Search

Background and Purpose: The effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, were investigated on human prostate cancer cells and its mechanism of action elucidated.Experimental Approach: The anti-cancer effects of MH were examined in prostate cancer and normal cells. The effects were validated in vivo using a mouse xenograft model.Key Results: MH increased the expression of PPARγ in prostate PC-3 and LNCap cells. The pull-down assay and molecular docking study indicated that MH directly binds to PPARγ. MH also increased transcriptional activity of PPARγ but decreased NF-κB activity. MH inhibited the growth of human prostate cancer cells, an effect attenuated by the PPARγ antagonist GW9662. MH induced apoptotic cell death and this was related to G(0) -G(1) phase cell cycle arrest. MH increased the expression of the cell cycle regulator p21, and apoptotic proteins, whereas it decreased phosphorylation of Rb and anti-apoptotic proteins. Transfection of PC3 cells with p21 siRNA or a p21 mutant plasmid on the cyclin D1/ cycline-dependent kinase 4 binding site abolished the effects of MH on cell growth, cell viability and related protein expression. In the animal studies, MH inhibited tumour growth, NF-κB activity and expression of anti-apoptotic proteins, whereas it increased the transcriptional activity and expression of PPARγ, and the expression of apoptotic proteins and p21 in tumour tissues.Conclusions and Implication: MH inhibits growth of human prostate cancer cells through activation of PPARγ, suppression of NF-κB and arrest of the cell cycle. Thus, MH might be a useful tool for treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

Objective: The role of (18)F-fluorodeocyglucose positron emission tomography (PET)/computed tomography (CT) in only PET/CT-positive lymph nodes (LNs) is not well elucidated yet. This study was conducted to evaluate the diagnostic value of only PET/CT-positive LNs without correlating positive findings on conventional imaging modalities (CT, magnetic resonance imaging [MRI], and ultrasound [US]) in patients with head and neck squamous cell carcinoma (HNSCC). Study Design: Case series with chart review. Setting: Hallym University School of Medicine. Subjects and Methods: From January 2006 to September 2009, 114 patients with HNSCC who underwent CT, MRI, US, and PET/CT before definitive surgery with neck dissection were reviewed. All imaging tests were interpreted on imaging-based nodal classification and were compared with histopathological findings. Results: Only PET/CT-positive LNs were found at 48 nodal levels in 33 patients. Thirteen of 48 (27%) nodal levels were true-positive (TP), and 35 of 48 (73%) were false-positive (FP). Fourteen nodal levels were included on N+ necks, and 34 were included on N0 necks. In N0 necks, the FP rate was significantly higher than the TP rate (28 vs 6, P = .034). Eleven only PET/CT-positive nodal levels in 10 patients were found on the contralateral neck side, and FP was significantly more prevalent than TP (8 vs 3, P = .041). No significant difference was observed for mean standardized uptake value and LN sizes between TP and FP. Conclusion: Only PET/CT-positive LNs can frequently be found and do not predict LN metastasis, because a high percentage of results were FP. Our results suggest that only PET/CT-positive LNs should be considered negative, especially in N0 and contralateral necks. [ABSTRACT FROM AUTHOR]

Objective: This study investigated whether preoperative (18)fluorine-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scanning improved the diagnosis of retropharyngeal lymph node (RPLN) metastasis in patients with head and neck squamous cell carcinoma (HNSCC) relative to conventional imaging alone. Study Design: Case series with chart review. Setting: University hospital cancer center. Subjects and Methods: Sixty-three patients with HNSCC underwent RPLN dissection in accordance with our indications and were subsequently divided into two groups: CT/magnetic resonance imaging (MRI) only (group A, n = 33) and CT/MRI with PET-CT (group B, n = 30). The preoperative radiological findings of each group were compared with the RPLN histopathologic findings, which served as the standard of reference. Results: RPLN metastasis was confirmed histopathologically in 17 of 63 patients (27.0%): eight from group A and nine from group B. With the additional use of PET-CT in group B, the sensitivity (88.9%), specificity (85.7%), and accuracy (86.7%) were higher than the respective values in group A (62.5%, 60.0%, and 60.6%). The positive and negative predictive values for group B (72.7% and 94.7%, respectively) were also higher than those for group A (33.3% and 83.3%, respectively). False-positive results were obtained in 10 patients from group A and three patients from B; false-negative findings occurred in three patients from group A and one patient from group B. The predictive power of the radiological findings was statistically significant in group B (P = 0.0017), with an odds ratio of 47.987 (95% confidence interval, 4.3-535.0). Conclusion: (18)F-FDG PET-CT, when used in combination with CT/MRI, increases diagnostic efficacy in the detection of RPLN metastases and may therefore be useful in screening high-risk patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the molecular mechanisms of the antiarthritic effects of bee venom (BV) and melittin (a major component of BV) in a murine macrophage cell line (Raw 264.7) and in synoviocytes obtained from patients with rheumatoid arthritis. METHODS: We evaluated the antiarthritic effects of BV in a rat model of carrageenan-induced acute edema in the paw and in a rat model of chronic adjuvant-induced arthritis. The inhibitory effects of BV and melittin on inflammatory gene expression were measured by Western blotting, and the generation of prostaglandin E(2) (PGE(2)) and nitric oxide (NO) and the intracellular calcium level were assayed. NF-kappaB DNA binding and transcriptional activity were determined by gel mobility shift assay or by luciferase assay. Direct binding of BV and melittin to the p50 subunit of NF-kappaB was determined with a surface plasmon resonance analyzer. RESULTS: BV (0.8 and 1.6 mug/kg) reduced the effects of carrageenan- and adjuvant-induced arthritis. This reducing effect was consistent with the inhibitory effects of BV (0.5, 1, and 5 mug/ml) and melittin (5 and 10 mug/ml) on lipopolysaccharide (LPS; 1 mug/ml)-induced expression of cyclooxygenase 2, cytosolic phospholipase A(2), inducible NO synthase, generation of PGE(2) and NO, and the intracellular calcium level. BV and melittin prevented LPS-induced transcriptional and DNA binding activity of NF-kappaB via the inhibition of IkappaB release and p50 translocation. BV (affinity [K(d)] = 4.6 x 10(-6)M) and melittin (K(d) = 1.2 x 10(-8)M) bound directly to p50. CONCLUSION: Target inactivation of NF-kappaB by directly binding to the p50 subunit is an important mechanism of the antiarthritic effects of BV. [ABSTRACT FROM AUTHOR]

Aims: This study aims to evaluate the exposure-efficacy relationship of nilotinib and longitudinal BCR::ABL1 levels in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase (CML-CP) and those who are imatinib-resistant or intolerant using a semimechanistic disease model., Methods: The analysis included 489 CML-CP patients from 3 nilotinib trials (NCT00109707; NCT00471497; NCT01043874) with duration of follow-up ranging from 2 to 9 years. The semimechanistic disease model of CML-CP consisted of quiescent leukaemic stem cells, proliferating drug-susceptible and -resistant bone marrow cells. Drug effect on the elimination of susceptible cells was characterized by a maximum response model based on the individual daily area under the concentration-time curve over the last 24 h simulated using their empirical Bayes estimates from a population pharmacokinetic model. The influence of line of therapy was evaluated on model parameters and its impact was investigated through simulations of the major molecular response (MMR) rate, defined as the proportion of the simulated profiles that achieved BCR::ABL1 level of ≤0.1% at 48 and 96 weeks of treatment., Results: The final disease model was based on a truncated 3-year data that characterized the biphasic pattern of BCR::ABL1 transcript profiles. Line of therapy was a significant covariate of the drug kill effect, susceptible and resistant cells. Simulations of BCR::ABL1 time course predicted MMR rates at 48 weeks and 96 weeks for both nilotinib 300 and 400 mg twice-daily of 66-71 and 77-82% in first-line, and 34-39 and 46-54% in second-line, respectively. Results are consistent with observed MMR rates in the respective trials., Conclusion: The ability to distinguish molecular response between lines of therapy is demonstrated using model-based analysis. These nilotinib information enable the extrapolation of novel tyrosine kinase inhibitors (e.g., asciminib) response to other lines of therapy in patients with CML-CP., (© 2024 British Pharmacological Society.)

Aims: This study evaluates how changes in intestinal bile acid composition, induced by cholestyramine, a bile acid sequestrant, affect metformin's pharmacodynamics (PD)., Methods: An open-label, 2-period 1-sequence crossover study was conducted with healthy male adults. Each period consisted of both before and after metformin treatments. Cholestyramine was administered during the second period to change the bile acid pool. For, PD assessment, an oral glucose tolerance test was conducted at each treatment in both periods. Metformin was administered 3 times during each period, and cholestyramine was administered 3 times per day for 7 days during the second period. Maximum serum glucose concentration, area under the glucose concentration curve and homeostatic model assessment of insulin resistance were calculated. Baseline-corrected PD parameters were derived by subtracting pre-metformin values from post-metformin values. Lipid and panels and bile acid profiles in stool were measured. Adverse events were monitored throughout the study., Results: Fourteen subjects completed the study. The mean values of 3 PD parameters were all decreased after metformin administration in both periods. Cholestyramine administration led to a further decrease in baseline-corrected PD parameters, significantly reducing the area under the glucose concentration curve by 44.7%. Diarrhoea, the most common adverse event, was reported in 10 subjects during the metformin alone treatment and in 1 subject during the cholestyramine combined treatment (P < .01)., Conclusion: Cholestyramine affected the glucose-lowering effect of metformin by the possible change in the bile acid pool in the gut, and metformin-associated diarrhoea was improved by cholestyramine., (© 2024 British Pharmacological Society.)

Background: This study aimed to investigate the hemodynamic and anatomic factors associated with sinus thrombosis following transcatheter aortic valve replacement (TAVR), integrating in vivo patient data analysis and in vitro experiments., Methods and Results: Postprocedural, 4-dimensional, multiphase computed tomography data from 211 patients enrolled in the ADAPT-TAVR (Anticoagulation Versus Dual Antiplatelet Therapy for Prevention of Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement) study were analyzed. The prevalence of native sinus thrombosis was examined in relation to valve type, implant depth, and anatomic features. In vitro experiments used particle image velocimetry to observe changes in sinus flow based on the transcatheter heart valves (23-mm SAPIEN3, Edwards Lifesciences; and 29-mm CoreValve, Medtronic) height and coronary artery flow. Native sinus thrombosis was more common in self-expanding valves (39.1% versus 14.9%, P =0.004). In per-cusp analysis of in vivo patient data, adjusted transcatheter heart valve implant depth (odds ratio, 1.2 [95% CI, 1.1-1.3]; P <0.001), noncoronary sinus of Valsalva (odds ratio, 4.0 [95% CI, 2.0-7.8]; P <0.001), sinus inflow diameter (odds ratio, 0.8 [95% CI, 0.6-0.9]; P =0.008), and implanted valve size (odds ratio, 0.8 [95% CI, 0.7-1.0]; P =0.025) were significant factors associated with native sinus thrombosis. In the in vitro experiments, CoreValve showed noticeable flow stasis compared with SAPIEN3. High-positioned SAPIEN3 was linked to reduced velocity within the native sinus of Valsalva. Coronary artery flow led to higher sinus velocity and improved particle washout, reducing sinus thrombosis risk., Conclusions: This study provides insights into the relationship between transcatheter heart valve deployment and native sinus thrombosis, emphasizing the role of anatomic factors in relation to the risk of sinus thrombosis.

The relationship between aging and RNA biogenesis and trafficking is attracting growing interest, yet the precise mechanisms are unknown. The THO complex is crucial for mRNA cotranscriptional maturation and export. Herein, we report that the THO complex is closely linked to the regulation of lifespan. Deficiencies in Hpr1 and Tho2, components of the THO complex, reduced replicative lifespan (RLS) and are linked to a novel Sir2-independent RLS control pathway. Although transcript sequestration in hpr1Δ or tho2Δ mutants was countered by exosome component Rrp6, loss of this failed to mitigate RLS defects in hpr1Δ. However, RLS impairment in hpr1Δ or tho2Δ was counteracted by the additional expression of Nrd1-specific mutants that interacted with Rrp6. This effect relied on the interaction of Nrd1, a transcriptional regulator of aging-related genes, including ribosome biogenesis or RNA metabolism genes, with RNA polymerase II. Nrd1 overexpression reduced RLS in a Tho2-dependent pathway. Intriguingly, Tho2 deletion mirrored Nrd1 overexpression effects by inducing arbitrary Nrd1 chromatin binding. Furthermore, our genome-wide ChIP-seq analysis revealed an increase in the recruitment of Nrd1 to translation-associated genes, known to be related to aging, upon Tho2 loss. Taken together, these findings underscore the importance of Tho2-mediated Nrd1 escorting in the regulation of lifespan pathway through transcriptional regulation of aging-related genes., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background There are still limited data about the differential effect of sex on long-term outcomes after percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) for left main coronary artery disease. This extended follow-up study of the MAIN-COMPARE (Ten-Year Outcomes of Stents Versus Coronary-Artery Bypass Grafting for Left Main Coronary Artery Disease) registry evaluated clinical outcomes beyond 10 years. Methods and Results Of 2240 patients with unprotected left main coronary artery disease (PCI=1102 and CABG=1138), all-cause mortality, the composite of death, Q-wave myocardial infarction, or stroke, and target vessel revascularization were separately evaluated in both sexes. Of 2240 patients, 631 (28.2%) were women and 1609 (71.8%) were men. Women had lower 10-year incidences of death and serious composite outcomes than men. The adjusted 10-year risks of adverse outcomes were similar in men. However, the adjusted 10-year risks were different according to a prespecified period in women. In the short-term (0-1 year) period, PCI had a significantly lower risk for serious composite outcomes (adjusted hazard ratio [HR], 0.41; 95% CI, 0.19-0.91; P =0.03) compared with CABG. The adjusted risks for death and serious composite outcomes were significantly higher after PCI than after CABG, during the midterm (1-5 years) period (death; adjusted HR, 3.99; 95% CI, 2.01-7.92; P <0.001 and composite outcome; adjusted HR, 2.93; 95% CI, 1.59-5.39; P =0.001). Beyond 5 years, adjusted risks were similar after PCI and CABG in women. Conclusions In this 10-year extended follow-up study of patients undergoing left main coronary artery revascularization, we observed a time-dependent impact of sex on the long-term outcomes after PCI and CABG, especially in women, with significant interactions. However, these results warrant confirmation on larger series of studies. Registration URl: https://www.clinicaltrials.gov; Unique identifier: NCT02791412.

Background Various ECG criteria for left ventricular hypertrophy (LVH) have been proposed, but their association with clinical outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement is unknown. We investigated the prevalence of ECG LVH according to different criteria and its prognostic impact on clinical outcomes after transcatheter aortic valve replacement. Methods and Results In this prospective observational cohort, we evaluated 700 patients who underwent transcatheter aortic valve replacement between March 2010 and December 2019. Baseline preprocedural LVH was defined by 3 ECG criteria-Sokolow-Lyon, Romhilt-Estes, and Cornell voltage criteria. The primary outcome was major adverse cardiac or cerebrovascular event (MACCE; composite of death, myocardial infarction, stroke, or rehospitalization from cardiovascular cause); the key secondary outcome was all-cause and cardiovascular mortality. Among 596 eligible patients, the prevalence of LVH was determined as 56.3% by Sokolow-Lyon, 31.1% by Romhilt-Estes, and 48.1% by Cornell criteria. Regardless of the criteria, patients with ECG LVH had more severe aortic stenosis hemodynamics and higher left ventricular mass index. After multivariate adjustment, the presence of LVH by the Cornell criteria was significantly associated with lower risks of MACCE (adjusted hazard ratio [HR], 0.68; 95% CI, 0.51-0.91; P =0.009), all-cause mortality (adjusted HR, 0.55; 95% CI, 0.34-0.90 [ P =0.017]), and cardiovascular mortality (adjusted HR, 0.40; 95% CI, 0.20-0.79 [ P =0.008]). However, this association was absent with the Sokolow-Lyon and Romhilt-Estes criteria. Conclusions ECG LVH by Cornell criteria only was significantly associated with lower risks of MACCE and all-cause or cardiovascular mortality. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03298178.

Background Limited data are available on intracranial hemorrhage (ICH) in patients undergoing antithrombotic therapy after percutaneous coronary intervention (PCI). Methods and Results Using the Korean National Health Insurance Service database, we identified 219 274 patients without prior ICH and who underwent a first PCI procedure between 2007 and 2016 and analyzed nontraumatic ICH and all-cause mortality. ICH after PCI occurred in 4171 patients during a median follow-up of 5.6 years (overall incidence rate: 3.32 cases per 1000 person-years). The incidence rate of ICH showed an early peak of 21.66 cases per 1000 person-years within the first 30 days, followed by a sharp decrease to 3.68 cases per 1000 person-years between 30 days and 1 year, and to <1 case per 1000 patient-years from the second year until 10 years after PCI. The 1-year mortality rate was 38.2% after ICH, with most deaths occurring within 30 days (n=999, mortality rate: 24.2%). No significant difference in mortality risk was observed between patients who had ICH within and after 1 year following PCI (adjusted hazard ratio, 1.04; 95% CI, 0.95-1.14; P =0.43). The predictors of post-PCI ICH were age ≥75 years, hypertension, atrial fibrillation, end-stage renal disease, history of stroke or transient ischemic attack, dementia, and use of vitamin K antagonists. Conclusions New ICH most frequently occurs in the early period after PCI and is associated with a high risk of early death, regardless of the occurrence time of ICH. Careful implementation of antithrombotic strategies is needed in patients at an increased risk for ICH, particularly in the peri-PCI period.

Background The long-term prognostic effect of the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score (SS) after percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) for left main coronary artery disease is controversial. Methods and Results In the PRECOMBAT (Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) trial, 600 patients with left main coronary artery disease were randomized to undergo PCI with drug-eluting stents (n=300) or CABG (n=300). We compared 10-year outcomes after PCI and CABG according to SS categories and evaluated the predictive value of SS in each revascularization arm. The primary outcome was a major adverse cardiac or cerebrovascular event (composite of death, myocardial infarction, stroke, or ischemia-driven target-vessel revascularization) at 10 years. Among 566 patients with valid SS measurement at baseline, 240 (42.4%) had low SS, 200 (35.3%) had intermediate SS, and 126 (22.3%) had high SS. The 10-year rates of major adverse cardiac or cerebrovascular events were not significantly different between PCI and CABG in low (21.6% versus 22.2%, P =0.97), intermediate (31.8% versus 22.2%; P =0.13), and high SS (46.2% versus 35.7%; P =0.31) ( P -for-interaction=0.46). There were no significant interactions between SS categories and revascularization modalities for death ( P =0.92); composite of death, myocardial infarction, or stroke ( P =0.87); and target-vessel revascularization ( P =0.06). Higher SS categories were associated with higher risks for major adverse cardiac or cerebrovascular events in the PCI arm but not in the CABG arm. Conclusions Ten-year clinical outcomes between PCI and CABG were not significantly different according to the SS. The SS was predictive of major adverse cardiac or cerebrovascular events after PCI but not after CABG. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871127.

Background Several trials reported differential outcomes after percutaneous coronary intervention with drug-eluting stents (DES) and coronary-artery bypass grafting (CABG) for multivessel coronary disease according to the presence of diabetes mellitus (DM). However, it is not well recognized how DM status affects very-long-term (10-year) outcomes after DES and CABG for left main coronary artery disease. Methods and Results In the PRECOMBAT (Premier of Randomized Comparison of Bypass Surgery versus Angioplasty using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease) trial, patients with LMCA were randomly assigned to undergo PCI with sirolimus-eluting stents (n=300) or CABG (n=300). The primary outcome was the incidence of major adverse cardiac or cerebrovascular events (MACCE; a composite of death from any cause, myocardial infarction, stroke, or ischemia-driven target-vessel revascularization). Outcomes were examined in patients with (n=192) and without (n=408) medically treated diabetes. The follow-up was extended to at least 10 years for all patients (median, 11.3 years). The 10-year rates of MACCE were not significantly different between DES and CABG in patients with DM (36.3% versus 26.7%, respectively; hazard ratio [HR], 1.35; 95% CI, 0.83-2.19; P =0.23) and without DM (25.3% versus 22.9%, respectively; HR, 1.15; 95% CI, 0.79-1.67; P =0.48) ( P -for-interaction=0.48). There were no significant between-group differences in composite of death, MI, or stroke, and all-cause mortality, regardless of DM status. TVR rates were consistently higher after DES than CABG. Conclusions In this 10-year extended follow-up of PRECOMBAT, we found no significant difference between DES and CABG with respect to the incidences of MACCE, serious composite outcome, and all-cause mortality in patients with and without DM with LMCA disease. However, owing to the limited number of patients and no adjustment for multiple testing, overall findings should be considered hypothesis-generating, highlighting the need for further research. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871127 and NCT00422968.

Background Although guidelines recommend the use of coronary computed tomographic angiography (CTA) in patients with stable pain syndromes, the clinical benefits of the use of coronary CTA in a broad spectrum of patients is unknown. We evaluated the contemporary practice pattern and diagnostic yield of coronary CTA and their impact on the subsequent diagnostic-therapeutic cascade and clinical outcomes. Methods and Results We identified 39 906 patients without known coronary artery disease (CAD) who underwent coronary CTA between January 2007 and December 2013. The patients' demographic characteristics, risk factors, symptoms, results of coronary CTA, the appropriateness of downstream diagnostic and therapeutic interventions, and long-term outcomes (death or myocardial infarction) were evaluated. The number of coronary CTAs had increased over time, especially in asymptomatic patients. Coronary CTA revealed that 6108 patients (15.3%) had obstructive CAD (23.7% of symptomatic and 9.3% of asymptomatic patients). Subsequent cardiac catheterization was performed in 19.2% of symptomatic patients (appropriate, 80.6%) and in 3.9% of asymptomatic patients (appropriate, 7.9%). The 5-year rate of death or myocardial infarction was significantly higher in patients with obstructive CAD on CTA than those without (7.2% versus 3.0%; P <0.001; adjusted hazard ratio [95% CI], 1.34 [1.17-1.54]). However, obstructive CAD on CTA had limited added value over conventional risk factors for predicting death or myocardial infarction. Conclusions Although the use of coronary CTA had substantially increased, CTA had a low diagnostic yield for obstructive CAD, especially in asymptomatic patients. The use of CTA in asymptomatic patients seemed to have led to inappropriate subsequent diagnostic or therapeutic interventions without clinical benefit.

Background Data are still limited regarding whether there are differential long-term outcomes after percutaneous coronary intervention versus coronary artery bypass grafting (CABG) for left main coronary artery disease with or without diabetes mellitus (DM). Methods and Results Using the 10-year data from the MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization) registry, we sought to examine the effect of DM on comparative outcomes after percutaneous coronary intervention or CABG in patients with unprotected left main coronary artery disease. The outcomes of interest were all-cause mortality; a composite of death, Q-wave myocardial infarction, or stroke; and target-vessel revascularization. The primary adjusted analyses were performed with the use of propensity scores and inverse-probability weighting. Of 2240 patients with left main coronary artery revascularization, 722 (32%) had DM. In the overall population, the adjusted 10-year risks of death and composite outcome were similar between percutaneous coronary intervention and CABG, irrespective of DM status ( P interaction : 0.41, mortality; 0.40, composite outcome). However, in the cohort of bare-metal stents and concurrent CABG, we observed differential outcomes after stenting and CABG by DM status ( P interaction : 0.09, mortality; 0.04, composite outcome), favoring CABG in patients with DM. In the cohort of drug-eluting stents and concurrent CABG, the better effect of CABG over stenting was narrowed in patients with DM without a significant interaction ( P interaction : 0.63, mortality; 0.47, composite outcome). Conclusions In this cohort of patients with longest follow-up who underwent left main coronary artery revascularization, the clinical impact of DM favoring CABG over percutaneous coronary intervention has diminished over time from the bare-metal stent to the drug-eluting stent era. Registration URL: http://www.clini​caltr​ials.gov. Unique identifier: NCT02791412.

Background An angiography-based supervised machine learning ( ML ) algorithm was developed to classify lesions as having fractional flow reserve ≤0.80 versus >0.80. Methods and Results With a 4:1 ratio, 1501 patients with 1501 intermediate lesions were randomized into training versus test sets. Between the ostium and 10 mm distal to the target lesion, a series of angiographic lumen diameter measurements along the centerline was plotted. The 24 computed angiographic features based on the diameter plot and 4 clinical features (age, sex, body surface area, and involve segment) were used for ML by XGBoost. The model was independently trained and tested by 2000 bootstrap iterations. External validation with 79 patients was conducted. Including all 28 features, the ML model with 5-fold cross-validation in the 1204 training samples predicted fractional flow reserve ≤0.80 with overall diagnostic accuracy of 78±4% (averaged area under the curve: 0.84±0.03). The 12 high-ranking features selected by scatter search were involved segment; body surface area; distal lumen diameter; minimal lumen diameter; length of a lumen diameter <2.0 mm, <1.5 mm, and <1.25 mm; mean lumen diameter within the worst segment; sex; diameter stenosis; distal 5-mm reference lumen diameter; and length of diameter stenosis >70%. Using those 12 features, the ML predicted fractional flow reserve ≤0.80 in the test set with sensitivity of 84%, specificity of 80%, and overall accuracy of 82% (area under the curve: 0.87). The averaged diagnostic accuracy in bootstrap replicates was 81±1% (averaged area under the curve: 0.87±0.01). External validation showed accuracy of 85% (area under the curve: 0.87). Conclusions Angiography-based ML showed good diagnostic performance in identifying ischemia-producing lesions and reduced the need for pressure wires.

Aim: This survey evaluates the awareness of bisphosphonate-related osteonecrosis of the jaws among Korean dentists., Methods: We prepared a questionnaire based on bisphosphonate-related osteonecrosis of the jaw guidelines, suggested by The American Association of Oral Maxillofacial Surgeons. Among 13,405 dentists, we randomly selected 264 (2%) practitioners., Results: A total of 56.5% of respondents had heard of bisphosphonates as medication related to osteonecrosis, but only 31.4% routinely recorded bisphosphonate medication history. The cross-sectional analysis demonstrated that most dentists were unaware of The American Association of Oral Maxillofacial Surgeons' guidelines. Dentists with <5 years' clinical experience were significantly more aware than those with >5 years' experience. Experience with treating osteonecrosis of the jaw patients and recording medication histories were significantly greater in dental hospitals with >300 beds or university hospitals. Awareness of the severity of bisphosphonate-related osteonecrosis of the jaws was greatest among oral surgeons., Conclusion: Dentists should thoroughly check patients' medical histories, including bisphosphonate intake. With the exception of oral surgeons, most Korean dentists were not adequately aware of bisphosphonate-related osteonecrosis of the jaws and its seriousness, making it a potential risk in Korean dentistry. Therefore, it is important to educate clinicians regarding the potential risk of bisphosphonate medication in dentistry through education programs., (© 2010 Blackwell Publishing Asia Pty Ltd.)

Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by involuntary motor and phonic tics. The pattern of inheritance and associated genetic abnormality has yet to be fully characterized. A dopaminergic abnormality in this disorder is supported by response to specific therapies, nuclear imaging, and postmortem studies. In this protocol, dopaminergic polymorphisms were examined for associations with TS and attention-deficit hyperactivity disorder (ADHD). Polymorphisms investigated included the dopamine transporter (DAT1 DdeI and DAT1 VNTR), dopamine receptor (D4 Upstream Repeat and D4 VNTR), dopamine converting enzyme (dopamine beta-hydroxylase), and the acid phosphatase locus 1 (ACP1) gene. DNA was obtained from 266 TS individuals +/- ADHD and 236 controls that were ethnicity-matched. A significant association, using a genotype-based association analysis, was identified for the TS-total and TS-only versus control groups for the DAT1 DdeI polymorphism (AG vs. AA, P = 0.004 and P = 0.01, respectively). Population structure, estimated by the genotyping of 27 informative SNP markers, identified 3 subgroups. A statistical re-evaluation of the DAT1 DdeI polymorphism following population stratification confirmed the association for the TS-total and TS-only groups, but the degree of significance was reduced (P = 0.017 and P = 0.016, respectively). This study has identified a significant association between the presence of TS and a DAT polymorphism. Since abnormalities of the dopamine transporter have been hypothesized in the pathophysiology of TS, it is possible that this could be a functional allele associated with clinical expression.

The dopamine transporter gene (DAT1) is of particular interest in the genetic study of attention deficit hyperactivity disorder (ADHD), because psychostimulants interact directly with the dopamine transporter protein. Association between ADHD and the 10-repeat allele of a 40 base pair (bp) variable number of tandem repeats (VNTR) polymorphism of DAT1 was first reported in 1995 [Cook et al. (1995); Am J Hum Genet 56:993-998]. Subsequently, several investigators have also confirmed this association, although others reported conflicting results. We analyzed the DAT1 polymorphism in a sample of 33 Korean probands with a Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV) diagnosis of ADHD and found evidence of increased transmission of the 10-repeat allele using transmission disequilibrium test (TDT) (P = 0.001; OR = 7.88, CI = 2.20-28.29). These data support the role of DAT1 in ADHD susceptibility among Asian populations., (Copyright 2006 Wiley-Liss, Inc.)

Gene transfer was performed using asialo-oroso-mucoid-polylysine (ASOR-PL) conjugates to allow targeted expression of the gene in cells of hepatic origin. In a gel-electrophoretic analysis, the ASOR-PL conjugate produced a complete DNA retardation effect at the optimal ratio of 222:1 (ASOR-PL conjugate/pCMV beta-gal plasmid). The gene-transfer efficiency of the ASOR-PL conjugate was evaluated in HepG2 cells that express asialoglycoprotein receptor and NIH 3T3 cells that do not. The expression was assayed by 5-bromo-4-chloroindol-3-yl beta-D-galactopyranoside ('X-Gal') staining and Chlorophenol Red beta-D-galactopyranoside. When an expression vector for the tumour-suppressor gene p53, pCMVp53, complexed to ASOR-PL conjugate, was transfected into HepG2 cells, the exogenously provided p53 gene was detected in the HepG2 cells by PCR. To improve the efficiency of DNA delivery and expression of the therapeutic proteins poloxamer 407, a fusogenic peptide, influenza-virus haemagglutinin HA2 and chloroquine were individually incorporated into the system. The expression level of beta-galactosidase in HepG2 cells was increased by about four times by the presence of poloxamer 407, whereas the fusogenic peptide HA2 and chloroquine had no effects. When HepG2 cells were transfected with pCMVp53 in the presence of poloxamer 407, the mRNA of transfected p53 could be detected by reverse transcriptase PCR. The current findings open the possibility that a receptor-mediated gene-delivery system for hepatic gene therapy using ASOR-PL conjugate in combination with poloxamer 407 may be developed in the future.