Leukocyte-depleted terminal blood cardioplegia provides superior myocardial protective effects in association with myocardium-derived nitric oxide and peroxynitrite production for patients undergoing prolonged aortic crossclamping for more than 120 minutes

AbstractObjectivesThis study was designed to examine the myocardial protective effect of leukocyte-depleted terminal blood cardioplegia in association with nitric oxide and peroxynitrite production, especially for patients undergoing prolonged aortic crossclamping.MethodsFifty-four patients (34 men, 20 women, mean age 56.7 ± 12.7 years) undergoing aortic valve replacement were randomly allocated to one of two groups; group LDTC (n = 27) received 10 minutes of leukocyte-depleted terminal blood cardioplegic solution, and group CONT (n = 27) served as controls. Each group was subdivided into 2 groups: aortic crossclamping for less than 120 minutes in groups LDTC-S (n = 13) and CONT-S (n = 14); aortic crossclamping for 120 minutes or more in groups LDTC-L (n = 14) and CONT-L (n = 13).ResultsAfter aortic unclamping, group LDTC-L showed higher incidence of spontaneous defibrillation (78.6% vs 30.8%, P = .0213), higher plasma nitrate + nitrite in the coronary sinus effluent (32.5 ± 4.1 vs 28.7 ± 3.0 μmol/L, P = .0013), lower differences between coronary sinus effluent and arterial blood in the percentage ratio of nitrotyrosine to tyrosine (myocardium-derived peroxynitrite; 2.987% ± 0.576% vs 3.951% ± 0.952%, P = .0036), and plasma polymorphonuclear-elastase (113.9 ± 21.3 vs 155.5 ± 41.6 μg/L, P = .0029) and malondialdehyde (2.75 ± 0.67 vs 4.02 ± 0.96 μmol/L, P = .0005) than group CONT did. Postoperatively, group LDTC-L showed lower human-heart fatty acid–binding protein (111.4 ± 25.2 vs 156.4 ± 38.6 IU/L, P = .0013), lower creatine kinase–muscle and brain (19.2 ± 4.7 vs 24.8 ± 6.5 IU/L, P = .0120), and smaller requirement of catecholamine (5.44 ± 2.29 vs 8.45 ± 3.42 μg · kg−1 · min−1, P = .0122). There were no significant differences in these parameters between groups LDTC-S and CONT-S.ConclusionsThis study demonstrated that leukocyte-depleted terminal blood cardioplegia provided superior myocardial protective effects and regulated myocardial-derived nitric oxide and peroxynitrite production only for patients undergoing aortic crossclamping for more than 120 minutes. The results suggest that prolonged aortic crossclamping deteriorates the tolerance to leukocyte-mediated myocardial injury accompanied by endothelial dysfunction associated with nitric oxide and peroxynitrite production

Nutrient intake, serum lipids and iron status of colligiate rugby players

BACKGROUND: There are two main playing positions in rugby (backs and forwards), which demonstrate different exercise patterns, roles, and physical characteristics. The purpose of this study was: 1) to collect baseline data on nutrient intake in order to advise the athletes about nutrition practices that might enhance performance, and 2) to compare serum lipids, lipoproteins, apolipoproteins (apo), lecithin:cholesterol acyltransferase (LCAT) activity, and iron status of forwards and backs. METHODS: The sporting group was divided into 18 forwards and 16 backs and were compared with 26 sedentary controls. Dietary information was obtained with a food frequency questionnaire. RESULTS: There were significant differences among the three groups. The forwards had the highest body weight, body mass index, percentage of body fat (calculated by sum of four skinfold thicknesses), as well as the highest lean body mass, followed by the backs and the control group. The mean carbohydrate intake was marginal and protein intake was lower than the respective recommended targets in all three groups. The mean intakes of calcium, magnesium, and vitamins A, B(1), B(2), and C were lower than the respective Japanese recommended dietary allowances or adequate dietary intakes for the rugby players. The forwards had significantly lower high-density lipoprotein cholesterol (HDL-C) and HDL(2)-C than the backs and had significantly higher apo B and LCAT activity than the controls. The backs showed significantly higher HDL-C, HDL(3)-C, low-density lipoprotein cholesterol, and apo A-I, and LCAT activity than the controls. Four forwards (22%), five backs (31%), and three controls (12%) had hemolysis. None of the rugby players had anemia or iron depletion. CONCLUSION: The findings of our study indicate that as the athletes increased their carbohydrate and protein intake, their performance and lean body mass increased. Further, to increase mineral and vitamin intakes, we recommended athletes increase their consumption of green and other vegetables, milk and dairy products, and fruits. The forwards showed more atherogenic lipid profiles than the backs, whereas the backs showed not only anti-atherogenic lipid profile, but also showed more atherogenic lipid profile relative to the control group. Additionally, our study showed none of the rugby players experienced anemia and/or iron depletion

New readout and data-acquisition system in an electron-tracking Compton camera for MeV gamma-ray astronomy (SMILE-II)

For MeV gamma-ray astronomy, we have developed an electron-tracking Compton camera (ETCC) as a MeV gamma-ray telescope capable of rejecting the radiation background and attaining the high sensitivity of near 1 mCrab in space. Our ETCC comprises a gaseous time-projection chamber (TPC) with a micro pattern gas detector for tracking recoil electrons and a position-sensitive scintillation camera for detecting scattered gamma rays. After the success of a first balloon experiment in 2006 with a small ETCC (using a 10$\times$10$\times$15 cm$^3$ TPC) for measuring diffuse cosmic and atmospheric sub-MeV gamma rays (Sub-MeV gamma-ray Imaging Loaded-on-balloon Experiment I; SMILE-I), a (30 cm)$^{3}$ medium-sized ETCC was developed to measure MeV gamma-ray spectra from celestial sources, such as the Crab Nebula, with single-day balloon flights (SMILE-II). To achieve this goal, a 100-times-larger detection area compared with that of SMILE-I is required without changing the weight or power consumption of the detector system. In addition, the event rate is also expected to dramatically increase during observation. Here, we describe both the concept and the performance of the new data-acquisition system with this (30 cm)$^{3}$ ETCC to manage 100 times more data while satisfying the severe restrictions regarding the weight and power consumption imposed by a balloon-borne observation. In particular, to improve the detection efficiency of the fine tracks in the TPC from $\sim$10\% to $\sim$100\%, we introduce a new data-handling algorithm in the TPC. Therefore, for efficient management of such large amounts of data, we developed a data-acquisition system with parallel data flow.Comment: 11 pages, 24 figure

脳梗塞モデルラットにおける虚血後の時期依存的な抗炎症性M2マクロファージ活性化変調の役割

Cerebral ischemia triggers inflammatory changes, and early complications and unfavorable outcomes of endovascular thrombectomy for brain occlusion promote the recruitment of various cell types to the ischemic area. Although anti-inflammatory M2-type macrophages are thought to exert protective effects against cerebral ischemia, little has been clarified regarding the significance of post-ischemic phase-dependent modulation of M2-type macrophages. To test our hypothesis that post-ischemic phase-dependent modulation of macrophages represents a potential therapy against ischemic brain damage, the effects on rats of an M2-type macrophage-specific activator, Gc-protein macrophage-activating factor (GcMAF), were compared with vehicle-treated control rats in the acute (day 0–6) or subacute (day 7–13) phase after ischemia induction. Acute-phase GcMAF treatment augmented both anti-inflammatory CD163+M2-type- and pro-inflammatory CD16+ M1-type macrophages, resulting in no beneficial effects. Conversely, subacute-phase GcMAF injection increased only CD163+ M2-type macrophages accompanied by elevated mRNA levels of arginase-1 and interleukin-4. M2-type macrophages co-localized with CD36+ phagocytic cells led to clearance of the infarct area, which were abrogated by clodronate-liposomes. Expression of survival-related molecules on day 28 at the infarct border was augmented by GcMAF. These data provide new and important insights into the significance of M2-type macrophage-specific activation as post-ischemic phase-dependent therapy

Angiotensin II alters the expression of duodenal iron transporters, hepatic hepcidin, and body iron distribution in mice

Purpose: Angiotensin II (ANG II) has been shown to affect iron metabolism through alteration of iron transporters, leading to increased cellular and tissue iron contents. Serum ferritin, a marker of body iron storage, is elevated in various cardiovascular diseases, including hypertension. However, the associated changes in iron absorption and the mechanism underlying increased iron content in a hypertensive state remain unclear. Methods: C57BL6/J mice were treated with ANG II to generate a model of hypertension. Mice were divided into 3 groups: (1) control, (2) ANG II-treated, and (3) ANG II-treated and ANG II receptor blocker (ARB)-administered (ANG II-ARB) groups. Results: Mice treated with ANG II showed increased serum ferritin levels compared to vehicle-treated control mice. In ANG II-treated mice, duodenal divalent metal transporter-1 (DMT1) and ferroportin (FPN) expression levels were increased and hepatic hepcidin mRNA expression and serum hepcidin concentration were reduced. The mRNA expression of bone morphogenetic protein 6 (BMP6) and CCAAT/enhancer binding protein alpha (C/EBPα), which are regulators of hepcidin, was also down-regulated in the livers of ANG II-treated mice. In terms of tissue iron content, macrophage iron content and renal iron content were increased by ANG II treatment, and these increases were associated with reduced expression of transferrin receptor 1 and FPN and increased expression of ferritin. These changes induced by ANG II treatment were ameliorated by administration of an ARB. Conclusions: ANG II altered the expression of duodenal iron transporters and reduced hepcidin levels, contributing to the alteration of body iron distribution

Effect of Deferoxamine on Renal Fibrosis

Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD). Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO), on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO). Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1)-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22phox expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses

Complexity and Conservation of Thermospermine-Responsive uORFs of SAC51 Family Genes in Angiosperms

ACAULIS5 (ACL5) encodes thermospermine synthase in Arabidopsis and its loss-of-function mutant acl5 shows excess xylem differentiation and severe dwarfism. SAC51 encodes a basic helix-loop-helix (bHLH) protein and was identified from sac51-d, a dominant suppressor mutant of acl5, which restores the wild-type phenotype without thermospermine. The 5′ leader of the SAC51 mRNA contains multiple upstream open-reading frames (uORFs) and sac51-d has a premature stop codon in the fourth uORF. This uORF is conserved among SAC51 family genes in vascular plants. According to the GUS reporter assay, the SAC51 promoter was not responsive to thermospermine but the SAC51 5′ leader fused to the constitutive 35S promoter enhanced the GUS activity in response to thermospermine. Disruption experiments of each start codon of the SAC51 uORFs revealed that uORF4 and uORF6 whose start codon corresponds to the second methionine codon of uORF4 had an inhibitory effect on the main ORF translation while the other four uORFs rather had a stimulatory effect. The response of the 5′ leader to thermospermine was retained after disruption of each one of six start codons of these uORFs but abolished by mutating both uORF4 and uORF6 start codons, suggesting the importance of the C-terminal sequence shared by these uORFs in the action of thermospermine. We introduced GUS fusions with 5′ leaders of SAC51 family genes from other angiosperm species into Arabidopsis and found that all 5′ leaders responsive to thermospermine, so far examined, contained these two conserved, and overlapping uORFs

Iron-induced atrophy via Akt-FOXO3-E3 Ubiquitin ligase pathway

Skeletal muscle wasting or sarcopenia is a critical health problem. Skeletal muscle atrophy is induced by an excess of iron, which is an essential trace metal for all living organisms. Excessive amounts of iron catalyze the formation of highly toxic hydroxyl radicals via the Fenton reaction. However, the molecular mechanism of iron-induced skeletal muscle atrophy has remained unclear. In this study, 8-weeks-old C57BL6/J mice were divided into 2 groups: vehicle-treated group and the iron-injected group (10 mg iron·day-1·mouse-1) during 2 weeks. Mice in the iron-injected group showed an increase in the iron content of the skeletal muscle and serum and ferritin levels in the muscle, along with reduced skeletal muscle mass. The skeletal muscle showed elevated mRNA expression of the muscle atrophy-related E3 ubiquitin ligases, atrogin-1 and muscle ring finger-1(MuRF1), on days 7 and 14 of iron treatment. Moreover, iron-treated mice showed reduced phosphorylation of Akt and forkhead box O3 (FOXO3a) in skeletal muscles. Inhibition of FOXO3a using siRNA in vitro in C2C12 myotube cells inhibited iron-induced upregulation of atrogin-1 and MuRF1 and reversed the reduction in myotube diameters. Iron-load caused oxidative stress, and an oxidative stress inhibitor abrogated iron-induced muscle atrophy by reactivating the Akt-FOXO3 pathway. Iron-induced skeletal muscle atrophy is suggested to involve the E3 ubiquitin ligase mediated by the reduction of Akt-FOXO3a signaling by oxidative stress

チョウカン トランス ポーター オ ブンシ ヒョウテキ トシタ ジンシッカン チリョウホウ ノ カクリツ オ メザシテ

The understanding of intestinal function in chronic kidney disease（CKD）has been important elements in the clinical management of CKD with dietary and drug therapy. Numerous studies have indicated that CKD patients or model rats have enzymatic abnormalities and impairments of absorptive function in the small intestine. However, it has been still unclear how different of the intestinal function in CKD. In this study, we demonstrated the microarray analysis of global gene expression in intestine of adenine-induced CKD rat. DNA microarray analysis using Affymextrix rat gene chip revealed that CKD caused great changes in gene expression in the rat duodenum : about４００genes exhibited more than a two-fold change in expression level. Gene ontology analysis showed that a global regulation of genes by CKD involved in iron ion binding, alcoholic, organic acid and lipid metabolism. Furthermore, we found markedly changes of a number of intestinal transporters gene expression. These results suggest that CKD may alter some nutrient metabolism in the small intestine by modifying the expression of specific genes. The intestinal transcriptome database of CKD might be useful to develop the novel drugs or functional foods targeting several intestinal genes including transporters for the management of CKD