Impact of hyper-polypharmacy due to non-cardiovascular medications on long-term clinical outcomes following endovascular treatment for lower limb artery disease: A sub-analysis of the I-PAD Nagano registry.

BACKGROUND: Lower limb artery disease (LEAD) is accompanied by multiple comorbidities; however, the effect of hyperpolypharmacy on patients with LEAD has not been established. This study investigated the associations between hyperpolypharmacy, medication class, and adverse clinical outcomes in patients with LEAD. METHODS: This study used data from a prospective multicenter observational Japanese registry. A total of 366 patients who underwent endovascular treatment (EVT) for LEAD were enrolled in this study. The primary endpoints were major adverse cardiac events (MACE), including myocardial infarction, stroke, and all-cause death. RESULTS: Of 366 patients with LEAD, 12 with missing medication information were excluded. Of the 354 remaining patients, 166 had hyperpolypharmacy (≥10 medications, 46.9 %), 162 had polypharmacy (5-9 medications, 45.8 %), and 26 had nonpolypharmacy (<5 medications, 7.3 %). Over a 4.7-year median follow-up period, patients in the hyperpolypharmacy group showed worse outcomes than those in the other two groups (log-rank test, p < 0.001). Multivariate analysis revealed that the total number of medications was significantly associated with an increased risk of MACE (hazard ratio per medication increase 1.07, 95 % confidence interval 1.02-1.13 p = 0.012). Although an increased number of non-cardiovascular medications was associated with an elevated risk of MACE, the increase in cardiovascular medications was not statistically significant (log-rank test, p = 0.002 and 0.35, respectively). CONCLUSIONS: Hyperpolypharmacy due to non-cardiovascular medications was significantly associated with adverse outcomes in patients with LEAD who underwent EVT, suggesting the importance of medication reviews, including non-cardiovascular medications.

Association between complete revascularization of the coronary artery and clinical outcomes in peripheral artery disease: a sub-analysis of the I-PAD Nagano registry.

Peripheral artery disease (PAD) is commonly caused by atherosclerosis and has an unfavorable prognosis. Complete revascularization (CR) of the coronary artery reduces the risk of major adverse cardiovascular event (MACE) in patients with coronary artery disease (CAD). However, the impact of CR in patients with PAD has not been established to date. Therefore, we evaluated the impact of CR of CAD on the five-year clinical outcomes in patients with PAD. This study was based on a prospective, multicenter, observational registry in Japan. We enrolled 366 patients with PAD undergoing endovascular treatment. The primary endpoint was MACE, defined as a composite of all-cause death, non-fatal myocardial infarction, and non-fatal stroke. After excluding ineligible patients, 96 and 68 patients received complete revascularization of the coronary artery (CR group) and incomplete revascularization of the coronary artery (ICR group), respectively. Freedom from MACE in the CR group was significantly higher than in the ICR group at 5 years (66.7% vs 46.0%, p < 0.01). Multivariate analysis revealed that CR emerged as an independent predictor of MACE (Hazard ratio: 0.56, 95% confidential interval: 0.34-0.94, p = 0.03). CR of CAD was significantly associated with improved clinical outcomes in patients with PAD undergoing endovascular treatment.

Endovascular Retrieval of a Fractured Tunneled Hemodialysis Central Venous Catheter Using the Loop Snare Technique.

The tunneled cuffed hemodialysis catheter is a valuable vascular access option for patients with end-stage renal disease (ESRD). Healthcare providers have become more familiar with the insertion of medical devices, including central venous catheters, in their daily practice. The occurrence of foreign body fragmentation is rare with these catheters. This article presents a case in which a fracture of the distal portion of the hemodialysis catheter was inadvertently identified during a coronary angiography. Percutaneous removal of the fractured venous catheter was performed successfully using a loop snare catheter, which prevented the patient from experiencing further complications.

Validation and Comparison of the Prognosis Predicting Ability of Inflammation-Based Scores Following Endovascular Treatment for Peripheral Artery Disease.

We assessed the prognostic ability of several inflammation-based scores and compared their long-term outcomes in patients with peripheral artery disease (PAD) following endovascular treatment (EVT). We included 278 patients with PAD who underwent EVT and classified them according to their inflammation-based scores (Glasgow prognostic score [GPS], modified GPS [mGPS], platelet to lymphocyte ratio [PLR], prognostic index [PI], and prognostic nutritional index [PNI]). Major adverse cardiovascular events (MACE) at 5 years were examined, and C-statistics in each measure were calculated to compare their MACE predictive ability. During the follow-up period, 96 patients experienced MACE. Kaplan-Meier analysis showed that higher scores of all measures were associated with a higher MACE incidence. Multivariate Cox proportional hazard analysis showed that GPS 2, mGPS 2, PLR 1, and PNI 1, compared with GPS 0, mGPS 0, PLR 0, and PNI 0, were associated with an increased risk of MACE. C-statistics for MACE for PNI (.683) were greater than those for GPS (.635, P = .021), mGPS (.580, P = .019), PLR (.604, P = .024), and PI (.553, P < .001). PNI is associated with MACE risk and has a better prognosis-predicting ability than other inflammation-scoring models for patients with PAD following EVT.

Difamilast Ointment in Japanese Adult and Pediatric Patients with Atopic Dermatitis: A Phase III, Long-Term, Open-Label Study.

INTRODUCTION: Phosphodiesterase 4 (PDE4), which regulates inflammatory cytokine production leading to atopic dermatitis (AD), is selectively inhibited by difamilast. The objective of this phase III, long-term, open-label study was to evaluate the safety and efficacy of topical difamilast in Japanese adult and pediatric patients with AD. METHODS: Adult patients (n = 166) began treatment with difamilast 1% ointment, and pediatric patients began treatment with difamilast 0.3% ointment (n = 144) or difamilast 1% ointment (n = 56). Treatment was continued twice daily for 52 weeks. All patients had an Investigator's Global Assessment (IGA) score of 2 (mild), 3 (moderate), or 4 (severe/very severe), and an AD-affected body surface area (BSA) of ≥ 5% before treatment, with no restriction on the upper limit for the AD-affected BSA. RESULTS: During therapy, 120 adult patients (72.3%) and 178 pediatric patients (89.0%) experienced treatment-emergent adverse events (TEAEs), most of which were mild or moderate in severity. Discontinuation due to TEAEs was reported in 13 adult patients (7.8%) and in 7 pediatric patients (3.5%). Treatment-related adverse events were reported in 14 adult patients (8.4%) and 16 pediatric patients (8.0%), most frequently dermatitis atopic (1.8%) and acne (1.2%) in adult patients and dermatitis atopic and pigmentation disorder (each 2.0%) in pediatric patients. The cumulative success rates in Eczema Area and Severity Index (EASI)-75 in adult and pediatric patients were 55.4% and 73.5%, respectively, at week 52, and the cumulative success rates increased from week 4 to week 52. The cumulative success rates in IGA score showed the same trend as those in EASI -75. CONCLUSIONS: This study demonstrates that difamilast ointments are well tolerated and effective in Japanese adult and pediatric patients with AD when applied twice daily for 52 weeks, and are expected to be used for a long-term treatment for AD. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT03961529.

Impact of Frailty and Age on Clinical Outcomes in Patients Who Underwent Endovascular Therapy.

PURPOSE: Information on the relationship between frailty and the outcome of endovascular therapy (EVT) in elderly patients with lower extremity peripheral artery disease (PAD) is scarce. This study aimed to reveal the impact of frailty on the prognosis of super-elderly patients who underwent EVT. MATERIALS AND METHODS: From August 2015 to August 2016, 335 consecutive patients who underwent EVT were enrolled in the I-PAD registry from 7 institutes in Nagano prefecture. Among them, we categorized 323 patients into 4 groups according to age and the presence or absence of frailty as follows: elderly with frailty (age ≥ 75, Clinical Frailty Scale [CFS] ≥ 5), elderly without frailty (age ≥ 75, CFS ≤ 4), young with frailty (age < 75, CFS ≥ 5), and young without frailty (age < 75, CFS ≤ 4); we analyzed them accordingly. The primary endpoints were major adverse cardiovascular and limb events (MACLE), defined as a composite of cardiovascular death, myocardial infarction, stroke, admission for heart failure, major amputation, and revascularization. The secondary endpoint was cardiovascular death. RESULTS: The median follow-up period was 2.7 years. In the elderly with frailty, elderly without frailty, young with frailty, and young without frailty groups, the freedom rates from MACLE were 34.9%, 55.7%, 35.4%, and 63.0%, respectively (p<0.001) and from all-cause death were 43.5%, 73.4%, 50.7%, and 90.9%, respectively (p<0.001). The freedom rates from MACLE were significantly higher among elderly patients with frailty than among young patients without frailty (55.7% vs 35.4%, p=0.01). In multivariate analysis, frailty was independently associated with MACLE incidence. CONCLUSION: Frailty as defined by CFS might be a predictor of MACLE incidence in patients with PAD who underwent EVT. By considering treatment indications for patients with PAD by focusing on frailty rather than age, we may examine whether EVT policies are appropriate and manage patient and caregiver expectations for potential improvement in functional outcomes. Further studies are expected to investigate whether changes in frailty after EVT change prognosis.

Difamilast ointment in adult patients with atopic dermatitis: A phase 3 randomized, double-blind, vehicle-controlled trial.

BACKGROUND: Difamilast is a selective phosphodiesterase 4 inhibitor. Phosphodiesterase 4 is involved in cytokine production linked with inflammatory disorders, including atopic dermatitis. OBJECTIVE: To demonstrate the superiority of difamilast ointment 1% to vehicle in adult Japanese patients with atopic dermatitis. METHODS: In this phase 3, randomized, double-blind trial, patients aged 15-70 years with an investigator global assessment score of 2 or 3 received topical difamilast ointment 1% (n = 182) or a vehicle (n = 182) twice daily for 4 weeks. RESULTS: The success rate in investigator global assessment score at week 4 (primary endpoint)-the percentage of patients achieving an investigator global assessment score of 0 or 1 with ≥2-grade improvement-was significantly higher with 1% difamilast than with the vehicle (38.46% vs 12.64%, respectively, P < .0001). The success rates in ≥50%, ≥75%, and ≥90% improvement in overall eczema area and severity index score at week 4 followed the same trend. Difamilast at 1% provided significant mean percent improvement from baseline in overall eczema area and severity index score versus vehicle from week 1 to 4. Treatment-emergent adverse events were mostly mild or moderate and less frequent with difamilast. LIMITATIONS: Study treatment was limited to 4 weeks. CONCLUSION: Difamilast ointment 1% demonstrated superiority to the vehicle and favorable safety in adult Japanese patients with atopic dermatitis.

Prognostic impact of the dosage of methotrexate combined with tacrolimus for graft-versus-host disease prophylaxis after cord blood transplantation.

The optimal dosage of methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after cord blood transplantation (CBT) has not been well elucidated. Therefore, we conducted a retrospective study comparing a mini-MTX group (5 mg/m2 on day 1, 3 and 6) to a short-MTX group (10 mg/m2 on day 1 and 7 mg/m2 on day 3 and 6) after CBT. Sixty-three patients were classified as the mini-MTX group and 20 as the short-MTX group. The median time and cumulative incidence of neutrophil engraftment did not vary between the two groups. The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD was similar in both groups. Overall survival in the mini-MTX group was significantly lower than in the short-MTX group (46.9% vs. 88.7% at 1 year, p < 0.01), contributing to higher non-relapse mortality (NRM) in the mini-MTX group (32.0% vs. 5.0% at 1 year, p = 0.02). In multivariate analysis, the mini-MTX regimen was the most powerful prognostic factor for OS (hazard ratio 4.11; p = 0.03). Although the reduced dosage of MTX had no effect on neutrophil engraftment, increased NRM due to higher incidence of infection, graft failure, and severe acute GVHD resulted in a lower survival rate in the mini-MTX group after CBT.

Body composition and mortality in patients undergoing endovascular treatment for peripheral artery disease.

An inverse correlation between body mass index and mortality in patients with peripheral artery disease (PAD) has been reported. However, little information is available regarding the impact of body composition on the clinical outcomes in patients with PAD. This study evaluated the relationships between the lean body mass index (LBMI), body fat % (BF%), and mortality and major amputation rate in patients with PAD. We evaluated 320 patients with PAD after endovascular treatment (EVT) enrolled from August 2015 to July 2016 and divided them into low and high LBMI and BF% groups based on their median values (17.47 kg/m2 and 22.07%, respectively). We assessed 3-year mortality and major amputation for the following patient groups: Low LBMI/Low BF%, Low LBMI/High BF%, High LBMI/Low BF%, and High LBMI/High BF%. During the median 3.1-year follow-up period, 70 (21.9%) patients died and 9 (2.9%) patients experienced major amputation. The survival rate was lower in the Low LBMI than in the High LBMI group, and was not significantly different between the Low and High BF% groups. Survival rates were lowest in the Low LBMI/Low BF% group (57.5%) and highest in the High LBMI/High BF% group (94.4%). There were no significant differences in major amputation rate between the Low LBMI and High LBMI groups, and between the Low BF% and High BF% groups. The Low LBMI and Low BF% groups were associated with an increased risk of mortality after adjustment for age, sex, frailty and conventional risk factors [hazard ratio (HR): 4.02; 95% confidence interval (CI) 2.10-7.70; p < 0.001 and HR: 4.48; 95% CI 1.58-12.68, p = 0.005, respectively], for age, sex, hemodialysis, and prior cerebral cardiovascular disease (HR: 3.63; 95% CI 1.93-6.82; p < 0.001 and HR: 4.03; 95% CI 1.43-11.42, p = 0.009, respectively) and for age, sex, and laboratory date (HR: 3.97; 95% CI 1.88-8.37; p < 0.001 and HR: 3.31; 95% CI 1.15-9.53, p = 0.026, respectively). In conclusion, Low LBMI and Low BF% were associated with poor prognosis in patients undergoing EVT for PAD, and mortality was the lowest in the High LBMI/High BF% group compared with other body composition groups.

Association of the Prognosis of Ankle-brachial Index Improvement One Year Following Endovascular Therapy in Patients with Peripheral Artery Disease: Data from the I-PAD NAGANO Registry.

Objective Despite reports on the effects of ankle-brachial index (ABI) improvement following endovascular therapy (EVT) on the limb prognosis, studies evaluating cardiovascular events are limited. We investigated whether or not ABI improvement 1 year following EVT was associated with cardiovascular events. Methods The I-PAD NAGANO registry is an observational multicenter cohort study that enrolled 337 patients with peripheral artery disease (PAD) who underwent EVT between August 2015 and July 2016. From this cohort, we identified 232 patients whose ABI data 1 year following EVT were available, after excluding patients with critical limb ischemia. We divided the patients into two groups according to the degree of ABI improvement 1 year following EVT (ΔABI) - the ΔABI <0.15 group and the ΔABI ≥0.15 group - and compared the outcomes. The primary endpoint was major adverse cardiovascular events (MACEs), including all - cause death, myocardial infarction (MI), and stroke. The secondary endpoints were major adverse limb events (MALEs), defined as a composite of target lesion revascularization and major amputation, all - cause death, MI, and stroke. The median follow-up period was 3.3 years. Results The incidence of MACEs was significantly higher in the ΔABI <0.15 group than in the ΔABI ≥0.15 group (ΔABI <0.15 vs. ΔABI ≥0.15, 25.8% vs. 11.9%, log-rank p=0.036), as was the incidence of stroke (14.1% vs. 2.2%, log-rank p=0.016). A Cox regression analysis revealed that ΔABI ≥0.15 was significantly associated with fewer MACEs (hazard ratio 0.38, 95% confidence interval 0.17-0.83, p=0.016). Conclusion An increase in ABI ≥0.15 at 1 year following EVT was a predictor of reduced MACEs.

Transcriptional autoregulation of zebrafish tbx6 is required for somite segmentation.

The presumptive somite boundary in the presomitic mesoderm (PSM) is defined by the anterior border of the expression domain of Tbx6 protein. During somite segmentation, the expression domain of Tbx6 is regressed by Ripply-meditated degradation of Tbx6 protein. Although the expression of zebrafish tbx6 remains restricted to the PSM, the transcriptional regulation of tbx6 remains poorly understood. Here, we show that the expression of zebrafish tbx6 is maintained by transcriptional autoregulation. We find that a proximal-located cis-regulatory module, TR1, which contains two putative T-box sites, is required for somite segmentation in the intermediate body and for proper expression of segmentation genes. Embryos with deletion of TR1 exhibit significant reduction of tbx6 expression at the 12-somite stage, although its expression is initially observed. Additionally, Tbx6 is associated with TR1 and activates its own expression in the anterior PSM. Furthermore, the anterior expansion of tbx6 expression in ripply gene mutants is suppressed in a TR1-dependent manner. The results suggest that the autoregulatory loop of zebrafish tbx6 facilitates immediate removal of Tbx6 protein through termination of its own transcription at the anterior PSM.

Functional roles of the Ripply-mediated suppression of segmentation gene expression at the anterior presomitic mesoderm in zebrafish.

Somites sequentially form with a regular interval by the segmentation from the anterior region of the presomitic mesoderm (PSM). The expression of several genes involved in the somite segmentation is switched off at the transition from the anterior PSM to somites. Zebrafish Ripply1, which down-regulates a T-box transcription factor Tbx6, is required for the suppression of segmentation gene expression. However, the functional roles of the Ripply-mediated suppression of segmentation gene expression at the anterior PSM remain elusive. In this study, we generated ripply1 mutants and examined genetic interaction between ripply1/2 and tbx6. Zebrafish ripply1-/- embryos failed to form the somite boundaries as was observed in knockdown embryos. We found that somite segmentation defects in ripply1 mutants were suppressed by heterozygous mutation of tbx6 or partial translational inhibition of tbx6 by antisense morpholino. We further showed that somite boundaries that were recovered in tbx6+/-; ripply1-/- embryos were dependent on the function of ripply2, indicating that relative gene dosage between ripply1/2 and tbx6 plays a critical role in the somite formation. Interestingly, the expression of segmentation genes such mesp as was still not fully suppressed at the anterior PSM of tbx6+/-; ripply1-/- embryos although the somite formation and rostral-caudal polarity of somites were properly established. Furthermore, impaired myogenesis was observed in the segmented somites in tbx6+/-; ripply1-/- embryos. These results revealed that partial suppression of the segmentation gene expression by Ripply is sufficient to establish the rostral-caudal polarity of somites, and that stronger suppression of the segmentation gene expression by Ripply is required for proper myogenesis in zebrafish embryos.

Enhancer activity-based identification of functional enhancers using zebrafish embryos.

Chromatin immunoprecipitation (ChIP) against enhancer-associated marks with massive sequencing is a powerful approach to identify genome-wide distributions of putative enhancers. However, functional in vivo analysis is required to elucidate the activities of predicted enhancers. Using zebrafish embryos, we established a ChIP-Injection method that enables identification of functional enhancers based on their enhancer activities in embryos. Each reporter gene possessing the enhancer-associated genomic region enriched by ChIP was injected into zebrafish embryos to analyze the activity of putative enhancers. By using the ChIP-Injection, we identified 32 distinct putative enhancers that drove specific expression. Additionally, we generated transgenic lines that exhibit distributions of the EGFP signal as was observed in the screening. Furthermore, the expression pattern driven by the identified somite-specific enhancer resembled that of the gene acta2. The results indicate that ChIP-Injection provides an efficient approach for identification of active enhancers in a potentially wide variety of developmental tissues and stages.

Posterior-anterior gradient of zebrafish hes6 expression in the presomitic mesoderm is established by the combinatorial functions of the downstream enhancer and 3'UTR.

In vertebrates, the periodic formation of somites from the presomitic mesoderm (PSM) is driven by the molecular oscillator known as the segmentation clock. The hairy-related gene, hes6/her13.2, functions as a hub by dimerizing with other oscillators of the segmentation clock in zebrafish embryos. Although hes6 exhibits a posterior-anterior expression gradient in the posterior PSM with a peak at the tailbud, the detailed mechanisms underlying this unique expression pattern have not yet been clarified. By establishing several transgenic lines, we found that the transcriptional regulatory region downstream of hes6 in combination with the hes6 3'UTR recapitulates the endogenous gradient of hes6 mRNA expression. This downstream region, which we termed the PT enhancer, possessed several putative binding sites for the T-box and Ets transcription factors that were required for the regulatory activity. Indeed, the T-box transcription factor (Tbx16) and Ets transcription factor (Pea3) bound specifically to the putative binding sites and regulated the enhancer activity in zebrafish embryos. In addition, the 3'UTR of hes6 is required for recapitulation of the endogenous mRNA expression. Furthermore, the PT enhancer with the 3'UTR of hes6 responded to the inhibition of retinoic acid synthesis and fibroblast growth factor signaling in a manner similar to endogenous hes6. The results showed that transcriptional regulation by the T-box and Ets transcription factors, combined with the mRNA stability given by the 3'UTR, is responsible for the unique expression gradient of hes6 mRNA in the posterior PSM of zebrafish embryos.

Acquired factor X deficiency developed four years after autologous transplantation in a patient with multiple myeloma associated with systemic AL amyloidosis.

We describe a case of acquired factor X deficiency after high-dose melphalan with autologous stem cell transplantation (HDM/ASCT) for multiple myeloma (MM) with systemic AL amyloidosis. A 68-year-old woman with renal amyloidosis was diagnosed as having MM in 2007. She achieved a partial response after VAD (vincristine, adriamycin, dexamethasone) therapy and HDM/ASCT. In December 2011, coagulation tests revealed a prolonged prothrombin time (PT) of 17.6 sec and she was administered vitamin K. In January 2012, she received low anterior resection with colostomy for rectal cancer. She received fresh frozen plasma (FFP) infusion but the perioperative bleeding tendency persisted. In February 2012, she was referred from surgery for colostomy closure. She showed no progression of MM and had prolonged PT, corrected by mixing with normal plasma. Factor X activity was markedly decreased. She was diagnosed as having an acquired factor X deficiency and was given FFP infusion for colostomy closure. Although acquired factor X deficiency after HDM/ASCT for MM with systemic AL amyloidosis is rare, we should be aware of the possibility of this disease in MM patients with a bleeding tendency.

Impact on optical coherence tomographic coronary findings of fluvastatin alone versus fluvastatin + ezetimibe.

Although lipid-lowering therapy with statin and ezetimibe has been reported to provide greater reduction in low-density lipoprotein cholesterol levels than statin monotherapy, the effect of supplemental therapy on plaque stabilization is yet to be fully elucidated. Cap thickness of fibroatheroma evaluated by optical coherence tomography (OCT) is a major determinant of vulnerable plaque. The primary objective of this study is to evaluate the effect of ezetimibe in addition to fluvastatin on the progression of coronary atherosclerotic plaque evaluated by OCT. Sixty-three patients with angina pectoris with intermediate, nonculprit, lipid-rich plaque lesions evaluated by OCT were enrolled. The patients were divided into 2 groups: ezetimibe (10 mg/day) + fluvastatin (30 mg/day), and fluvastatin (30 mg/day) alone, and serial OCT examinations were performed at baseline and 9-month follow-up. A total of 57 patients (ezetimibe + fluvastatin, n = 31; fluvastatin alone, n = 26) underwent serial OCT examinations. The change in low-density lipoprotein cholesterol level was significantly larger in the ezetimibe + fluvastatin group compared with fluvastatin-alone group (-34.0 ± 32.0 vs -8.3 ± 17.4 mg/dl, p <0.001). Fibrous cap thickness was significantly increased and the angle of the lipid plaque was significantly decreased in both groups. The change in the fibrous cap thickness was significantly greater in the ezetimibe + fluvastatin group (0.08 ± 0.08 mm vs 0.04 ± 0.06 mm, p <0.001). In conclusion, lipid-lowering therapy by ezetimibe + fluvastatin could increase the fibrous cap thickness of lipid-rich plaque compared with fluvastatin monotherapy.

Impact of cholesterol metabolism on coronary plaque vulnerability of target vessels: a combined analysis of virtual histology intravascular ultrasound and optical coherence tomography.

OBJECTIVES: The aim of this study was to evaluate the relationship between cholesterol metabolism and coronary plaque vulnerability. BACKGROUND: Cholesterol homeostasis, defined as the balance between absorption and synthesis, influences the progression of coronary atherosclerosis. METHODS: Consecutive stable angina pectoris patients (N = 80) not receiving any lipid-lowering therapy were divided into 2 groups based on the presence of in vivo thin cap fibroatheroma (TCFA) in de novo target vessels assessed by the combined use of virtual histology intravascular ultrasound and optical coherence tomography. RESULTS: Patients with in vivo TCFA (n = 42) showed a higher campesterol-to-lathosterol ratio (3.36 [interquartile range, 2.10 to 4.26] vs. 1.50 [1.20 to 2.50], p < 0.0001). The campesterol-to-lathosterol ratio, low-density lipoprotein (LDL) cholesterol, and high-sensitivity C-reactive protein (hsCRP) were positively correlated with the percentage of necrotic core volume (r = 0.520, p < 0.0001; r = 0.520, p < 0.0001; and r = 0.539, p < 0.0001, respectively) and negatively correlated with thinnest fibrous cap thickness (r = -0.566, p < 0.0001; r = -0.530, p < 0.0001; and r = -0.358, p = 0.007, respectively) . The independent predictors of the incidence of TCFA were the campesterol-to-lathosterol ratio (odds ratio: 3.989, 95% confidence interval: 1.688 to 9.428; p = 0.002), LDL cholesterol (odds ratio: 1.425, 95% confidence interval: 1.023 to 1.985; p = 0.03), hsCRP (odds ratio: 1.025, 95% confidence interval: 1.003 to 1.047; p = 0.02), and the percentage of necrotic core volume (odds ratio:1.084, 95% confidence interval: 1.012 to 1.161; p = 0.02). CONCLUSIONS: Enhanced absorption and reduced synthesis of cholesterol may be related to coronary plaque vulnerability.

Morphological differences of tissue characteristics between early, late, and very late restenosis lesions after first generation drug-eluting stent implantation: an optical coherence tomography study.

AIMS: Restenosis of drug-eluting stents (DESs) might be different from that of bare metal stent restenosis in diverse ways including mechanisms and time course; however, these have not been fully examined. To gain insight into the mechanisms and time course of DES restenosis, we evaluated the characteristics of restenotic lesions of first generation DES using optical coherence tomography (OCT). METHODS AND RESULTS: We compared the morphological characteristics of early in-stent restenosis (<1 year: E-ISR, n = 43), late ISR (1-3 years: L-ISR, n = 22), and very late ISR (>3 years: VL-ISR, n = 21). OCT qualitative restenotic tissue analysis included the assessment of tissue structure [homogeneous or four types of heterogeneous intima (thin-cap fibroatheroma (TCFA)-like, layered, patchy or speckled pattern)], the presence of the peri-strut low intensity area (PLIA), microvessels, disruption with cavity, and intraluminal material and was performed at every 1 mm slice of the entire stent length. In addition to a greater trend for heterogeneous intima at the later phase, TCFA-like pattern image, intra-intima microvessels were increased from the early to the very late phase. On the other hand, the speckled pattern image was decreased from the early to the very late phase. CONCLUSION: The OCT morphological characteristics of DES restenotic tissue varied at different time-points. OCT images in early DES ISR might be associated with delayed arterial healing, and neoatherosclerosis might contribute to late catch-up phenomenon (L-ISR and VL-ISR) after DES implantation.

JmjC-domain containing histone demethylase 1B-mediated p15(Ink4b) suppression promotes the proliferation of leukemic progenitor cells through modulation of cell cycle progression in acute myeloid leukemia.

The histone demethylase JHDM1B has been implicated in cell cycle regulation and tumorigenesis. In addition, it has been reported that JHDM1B is highly expressed in various human tumors, including leukemias. However, it is not clearly understood how JHDM1B contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of JHDM1B in AML cells. In AML cell lines and AML-derived ALDH(hi) (high aldehyde dehydrogenase activity)/CD34(+) cells, the levels of JHDM1B mRNA were significantly higher than in normal ALDH(hi) /CD34(+) cells. Reduction of JHDM1B expression in AML cells inhibited cell proliferation compared to control cells, through induction of G1 cell cycle arrest, an increase in the p15(Ink4b) mRNA and protein expression. JHDM1B mRNA was overexpressed in all 133 AML clinical specimens tested (n = 22, 57, 34, and 20 for M1, 2, 4, and 5 subtypes respectively). Compared to normal ALDH(hi) /CD34(+) cells, JHDM1B gene expression was 1.57- to 1.87-fold higher in AML-derived ALDH(hi) /CD34(+) cells. Moreover, the JHDM1B protein was more strongly expressed in AML-derived ALDH(hi) /CD34(+) cells from compared to normal ALDH(hi) /CD34(+) cells. In addition, depletion of JHDM1B reduced colony formation of AML-derived ALDH(hi) /CD34(+) cells due to induction of p15(Ink4b) expression through direct binding to p15(Ink4b) promoter and loss of demethylation of H3K36me2. In summary, we found that JHDM1B mRNA is predominantly expressed in AML-derived ALDH(hi) /CD34(+) cells, and that aberrant expression of JHDM1B induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of JHDM1B expression represents an attractive target for AML therapy.

Impact of frequency-domain optical coherence tomography guidance for optimal coronary stent implantation in comparison with intravascular ultrasound guidance.

BACKGROUND: Frequency-domain optical coherence tomography (FD-OCT) is a novel, high resolution intravascular imaging modality. Intravascular ultrasound (IVUS) is a widely used conventional imaging modality for achieving optimal stent deployment. The aim of this study was to evaluate the impact of FD-OCT guidance for coronary stent implantation compared with IVUS guidance. METHODS AND RESULTS: A total of 70 patients with de novo coronary artery lesions and either unstable or stable angina pectoris were enrolled in this randomized study (optical coherence tomography [OCT] group: n=35, IVUS group: n=35). In the OCT group, stent implantation was performed under FD-OCT guidance alone and final stent expansion was evaluated by IVUS. In the IVUS group, conventional IVUS guidance was used and final stent apposition was evaluated by FD-OCT. There were no significant differences regarding the procedural, fluoroscopy time, and contrast volume. Although device and clinical success rates also were similar, the visibility of vessel border was significantly lower in the OCT group (P<0.05). Minimum and mean stent area and focal and diffuse stent expansion were smaller (6.1±2.2 mm versus 7.1±2.1 mm, 7.5±2.5 versus 8.7±2.4 mm, 64.7±13.7% versus 80.3±13.4%, 84.2±15.8% versus 98.8±16.5%, P<0.05, respectively), and the frequency of significant residual reference segment stenosis at the proximal edge was higher in the OCT group (P<0.05). Incomplete apposed struts in both groups were similar (P=0.34). CONCLUSIONS: FD-OCT guidance for stent implantation was associated with smaller stent expansion and more frequent significant residual reference segment stenosis compared with conventional IVUS guidance.