Long-term outcomes after definitive repair for tetralogy of Fallot with preservation of the pulmonary valve annulus

ObjectivesThe aim of our study was to evaluate the long-term outcomes after definitive repair of tetralogy of Fallot with preservation of the pulmonary valve (PV) annulus.MethodsFrom 1989 to 2000, 84 of 222 patients (37.8%) with tetralogy of Fallot and PV stenosis underwent definitive repair with preservation of the PV annulus without right ventriculotomy. PV commissurotomy was concomitantly performed in 74 patients (88.1%). The PV was bicuspid in 56 patients (66.7%); the mean Z value was −1.2 ± 1.5 (range, −4.9 to 2.4). The mean follow-up period was 15.8 ± 5.7 years (maximum, 22.8), and follow-up data were complete for 75 patients (89.3%).ResultsThe actuarial survival and freedom from reoperation rates at 20 years was 98.6% and 95.8%. The freedom from ventricular arrhythmia at 5, 10, 15, and 20 years was 98.7%, 89.6%, 74.1%, and 58.0%, respectively. All detected ventricular arrhythmias were isolated monofocal premature ventricular contractions. Freedom from moderate or greater pulmonary regurgitation at 5, 10, 15 and 20 years was 50.4%, 44.9%, 38.4%, and 35.7%, respectively. A bicuspid PV (hazard ratio, 2.910; 95% confidence interval, 1.404-6.204, P = .004) and a Z-value of less than −2 (hazard ratio, 1.948; 95% confidence interval, 0.915-5.857; P = .034) were the risk factors for developing moderate or greater pulmonary regurgitation.ConclusionsThe long-term outcomes after definitive repair of tetralogy of Fallot with preservation of the PV annulus were excellent. Although isolated, monofocal premature ventricular contractions were frequently observed, fatal ventricular arrhythmia was not. The indication should not only be decided by the PV annulus size, but also by the valvular morphology to maintain long-term PV competency

Integration-Free iPS Cells Engineered Using Human Artificial Chromosome Vectors

Human artificial chromosomes (HACs) have unique characteristics as gene-delivery vectors, including episomal transmission and transfer of multiple, large transgenes. Here, we demonstrate the advantages of HAC vectors for reprogramming mouse embryonic fibroblasts (MEFs) into induced pluripotent stem (iPS) cells. Two HAC vectors (iHAC1 and iHAC2) were constructed. Both carried four reprogramming factors, and iHAC2 also encoded a p53-knockdown cassette. iHAC1 partially reprogrammed MEFs, and iHAC2 efficiently reprogrammed MEFs. Global gene expression patterns showed that the iHACs, unlike other vectors, generated relatively uniform iPS cells. Under non-selecting conditions, we established iHAC-free iPS cells by isolating cells that spontaneously lost iHAC2. Analyses of pluripotent markers, teratomas and chimeras confirmed that these iHAC-free iPS cells were pluripotent. Moreover, iHAC-free iPS cells with a re-introduced HAC encoding Herpes Simplex virus thymidine kinase were eliminated by ganciclovir treatment, indicating that the HAC safeguard system functioned in iPS cells. Thus, the HAC vector could generate uniform, integration-free iPS cells with a built-in safeguard system

Gene expression in rat striatum following carbon monoxide poisoning

Carbon monoxide (CO) poisoning causes brain damage, which is attenuated by treatment with hydrogen [1,2], a scavenger selective to hydroxyl radical (·≡OH) [3]. This suggests a role of ·≡OH in brain damage due to CO poisoning. Studies have shown strong enhancement of ·≡OH production in rat striatum by severe CO poisoning with a blood carboxyhemoglobin (COHb) level >70% due to 3000 ppm CO, but not less severe CO poisoning with a blood COHb level at approximately 50% due to 1000 ppm CO [4]. Interestingly, 5% O2 causes hypoxia comparable with that by 3000 ppm CO and produces much less •OH than 3000 ppm CO does [4]. In addition, cAMP production in parallel with ·≡OH production [5] might contribute to ·≡OH production [6]. It is likely that mechanisms other than hypoxia contribute to brain damage due to CO poisoning [7]. To search for the mechanisms, we examined the effects of 1000 ppm CO, 3000 ppm CO and 5% O2 on gene expression in rat striatum. All array data have been deposited in the Gene Expression Omnibus (GEO) database under accession number GSE94780

Anti-Tumor Effects of MAPK-Dependent Tumor-Selective Oncolytic Vaccinia Virus Armed with CD/UPRT against Pancreatic Ductal Adenocarcinoma in Mice

Engineered vaccinia virus serves as an oncolytic virus for cancer virotherapy. We evaluated the oncolytic characteristics of VGF- and O1-deleted recombinant mitogen-activated protein kinase (MAPK)-dependent vaccinia virus (MDRVV). We found that compared with viruses with the deletion of either gene alone, MDRVV is more attenuated in normal cells and can replicate in cancer cells that exhibit constitutive ERK1/2 activation in the MAPK pathway. We armed MDRVV with a bifunctional fusion gene encoding cytosine deaminase and uracil phosphoribosyltransferase (CD/UPRT), which converts 5-fluorocytosine (5-FC) into chemotherapeutic agents, and evaluated its oncolytic activity alone or in combination with 5-FC in human pancreatic cancer cell lines, tumor mouse models of peritoneal dissemination and liver metastasis, and ex vivo-infected live pancreatic cancer patient-derived tissues. CD/UPRT-armed MDRVV alone could efficiently eliminate pancreatic cancers, and its antitumor effects were partially enhanced in combination with 5-FC in vitro and in vivo. Moreover, the replication of MDRVV was detected in tumor cells of patient-derived, surgically resected tissues, which showed enlarged nuclei and high expression of pERK1/2 and Ki-67, and not in stromal cells. Our findings suggest that systemic injections of CD/UPRT-armed MDRVV alone or in combination with 5-FC are promising therapeutic strategies for pancreatic ductal adenocarcinoma

A Cohort Study on Respiratory Symptoms and Diseases Caused by Toner-Handling Work: Longitudinal Analyses from 2003 to 2013

The purpose of this study was to examine the effects of toner-handling work on respiratory symptoms and diseases. We conducted a prospective cohort study of 1468 workers between 2003 and 2013. The cohort included 887 toner-handling workers and 581 non-toner-handling workers, employed in one toner and copier manufacturing enterprise. Toner-handling workers were subdivided into two groups based on the 8-h time-weighted average toner exposure concentration for each work category in the baseline survey. We compared the incidence of respiratory disease and longitudinal changes in the prevalence of subjective respiratory symptoms among three groups, as follows: High-concentration toner exposure group, the low-concentration toner exposure group, and a control group. The incidence of respiratory disease and changes in the prevalence of subjective respiratory symptoms were not significantly different between the non-toner-handling group and the toner-handling group. In contrast, the odds ratio for yearly changes in the prevalence of wheezing without asthmatic response was significantly lower in the high-concentration toner exposure group than in the control group. At the study site, dust scattering was well controlled and workers used respiratory protection appropriately. These findings suggest that toner-handling work had little adverse effect on respiratory function in a work environment with sufficiently controlled ventilation