Wonkwang University Hospital

Importance: Discontinuing aspirin after short-term dual antiplatelet therapy (DAPT) was evaluated as a bleeding reduction strategy. However, the strategy of ticagrelor monotherapy has not been exclusively evaluated in patients with acute coronary syndromes (ACS). Objective: To determine whether switching to ticagrelor monotherapy after 3 months of DAPT reduces net adverse clinical events compared with ticagrelor-based 12-month DAPT in patients with ACS treated with drug-eluting stents. Design, Setting, and Participants: A randomized multicenter trial was conducted in 3056 patients with ACS treated with drug-eluting stents between August 2015 and October 2018 at 38 centers in South Korea. Follow-up was completed in October 2019. Interventions: Patients were randomized to receive ticagrelor monotherapy (90 mg twice daily) after 3-month DAPT (n = 1527) or ticagrelor-based 12-month DAPT (n = 1529). Main Outcomes and Measures: The primary outcome was a 1-year net adverse clinical event, defined as a composite of major bleeding and adverse cardiac and cerebrovascular events (death, myocardial infarction, stent thrombosis, stroke, or target-vessel revascularization). Prespecified secondary outcomes included major bleeding and major adverse cardiac and cerebrovascular events. Results: Among 3056 patients who were randomized (mean age, 61 years; 628 women [20%]; 36% ST-elevation myocardial infarction), 2978 patients (97.4%) completed the trial. The primary outcome occurred in 59 patients (3.9%) receiving ticagrelor monotherapy after 3-month DAPT and in 89 patients (5.9%) receiving ticagrelor-based 12-month DAPT (absolute difference, -1.98% [95% CI, -3.50% to -0.45%]; hazard ratio [HR], 0.66 [95% CI, 0.48 to 0.92]; P = .01). Of 10 prespecified secondary outcomes, 8 showed no significant difference. Major bleeding occurred in 1.7% of patients with ticagrelor monotherapy after 3-month DAPT and in 3.0% of patients with ticagrelor-based 12-month DAPT (HR, 0.56 [95% CI, 0.34 to 0.91]; P = .02). The incidence of major adverse cardiac and cerebrovascular events was not significantly different between the ticagrelor monotherapy after 3-month DAPT group (2.3%) vs the ticagrelor-based 12-month DAPT group (3.4%) (HR, 0.69 [95% CI, 0.45 to 1.06]; P = .09). Conclusions and Relevance: Among patients with acute coronary syndromes treated with drug-eluting stents, ticagrelor monotherapy after 3 months of dual antiplatelet therapy, compared with ticagrelor-based 12-month dual antiplatelet therapy, resulted in a modest but statistically significant reduction in a composite outcome of major bleeding and cardiovascular events at 1 year. The study population and lower than expected event rates should be considered in interpreting the trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02494895.

BACKGROUND: Data regarding clinical outcomes after intravascular imaging-guided percutaneous coronary intervention (PCI) for complex coronary-artery lesions, as compared with outcomes after angiography-guided PCI, are limited. METHODS: In this prospective, multicenter, open-label trial in South Korea, we randomly assigned patients with complex coronary-artery lesions in a 2:1 ratio to undergo either intravascular imaging-guided PCI or angiography-guided PCI. In the intravascular imaging group, the choice between intravascular ultrasonography and optical coherence tomography was at the operators' discretion. The primary end point was a composite of death from cardiac causes, target-vessel-related myocardial infarction, or clinically driven target-vessel revascularization. Safety was also assessed. RESULTS: A total of 1639 patients underwent randomization, with 1092 assigned to undergo intravascular imaging-guided PCI and 547 assigned to undergo angiography-guided PCI. At a median follow-up of 2.1 years (interquartile range, 1.4 to 3.0), a primary end-point event had occurred in 76 patients (cumulative incidence, 7.7%) in the intravascular imaging group and in 60 patients (cumulative incidence, 12.3%) in the angiography group (hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.89; P = 0.008). Death from cardiac causes occurred in 16 patients (cumulative incidence, 1.7%) in the intravascular imaging group and in 17 patients (cumulative incidence, 3.8%) in the angiography group; target-vessel-related myocardial infarction occurred in 38 (cumulative incidence, 3.7%) and 30 (cumulative incidence, 5.6%), respectively; and clinically driven target-vessel revascularization in 32 (cumulative incidence, 3.4%) and 25 (cumulative incidence, 5.5%), respectively. There were no apparent between-group differences in the incidence of procedure-related safety events. CONCLUSIONS: Among patients with complex coronary-artery lesions, intravascular imaging-guided PCI led to a lower risk of a composite of death from cardiac causes, target-vessel-related myocardial infarction, or clinically driven target-vessel revascularization than angiography-guided PCI. (Supported by Abbott Vascular and Boston Scientific; RENOVATE-COMPLEX-PCI ClinicalTrials.gov number, NCT03381872).

The distribution of gut microbiota varies according to age (childhood, puberty, pregnancy, menopause, and old age) and sex. Gut microbiota are known to contribute to gastrointestinal (GI) diseases such as irritable bowel syndrome, inflammatory bowel disease, and colon cancer; however, the exact etiology remains elusive. Recently, sex and gender differences in GI diseases and their relation to gut microbiota has been suggested. Furthermore, the metabolism of estrogen and androgen was reported to be related to the gut microbiome. As gut microbiome is involved in the excretion and circulation process of sex hormones, the concept of "microgenderome" indicating the role of sex hormone on the gut microbiota has been suggested. However, further research is needed for this concept to be universally accepted. In this review, we summarize sex- and gender-differences in gut microbiota and the interplay of microbiota and GI diseases, focusing on sex hormones. We also describe the metabolic role of the microbiota in this regard. Finally, current subjects, such as medication including probiotics, are briefly discussed.

Matrix metalloproteinase-9 (MMP-9) is a matrix-degrading enzyme implicated in many biological processes, including inflammation. It is produced by many cells, including fibroblasts. When cultured in three-dimensional (3D) collagen gels, fibroblasts contract the surrounding matrix, a function that is thought to model the contraction that characterizes both normal wound repair and fibrosis. The current study was designed to evaluate the role of endogenously produced MMP-9 in fibroblast contraction of 3D collagen gels. Fibroblasts from mice lacking expression of MMP-9 and human lung fibroblasts (HFL-1) transfected with MMP-9 small-interfering RNA (siRNA) were used. Fibroblasts were cast into type I collagen gels and floated in culture medium with or without transforming growth factor (TGF)-β1 for 5 days. Gel size was determined daily using an image analysis system. Gels made from MMP-9 siRNA-treated human fibroblasts contracted less than control fibroblasts, as did fibroblasts incubated with a nonspecific MMP inhibitor. Similarly, fibroblasts cultured from MMP-9-deficient mice contracted gels less than did fibroblasts from control mice. Transfection of the MMP-9-deficient murine fibroblasts with a vector expressing murine MMP-9 restored contractile activity to MMP-9-deficient fibroblasts. Inhibition of MMP-9 reduced active TGF-β1 and reduced several TGF-β1-driven responses, including activity of a Smad3 reporter gene and production of fibronectin. Because TGF-β1 also drives fibroblast gel contraction, this suggests the mechanism for MMP-9 regulation of contraction is through the generation of active TGF-β1. This study provides direct evidence that endogenously produced MMP-9 has a role in regulation of tissue contraction of 3D collagen gels mediated by fibroblasts.

eases of the circulatory system was 187 men per 100,000 population and 145 women per 100,000 population in 1983 and 111 men per 100,000 population and 125 women per 100,000 in 2016, indicating little change over the years. However, the age-adjusted mortality rate, which excludes the influence of aging of the population during this period, decreased to about one-fifth of the initial rate (Fig. Death from CAD has consistently increased since 1983, when the cause of death statistics were first measured, reaching 31 men per 100,000 and 26 women per 100,000 in 2016. However, age-adjusted mortality of CAD reached a peak in the early and mid-2000s and began to decline since then (Fig. Deaths from cerebrovascular disease declined since 2000s, reaching 44 men per 100,000 and 47 women per 100,000 in 2016. Age-adjusted mortality for cerebrovascular disease has declined very quickly (Fig. Among various cerebrovascular diseases, there were more deaths from cerebral hemorrhage (non-traumatic intracerebral hemorrhage and subarachnoid hemorrhage) until 2002, but deaths from cerebral infarction (ischemic stroke) have become more common since then. This is speculated to be due to the marked decline in the incidence and improved treatment outcomes of cerebral hemorrhage as a result 500 400

The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing recently and has become one of the most common clinical liver diseases. Since the pathogenesis of NAFLD has not been completely elucidated, few effective therapeutic drugs are available. As the “second genome” of human body, gut microbiota plays an important role in the digestion, absorption and metabolism of food and drugs. Gut microbiota can act as an important driver to advance the occurrence and development of NAFLD, and to accelerate its progression to cirrhosis and hepatocellular carcinoma. Growing evidence has demonstrated that gut microbiota and its metabolites directly affect intestinal morphology and immune response, resulting in the abnormal activation of inflammation and intestinal endotoxemia; gut dysbiosis also causes dysfunction of gut-liver axis via alteration of bile acid metabolism pathway. Because of its composition diversity and disease-specific expression characteristics, gut microbiota holds strong promise as novel biomarkers and therapeutic targets for NAFLD. Intervening intestinal microbiota, such as antibiotic/probiotic treatment and fecal transplantation, has been a novel strategy for preventing and treating NAFLD. In this article, we have reviewed the emerging functions and association of gut bacterial components in different stages of NAFLD progression and discussed its potential implications in NAFLD diagnosis and therapy.

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Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects, such as ototoxicity, nephrotoxicity, and neuropathy. Various mechanisms, such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses, are critically involved in cisplatin-induced adverse effects. As NAD+ is a cofactor for various enzymes associated with cellular homeostasis, we studied the effects of increased NAD+ levels by means of NAD(P)H:quinone oxidoreductase 1 (NQO1) activation using a known pharmacological activator (β-lapachone) in wild-type and NQO1-/- mice on cisplatin-induced renal dysfunction in vivo. The intracellular NAD+/NADH ratio in renal tissues was significantly increased in wild-type mice co-treated with cisplatin and β-lapachone compared with the ratio in mice treated with cisplatin alone. Inflammatory cytokines and biochemical markers for renal damage were significantly attenuated by β-lapachone co-treatment compared with those in the cisplatin alone group. Notably, the protective effects of β-lapachone in wild-type mice were completely abrogated in NQO1-/- mice. Moreover, β-lapachone enhanced the tumoricidal action of cisplatin in a xenograft tumor model. Thus, intracellular regulation of NAD+ levels through NQO1 activation might be a promising therapeutic target for the protection of cisplatin-induced acute kidney injury. Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects, such as ototoxicity, nephrotoxicity, and neuropathy. Various mechanisms, such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses, are critically involved in cisplatin-induced adverse effects. As NAD+ is a cofactor for various enzymes associated with cellular homeostasis, we studied the effects of increased NAD+ levels by means of NAD(P)H:quinone oxidoreductase 1 (NQO1) activation using a known pharmacological activator (β-lapachone) in wild-type and NQO1-/- mice on cisplatin-induced renal dysfunction in vivo. The intracellular NAD+/NADH ratio in renal tissues was significantly increased in wild-type mice co-treated with cisplatin and β-lapachone compared with the ratio in mice treated with cisplatin alone. Inflammatory cytokines and biochemical markers for renal damage were significantly attenuated by β-lapachone co-treatment compared with those in the cisplatin alone group. Notably, the protective effects of β-lapachone in wild-type mice were completely abrogated in NQO1-/- mice. Moreover, β-lapachone enhanced the tumoricidal action of cisplatin in a xenograft tumor model. Thus, intracellular regulation of NAD+ levels through NQO1 activation might be a promising therapeutic target for the protection of cisplatin-induced acute kidney injury. cis-Diamminedichloroplatinum II (CDDP, cisplatin) is a widely used chemotherapeutic drug for the treatment of various solid tumors in the head and neck, bladder, lung, ovaries, testicles, and uterus.1.Rosenberg B. Vancamp L. Krigas T. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode.Nature. 1965; 205: 698-699Crossref PubMed Scopus (2284) Google Scholar, 2.Wang D. Lippard S.J. Cellular processing of platinum anticancer drugs.Nat Rev Drug Discov. 2005; 4: 307-320Crossref PubMed Scopus (3008) Google Scholar, 3.Cohen S.M. Lippard S.J. Cisplatin: from DNA damage to cancer chemotherapy.Prog Nucleic Acid Res Mol Biol. 2001; 67: 93-130Crossref PubMed Scopus (545) Google Scholar, 4.Arany I. Safirstein R.L. 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Cisplatin and DNA repair in cancer chemotherapy.Trends Biochem Sci. 1995; 20: 435-439Abstract Full Text PDF PubMed Scopus (482) Google Scholar, 12.Jamieson E.R. Lippard S.J. Structure, recognition, and processing of cisplatin-DNA adducts.Chem Rev. 1999; 99: 2467-2498Crossref PubMed Scopus (2614) Google Scholar, 13.Eastman A. The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes.Pharmacol Ther. 1987; 34: 155-166Crossref PubMed Scopus (503) Google Scholar Post-translational modification of nuclear factor (NF)-κB p65 and p53, including phosphorylation and acetylation, may be an important factor in cisplatin-mediated cytotoxicity, because activation of these molecules has been linked to both inflammatory responses and apoptosis.14.Huang B. Yang X.D. Lamb A. et al.Posttranslational modifications of NF-kappaB: another layer of regulation for NF-kappaB signaling pathway.Cell Signal. 2010; 22: 1282-1290Crossref PubMed Scopus (238) Google Scholar, 15.Ghizzoni M. Haisma H.J. Maarsingh H. et al.Histone acetyltransferases are crucial regulators in NF-kappaB mediated inflammation.Drug Discov Today. 2011; 16: 504-511Crossref PubMed Scopus (100) Google Scholar, 16.Taira N. Yoshida K. Post-translational modifications of p53 tumor suppressor: determinants of its functional targets.Histol Histopathol. 2012; 27: 437-443PubMed Google Scholar Furthermore, oxidative stress, particularly hydroxyl radical, has a major role in cisplatin-induced p53 activation through DNA damage.6.Pabla N. Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies.Kidney Int. 2008; 73: 994-1007Abstract Full Text Full Text PDF PubMed Scopus (1345) Google Scholar In particular, activation of p53 by its acetylation was also critically involved in cisplatin-induced renal injury.17.Kim D.H. Jung Y.J. Lee J.E. et al.SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53.Am J Physiol Renal Physiol. 2011; 301: F427-F435Crossref PubMed Scopus (144) Google Scholar NADH: quinone oxidoreductase 1 (NQO1) is a cytosolic antioxidant flavoprotein the reduction of to by as an intracellular NAD+ D. et oxidoreductase 1 regulation and PubMed Scopus Google Scholar, A. et al.In vivo role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the regulation of intracellular and of 2001; PubMed Scopus Google Scholar In is NQO1 has a role in including the of and the of p53 and et is a for the activation of Res 2011; PubMed Scopus Google Scholar, M. A. 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B. et in and cancer a 1995; Google Scholar However, the activation of NQO1 by has effects on of for of in of of and protection renal et of ameliorates and related in PubMed Scopus Google Scholar, et of NAD(P)H:quinone oxidoreductase 1 by vascular cell PubMed Scopus Google Scholar, et of an signaling Rev. 2010; PubMed Scopus Google Scholar, et of NAD(P)H:quinone oxidoreductase ameliorates in an of 2011; PubMed Scopus Google Scholar, Lee et a of in 2012; 7: PubMed Scopus Google Scholar, et of renal injury by activation of NAD(P)H:quinone oxidoreductase associated with 2012; PubMed Scopus Google Scholar with these cellular NAD+ and levels been to be important of and cellular of cell and by 2012; PubMed Scopus Google Scholar, regulation of 2012; PubMed Scopus Google Scholar, M. and 2012; PubMed Scopus Google Scholar, M. A. et and renal with and PubMed Scopus Google Scholar As NAD+ as a cofactor for various including and M. et in are we and are we Mol Rev. PubMed Scopus Google Scholar, N. K. T. et of cellular levels by and of in PubMed Scopus Google Scholar, of and in PubMed Google Scholar, NAD+ in and Biochem Sci. Full Text Full Text PDF PubMed Scopus Google Scholar the regulation of NAD+ may therapeutic through its effect on In particular, are been reported to be molecules associated with et of 2003; PubMed Scopus Google Scholar, S.J. M. et by PubMed Scopus Google Scholar In are of differential M. and 2012; PubMed Scopus Google Scholar, S.J. M. et by PubMed Scopus Google Scholar is stress such as M. et by through regulation of 2008; Full Text Full Text PDF PubMed Scopus Google Scholar has a role in stress responses, and D. et al.SIRT1 in for and PubMed Scopus Google Scholar, D. in PubMed Scopus Google Scholar by deacetylation of such as p53, and et of p53 by cell 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, N. M. et Full Text Full Text PDF PubMed Scopus Google Scholar, H. et as an p53 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J.E. et of and cell by the 23: PubMed Scopus Google Scholar In inflammatory responses through p65 In the of in vivo is inflammatory activation in with increased inflammatory T. T. et al.SIRT1 effects and in Biol. 29: PubMed Scopus Google Scholar mitochondrial homeostasis, and cellular T. et a mitochondrial mitochondrial function and in 2005; PubMed Scopus Google Scholar, et role for the mitochondrial in 2008; PubMed Scopus Google Scholar, H. Yang T. et mitochondrial NAD+ levels cell Full Text Full Text PDF PubMed Scopus Google Scholar effects through the deacetylation and activation of mitochondrial and the of the antioxidant Furthermore, p53 function through and deacetylation of p53 in the M. et is by the mitochondrial 2010; PubMed Scopus Google Scholar a between molecular and cellular is of NAD+ levels has an on cisplatin-induced renal injury. In we the protective effects of on cisplatin-induced acute kidney injury in wild-type compared with NQO1 mice. cisplatin-induced renal dysfunction and effect is mediated by and through NQO1 from mice were and treated with to NQO1 As in NQO1 was significantly increased by treatment was attenuated to the by the addition of the NQO1 completely abrogated NQO1 we NQO1 activation with intracellular NAD+ and levels in kidney mice were for and NAD+/NADH were from kidney a significant in the NAD+/NADH ratio in mice compared with the ratio in mice with mice were treated with as in and the levels of and markers for kidney were As in and cisplatin increased the levels of and and compared with and However, significantly the levels of both and as compared with cisplatin alone. in and mice were In to the effect of on cisplatin-induced acute kidney we the kidney function for cisplatin As in and cisplatin-induced and were by treatment in a may cisplatin-induced kidney with The of cisplatin-induced renal injury be tubular vascular damage, and injury. The in renal damage are by the of in the tubular the tubular has a molecular and is is the and by renal tubular its in the tubular cells of the and G. H. cellular mechanisms of cisplatin and Dial Transplant. PubMed Scopus Google Scholar Thus, these are the major for cisplatin-induced renal damage, in injury to tubular including the and I. Safirstein R.L. Cisplatin nephrotoxicity.Semin Nephrol. 2003; 23: 460-464Abstract Full Text Full Text PDF PubMed Scopus (807) Google Scholar, cisplatin and in renal cell PubMed Scopus Google Scholar, T. A. et and Nephrol. 2005; PubMed Scopus Google Scholar the tubular damage by cisplatin and the protective effect of kidney from were with and As in mice treated with cisplatin various tubular such as tubular formation, and mice treated with significantly tubular Renal in alone was to in with mice including of the of and formation, of abrogated these effects of injury the tubular were on the of tubular in the As in cisplatin significantly increased tubular injury compared with significantly attenuated the cisplatin-induced tubular injury in and mice were cisplatin-induced tubular injury. inflammatory cytokines such as tumor factor and may cisplatin-induced we the of these by cisplatin is by we in and as a of the of cisplatin-induced acute kidney injury and Cisplatin produced a in and levels and significantly attenuated and levels and and levels in mice and and mice and were also in kidney by and in kidney was attenuated by as by of was by also and in kidney As in and levels were also increased by cisplatin attenuated cisplatin-induced of those with stress by has also been in the of cisplatin-induced renal and are one of the major for we the renal of and in to by and from kidney and from kidney cisplatin treatment the of and in completely attenuated the of these and alone was to attenuated cisplatin-induced and levels and with cisplatin-induced was abrogated by as in As the of cells to the of injury is by the of we one of the for in a kidney As in and by also the of to the The of was increased by cisplatin was completely by activation as one of the major for inflammatory responses and we p65 by and of p65 was by in the renal tubular of co-treatment attenuated the of we p65 nuclear by using the nuclear of kidney As in and cisplatin-induced p65 nuclear was significantly by these cisplatin-induced acute kidney injury by for and protective effects are mediated through NQO1 a of using NQO1-/- to those in using mice. the biochemical markers and of renal injury in NQO1-/- mice The levels of and and in NQO1-/- mice were to a those in mice. As the levels of these markers in NQO1-/- mice. In the cisplatin treatment of NQO1-/- mice renal damage tubular of the tubular and However, the cisplatin-induced tubular damage in NQO1-/- mice the protective effects are mediated through NQO1 also in and of and cisplatin co-treated NQO1-/- mice. As levels were increased in both and NQO1-/- mice in renal was also in both and NQO1-/- mice and of and were also by in NQO1-/- mice In in NQO1-/- mice of and levels were abrogated by in NQO1-/- mice through NQO1 to cisplatin-induced acute kidney of on cisplatin-induced renal damage in NQO1-/- mice. of tumor factor was using the by of compared with the cisplatin were with 1 and for cisplatin cisplatin and group. kidney were for the levels of and using the by compared with the with we the effect of on the cellular NAD+/NADH ratio in the of NQO1-/- mice. As in the cellular NAD+/NADH ratio in mice was cisplatin treatment compared with the cellular NAD+/NADH ratio to levels alone the cellular NAD+/NADH in the kidney compared with In NQO1-/- the cellular NAD+/NADH ratio in the kidney was by cisplatin the cellular NAD+/NADH in the and alone were compared with levels in mice has been reported acetylation of p65 and p53 has significant in activation of and associated with and in the and p65 and B. Yang X.D. Lamb A. et al.Posttranslational modifications of NF-kappaB: another layer of regulation for NF-kappaB signaling pathway.Cell Signal. 2010; 22: 1282-1290Crossref PubMed Scopus (238) Google Scholar, 15.Ghizzoni M. Haisma H.J. Maarsingh H. et al.Histone acetyltransferases are crucial regulators in NF-kappaB mediated inflammation.Drug Discov Today. 2011; 16: 504-511Crossref PubMed Scopus (100) Google Scholar, 16.Taira N. Yoshida K. Post-translational modifications of p53 tumor suppressor: determinants of its functional targets.Histol Histopathol. 2012; 27: 437-443PubMed Google Scholar we the p65 and p53 acetylation levels following cisplatin as a to and in NQO1-/- mice. As in and mice increased p65 and p53 acetylation levels compared with significantly the of the compared with cisplatin treatment alone. alone by the of p65 and p53 was increased in was significantly attenuated in co-treated mice In the of cisplatin-induced p65 and p53 acetylation by treatment was in NQO1-/- mice NQO1 is for deacetylation of p65 and we the and of and As in and and increased in kidney tissues from was by However, the increased of and by cisplatin was by in NQO1-/- mice a in in of these were significantly compared with those in with with chemotherapeutic such as effects. Cisplatin is widely used for the treatment of various of N. Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies.Kidney Int. 2008; 73: 994-1007Abstract Full Text Full Text PDF PubMed Scopus (1345) Google Scholar its use be limited by and adverse effects in normal D. Lippard S.J. Cellular processing of platinum anticancer drugs.Nat Rev Drug Discov. 2005; 4: 307-320Crossref PubMed Scopus (3008) Google Scholar, 5.Siddik Z.H. Cisplatin: mode of cytotoxic action and molecular basis of resistance.Oncogene. 2003; 22: 7265-7279Crossref PubMed Scopus (2630) Google Scholar The to increased of cisplatin and to signaling in to cisplatin-induced DNA Z.H. Cisplatin: mode of cytotoxic action and molecular basis of resistance.Oncogene. 2003; 22: 7265-7279Crossref PubMed Scopus (2630) Google Scholar, 11.Zamble D.B. Lippard S.J. Cisplatin and DNA repair in cancer chemotherapy.Trends Biochem Sci. 1995; 20: 435-439Abstract Full Text PDF PubMed Scopus (482) Google Scholar, 12.Jamieson E.R. Lippard S.J. Structure, recognition, and processing of cisplatin-DNA adducts.Chem Rev. 1999; 99: 2467-2498Crossref PubMed Scopus (2614) Google Scholar, 13.Eastman A. The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes.Pharmacol Ther. 1987; 34: 155-166Crossref PubMed Scopus (503) Google Scholar The ototoxicity, and The cytotoxic mechanisms of cisplatin oxidative stress by mitochondrial dysfunction, and the of DNA In positive feedback between the of from renal tubular the activation of and cytokines may also cause renal damage cisplatin G. and and renal injury in cisplatin PubMed Scopus Google Scholar Inflammatory cytokines in and in the induce cell through a in the of and may cells to the of M.J. D.H. Jung Y.J. et the kidney from cisplatin-induced Int. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, L. et acute renal failure is associated with an in the cytokines and in the Ther. PubMed Scopus Google Scholar In we treatment cisplatin-induced renal dysfunction by the levels of and and 1 and In the of renal damage including inflammatory the the and and and also the of p65 and activation of by its nuclear in kidney tissues In cellular NAD+ levels in a and may cisplatin-induced acute kidney injury through NQO1 activation and the NAD+/NADH ratio we the protective role of in NQO1-/- mice. In the of cisplatin-induced renal damage and and these the kidney from cisplatin-induced damage are a of NQO1 and in NQO1 and of various quinone and in the of these and the of In NQO1 such as of and of the p53, may as the basis for its in H. quinone oxidoreductase 1 and its protective role in and related 2012; PubMed Scopus Google Scholar However, these various of mice NQO1 and were from NQO1 mice increased toxicity compared with Lee et of the (NQO1) in mice to increased PubMed Scopus Google Scholar is in NQO1 mice may for the of Lee et of the (NQO1) in mice to increased PubMed Scopus Google Scholar and may renal dysfunction compared with in cisplatin-induced acute kidney injury. In we also is in the of cisplatin-induced acute kidney injury between and NQO1-/- mice. used these NQO1 mice to the activation of NQO1 is for the effect of intracellular NAD+ is important for cell in various including and is through the from the from and In NAD+ also be from by reduction of such as is is NQO1 a in the regulation of cellular NAD+ levels in normal In we significant in intracellular NAD+ levels in kidney tissues between and NQO1-/- mice reported the activation of NQO1 by the effects on of including and renal et of ameliorates and related in PubMed Scopus Google Scholar, et of NAD(P)H:quinone oxidoreductase 1 by vascular cell PubMed Scopus Google Scholar, et of NAD(P)H:quinone oxidoreductase ameliorates in an of 2011; PubMed Scopus Google Scholar, Lee et a of in 2012; 7: PubMed Scopus Google Scholar the intracellular NAD+ through NQO1 activation may be a therapeutic target for various In we NQO1 activation by ameliorates cisplatin-induced renal with the cisplatin-induced reduction of the cellular NAD+/NADH ratio in renal in mice in NQO1-/- mice the major for the cellular in the NAD+/NADH ratio by in mice is the reduction in the in NAD+ levels of NAD+ levels may a on such as cell and cellular of cell and by 2012; PubMed Scopus Google Scholar, regulation of 2012; PubMed Scopus Google Scholar, M. and 2012; PubMed Scopus Google Scholar, M. A. et and renal with and PubMed Scopus Google Scholar as NAD+ as a cofactor for various including and et of an signaling Rev. 2010; PubMed Scopus Google Scholar use NAD+ as a to various including and p65 in the J.E. et of and cell by the 23: PubMed Scopus Google Scholar and and p53 in the H. et as an p53 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M. et is by the mitochondrial 2010; PubMed Scopus Google Scholar, J.M. and mitochondrial 2012; PubMed Scopus Google Scholar In the of nuclear may cause activation of target modification of the p65 by acetylation its B. Yang X.D. Lamb A. et al.Posttranslational modifications of NF-kappaB: another layer of regulation for NF-kappaB signaling pathway.Cell Signal. 2010; 22: 1282-1290Crossref PubMed Scopus (238) Google Scholar, 15.Ghizzoni M. Haisma H.J. Maarsingh H. et al.Histone acetyltransferases are crucial regulators in NF-kappaB mediated inflammation.Drug Discov Today. 2011; 16: 504-511Crossref PubMed Scopus (100) Google Scholar Furthermore, acetylation and of p53 cell are by in the N. Yoshida K. Post-translational modifications of p53 tumor suppressor: determinants of its functional targets.Histol Histopathol. 2012; 27: 437-443PubMed Google Scholar of p65 and p53 in renal The was by in mice in NQO1-/- mice and increased in kidney tissues from was by However, the increased of and by cisplatin was by in NQO1-/- mice increased intracellular NAD+ levels through NQO1 activation by treatment in the activation of and and cisplatin-induced acute kidney injury. effect may be to in activation was by K. K. et of acute kidney injury by 2010; PubMed Scopus Google Scholar by treatment with D.H. Jung Y.J. 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Apoptosis is a tightly regulated, cell deletion process that plays an important role in various cardiovascular diseases, such as myocardial infarction, reperfusion injury, and heart failure. Since cardiomyocyte loss is the most important determinant of patient morbidity and mortality, fully understanding the regulatory mechanisms of apoptotic signaling is crucial. In fact, the inhibition of cardiac apoptosis holds promise as an effective therapeutic strategy for cardiovascular diseases. Caspase, a critical enzyme in the induction and execution of apoptosis, has been the main potential target for achieving anti-apoptotic therapy. Studies suggest, however, that a caspase-independent pathway may also play an important role in cardiac apoptosis, although the mechanism and potential significance of caspase-independent apoptosis in the heart remain poorly understood. Herein we discuss the role of apoptosis in various cardiovascular diseases, provide an update on current knowledge about the molecular mechanisms that govern apoptosis, and discuss the clinical implications of anti-apoptotic therapies.

OBJECTIVE: The purpose of this study was to explore the effect of aromatherapy on menstrual cramps and symptoms of dysmenorrhea. DESIGN: The study was a randomized placebo-controlled trial. SUBJECTS: The subjects were 67 female college students who rated their menstrual cramps to be greater than 6 on a 10-point visual analogue scale, who had no systemic or reproductive diseases, and who did not use contraceptive drugs. INTERVENTION: Subjects were randomized into three groups: (1) an experimental group (n = 25) who received aromatherapy, (2) a placebo group (n = 20), and (3) a control group (n = 22). Aromatherapy was applied topically to the experimental group in the form of an abdominal massage using two drops of lavender (Lavandula officinalis), one drop of clary sage (Salvia sclarea), and one drop of rose (Rosa centifolia) in 5 cc of almond oil. The placebo group received the same treatment but with almond oil only, and the control group received no treatment. OUTCOME MEASURES: The menstrual cramps levels was assessed using a visual analogue scale and severity of dysmenorrhea was measured with a verbal multidimensional scoring system. RESULTS: The menstrual cramps were significantly lowered in the aromatherapy group than in the other two groups at both post-test time points (first and second day of menstruation after treatment). From the multiple regression aromatherapy was found to be associated with the changes in menstrual cramp levels (first day: Beta = -2.48, 95% CI: -3.68 to -1.29, p < 0.001; second day: Beta = -1.97, 95% CI: -3.66 to -0.29, p = 0.02 and the severity of dysmenorrhea (first day: Beta = 0.31, 95% CI: 0.05 to 0.57, p = 0.02; second day: Beta = 0.33, 95% CI: 0.10 to 0.56, p = 0.006) than that found in the other two groups. CONCLUSIONS: These findings suggest that aromatherapy using topically applied lavender, clary sage, and rose is effective in decreasing the severity of menstrual cramps. Aromatherapy can be offered as part of the nursing care to women experiencing menstrual cramps or dysmenorrhea.

OBJECTIVES: To assess systematically the clinical evidence of qigong for hypertension. METHODS: Databases were searched up to August 2006. All randomized clinical trials (RCTs) testing qigong in patients with hypertension of any origin and assessing clinically relevant outcomes were considered. Trials using any type of control intervention were included. The selection of studies, data extraction and quality assessment were performed independently by at least two reviewers. Methodological quality was evaluated using the Jadad score. RESULTS: A total of 121 potentially relevant articles were identified and 12 RCTs were included. Seven RCTs tested qigong in combination with antihypertensive drugs compared with antihypertensive drugs alone. The meta-analysis of two trials reporting adequate data suggested beneficial effects in favour of qigong [weighted mean difference, systolic blood pressure (SBP) -12.1 mmHg, 95% confidence interval (CI) -17.1 to -7.0; diastolic blood pressure -8.5 mmHg, 95% CI -12.6 to -4.4]. Qigong was compared with waiting list control in two RCTs and was found to reduce SBP significantly (weighted mean difference -18.5 mmHg, 95% CI -23.1 to -13.9). In three further RCTs the comparisons made were: qigong combined with conventional therapy versus muscle relaxation combined with conventional therapy; qigong as a sole treatment versus exercise. All reported positive results in at least some of the relevant outcome measures. The methodological quality of the studies was low. CONCLUSION: There is some encouraging evidence of qigong for lowering SBP, but the conclusiveness of these findings is limited. Rigorously designed trials are warranted to confirm these results.

OBJECTIVE: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). METHODS: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion. RESULTS: The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 × 10(-5)) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p = 8 × 10(-4)). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p = 9 × 10(-4)). CONCLUSIONS: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.

OBJECTIVE: The purpose of this study was to evaluate associated knee injuries using MR imaging in patients with the "arcuate" sign, a term referring to avulsion fracture of the proximal fibula on conventional radiographs. MATERIAL AND METHODS: MR imaging of 18 cases (17 patients, both knees in one patient) with the arcuate sign on conventional radiographs was retrospectively interpreted to evaluate the associated meniscal, ligamentous, and bony injuries. In 12 cases, MR findings were correlated with surgical results. RESULTS: In all cases, avulsed bony fragments from the proximal pole of the fibula were attached to the fibular collateral ligament, the biceps femoris tendon, or both. Tear of the posterolateral capsule was seen in 12 cases (67%). Injury of the cruciate ligaments was noted in 16 cases (89%): injury to both the anterior cruciate ligament and posterior cruciate ligament was seen in nine cases (50%), injury to only the anterior cruciate ligament was seen in four, and injury to the posterior cruciate ligament only was noted in three. Bone bruises or gross fractures were seen in all cases: bone bruises on the anteromedial femoral condyle were noted in nine cases (50%) and were seen on the anteromedial tibial condyle in five cases (28%). Tear of the medial meniscus was seen in five cases (28%) and tear of the lateral meniscus in four cases (22%). Injury to the popliteus was seen in six cases (33%). Joint effusion was associated in all cases. CONCLUSION: MR imaging is useful for evaluation of associated soft-tissue injuries in patients with the arcuate sign on conventional radiographs. Avulsion injury to the proximal fibula is an important indicator of the internal derangement of the knee and for predicting the mechanism of an injury with varus stress. Cruciate ligament tear and bone bruises on the anteromedial condyle of the femur and tibia are common associated findings.

This study was designed to investigate the efficacy of Qigong as a non-pharmacological treatment of hypertension and evaluate the contribution of Qigong in the blood pressure (BP) reduction of essential hypertension patients. Fifty-eight patients volunteered to participate in this study and were randomly divided into either a Qigong group (n = 29), or a wait list control group (n = 29). In response to 10 weeks of Qigong, systolic blood pressure (SBP), diastolic blood pressure (DBP), and rate pressure product (RPP) were decreased significantly. There was a significant reduction of norepinephrine, epinephrine, cortisol, and stress level by the Qigong. These results suggest that Qigong may reduce BP and catecholamines via stabilizing the sympathetic nervous system. Therefore, Qigong is an effective nonpharmacological modality to reduce BP in essential hypertensive patients.

BACKGROUND: Shikonin, a natural naphthoquinone pigment purified from Lithospermum erythrorhizon, induces necroptosis in various cancer types, but the mechanisms underlying the anticancer activity of shikonin in lung cancer are not fully understood. This study was designed to clarify whether shikonin causes necroptosis in non-small cell lung cancer (NSCLC) cells and to investigate the mechanism of action. METHODS: Multiplex and caspase 8 assays were used to analyze effect of shikonin on A549 cells. Cytometry with annexin V/PI staining and MTT assays were used to analyze the mode of cell death. Western blotting was used to determine the effect of shikonin-induced necroptosis and autophagy. Xenograft and orthotopic models with A549 cells were used to evaluate the anti-tumor effect of shikonin in vivo. RESULTS: Most of the cell death induced by shikonin could be rescued by the specific necroptosis inhibitor necrostatin-1, but not by the general caspase inhibitor Z-VAD-FMK. Tumor growth was significantly lower in animals treated with shikonin than in the control group. Shikonin also increased RIP1 protein expression in tumor tissues. Autophagy inhibitors, including methyladenine (3-MA), ATG5 siRNA, and bafilomycin A, enhanced shikonin-induced necroptosis, whereas RIP1 siRNA had no effect on the apoptotic potential of shikonin. CONCLUSIONS: Our data indicated that shikonin treatment induced necroptosis and autophagy in NSCLC cells. In addition, the inhibition of shikonin-induced autophagy enhanced necroptosis, suggesting that shikonin could be a novel therapeutic strategy against NSCLC.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) has recently been found to be a novel component of metabolic syndrome (MS), which is one of the leading causes of chronic liver disease. The serum alanine aminotransferase (ALT) and ⟨-glutamyltransferase (GGT) levels are suggested to affect liver fat accumulation and insulin resistance. We assessed the associations of serum ALT and GGT concentrations within the reference ranges with MS and NAFLD. METHODS: In total, 1,069 subjects enrolled at the health promotion center of Wonkwang University Hospital were divided into 4 groups according to serum ALT and GGT concentrations levels within the reference ranges. We performed biochemical tests, including liver function tests and lipid profiles, and diagnosed fatty liver by ultrasonography. Associations of ALT and GGT concentrationgrading within the reference range with fatty liver and/or MS were investigated. RESULTS: The presence of MS, its components, and the number of metabolic abnormalities [except for high-density lipoprotein-cholesterol (HDL-C) and fasting blood glucose] increased with the ALT level, while the presence of MS, its components, and the number of metabolic abnormalities (except for HDL-C) increased with the GGT level. The odds ratios for fatty liver and MS increased with the ALT level (P⟨0.001 and P=0.049, respectively) and the GGT level (P=0.044 and P=0.039, respectively). CONCLUSIONS: Serum ALT and GGT concentrations within the reference ranges correlated with the incidence of NAFLD and MS in a dose-dependent manner. There associations need to be confirmed in large, prospective studies.

BACKGROUNDS: We conducted a pilot study of the infusion of intravenous autologous cord blood (CB) in children with cerebral palsy (CP) to assess the safety and feasibility of the procedure as well as its potential efficacy in countering neurological impairment. METHODS: Patients diagnosed with CP were enrolled in this study if their parents had elected to bank their CB at birth. Cryopreserved CB units were thawed and infused intravenously over 10~20 minutes. We assessed potential efficacy over 6 months by brain magnetic resonance imaging (MRI)-diffusion tensor imaging (DTI), brain perfusion single-photon emission computed tomography (SPECT), and various evaluation tools for motor and cognitive functions. RESULTS: Twenty patients received autologous CB infusion and were evaluated. The types of CP were as follows: 11 quadriplegics, 6 hemiplegics, and 3 diplegics. Infusion was generally well-tolerated, although 5 patients experienced temporary nausea, hemoglobinuria, or urticaria during intravenous infusion. Diverse neurological domains improved in 5 patients (25%) as assessed with developmental evaluation tools as well as by fractional anisotropy values in brain MRI-DTI. The neurologic improvement occurred significantly in patients with diplegia or hemiplegia rather than quadriplegia. CONCLUSIONS: Autologous CB infusion is safe and feasible, and has yielded potential benefits in children with CP.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is characterized by clinical symptoms that are associated with bilateral and symmetric vasogenic edema in the parietal and occipital lobes. However, this is rarely present with predominant involvement of the brain stem and cerebellum (variant). PURPOSE: To evaluate which clinical or magnetic resonance imaging (MRI) findings can help to predict the prognosis of variant and classical type of PRES and whether or not there is difference between two types of PRES. MATERIAL AND METHODS: We retrospectively evaluated MRI and clinical findings from 49 patients with PRES. These patients were divided into two groups. In group I, patients had atypical distribution of lesions. In group II, patients had typical distribution of lesions. Follow-up MRI was performed on 26 patients. We assessed the MRI features, clinical data, and the patients' outcomes. RESULTS: The mean blood pressure (BP) was significantly higher in group I (195.52/121.09 mmHg and 156.78/99.53 mmHg for groups I and II, respectively). The other factors assessed were not significantly different between the two groups. Lesions in 24 of 26 patients reversed upon follow-up. Sequelae were observed in 11 patients (group I, 7; group II, 4). However, there were no significant differences between the two groups. Except for those patients who died, seven of the nine patients with sequelae upon follow-up imaging had hemorrhage or irreversibility of lesions. CONCLUSION: Even though BP influences the involvement of the brain stem, involvement of the brain stem is not influential on the prognosis. It seems that the influential factor to prognosis is the reversibility of lesions and hemorrhage.

OBJECTIVE: Unruptured intracranial aneurysms are now being detected with increasing frequency in clinical practice. Results of the largest studies, including those of the International Study of Unruptured Intracranial Aneurysms, indicate that surgical and endovascular treatments are rarely justified in small aneurysms. However, we have encountered several cases of rupture of small and very small aneurysms in our clinical practice. This retrospective study analyzed the incidence and clinical characteristics of very small ruptured aneurysms. MATERIALS AND METHODS: A total of 200 patients with aneurysmal subarachnoid hemorrhage between January 2012 and December 2014 were reviewed. Various factors were analyzed, including the aneurysm location and size as well as the associated risk factors. RESULTS: The mean age of patients was 56.31 ± 13.78 (range, 25-89) years, and the male to female ratio was 1:2.1. There were 94 (47%) small-sized (< 5 mm), 91 (45.5%) medium-sized (5-9.9 mm), and 15 large-sized (> 10 mm) aneurysms. Of these, 30 (15%) aneurysms were very small-sized (< 3 mm). The most frequent site of aneurysms was the anterior communicating artery (ACoA). However, the proportion of aneurysms at the ACoA was significantly high in very small aneurysms (53.3%, p = 0.013). Hypertension was a significant risk factor for rupture of very small aneurysms (p < 0.001). CONCLUSION: About half of our cases of ruptured aneurysms involved the rupture of small and very small aneurysms. The most common site of rupture of very small aneurysm was the ACoA. Rupture of small and very small aneurysms is unpredictable, and treatment may be considered in selected high-risk patients according to factors such as young age, ACoA location, and hypertension.

OBJECTIVES: The purpose of this study was to investigate the impact of practicing qigong on middle-age subjects with essential hypertension. Impacts on blood pressure, reported self-efficacy, perceived benefit, and emotion were observed. DESIGN: Thirty-six (36) adult volunteers were assigned to either a waiting list control or a qigong group that practiced two 30-minute qigong programs per week over 8 consecutive weeks. RESULTS: Systolic and diastolic blood pressure was significantly reduced in members of the qigong group after 8 weeks of exercise. Significant improvements in self-efficacy and other cognitive perceptual efficacy variables were also documented in the qigong group compared to the original situation described above. CONCLUSIONS: This pilot study demonstrates the positive effects of practicing qigong on controlling blood pressure and enhancing perceptions of self-efficacy.