Surgical Management of Coexisting Coronary Artery and Valvular Heart Disease

Purpose: Combined coronary artery bypass (CAB) and valve surgery is one of the most challenging surgical procedures, but the operative results have improved over the years. Materials and Methods: From 1989 through 2004, combined CAB and valve operations were performed in 125 patients. Mean age was 63 years, and 86 patients were male. Forty-six patients were diagnosed with coronary artery disease during preoperative evaluation for valvular heart disease (VHD). All patients underwent CAB, and one or more underwent valve replacement or repair (mitral: 54, aortic: 61, tricuspid: 3, DVR: 7) simultaneously. Results: Mean number of distal graft was 1.98 ± 1.07, and LIMA was used in 68 % of patients. Early mortality occurred in 6 patients (4.8%), and the causes were heart failure (4) and sepsis (2). Mean follow-up duration was 91.4 ± 40.9 months (range: 47-245), and late mortality occurred in 4 patients. Kaplan Meier estimated survival rates at 1, 5, and 10 years were 94.4 %, 92.3%, and 89.9%, respectively. Conclusion: Combined coronary and valve operations can be performed safely with optimal surgical results. Although the surgical mortality of coexisting coronary and VHD is higher than either isolated coronary or valvular operations, it may not affect the long-term survival

Technological Progress in Generation of Induced Pluripotent Stem Cells for Clinical Applications

Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is achieved by viral-mediated transduction of defined transcription factors. Generation of iPSCs is of great medical interest as they have the potential to be a source of patient-specific cells. For the eventual goal of clinical application, it is necessary to overcome the limitations of low reprogramming efficiency and chromosomal abnormalities due to viral DNA integration. In this paper, we summarize the current state of reprogramming technology for generation of iPSCs and also discuss potential approaches to the development of safe iPSCs for personalized cell-based replacement therapy

Mehanizam akutne neurotoksičnosti u Sprague-Dawley štakora izazvane trovanjem endosulfanom

The purpose of this study was to investigate the molecular mechanism underlying oxidative and inflammatory neuronal cell death induced by endosulfan, a pesticide belonging to the chemical family of organochlorines. The cortical and hippocampal tissues derived from Sprague-Dawley (SD) rats treated with endosulfan exhibited increased intracellular accumulation of reactive oxygen species and oxidative damages to cellular macromolecules such as depletion of glutathione, lipid peroxidation, and protein carbonylation. Conversely, the expression of antioxidant enzymes including γ-glutamylcysteine ligase (GCL), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1) was markedly reduced in the brain tissues exposed to endosulfan. Moreover, during endosulfan-induced neuronal cell death, mRNA expression of pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was elevated, which seemed to be mediated by the activation of nuclear factor-kappa B (NF-κB) by phosphorylation of p65 subunit. These results suggest a new molecular mechanism underlying the endosulfan-induced acute neurotoxicity via induction of oxidative stress and pro-inflammatory responses.Istražen je molekularni mehanizam koji dovodi do smrti neurona potaknute oksidativnim i upalnim procesima uzrokovanim organoklornim pesticidom endosulfanom. U tkivima korteksa i hipokampusa Sprague-Dawley (SD) štakora tretiranih endosulfanom uočena su oksidativna oštećenja staničnih makromolekula, poput smanjene razine glutationa, lipidne peroksidacije i karbonilacije proteina, te povećane unutarstanične akumulacije reaktivnih kisikovih spojeva. Isto tako, u moždanom tkivu nakon izlaganja endosulfanu značajno je smanjena ekspresija enzimskih antioksidansa, uključujući i γ-glutamilcistein ligazu (GCL), superoksidnu dismutazu (SOD) i hem oksigenazu-1 (HO-1). Tijekom endosulfanom izazvane smrti neurona povećala se i ekspresija mRNA pro-upalnih citokina poput čimbenika nekroze tumora-α (TNF-α) i interleukina-1β (IL-1β), što je čini se bilo posredovano aktivacijom nuklearnoga faktora kapa B (NF-κB) putem fosforilacije podjedinice p65. Navedeni rezultati upućuju na novi molekularni mehanizam koji stoji iza akutne neurotoksičnosti izazvane endosulfanom putem indukcije oksidativnoga stresa i pro-upalnih odgovora

Role of G{alpha}12 and G{alpha}13 as Novel Switches for the Activity of Nrf2, a Key Antioxidative Transcription Factor

G{alpha}12 and G{alpha}13 function as molecular regulators responding to extracellular stimuli. NF-E2-related factor 2 (Nrf2) is involved in a protective adaptive response to oxidative stress. This study investigated the regulation of Nrf2 by G{alpha}12 and G{alpha}13. A deficiency of G{alpha}12, but not of G{alpha}13, enhanced Nrf2 activity and target gene transactivation in embryo fibroblasts. In mice, G{alpha}12 knockout activated Nrf2 and thereby facilitated heme catabolism to bilirubin and its glucuronosyl conjugations. An oligonucleotide microarray demonstrated the transactivation of Nrf2 target genes by G{alpha}12 gene knockout. G{alpha}12 deficiency reduced Jun N-terminal protein kinase (JNK)-dependent Nrf2 ubiquitination required for proteasomal degradation, and so did G{alpha}13 deficiency. The absence of G{alpha}12, but not of G{alpha}13, increased protein kinase C {delta} (PKC {delta}) activation and the PKC {delta}-mediated serine phosphorylation of Nrf2. G{alpha}13 gene knockout or knockdown abrogated the Nrf2 phosphorylation induced by G{alpha}12 deficiency, suggesting that relief from G{alpha}12 repression leads to the G{alpha}13-mediated activation of Nrf2. Constitutive activation of G{alpha}13 promoted Nrf2 activity and target gene induction via Rho-mediated PKC {delta} activation, corroborating positive regulation by G{alpha}13. In summary, G{alpha}12 and G{alpha}13 transmit a JNK-dependent signal for Nrf2 ubiquitination, whereas G{alpha}13 regulates Rho-PKC {delta}-mediated Nrf2 phosphorylation, which is negatively balanced by G{alpha}12

Cryptococcus neoformans Overcomes Stress of Azole Drugs by Formation of Disomy in Specific Multiple Chromosomes

Cryptococcus neoformans is a haploid environmental organism and the major cause of fungal meningoencephalitis in AIDS patients. Fluconazole (FLC), a triazole, is widely used for the maintenance therapy of cryptococcosis. Heteroresistance to FLC, an adaptive mode of azole resistance, was associated with FLC therapy failure cases but the mechanism underlying the resistance was unknown. We used comparative genome hybridization and quantitative real-time PCR in order to show that C. neoformans adapts to high concentrations of FLC by duplication of multiple chromosomes. Formation of disomic chromosomes in response to FLC stress was observed in both serotype A and D strains. Strains that adapted to FLC concentrations higher than their minimal inhibitory concentration (MIC) contained disomies of chromosome 1 and stepwise exposure to even higher drug concentrations induced additional duplications of several other specific chromosomes. The number of disomic chromosomes in each resistant strain directly correlated with the concentration of FLC tolerated by each strain. Upon removal of the drug pressure, strains that had adapted to high concentrations of FLC returned to their original level of susceptibility by initially losing the extra copy of chromosome 1 followed by loss of the extra copies of the remaining disomic chromosomes. The duplication of chromosome 1 was closely associated with two of its resident genes: ERG11, the target of FLC and AFR1, the major transporter of azoles in C. neoformans. This adaptive mechanism in C. neoformans may play an important role in FLC therapy failure of cryptococcosis leading to relapse during azole maintenance therapy