Outcomes of Patients with Pulmonary Atresia with Intact Ventricular Septum Reaching Adulthood

Background: There is limited information on outcomes of adult patients with pulmonary atresia with intact ventricular septum (PA-IVS) due to the low incidence of disease and the large variation of surgical histories. Methods: Among 58 patients with repaired PA-IVS, a total of 32 patients aged ≥16 years and who were followed at our institution between January 2003 and December 2018 were reviewed. Surgical history, clinical outcomes, and laboratory, echocardiographic and electrocardiographic data were obtained by chart review. Results: Follow-up was from the age of 16 years and the median age at the latest follow-up was 23.7 years. Twenty-four patients had undergone biventricular repair (BVR), 3 had undergone one-and-a half ventricular repair (1.5VR), and 5 had undergone univentricular repair. Over a median follow-up period of 7.7 years (interquartile range: 4.1–11.0 years), 1 BVR patient died suddenly and 7 patients had heart failure. Arrhythmias were present in 5 patients. Ten patients underwent surgical re-interventions, including 4 BVR take-downs with conversion to 1.5VR and 3 Fontan conversions. Overall survival, heart failure-free, arrhythmia-free, and surgical re-intervention-free rates at 5 years and 10 years from the age of 16 years were 96.2% (95% confidence interval [CI], 77.2–99.4) and 96.2% (95% CI, 77.2– 99.4), 81.4% (95% CI, 62.1–92.1) and 74.6% (95%CI, 52.3–88.7), 88.7% (95% CI, 70.1–96.3) and 75.9% (95% CI, 51.7–90.2), and 80.7% (95% CI, 60.8–91.8) and 70.8% (95% CI, 49.7–85.7), respectively. Conclusion: Adults with PA-IVS have preserved long-term survival regardless of the early operative strategy, while they are at risk for heart failure, arrhythmia, and surgical re-intervention. Thus, detailed and continued follow-up is mandatory for all PA-IVS patients from childhood to adulthood

Tuning of Sry expression by H3K9 methylation and demethylation

Histone H3 lysine 9 (H3K9) methylation is a hallmark of heterochromatin. H3K9 demethylation is crucial in mouse sex determination; The H3K9 demethylase Jmjd1a deficiency leads to increased H3K9 methylation at the Sry locus in embryonic gonads, thereby compromising Sry expression and causing male-to-female sex reversal. We hypothesized that the H3K9 methylation level at the Sry locus is finely tuned by the balance in activities between the H3K9 demethylase Jmjd1a and an unidentified H3K9 methyltransferase to ensure correct Sry expression. Here we identified the GLP/G9a H3K9 methyltransferase complex as the enzyme catalyzing H3K9 methylation at the Sry locus. Based on this finding, we tried to rescue the sex-reversal phenotype of Jmjd1a-deficient mice by modulating GLP/G9a complex activity. A heterozygous GLP mutation rescued the sex-reversal phenotype of Jmjd1a-deficient mice by restoring Sry expression. The administration of a chemical inhibitor of GLP/G9a enzyme into Jmjd1a-deficient embryos also successfully rescued sex reversal. Our study not only reveals the molecular mechanism underlying the tuning of Sry expression but also provides proof on the principle of therapeutic strategies based on the pharmacological modulation of epigenetic balance

Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy

Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)–mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy

Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: Focusing on neuroprotective effects of stromal cell-derived factor-1α

<p>Abstract</p> <p>Background</p> <p>Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1α (SDF-1α) is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1α were explored. 6-hydroxydopamine (6-OHDA, 20 μg) was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 × 10⁷cells, respectively) or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1α were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA) assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining.</p> <p>Results</p> <p>Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH)-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc) compared to that of control rats. In the <it>in vitro </it>study, SDF-1α treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups.</p> <p>Conclusions</p> <p>Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1α. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.</p

Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons

<p>Abstract</p> <p>Background</p> <p>Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of nigrostriatal dopaminergic systems. Free radicals induced by oxidative stress are involved in the mechanisms of cell death in PD. This study clarifies the neuroprotective effects of edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one), which has already been used for the treatment of cerebral ischemia in Japan, on TH-positive dopaminergic neurons using PD model both <it>in vitro </it>and <it>in vivo</it>. 6-hydroxydopamine (6-OHDA), a neurotoxin for dopaminergic neurons, was added to cultured dopaminergic neurons derived from murine embryonal ventral mesencephalon with subsequet administration of edaravone or saline. The number of surviving TH-positive neurons and the degree of cell damage induced by free radicals were analyzed. In parallel, edaravone or saline was intravenously administered for PD model of rats receiving intrastriatal 6-OHDA lesion with subsequent behavioral and histological analyses.</p> <p>Results</p> <p><it>In vitro </it>study showed that edaravone significantly ameliorated the survival of TH-positive neurons in a dose-responsive manner. The number of apoptotic cells and HEt-positive cells significantly decreased, thus indicating that the neuroprotective effects of edaravone might be mediated by anti-apoptotic effects through the suppression of free radicals by edaravone. <it>In vivo </it>study demonstrated that edaravone-administration at 30 minutes after 6-OHDA lesion reduced the number of amphetamine-induced rotations significantly than edaravone-administration at 24 hours. Tyrosine hydroxylase (TH) staining of the striatum and substantia nigra pars compacta revealed that edaravone might exert neuroprotective effects on nigrostriatal dopaminergic systems. The neuroprotective effects were prominent when edaravone was administered early and in high concentration. TUNEL, HEt and Iba-1 staining <it>in vivo </it>might demonstrate the involvement of anti-apoptotic, anti-oxidative and anti-inflammatory effects of edaravone-administration.</p> <p>Conclusion</p> <p>Edaravone exerts neuroprotective effects on PD model both <it>in vitro and in vivo</it>. The underlying mechanisms might be involved in the anti-apoptotic effects, anti-oxidative effects, and/or anti-inflammatory effects of edaravone. Edaravone might be a hopeful therapeutic option for PD, although the high therapeutic dosage remains to be solved for the clinical application.</p

Pathobiological implications of mucin (MUC) expression in the outcome of small bowel cancer.

Mucins have been associated with survival in various cancer patients, but there have been no studies of mucins in small bowel carcinoma (SBC). In this study, we investigated the relationships between mucin expression and clinicopathologic factors in 60 SBC cases, in which expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6 and MUC16 in cancer and normal tissues were examined by immunohistochemistry. MUC1, MUC5AC and MUC16 expression was increased in SBC lesions compared to the normal epithelium, and expression of these mucins was related to clinicopathologic factors, as follows: MUC1 [tumor location (p = 0.019), depth (p = 0.017) and curability (p = 0.007)], MUC5AC [tumor location (p = 0.063) and lymph node metastasis (p = 0.059)], and MUC16 [venous invasion (p = 0.016) and curability (p = 0.016)]. Analysis of 58 cases with survival data revealed five factors associated with a poor prognosis: poorly-differentiated or neuroendocrine histological type (

グラヤノトキシンD環の化学修飾

Grayanotoxin (GTX), one of the lipid-soluble Na+ channel openers, contains four rings (A, B, C and D) and the chemical groups essential for the pharmacological action are located on the A- and B-rings. To study the biological significance of functional groups on the D-ring, 51 new derivatives were prepared from α-dihydro GTX- 11 . These new compounds and the previously prepared GTXS ere directly applied to the intracellular phase of internally perfused squid giant axons

YY1 modulates taxane response in epithelial ovarian cancer

The results of this study show that a high YY1 gene signature (characterized by coordinate elevated expression of transcription factor YY1 and putative YY1 target genes) within serous epithelial ovarian cancers is associated with enhanced response to taxane-based chemotherapy and improved survival. If confirmed in a prospective study, these results have important implications for the potential future use of individualized therapy in treating patients with ovarian cancer. Identification of the YY1 gene signature profile within a tumor prior to initiation of chemotherapy may provide valuable information about the anticipated response of these tumors to taxane-based drugs, leading to better informed decisions regarding chemotherapeutic choice. Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer (SEOC) were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary SEOC and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using siRNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in SEOC and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA crosslinking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility and proliferation, but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function

Factors Influencing Pregnant Women\u27s Injuries and Fetal Loss Due to Motor Vehicle Collisions: A National Crash Data-Based Study.

To examine the factors that influence substantial injuries for pregnant women and negative fetal outcomes in motor vehicle collisions (MVCs), a retrospective analysis using the National Automotive Sampling System/Crashworthiness Data System was performed in Shiga University of Medical Science. We analyzed data from 736 pregnant women who, between 2001 and 2015, had injuries that were an abbreviated injury scale (AIS) score of one or more. The mean age was 25.9 ± 6.4 years and the mean gestational age was 26.2 ± 8.2 weeks. Additionally, 568 pregnant women had mild injuries and 168 had moderate to severe injuries. Logistic regression analysis revealed that seatbelt use (odds ratio (OR), 0.30), airbag deployment (OR, 2.00), and changes in velocity (21-40 km/h: OR, 3.03; 41-60 km/h: OR, 13.47; ≥61 km/h: OR, 44.56) were identified as independent predictors of having a moderate to severe injury. The positive and negative outcome groups included 231 and 12 pregnant women, respectively. Injury severity in pregnant women was identified as an independent predictor of a negative outcome (OR, 2.79). Avoiding moderate to severe maternal injuries is a high priority for saving the fetus, and education on appropriate seatbelt use and limiting vehicle speed for pregnant women is required

Intracoronary Autologous Cardiac Progenitor Cell Transfer in Patients With Hypoplastic Left Heart Syndrome (TICAP) : A Prospective Phase 1 Controlled Trial

RATIONALE: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. OBJECTIVE: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. METHODS AND RESULTS: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P=0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P=0.049), improved somatic growth (P=0.0005), reduced heart failure status (P=0.003), and lower incidence of coil occlusion for collaterals (P=0.007). CONCLUSIONS: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes