/VF during hospitalization was 8.3%, and 75% of cases occurred by the end of PCI. Independent predictors associated with VT/VF occurrence by the end of PCI and after PCI, respectively, were identified. Additionally, the differences between patients with VT and VF were examined, which revealed that the characteristics of patients and predictors for VT and VF were clearly different. Additionally, the QRS duration during VT was measured, which demonstrated the possible involvement of Purkinje fibers for VT in the acute phase of AMI. Of the patients with VT/VF, 12% required ECMO support due to refractory VT/VF despite intravenous antiarrhythmic agents such as ß-blockers, amiodarone, and nifekalant. Among the patients discharged alive, 1,690 were followed up for a mean of 3.7 years. VT/VF occurrence during hospitalization did not affect the mid-term clinical outcomes even in patients with VT. CONCLUSIONS: The results clearly indicated that VT/VF is still a serious complications of AMI. We need to identify patients at high risk of developing VT/VF for careful observation and appropriate intervention.

Reduced Left Ventricular Ejection Fraction Is a Risk for Sudden Cardiac Death in the Early Period After Hospital Discharge in Patients With Acute Myocardial Infarction.

BACKGROUND: The incidence of sudden cardiac death (SCD) after discharge in Japanese acute myocardial infarction (AMI) patients with reduced left ventricular ejection fraction (LVEF) treated with primary percutaneous coronary intervention (PCI) remains unknown.Methods and Results:The study population included 1,429 AMI patients (199 with LVEF ≤35% and 1,230 with LVEF >35%) admitted to the Hirosaki University Hospital, treated with primary PCI within 12 h after onset, and survived to discharge. LVEF was evaluated in all patients before discharge, and the patients were followed up for a mean of 2.6±0.8 years. The Kaplan-Meier survival curves revealed LVEF ≤35% was associated with all-cause death and SCD. The incidence of SCD was 2.6% at 1 year and 3.1% at 3 years in patients with LVEF ≤35%, whereas it was 0.1% at 1 year and 0.3% at 3 years in patients with LVEF >35%. Sixty-seven percent of SCDs in patients with LVEF ≤35% occurred within 4 months after discharge, and the events became less frequent after this period. A Cox proportional hazard model indicated LVEF ≤35% as an independent predictor for all-cause death and SCD. CONCLUSIONS: The incidence of SCD was relatively low in Japanese AMI patients treated with primary PCI, even in patients with LVEF ≤35% upon discharge. Careful management of patients with reduced LVEF is required to prevent SCD, especially in the early phase after discharge.

Angiotensin-converting enzyme inhibitor prevents skeletal muscle fibrosis in diabetic mice.

NEW FINDINGS: What is the central question of this study? We questioned whether an angiotensin-converting enzyme (ACE) inhibitor prevents skeletal muscle fibrosis in diabetic mice. What is the main finding and its importance? Administration of ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after induction of diabetes by streptozotocin. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes. ABSTRACT: Fibrosis is characterized by the excessive production and accumulation of extracellular matrix components, including collagen. Although the extracellular matrix is an essential component of skeletal muscle, fibrosis can have negative effects on muscle function. Skeletal muscle fibrosis was shown to be increased in spontaneously hypertensive rats and to be prevented by an angiotensin-converting enzyme (ACE) inhibitor, an antihypertensive drug, in dystrophic mice or a mouse model of myocardial infarction. In this study, we therefore analysed whether (1) there is increased skeletal muscle fibrosis in streptozotocin (STZ)-induced diabetic mice, and (2) a preventive effect on skeletal muscle fibrosis by administration of an ACE inhibitor. Skeletal muscle fibrosis was significantly increased in STZ-induced diabetic mice compared with control mice from 2 to 14 days post-STZ. The ACE inhibitor prevented both skeletal muscle fibrosis and the reduction in muscle function in STZ-treated mice. Our study demonstrated that administration of an ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after onset of diabetes. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes. Future studies are required to clarify whether skeletal muscle fibrosis is also linked directly to physical activity.

Natural Killer T Cells Are Involved in Atherosclerotic Plaque Instability in Apolipoprotein-E Knockout Mice.

The infiltration and activation of macrophages as well as lymphocytes within atherosclerotic lesion contribute to the pathogenesis of plaque rupture. We have demonstrated that invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes that recognize glycolipid antigens, play a crucial role in atherogenesis. However, it remained unclear whether iNKT cells are also involved in plaque instability. Apolipoprotein E (apoE) knockout mice were fed a standard diet (SD) or a high-fat diet (HFD) for 8 weeks. Moreover, the SD- and the HFD-fed mice were divided into two groups according to the intraperitoneal injection of α-galactosylceramide (αGC) that specifically activates iNKT cells or phosphate-buffered saline alone (PBS). ApoE/Jα18 double knockout mice, which lack iNKT cells, were also fed an SD or HFD. Plaque instability was assessed at the brachiocephalic artery by the histological analysis. In the HFD group, αGC significantly enhanced iNKT cell infiltration and exacerbated atherosclerotic plaque instability, whereas the depletion of iNKT cells attenuated plaque instability compared to PBS-treated mice. Real-time PCR analyses in the aortic tissues showed that αGC administration significantly increased expressional levels of inflammatory genes such as IFN-γ and MMP-2, while the depletion of iNKT cells attenuated these expression levels compared to those in the PBS-treated mice. Our findings suggested that iNKT cells are involved in the exacerbation of plaque instability via the activation of inflammatory cells and upregulation of MMP-2 in the vascular tissues.

Enhanced Echo Intensity of Skeletal Muscle Is Associated With Exercise Intolerance in Patients With Heart Failure.

BACKGROUND: Skeletal muscle is quantitatively and qualitatively impaired in patients with heart failure (HF), which is closely linked to lowered exercise capacity. Ultrasonography (US) for skeletal muscle has emerged as a useful, noninvasive tool to evaluate muscle quality and quantity. Here we investigated whether muscle quality based on US-derived echo intensity (EI) is associated with exercise capacity in patients with HF. METHODS AND RESULTS: Fifty-eight patients with HF (61 ± 12 years) and 28 control subjects (58 ± 14 years) were studied. The quadriceps femoris echo intensity (QEI) was significantly higher and the quadriceps femoris muscle thickness (QMT) was significantly lower in the patients with HF than the controls (88.3 ± 13.4 vs 81.1 ± 7.5, P= .010; 5.21 ± 1.10 vs 6.54 ±1.34 cm, P< .001, respectively). By univariate analysis, QEI was significantly correlated with age, peak oxygen uptake (VO2), and New York Heart Association class in the HF group. A multivariable analysis revealed that the QEI was independently associated with peak VO2 after adjustment for age, gender, body mass index, and QMT: ß-coefficient = -11.80, 95%CI (-20.73, -2.86), P= .011. CONCLUSION: Enhanced EI in skeletal muscle was independently associated with lowered exercise capacity in HF. The measurement of EI is low-cost, easily accessible, and suitable for assessment of HF-related alterations in skeletal muscle quality.

Type 2 diabetes is an independent predictor of lowered peak aerobic capacity in heart failure patients with non-reduced or reduced left ventricular ejection fraction.

BACKGROUND: Although type 2 diabetes mellitus (T2DM) is one of the most frequent comorbidities in patients with chronic heart failure (CHF), the effects of T2DM on the exercise capacity of CHF patients are fully unknown. Here, we tested the hypothesis that the coexistence of T2DM lowers CHF patients' peak aerobic capacity. METHODS: We retrospectively analyzed the cases of 275 Japanese CHF patients with non-reduced ejection fraction (left ventricular ejection fraction [LVEF] ≥ 40%) or reduced EF (LVEF < 40%) who underwent cardiopulmonary exercise testing. We divided them into diabetic and nondiabetic groups in each CHF cohort. RESULTS: The mean peak oxygen uptake (VO2) value was 16.87 mL/kg/min in the non-reduced LVEF cohort and 15.52 mL/kg/min in the reduced LVEF cohort. The peak VO2 was lower in the diabetics versus the nondiabetics in the non-reduced LVEF cohort with the mean difference (95% confidence interval [95% CI]) of - 0.93 (- 1.82 to - 0.04) mL/kg/min and in the reduced LVEF cohort with the mean difference of - 1.05 (- 1.96 to - 0.15) mL/kg/min, after adjustment for age-squared, gender, anemia, renal function, LVEF, and log B-type natriuretic peptide (BNP). The adjusted VO2 at anaerobic threshold (AT), a submaximal aerobic capacity, was also decreased in the diabetic patients with both non-reduced and reduced LVEFs. Intriguingly, the diabetic patients had a lower adjusted peak O2 pulse than the nondiabetic patients in the reduced LVEF cohort, but not in the non-reduced LVEF cohort. A multivariate analysis showed that the presence of T2DM was an independent predictor of lowered peak VO2 in CHF patients with non-reduced LVEF and those with reduced LVEF. CONCLUSIONS: T2DM was associated with lowered peak VO2 in CHF patients with non-reduced or reduced LVEF. The presence of T2DM has a negative impact on CHF patients' exercise capacity, and the degree of impact is partly dependent on their LV systolic function.

Serum Brain-Derived Neurotrophic Factor Levels Are Associated with Skeletal Muscle Function but Not with Muscle Mass in Patients with Heart Failure.

Heart failure (HF) is associated with aberrant skeletal muscle impairments, which are closely linked to the severity of HF. A low level of brain-derived neurotrophic factor (BDNF), a myokine produced in the skeletal muscle, is known to be involved in reduced exercise capacity and poor prognosis in HF. However, little is known about the factors or conditions of skeletal muscle associated with BDNF levels. We investigated the association between serum BDNF levels and the skeletal muscle mass and function in HF patients (n = 60, 63 ± 13 years) and age-matched controls (n = 29, 61 ± 16 years). The serum BDNF level was significantly lower in the HF patients compared to the controls (24.9 ± 0.9 versus 28.6 ± 1.3, P = 0.021). In a univariate analysis, BDNF was significantly correlated with the peak oxygen uptake, estimated glomerular filtration rate, 10-m gait speed, and muscle strength, but not with the body mass index or lean mass in the HF group. A multiple linear regression analysis revealed that BDNF was independently associated with muscle strength (ß-coefficient = 2.80, 95%CI: 1.89-11.8, P = 0.008). Serum BDNF levels were associated with exercise capacity and skeletal muscle function, but not with muscle mass. These novel findings may suggest that BDNF production is controlled by muscle function and activity and consequently regulates exercise capacity, highlighting the importance of adequate training regarding skeletal muscle in HF patients.

C/EBPε ΔRS derived from a neutrophil-specific granule deficiency patient interacts with HDAC1 and its dysfunction is restored by trichostatin A.

CCAAT/enhancer binding protein epsilon (C/EBPε), a myeloid-specific transcription factor, plays an important role in granulopoiesis. A loss-of-function mutation in this protein can result in an abnormal development of neutrophils and eosinophils, known as neutrophil-specific granule deficiency (SGD). The transcriptional activity of C/EBPε is regulated by interactions with other transcription factors and/or post-translational modification, including acetylation. Previously, we reported a novel SGD patient who had a homozygous mutation for two amino acids, arginine (R247) and serine (S248), which were deleted in the basic leucine zipper domain of C/EBPε (ΔRS) and exhibited loss of transcriptional activity with aberrant protein-protein interactions. In the present study, we found that a single amino acid deletion of either R247 (ΔR) or S248 (ΔS) was sufficient for the loss of C/EBPε transcriptional activity, while an amino acid substitution at S248 to alanine in C/EBPε (SA) had comparable transcriptional activity with the wild-type C/EBPε (WT). Although acetylation at lysine residues (K121 and K198) is indispensable for C/EBPε transcriptional activity, an acetylation mimic form of ΔRS (ΔRS-K121/198Q) did not exhibit the transcriptional activity. Interestingly, we discovered that ΔRS, ΔR, ΔS, and ΔRS-K121/198Q interacted with histone deacetylase 1 (HDAC1), whereas WT and SA did not. Furthermore, the proteoglycan 2/eosinophil major basic protein induction activity of ΔRS, ΔR, and ΔS could be restored by the HDAC inhibitor, trichostatin A (TSA), and protein-protein interactions between ΔRS and Gata1 could also be recovered by TSA treatment. Taken together, our results show that TSA has the potential to restore the transcriptional activity of ΔRS, indicating that the inhibition of HDAC1 could be a molecularly targeted treatment for SGD with ΔRS.

Diastolic Intra-Left Ventricular Pressure Difference During Exercise: Strong Determinant and Predictor of Exercise Capacity in Patients With Heart Failure.

BACKGROUND: Although the enhancement of early-diastolic intra-left ventricular pressure difference (IVPD) during exercise is considered to maintain exercise capacity, little is known about their relationship in heart failure (HF). METHODS AND RESULTS: Cardiopulmonary exercise testing and exercise-stress echocardiography were performed in 50 HF patients (left ventricular [LV] ejection fraction 39 ± 15%). Echocardiographic images were obtained at rest and submaximal and peak exercise. Color M-mode Doppler images of LV inflow were used to determine IVPD. Thirty-five patients had preserved exercise capacity (peak oxygen consumption [VO2] ≥14 mL·kg-1·min-1; group 1) and 15 patients had reduced exercise capacity (group 2). During exercise, IVPD increased only in group 1 (group 1: 1.9 ± 0.9 mm Hg at rest, 4.1 ± 2.0 mm Hg at submaximum, 4.7 ± 2.1 mm Hg at peak; group 2: 1.9 ± 0.8 mm Hg at rest, 2.1 ± 0.9 mm Hg at submaximum, 2.1 ± 0.9 mm Hg at peak). Submaximal IVPD (r = 0.54) and peak IVPD (r = 0.69) were significantly correlated with peak VO2. Peak IVPD determined peak VO2 independently of LV ejection fraction. Moreover, submaximal IVPD could well predict the reduced exercise capacity. CONCLUSION: Early-diastolic IVPD during exercise was closely associated with exercise capacity in HF. In addition, submaximal IVPD could be a useful predictor of exercise capacity without peak exercise in HF patients.

The Embryonic Stem Cell-Specific Transcription Factor ZFP57 Promotes Liver Metastasis of Colorectal Cancer.

BACKGROUND: The embryonic stem cell-specific transcription factor, ZFP57, has been shown to play an important role in tumor formation. In this study, we examined if ZFP57 is involved in colorectal cancer metastasis. MATERIALS AND METHODS: First, we used colorectal cancer cell lines to perform in vivo metastatic experiments with nude mice. Next, we carried out immunohistochemical analysis of clinical specimens of colorectal cancers. RESULTS: In liver metastatic experiments using human colorectal cancer HT29 and HCT116 cells, liver polymetastases occurred at high frequency in ZFP57-overexpressing HT29 and HCT116 cells, whereas both control cells only resulted in oligometastases. Next, we analyzed ZFP57 expression using clinical specimens. Liver metastasis-positive cases were more frequently associated with ZFP57 overexpression than negative cases in primary lesions of colorectal cancer, and the overexpression was particularly remarkable in tumor invasive lesions. Furthermore, ZFP57 overexpression was significantly correlated not only with liver metastasis but also with lymph node metastasis. In addition, the expression level of ZFP57 was significantly correlated with that of the metastasis-related gene NANOG. We also found that ZFP57 overexpression reduced the progression-free survival rate of patients with colorectal cancer. CONCLUSIONS: This study demonstrated that ZFP57 plays an important role in the hematogenous metastasis of colorectal cancer, suggesting that it could be used as a novel treatment target.

Prognostic impact of body mass index and culprit lesion calcification in patients with acute myocardial infarction.

Patients with acute myocardial infarction (AMI) with low body mass index (BMI) have worse outcomes than obese patients, and this phenomenon is recognized as "obesity paradox." Coronary calcification is associated with cardiac events. However, the association between BMI and calcification and their involvement in the mortality of AMI patients remain unknown. This study consecutively enrolled 517 patients with AMI who underwent emergent coronary intervention within 24 h after onset. Patients were divided into four groups according to the baseline BMI interquartile ranges: Q1 (BMI < 21.9 kg/m2), Q2 (21.9 ≤ BMI < 24.0 kg/m2), Q3 (24.0 ≤ BMI < 26.0 kg/m2), and Q4 (BMI ≥ 26.0 kg/m2). Calcification in the culprit lesion was also evaluated. The Q1 group was older and had a lower frequency of coronary risk factors. Moderate/severe calcification was most frequently observed in Q1, followed by Q2, Q3, and Q4. The Q1 group had the highest all-cause mortality, and patients with moderate/severe calcification had a higher all-cause mortality than that in patients without calcification. The highest all-cause mortality was observed in Q1with calcification, and the lowest was in Q4 without calcification. Q1 and the presence of moderate/severe calcification were independently associated with all-cause mortality. Although low-BMI patients with AMI had a lower frequency of coronary risk factors, they had a worse all-cause mortality than that in high-BMI patients. Our findings suggest that lesion calcification and its possible association with low BMI are involved in the higher mortality rate in these patients.

Impact of admission liver stiffness on long-term clinical outcomes in patients with acute decompensated heart failure.

Liver stiffness (LS) has been reported to be a marker of liver congestion caused by elevated central venous pressure in heart failure (HF) patients. Recent studies demonstrated that LS could be non-invasively measured by virtual touch quantification (VTQ). However, its prognostic implication in patients with acute decompensated heart failure (ADHF) is unclear. This study sought to determine whether LS measured by VTQ could be a determinant of subsequent adverse events in ADHF patients. We prospectively recruited 70 ADHF patients who underwent LS measurement by VTQ on admission in our university hospital between June 2016 and April 2018. The primary outcome of interest was the composite of all-cause mortality and worsening HF. During a median follow-up period of 272 (interquartile range 122-578) days, there were 26 (37%) events, including 5 (7%) deaths and 21 (30%) cases of worsening HF. The c-index of LS for predicting the composite of adverse events was 0.77 (95% CI 0.66-0.88), and the optimal cut-off value of LS was 1.50 m/s. Adverse events were more frequently observed in patients with high LS (≥ 1.50 m/s) compared to those with low LS (< 1.50 m/s). Multivariable Cox regression analyzes revealed that higher LS was independently associated with increased subsequent risk of adverse events after adjustment for confounders. In conclusion, high admission LS was an independent determinant of worse clinical outcomes in patients with ADHF. This finding suggests that LS on admission is useful for risk stratification of patients with ADHF.

GA-Binding Protein Alpha Is Involved in the Survival of Mouse Embryonic Stem Cells.

Ets-related transcription factor GA-binding protein alpha (GABPα), which is encoded by Gabpa, is expressed in a variety of cell types and is involved in cellular functions such as cell cycle regulation, apoptosis, and differentiation. Here, we generated Gabpa conditional knockout embryonic stem cells (ESCs) and characterized its cellular phenotypes. Disruption of Gabpa revealed that the proliferation of Gabpa-null ESCs was drastically repressed and cells started to die within 2 days. The repressed proliferation of Gabpa-null ESCs was recovered by artificially forced expression of GABPα. Expression analysis showed that p53 mRNA levels were comparable; however, p53 target genes, including Cdkn1a/p21, Mdm2, and Gadd45a, were upregulated and cell cycle-related genes, including Cyclin D1/D2 and Cyclin E1/E2, were downregulated in Gabpa-null ESCs. Interestingly, p53 and cleaved Caspase3 expressions were enhanced in the cells and reduced proliferation as well as cell death of Gabpa-null ESCs were rescued by either transfection of p53 RNAi or treatment of the p53 inhibitor pifithrin-α. These results suggest that GABPα inhibits the accumulation of p53 and is involved in the proliferation and survival of ESCs. Stem Cells 2017;35:2229-2238.

Impact of High Respiratory Exchange Ratio During Submaximal Exercise on Adverse Clinical Outcome in Heart Failure.

BACKGROUND: Oxygen uptake (V̇O2) at peak workload and anaerobic threshold (AT) workload are often used for grading heart failure (HF) severity and predicting all-cause mortality. The clinical relevance of respiratory exchange ratio (RER) during exercise, however, is unknown. Methods and Results: We retrospectively studied 295 HF patients (57±15 years, NYHA class I-III) who underwent cardiopulmonary exercise testing. RER was measured at rest; at AT workload; and at peak workload. Peak V̇O2 had an inverse correlation with RER at AT workload (r=-0.256), but not at rest (r=-0.084) or at peak workload (r=0.090). Using median RER at AT workload, we divided the patients into high RER (≥0.97) and low RER (<0.97) groups. Patients with high RER at AT workload were characterized by older age, lower body mass index, anemia, and advanced NYHA class. After propensity score matching, peak V̇O2 tended to be lower in the high-RER than in the low-RER group (14.9±4.5 vs. 16.1±5.0 mL/kg/min, P=0.06). On Kaplan-Meier analysis, HF patients with a high RER at AT workload had significantly worse clinical outcomes, including all-cause mortality and rate of readmission due to HF worsening over 3 years (29% vs. 15%, P=0.01). CONCLUSIONS: High RER during submaximal exercise, particularly at AT workload, is associated with poor clinical outcome in HF patients.

Decomposition method for fast computation of gigapixel-sized Fresnel holograms on a graphics processing unit cluster.

A parallel computation method for large-size Fresnel computer-generated hologram (CGH) is reported. The method was introduced by us in an earlier report as a technique for calculating Fourier CGH from 2D object data. In this paper we extend the method to compute Fresnel CGH from 3D object data. The scale of the computation problem is also expanded to 2 gigapixels, making it closer to real application requirements. The significant feature of the reported method is its ability to avoid communication overhead and thereby fully utilize the computing power of parallel devices. The method exhibits three layers of parallelism that favor small to large scale parallel computing machines. Simulation and optical experiments were conducted to demonstrate the workability and to evaluate the efficiency of the proposed technique. A two-times improvement in computation speed has been achieved compared to the conventional method, on a 16-node cluster (one GPU per node) utilizing only one layer of parallelism. A 20-times improvement in computation speed has been estimated utilizing two layers of parallelism on a very large-scale parallel machine with 16 nodes, where each node has 16 GPUs.

Randomized Trial of Effect of Urate-Lowering Agent Febuxostat in Chronic Heart Failure Patients with Hyperuricemia (LEAF-CHF).

Hyperuricemia is an independent predictor of mortality in patients with chronic heart failure. The aim of the study is to determine whether a urate-lowering agent febuxostat, an inhibitor of xanthine oxidase, may improve the clinical outcomes in chronic heart failure patients with hyperuricemia when compared to conventional treatment. This multicenter, prospective, randomized, open-label, blinded endpoint study with a follow-up period of 24 weeks will enroll 200 Japanese chronic heart failure patients with hyperuricemia. The eligibility criteria include a diagnosis of chronic heart failure (New York Heart Association functional class II-III with a history of hospitalization due to worsening of heart failure within the last 2 years), reduced left ventricular systolic function (left ventricular ejection fraction < 40%) and increased plasma natriuretic peptide [plasma B-type natriuretic peptide (BNP) ≥ 100 pg/mL or N-terminal pro BNP (NT-proBNP) ≥ 400 pg/mL], and hyperuricemia (serum uric acid >7.0 mg/dL and ≤ 10 mg/dL) at the screening visit. The primary outcome is the difference in the plasma BNP levels between the baseline and 24 weeks of treatment. The plasma BNP levels are measured in the central laboratory in a blinded manner. This study investigates the efficacy and safety of febuxostat in chronic heart failure patients with hyperuricemia.

Pre-ischaemic mitochondrial substrate constraint by inhibition of malate-aspartate shuttle preserves mitochondrial function after ischaemia-reperfusion.

KEY POINTS: Pre-ischaemic administration of aminooxiacetate (AOA), an inhibitor of the malate-aspartate shuttle (MAS), provides cardioprotection against ischaemia-reperfusion injury. The underlying mechanism remains unknown. We examined whether transient inhibition of the MAS during ischaemia and early reperfusion by AOA treatment could prevent mitochondrial damage at later reperfusion. The AOA treatment preserved mitochondrial respiratory capacity with reduced mitochondrial oxidative stress during late reperfusion to the same extent as ischaemic preconditioning (IPC). However, AOA treatment, but not IPC, reduced the myocardial interstitial concentration of tricarboxylic acid cycle intermediates at the onset of reperfusion. The results obtained in the present study demonstrate that metabolic regulation by inhibition of the MAS at the onset of reperfusion may be beneficial for the preservation of mitochondrial function during late reperfusion in an IR-injured heart. ABSTRACT: Mitochondrial dysfunction plays a central role in ischaemia-reperfusion (IR) injury. Pre-ischaemic administration of aminooxyacetate (AOA), an inhibitor of the malate-aspartate shuttle (MAS), provides cardioprotection against IR injury, although the underlying mechanism remains unknown. We hypothesized that a transient inhibition of the MAS during ischaemia and early reperfusion could preserve mitochondrial function at later phase of reperfusion in the IR-injured heart to the same extent as ischaemic preconditioning (IPC), which is a well-validated cardioprotective strategy against IR injury. In the present study, we show that pre-ischaemic administration of AOA preserved mitochondrial complex I-linked state 3 respiration and fatty acid oxidation during late reperfusion in IR-injured isolated rat hearts. AOA treatment also attenuated the excessive emission of mitochondrial reactive oxygen species during state 3 with complex I-linked substrates during late reperfusion, which was consistent with reduced oxidative damage in the IR-injured heart. As a result, AOA treatment reduced infarct size after reperfusion. These protective effects of MAS inhibition on the mitochondria were similar to those of IPC. Intriguingly, the protection of mitochondrial function by AOA treatment appears to be different from that of IPC because AOA treatment, but not IPC, downregulated myocardial tricarboxilic acid (TCA)-cycle intermediates at the onset of reperfusion. MAS inhibition thus preserved mitochondrial respiratory capacity and decreased mitochondrial oxidative stress during late reperfusion in the IR-injured heart, at least in part, via metabolic regulation of TCA cycle intermediates in the mitochondria at the onset of reperfusion.

A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPε Leads to Neutrophil-Specific Granule Deficiency.

Neutrophil-specific granule deficiency (SGD) is a rare autosomal recessive primary immunodeficiency characterized by neutrophil dysfunction, bilobed neutrophil nuclei and lack of neutrophil-specific granules. Defects in a myeloid-specific transcription factor, CCAAT/enhancer binding protein-ε (C/EBPε), have been identified in two cases in which homozygous frameshift mutations led to loss of the leucine zipper domain. In this study, we report a 55-y-old woman affected with SGD caused by a novel homozygous 2-aa deletion (ΔRS) in the leucine zipper domain of the C/EBPε gene. The patient showed characteristic neutrophil abnormalities and recurrent skin infections; however, there was no history of deep organ infections. Biochemical analysis revealed that, in contrast to the two frameshift mutations, the ΔRS mutant maintained normal cellular localization, DNA-binding activity, and dimerization, and all three mutants exhibited marked reduction in transcriptional activity. The ΔRS mutant was defective in its association with Gata1 and PU.1, as well as aberrant cooperative transcriptional activation of eosinophil major basic protein. Thus, the ΔRS likely impairs protein-protein interaction with other transcription factors, resulting in a loss of transcriptional activation. These results further support the importance of the leucine zipper domain of C/EBPε for its essential function, and indicate that multiple molecular mechanisms lead to SGD.