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The aim of the present study was to examine the hypothesis that acceleration of gap junction (GJ) closure during ischemia contributes to anti-infarct tolerance afforded by preconditioning (PC). First, the effects of PC on GJ communication during ischemia were assessed. Isolated buffer-perfused rabbit hearts were subjected to 5-min global ischemia with or without PC with two cycles of 5-min ischemia/5-min reperfusion or a GJ blocker (2 mM heptanol), and then the tissue excised from the ischemic region was incubated in anoxic buffer containing lucifer yellow (LY; 2.5 mg/ml), a tracer of GJ permeability, for 20 min at 37 degrees C. PC and heptanol significantly reduced the area to which LY was transported in the ischemic myocardium by 39% and by 54%, respectively. In the second series of experiments, three GJ blockers (heptanol, 18beta-glycyrrhetinic acid, and 2,3-butanedione monoxime) infused after the onset of ischemia reduced infarct size after 30-min ischemia/2-h reperfusion to an extent equivalent to that in the case of PC. In the third series of experiments, Western blotting for connexin43 (Cx43) showed that PC shortened the time to the onset of ischemia-induced Cx43 dephosphorylation but reduced the extent of Cx43 dephosphorylation during a 30-min period of ischemia. Calphostin C, a protein kinase C (PKC) inhibitor, abolished preservation of phosphorylated Cx43 but not the early onset of Cx43 dephosphorylation after ischemia in the preconditioned myocardium. These results suggest that PC-induced reduction of GJ permeability during ischemia, presumably by PKC-mediated Cx43 phosphorylation, contributes to infarct size limitation.

PC activated AMPK and up-regulated GLUT4 expression in a PKC-dependent manner. This GLUT4 up-regulation at 24 h after PC may contribute to attenuation of myocardial stunning.

IntroductionMyelodysplastic syndrome (MDS) is a slowly progressing leukemic disorder that predominantly affects elderly people. 1,2 Individuals with MDS exhibit cytopenia in at least one lineage of peripheral blood (PB) cells. However, the bone marrow (BM) of many affected individuals is hyper-to normocellular, suggesting the presence of ineffective hematopoiesis. Another characteristic feature of MDS is the dysplasia of at least one lineage (myeloid, erythroid, or megakaryocyte-platelet lineage) of BM cells, such as neutrophils with pseudo-Pelger anomaly, hypersegmented neutrophils, ringed sideroblasts, and micromegakaryocytes. 3 The clinical course of MDS can be divided into several phases. Patients in the indolent, chronic phase exhibit a decrease in the number of PB cells and are diagnosed with either refractory anemia (RA) or RA with ringed sideroblasts (RARS). Individuals with dysplastic change in BM and monocytosis in PB are diagnosed with chronic myelomonocytic leukemia (CMMoL). After a variable interval, however, some individuals with MDS undergo a progressive transformation to overt leukemia. As the number of blast cells increases, the patients are diagnosed with RA with an excess of blasts (RAEB; 5%-19% blasts in BM), RAEB in transformation (RAEB-t; 20%-29% blasts in BM), and, finally, MDS-associated acute leukemia (Ͼ 20% blasts in BM).MDS-associated leukemia is rarely cured by conventional chemotherapy. Intensive treatment with anticancer drugs often results in prolonged myelosuppression, which is one of the main causes of disease-related death. 4 Individuals with acute leukemia that results from MDS therefore have a poor prognosis, which contrasts with the somewhat better outcome of de novo acute myeloid leukemia (AML) in this older group of patients. It is thus essential to differentiate MDS-associated leukemia from de novo AML to select the optimal therapeutic strategy.This task is complicated, however, by the fact that some patients with de novo AML may exhibit dysplastic changes in BM during the course of their disease. [5][6][7] It is thus extremely difficult to diagnose elderly individuals with overt leukemia if their BM exhibits dysplasia. The occurrence of a period of cytopenia before the development of leukemia indicates that the patient should be treated for MDS-associated leukemia. Without the clinical history, however, there are currently few other criteria with which to differentiate MDS-associated leukemia from de novo AML with The development of DNA microarrays or DNA chips has revolutionized the analysis of gene expression profiles. Such DNA microarrays can contain tens of thousands of test complementary DNAs (cDNAs) or oligonucleotides and, with a single hybridization step, allow a systematic comparison of the expression of the corresponding genes between 2 given samples. 8 The completion of the human genome sequencing project will increase further the analytical power of this technology. The use of DNA microarrays has already allowed the identification of candidate mammalian genes ...

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Background There have been a number of recent reports on the use of autologous bone marrow implantation (BMI) in the treatment of peripheral arterial disease, with a clinical response rate of approximately 70%. However, the factors that influence efficacy have not yet been clarified. We have analyzed the relationship between the number of implanted bone marrow cells and the clinical efficacy of BMI. Methods and ResultsEight patients with arteriosclerosis obliterans were treated with BMI. Bone marrow was aspirated from the ilium (500-1,000 ml), the mononuclear cells were separated and then were implanted. The clinical effectiveness of BMI was evaluated by assessing changes in the ankle-brachial pressure index (ABI) and the transcutaneous oxygen pressure (TcO2) between the pre-treatment baseline, with follow-up testing at 4 weeks. These changes were defined as ∆ABI and ∆TcO2. The mean number of CD34-positive cells was 1.04±0.60× 10 6 /kg body weight. There was a strong correlation between the number of CD34-positive cells and ∆ABI (r=0.754, p=0.028). Conclusions It is likely that the number of implanted CD34-positive cells is one of the primary factors that influence the clinical efficacy of BMI. (Circ J 2004; 68: 1189 -1193