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Background The long-term prognostic impact of IVUS findings following Absorb BVS implantation remains uncertain. This study aimed to identify the IVUS predictors of long-term clinical outcomes following ABSORB bioresorbable vascular scaffold (BVS) implantation from the pooled IVUS substudy cohorts of the ABSORB III and Japan trials. Methods A total of 298 lesions in 286 patients were enrolled with 2:1 randomization to ABSORB BVS vs. cobalt-chromium everolimus-eluting stents. This sub-analysis included 168 lesions of 160 patients in the Absorb arm whose post-procedural quantitative IVUS were available. The primary endpoint of this analysis was device-oriented composite endpoint (DOCE) of target lesion failure, including cardiac death, target vessel-related myocardial infarction, or ischemia-driven target lesion revascularization. The median follow-up duration was 4.9 [3.1–5.0] years. Results During follow-up, DOCE occurred in 10.1% of lesions treated with Absorb BVS. Among several post-procedural IVUS indices associated with DOCE, non-uniform device expansion (defined as uniformity index = minimum / maximum device area) (hazard ratio 0.47 per 0.1 increase [95%CI 0.28 to 0.77]; p = 0.003) and residual reference plaque burden (hazard ratio 4.01 per 10% increase [95%CI 1.50 to 10.77]; p = 0.006) were identified as independent predictors of DOCE by Cox multivariable analysis. Conclusions Nonuniform device expansion and substantial untreated residual plaque in reference segments were associated with long-term adverse events following BVS implantation. Baseline imaging to identify the appropriate device landing zone and procedural imaging to achieve uniform device expansion if possible (e.g. through post-dilatation) may improve clinical outcomes of BVS implantation. Clinical trial registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01751906 (ABSORB III); NCT01844284 (ABSORB Japan).

Background Bioresorbable vascular scaffolds (BVS) are promising alternatives to metallic drug-eluting stents (DES) in percutaneous coronary interventions. Absorb BVS was comparable to XIENCE (DES) for patient- and device-oriented composite endpoints through 1 year post-procedure. Mid-term results showed increased rates of device-oriented events with Absorb. The objective of this study was to evaluate the long-term safety and effectiveness of Absorb BVS compared with XIENCE metallic DES when implanted in patients in Japan with de novo coronary artery lesions.Methods and Results:ABSORB Japan randomized 400 patients into either Absorb (n=266) or XIENCE (n=134) treatment arm. Through 5-year follow-up, the composite endpoints of DMR (death, myocardial infarction [MI], and all revascularization), target vessel failure (TVF), major adverse cardiac events (MACE), target lesion failure (TLF), and cardiac death/all MI were evaluated. Individual endpoints included death, MI, coronary revascularization, and scaffold/stent thrombosis. There were no significant differences in the composite or individual endpoint outcomes between the Absorb and XIENCE arms through 5 years or between 3 and 5 years. Numerically lower TVF, MACE, and all MI rates were observed for the Absorb vs. XIENCE arm after 3 years. No scaffold/stent thrombosis was reported beyond 3 years. Post-procedure imaging subgroups showed comparable event rates. Conclusions Following resorption of the scaffold, between 3 and 5 years post-procedure, the Absorb BVS performed comparably to XIENCE in all patient- and device-oriented endpoints (ClinicalTrials.gov, #NCT01844284).

Objectives: The aim of this study was to investigate the vascular responses and fates of the scaffold after bioresorbable vascular scaffold (BVS) implantation using multimodality imaging. Background: Serial comprehensive image assessments after BVS implantation in the context of a randomized trial have not yet been reported. Methods: In the ABSORB Japan trial, 400 patients were randomized to a BVS (n = 266) or a cobalt-chromium everolimus-eluting stent (n = 134). Through 3 years, patients underwent serial angiography and intravascular ultrasound or optical coherence tomography (OCT). Results: Luminal dimension at 3 years was consistently smaller with the BVS than with the cobalt-chromium everolimus-eluting stent (mean angiographic minimal luminal diameter 2.04 ± 0.63 mm vs. 2.40 ± 0.56 mm, mean difference −0.37 mm [95% confidence interval: −0.50 to −0.24 mm]; p < 0.001), mainly because of smaller device area (6.13 ± 2.03 mm2 vs. 7.15 ± 2.16 mm2, mean difference −1.04 mm2 [95% confidence interval: −1.66 to −0.42 mm2]; p < 0.001), and larger neointimal area (2.10 ± 0.61 mm2 vs. 1.86 ± 0.64 mm2, mean difference 0.24 mm2 [95% confidence interval: 0.06 to 0.43 mm2]; p = 0.01) by OCT. BVS-treated vessels did not show previously reported favorable vessel responses, such as positive vessel remodeling, late luminal enlargement, and restoration of vasomotion, although the OCT-based healing score was on average zero (interquartile range: 0.00 to 0.00). At 3 years, intraluminal scaffold dismantling (ISD) was observed in 14% of BVS. On serial OCT, ISD was observed in 6 lesions at 2 years, where the struts had been fully apposed at post-procedure, while ISD was observed in 12 lesions at 3 years, where 8 lesions were free from ISD on 2-year OCT. In 5 cases of very late scaffold thrombosis, strut discontinuities were detected in all 4 cases with available OCT immediately before reintervention. Conclusions: In this multimodality serial imaging study, luminal dimension at 3 years was smaller with the BVS than with the cobalt-chromium everolimus-eluting stent. ISD, suspected to be one of the mechanisms of very late BVS thrombosis, was observed in a substantial proportion of cases at 3 years, which developed between post-procedure and 2 years and even beyond 2 years. (AVJ-301 Clinical Trial: A Clinical Evaluation of AVJ-301 [Absorb™ BVS] in Japanese Population [ABSORB JAPAN]; NCT01844284)

Objectives: The aim of this study was to investigate the vascular responses and fates of the scaffold after bioresorbable vascular scaffold (BVS) implantation using multimodality imaging. Background: Serial comprehensive image assessments after BVS implantation in the context of a randomized trial have not yet been reported. Methods: In the ABSORB Japan trial, 400 patients were randomized to a BVS (n = 266) or a cobalt-chromium everolimus-eluting stent (n = 134). Through 3 years, patients underwent serial angiography and intravascular ultrasound or optical coherence tomography (OCT). Results: Luminal dimension at 3 years was consistently smaller with the BVS than with the cobalt-chromium everolimus-eluting stent (mean angiographic minimal luminal diameter 2.04 ± 0.63 mm vs. 2.40 ± 0.56 mm, mean difference −0.37 mm [95% confidence interval: −0.50 to −0.24 mm]; p < 0.001), mainly because of smaller device area (6.13 ± 2.03 mm2 vs. 7.15 ± 2.16 mm2, mean difference −1.04 mm2 [95% confidence interval: −1.66 to −0.42 mm2]; p < 0.001), and larger neointimal area (2.10 ± 0.61 mm2 vs. 1.86 ± 0.64 mm2, mean difference 0.24 mm2 [95% confidence interval: 0.06 to 0.43 mm2]; p = 0.01) by OCT. BVS-treated vessels did not show previously reported favorable vessel responses, such as positive vessel remodeling, late luminal enlargement, and restoration of vasomotion, although the OCT-based healing score was on average zero (interquartile range: 0.00 to 0.00). At 3 years, intraluminal scaffold dismantling (ISD) was observed in 14% of BVS. On serial OCT, ISD was observed in 6 lesions at 2 years, where the struts had been fully apposed at post-procedure, while ISD was observed in 12 lesions at 3 years, where 8 lesions were free from ISD on 2-year OCT. In 5 cases of very late scaffold thrombosis, strut discontinuities were detected in all 4 cases with available OCT immediately before reintervention. Conclusions: In this multimodality serial imaging study, luminal dimension at 3 years was smaller with the BVS than with the cobalt-chromium everolimus-eluting stent. ISD, suspected to be one of the mechanisms of very late BVS thrombosis, was observed in a substantial proportion of cases at 3 years, which developed between post-procedure and 2 years and even beyond 2 years. (AVJ-301 Clinical Trial: A Clinical Evaluation of AVJ-301 [Absorb™ BVS] in Japanese Population [ABSORB JAPAN]; NCT01844284)

Objectives The aim of this study was to characterize post-procedural intravascular ultrasound (IVUS) findings in the ABSORB Japan trial, specifically stratified by the size of target coronary arteries. Background Despite overall noninferiority confirmed in recent randomized trials comparing bioresorbable vascular scaffolds (BVS) (Absorb BVS) and cobalt-chromium everolimus-eluting metallic stents (CoCr-EES), higher event rates of Absorb BVS have been reported with suboptimal deployment, especially in small coronary arteries. Methods In the ABSORB Japan trial, 150 patients (2:1 randomization) were scheduled in the IVUS cohort. Small vessel was defined as mean reference lumen diameter Results Overall, IVUS revealed that the Absorb BVS arm had smaller device expansion than the CoCr-EES arm did, which was particularly prominent in small- and tapered-vessel lesions. Higher tapering index was also associated with higher rates of incomplete strut apposition in Absorb BVS, but not in CoCr-EES. With respect to procedural techniques, small-vessel lesions were treated more frequently with noncompliant balloons at post-dilatation but using significantly lower pressure in the Absorb BVS arm. In contrast, tapered-vessel lesions were post-dilated at equivalent pressure but with significantly smaller balloon catheters in the Absorb BVS arm, compared with the CoCr-EES arm. Conclusions The significantly smaller device expansion especially in small vessels may account for the poorer outcomes of Absorb BVS in this lesion type. Appropriate optimization strategy, possibly different between polymeric and metallic devices, needs to be established for bioresorbable scaffold technology. (AVJ-301 Clinical Trial: A Clinical Evaluation of AVJ-301 Absorb™ BVS) in Japanese Population [ABSORB JAPAN]; NCT01844284)

The Cobalt Chromium Everolimus-Eluting Stent (CoCr-EES) Post Marketing Surveillance (PMS) Japan study is a prospective multicenter registry designed to evaluate the safety and efficacy of XIENCE V/PROMUS everolimus-eluting stents in routine clinical practice at 47 centers representative of the clinical environment in Japan. We enrolled 2010 consecutive patients (2649 lesions) who underwent percutaneous coronary intervention using CoCr-EES. Clinical outcomes were evaluated through 5 years. Mean age was 68.8 years, 41.9% had diabetes, 4.9% received hemodialysis. Five-year clinical follow up was available for 1704 (84.8%) patients. Major adverse cardiovascular events (MACE) occurred in 10.7% of patients, including cardiac death (3.8%), myocardial infarction (1.8%), and clinically driven target lesion revascularization (TLR) (6.0%). Beyond 1 year, annual incidence of clinically driven TLR was 0.5–0.8%. Definite or probable stent thrombosis occurred in 9 (0.5%) patients at 5 years. After 1 year, definite stent thrombosis occurred in only 1 patient. Significant predictors for MACE were dialysis (ODDs ratio 4.58, 95% CI 2.75–7.64), prior cardiac intervention (ODDs ratio 2.47, 95% CI 1.75–3.49), total stent length (ODDs ratio 1.01, 95% CI 1.01–1.02), and number of diseased vessels (ODDs ratio 1.66, 95% CI 1.08–2.55). Five-year clinical outcomes from the CoCr-EES PMS Japan study demonstrated a low incidence of clinical events in the daily practice up to 5 years. Clinical Trial Registration Information: https://clinicaltrials.gov/ct2/show/NCT01086228 .

Aims: Blooming artefacts limit accurate coronary assessment by multislice computed tomography (MSCT) in metallic stents. We sought to investigate whether bioresorbable vascular scaffolds (BVS) could be better assessed by MSCT. Methods and results: Among 400 patients in the randomised ABSORB Japan trial, a pre-specified MSCT substudy was performed in 98 patients (103 lesions) in the BVS arm and 49 patients (49 lesions) in the cobalt-chromium everolimus-eluting stent (CoCr-EES) arm at 13 months prior to follow-up angiography. The assessability of BVS by MSCT was superior to that of CoCr-EES (94% versus 67%, p

Aims: We aimed to investigate the impact of lesion calcification on angiographic outcomes after Absorb everolimus-eluting bioresorbable vascular scaffold (BVS) implantation in comparison with those after cobalt-chromium everolimus-eluting stent (CoCr-EES) implantation. Methods and results: The present post hoc analysis of the ABSORB Japan randomised trial compared post-procedure and 13-month angiographic outcomes between patients implanted with BVS and CoCr-EES based on the presence or absence of calcification, excluding extremely heavily calcified lesions or lesions requiring rotational atherectomy. The study population comprised 384 patients with 384 lesions (including 114 lesions [29.7%] with moderate or severe calcification), classified into two subgroups: calcification, 114 (BVS: n=72 and CoCr-EES: n=42) and non-calcification, 270 (BVS: n=181 and CoCr-EES: n=89). Follow-up angiography was performed in 94.8% of patients. Both post-procedure and follow-up indevice minimal lumen diameters were comparable in both the BVS arm (calcification vs. non-calcification: 2.43±0.32 mm vs. 2.43±0.39 mm, p=0.91 and 2.17±0.49 mm vs. 2.27±0.47 mm, p=0.17) and in the CoCr-EES arm (2.68±0.34 mm vs. 2.65±0.42 mm, p=0.62 and 2.57±0.52 mm vs. 2.47±0.53 mm, p=0.36). Conclusions: Moderate or severe lesion calcification (excluding patients with extremely heavily calcified lesions or lesions requiring rotational atherectomy) does not negatively affect angiographic outcomes at both post-procedure and 13-month follow-up after BVS implantation.

Background The Japan post-marketing surveillance (PMS) for the Absorb GT1 bioresorbable vascular scaffold (BVS) mandated an intracoronary imaging-guided implantation technique.Methods and Results:We enrolled 135 patients who were planned to undergo PCI with THE Absorb GT1. Adequate lesion preparation, imaging-guided appropriate sizing, and high-pressure post-dilatation using a noncompliant balloon to minimize final diameter stenosis were recommended. The primary endpoint was the scaffold thrombosis rate at 3 months. All patients successfully received at least 1 Absorb GT1 at the index procedure and completed 1-year follow-up. All 139 lesions were predilatated: cutting/scoring balloon and noncompliant balloon were used in 48 (34.5%) and 58 (41.7%) lesions, respectively. Post-dilatation was performed in 137 (98.5%) lesions with mean high pressure of 18.8 atm. Optical coherence tomography (OCT) was used in 127 of 139 (91.4%) lesions, and revealed 56.7% of lesions had incomplete scaffold apposition (ISA) but only in 1.89% in the per strut analysis. All patients received adenosine diphosphate receptor antagonist at discharge, and 132 (97.8%) patients continued therapy through the year. No definite/probable scaffold thrombosis, cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization was reported up to 1 year follow-up. Conclusions Appropriate OCT-guided BVS implantation may prevent incomplete strut apposition, thereby reducing the risk of target lesion failure and scaffold thrombosis.

Background Device underexpansion is associated with late adverse outcomes after bioresorbable vascular scaffold (BVS) implantation. This study, representing official IVUS results of the ABSORB Japan trial, aimed to characterize IVUS findings, focusing specifically on acute device expansion, and to investigate its impact on late lumen loss (LLL) with Absorb-BVS compared with cobalt-chromium everolimus-eluting stents (CoCr-EES). Methods ABSORB Japan enrolled 148 patients (2:1 randomization) in the IVUS cohort. Serial IVUS was prescheduled at post-procedure and 3 years. Acute device expansion was evaluated with respect to the degree and uniformity of the implanted device. Results Overall, Absorb-BVS showed smaller and more nonuniform device expansion at post-procedure, compared with CoCr-EES, which was particularly prominent in small-vessel lesions. In serial analysis, Absorb-BVS showed unique associations of smaller device expansion (r = 0.40, p = 0.001) and more nonuniformity (r = 0.29, p = 0.007) at post-procedure with greater LLL at 3 years, primarily attributable to greater negative remodeling (r = 0.39, p = 0.006). In contrast, acute device expansion showed no relation with subsequent lumen change in CoCr-EES. In Absorb-BVS, ischemic-driven target lesion or vessel revascularization (ID-TLR or ID-TVR) at 3 years occurred more frequently in small- versus large-vessel lesions (12.5% vs. 0%, p = 0.04 for ID-TLR and 15.6% vs. 2.3%, p = 0.08 for ID-TVR). Conversely, Absorb BVS had no target lesion nor vessel failure, even in small-vessel lesions, when adequate device expansion was achieved at post-procedure. Conclusions Unlike CoCr-EES, underexpansion was associated with greater negative remodeling and LLL in Absorb-BVS. This may in part account for the poorer outcomes of Absorb-BVS than CoCr-EES when under-expanded.

The pivotal ABSORB III and Japan trials randomized patients with noncomplex coronary artery disease to Absorb bioresorbable vascular scaffolds (BVS) versus cobalt-chromium Xience everolimus-eluting stents (EES) (both Abbott Vascular, Santa Clara, California). Formal intravascular ultrasound (IVUS)

BACKGROUND The Cobalt-Chromium Everolimus-Eluting Stent (CoCr-EES) Post-marketing Surveillance (PMS) is a prospective multicenter registry designed to evaluate the safety and efficacy of XIENCE V/PROMUS everolimus-eluting stents in routine clinical practice at 47 centers representative of the clinical environment in Japan. METHODS AND RESULTS We enrolled 2,010 consecutive patients (2,649 lesions) who underwent PCI using CoCr-EES. Clinical outcomes were evaluated for up to 3 years. Clinical follow-up was available in 1,930 patients (96%) at 3 years. Major adverse cardiovascular events (MACE) occurred in 6.8% of patients, including cardiac death (1.7%), myocardial infarction (1.5%), and clinically driven target lesion revascularization (CD-TLR, 4.2%). Late CD-TLR rate was 0.8% from 1 to 2 years, and 0.5% from 2 to 3 years. Definite or probable stent thrombosis occurred in 7 patients (0.3%) up to 1 year. There was no very late definite or probable stent thrombosis from 1 to 3 years. Significant independent predictors for MACE were hemodialysis, prior coronary intervention, triple-vessel coronary artery disease, and age >70 years. CONCLUSIONS Three-year clinical outcomes from the CoCr-EES PMS demonstrated a low incidence of clinical events. There was no major concern about very late stent thrombosis or late catch-up phenomenon in patients treated with EES in routine clinical practice in Japan.

Aims We sought to investigate two-year clinical and serial optical coherence tomography (OCT) outcomes after implantation of a fully bioresorbable vascular scaffold (BVS) or a cobalt-chromium everolimus-eluting stent (CoCr-EES). Methods and results In the ABSORB Japan trial, 400 patients were randomised in a 2:1 ratio to BVS (N=266) or CoCr-EES (N=134). A pre-specified OCT subgroup (N=125, OCT-1 group) underwent angio-graphy and OCT post procedure and at two years. Overall, the two-year TLF rates were 7.3% and 3.8% in the BVS and CoCr-EES arms (p=0.18), respectively. Very late scaffold thrombosis (VLST) beyond one year was observed in 1.6% (four cases: all in non-OCT-1 subgroups) of the BVS arm, while there was no VLST in the CoCr-EES arm. In three cases, OCT at the time of or shortly after VLST demonstrated strut discontinuities, malapposition and/or uncovered struts. However, the vessel healing by two-year OCT was nearly complete in both BVS and CoCr-EES arms with almost fully covered struts, and minimal malapposition. The flow area by two-year OCT was smaller in the BVS arm than in the CoCr-EES arm, mainly due to tissue growth inside the device. However, there were no differences between the BVS and CoCr-EES with regard to the quality of homogenous tissues growing inside the devices. Conclusions The rate of TLF was numerically higher in the BVS arm than in the CoCr-EES arm, although this difference was not statistically significant. VLST was observed only in the BVS arm at a rate of 1.6% between one and two years. Further studies are mandatory to investigate the risk of BVS relative to metallic stents for VLST, and the underlying mechanisms of BVS VLST.

Cobblestone (type II) lissencephaly and mental retardation are characteristic features of a subset of congenital muscular dystrophies that include Walker–Warburg syndrome, muscle-eye-brain disease, and Fukuyama-type congenital muscular dystrophy. Although the majority of clinical cases are genetically undefined, several causative genes have been identified that encode known or putative glycosyltransferases in the biosynthetic pathway of dystroglycan. Here we test the effects of brain-specific deletion of dystroglycan, and show distinct functions for neuronal and glial dystroglycan. Deletion of dystroglycan in the whole brain produced glial/neuronal heterotopia resembling the cerebral cortex malformation in cobblestone lissencephaly. In wild-type mice, dystroglycan stabilizes the basement membrane of the glia limitans, thereby supporting the cortical infrastructure necessary for neuronal migration. This function depends on extracellular dystroglycan interactions, since the cerebral cortex developed normally in transgenic mice that lack the dystroglycan intracellular domain. Also, forebrain histogenesis was preserved in mice with neuron-specific deletion of dystroglycan, but hippocampal long-term potentiation was blunted, as is also the case in theLargemydmouse, in which dystroglycan glycosylation is disrupted. Our findings provide genetic evidence that neuronal dystroglycan plays a role in synaptic plasticity and that glial dystroglycan is involved in forebrain development. Differences in dystroglycan glycosylation in distinct cell types of the CNS may contribute to the diversity of dystroglycan function in the CNS, as well as to the broad clinical spectrum of type II lissencephalies.

Attenuated-signal plaque (ASP) on IVUS has been shown to be indicative of plaque instability (inflammatory plaque). This study aimed to investigate possible association between underlying ASP and long-term arterial responseto bioresorbable scaffolds (BRS) vs. everolimus-eluting stents (EES). In the

Scaffold under-expansion is associated with late adverse outcomes after polymeric scaffold (BVS) implantation, while underlying mechanism of this association remains unknown. The IVUS cohort of ABSORB JAPAN trial was designed to characterize detailed device performance and long-term vessel response

Aims Theoretically, bioresorbable vascular scaffolds (BVSs) may provide superior long-term results compared with permanent metallic drug-eluting stents (DESs). However, whether BVSs are as safe and effective as metallic DESs prior to complete bioresorption is unknown. Methods and results ABSORB Japan was a single-blind, multicentre, active-controlled, randomized trial designed to support regulatory approval of the Absorb BVS in Japan. Eligible patients with one or two de novo lesions in different epicardial vessels were randomized at 38 Japanese sites in a 2:1 ratio to Absorb BVS vs. cobalt-chromium everolimus-eluting stents (CoCr-EESs). The primary endpoint was target lesion failure [TLF: a composite of cardiac death, myocardial infarction attributable to target vessel, or ischaemia-driven target lesion revascularization (ID-TLR)] at 12 months, powered for non-inferiority. The major secondary endpoint was angiographic in-segment late lumen loss (LLL) at 13 months. A total of 400 patients were randomized to BVSs (266 patients and 275 lesions) or CoCr-EESs (134 patients and 137 lesions). TLF through 12 months was 4.2% with BVSs and 3.8% with CoCr-EESs [difference (upper one-sided 95% confidence limit) = 0.39% (3.95%); P non-inferiority < 0.0001]. Definite/probable stent/scaffold thrombosis at 12 months occurred in 1.5% of the patients with both devices ( P = 1.0), and ID-TLR for restenosis was infrequent (1.1% with BVSs and 1.5% with CoCr-EESs, P = 1.0). With 96.0% angiographic follow-up, in-segment LLL at 13 months was 0.13 ± 0.30 mm with BVSs and 0.12 ± 0.32 mm with CoCr-EESs [difference (upper one-sided 95% confidence limit) = 0.01 (0.07); P non-inferiority < 0.0001). Conclusion In the ABSORB Japan randomized trial, 12-month clinical and 13-month angiographic outcomes of BVSs were comparable to CoCr-EESs. Clinical registration ClinicalTrials.gov, number [NCT01844284][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01844284&atom=%2Fehj%2Fearly%2F2015%2F08%2F28%2Feurheartj.ehv435.atom

Dystroglycan is a cell-surface matrix receptor that requires LARGE-dependent glycosylation for laminin binding. Although the interaction of dystroglycan with laminin has been well characterized, less is known about the role of dystroglycan glycosylation in the binding and assembly of perlecan. We report reduced perlecan-binding activity and mislocalization of perlecan in the LARGE-deficient Large myd mouse. Cell-surface ligand clustering assays show that laminin polymerization promotes perlecan assembly. Solid-phase binding assays provide evidence for the first time of a trimolecular complex formation of dystro- glycan, laminin and perlecan. These data suggest functional dis- ruption of the trimolecular complex in glycosylation-deficient muscular dystrophy. 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

α-Helical polypeptides containing a pair of L-1-pyrenylalanine and L-p-nitrophenylalanine that are separated by 0−8 amino acid units were synthesized. The rates of photoinduced electron transfer (ET) from the pyrenyl group to the nitrophenyl group were evaluated from the decay curves of pyrenyl fluorescence recorded at different temperatures from −58 to +30 °C. The rate constants showed a complex dependence on the number of spacer amino acids. In particular, recoveries of the ET rates with increasing the number of spacer amino acids from 1 to 2 and from 5 to 6 were found. The ET rate constants, however, exhibited a simple exponential dependence on the edge-to-edge distance between the two chromophores, with a distance decay factor β = 0.66 ± 0.1 (A-1). The ET data on the α-helical polypeptides were analyzed on the basis of the tunneling pathway model. The optimum ET pathways from the pyrenyl group to the nitrophenyl group were searched, and the relative values of the ET matrix elements were evaluated for ...

Gelsolin is a Ca2+-dependent actin-regulatory protein that modulates actin assembly and disassembly, and is believed to regulate cell motility through modulation of the actin network. Gelsolin was also recently suggested to be involved in the regulation of apoptosis: human gelsolin (hGsn) has anti-apoptotic activity, whereas mouse gelsolin (mGsn) exerts either proapoptotic or anti-apoptotic activity depending on different cell types. Here, we studied the basis of anti-apoptotic activity of hGsn. We showed that both endogenous and overexpressed hGsn has anti-apoptotic activity, that depends on its C-terminal half. We also found that hGsn and its C-terminal half but not mGsn could prevent apoptotic mitochondrial changes such as Apsi loss and cytochrome c release in isolated mitochondria to a similar extent as Bcl-xL, indicating that hGsn targets the mitochondria to prevent apoptosis via its C-terminal half. In the same way as anti-apoptotic Bcl-xL, which we recently found to prevent apoptotic mitochondrial changes by binding and closing the voltage-dependent anion channel (VDAC), hGsn and its C-terminal half inhibited the activity of VDAC on liposomes through direct binding in a Ca2+-dependent manner. These results suggest that hGsn inhibits apoptosis by blocking mitochondrial VDAC activity.

Objectives: The SPIRIT Small Vessel (SV) was designed to evaluate the safety and effectiveness of the 2.25-mm XIENCE V everolimus eluting coronary stent system (EECSS), known as the XIENCE nano EECSS, in subjects with SVs and ischemic heart disease. Background: The core sizes of XIENCE V EECSS are associated with low rates of restenosis and thrombosis in the general population, but the XIENCE nano EECSS has not been tested in the United States. Methods: This prospective, single-arm, open-label study was conducted at 33 centers and in 150 patients in the United States. The primary endpoint was the target lesion failure (TLF) rate at 1 year, required to meet the prespecified performance goal (PG) of 20.4%, derived from historical data. Results: The mean patient age was 63 years, 38% were women, 39.2% were diabetic, 49.3% had multivessel disease, and the reference vessel diameter was 2.13 ± 0.23 mm. The 1-year TLF rate was 8.1% in with an upper limit of the one-sided 95% confidence interval of 13.0%, which met the PG of 20.4% (P < 0.0001). At 1 year, the rate of cardiac death was 1.5%, the target vessel myocardial infarction rate was 1.5%, and clinically indicated target lesion revascularization rate was 5.1%. The 8-month angiographic in-stent late loss was 0.2 ± 0.4 mm, respectively. The 1-year academic research consortium defined definite/probable stent thrombosis rate was 1.5%. Conclusions: Based on the 1-year clinical and 8-month angiographic SPIRIT SV data, the XIENCE nano EECSS is considered safe and effective in the treatment of SVs. © 2011 Wiley Periodicals, Inc.

Ocular involvement in muscular dystrophy ranges from structural defects to abnormal electroretinograms. While the mechanisms underlying the abnormal retinal physiology in patients are not understood, it is thought that α-dystroglycan extracellular interactions are critical for normal visual function. Here we show that β-dystroglycan anchors dystrophin and the inward rectifying K+channel Kir4.1 at glial endfeet and that disruption of dystrophin and potassium channel clustering in dystroglycan mutant mice is associated with an attenuation of the electroretinogram b-wave. Glial-specific inactivation of dystroglycan or deletion of the cytoplasmic domain of β-dystroglycan was sufficient to attenuate the electroretinogram b-wave. Unexpectedly, deletion of the β-dystroglycan cytoplasmic domain did not disrupt the laminar structure of the retina. In contrast to the role of α-dystroglycan extracellular interactions during early development of the CNS, β-dystroglycan intracellular interactions are important for visual function but not the laminar development of the retina.

The aim of this study was to evaluate the vascular response after everolimus-eluting stent (EES) implantation in the SPIRIT III Japan Registry (JAPAN) compared to EES implantation in the SPIRIT III United States (USA) trial using serial intravascular ultrasound (IVUS) analysis. Data were obtained from the JAPAN and the randomized EES arm of the USA trial. Serial (postprocedure and 8-month follow-up) IVUS analysis was available in 199 lesions (JAPAN 82, USA 117) of 183 patients (JAPAN 73, USA 110). Although no difference was observed in vessel size in the reference segment between the 2 groups, postprocedure minimum lumen area and stent volume index were significantly greater in the JAPAN arm (minimum lumen area 5.8 +/- 2.2 vs 5.1 +/- 1.5 mm(2), p = 0.03; stent volume index 7.0 +/- 2.4 vs 6.3 +/- 1.7 mm(3)/mm, p = 0.03). Postprocedure incomplete stent apposition (ISA) was less frequently observed in the JAPAN arm (15.9% vs 33.3%, p = 0.006), possibly related to higher maximum balloon pressure and/or more postdilatation without excess tissue prolapse or edge dissection. In the JAPAN arm, percent neointimal obstruction and maximum percent cross-sectional narrowing were significantly lower at 8-month follow-up (percent neointimal obstruction 3.5 +/- 4.2% vs 6.8 +/- 6.4%, p = 0.0004). Late acquired ISA was infrequent in the 2 arms. In conclusion, comparative IVUS analysis between the JAPAN and USA arms showed more optimal stent deployment in the JAPAN arm as evidenced by the lower incidence of postprocedure ISA and larger minimum lumen area after the procedure. Moreover, there was less neointimal hyperplasia in patients with EES implants from the JAPAN arm compared to the USA arm.

Aims In this study, we investigated the involvement of apoptosis signal-regulating kinase 1 (ASK1) in oxidative stress and osmotic stress-induced hepatocyte death. Main methods Activation of ASK1–JNK/p38 cascade and resulting cell death induced by oxidative and osmotic stress was investigated by Western immunoblot analysis and cell toxicity assay using human hepatoma cell lines, Huh7 expressing high level of ASK1 and HepG2 cells expressing low level of ASK1. Gene knock-down of ASK1 using shRNA against ASK1 was conducted using mouse hepatocyte cell line, AML12. Key findings Activation of ASK1–JNK/p38 cascade and cell death in Huh7 expressing high level of ASK1 was markedly induced by the oxidative stress. HepG2 expressing low level of ASK1 was resistant to oxidative stress while cell death induced by osmotic stress was comparable between Huh7 and HepG2 cells. Although the phosphorylation of ASK1 was not observed by osmotic stress, the phosphorylation of p38 and JNK and resulting cell death was induced in both cell lines. The phosphorylation of ASK1 and p38/JNK in the mouse primary hepatocyte were also increased by oxidative stress. Knock-down of ASK1 mRNA in AML12 in vitro significantly reduced oxidative stress-induced cell death, however, knock-down of ASK1 in cells did not affect the osmotic stress-induced cell death. Significance This study revealed that ASK1 regulates oxidative stress- but not osmotic stress-induced hepatocyte death, suggesting ASK1 plays a critical role in oxidative-stress induced hepatocyte death. These results raise the possibility that an ASK1 may be a promising therapeutic target for liver diseases caused by oxidative stress.

Myocyte enhancer factor 2 (MEF2) plays essential roles in transcriptional control of muscle development. However, signaling pathways acting downstream of MEF2 are largely unknown. Here, we performed a microarray analysis using Mef2c-null mouse embryos and identified a novel MEF2-regulated gene encoding a muscle-specific protein kinase, Srpk3, belonging to the serine arginine protein kinase (SRPK) family, which phosphorylates serine/arginine repeat-containing proteins. The Srpk3 gene is specifically expressed in the heart and skeletal muscle from embryogenesis to adulthood and is controlled by a muscle-specific enhancer directly regulated by MEF2. Srpk3-null mice display a new entity of type 2 fiber-specific myopathy with a marked increase in centrally placed nuclei; while transgenic mice overexpressing Srpk3 in skeletal muscle show severe myofiber degeneration and early lethality. We conclude that normal muscle growth and homeostasis require MEF2-dependent signaling by Srpk3.

Caspase-mediated proteolysis is a critical and central element of the apoptotic process; therefore, it is important to identify the downstream molecular targets of caspases. We established a method for cloning the genes of caspase substrates by two major modifications of the yeast two-hybrid system: ( i ) both large and small subunits of active caspases were expressed in yeast under ADH1 promoters and the small subunit was fused to the LexA DNA-binding domain; and ( ii ) a point mutation was introduced that substituted serine for the active site cysteine and thereby prevented proteolytic cleavage of the substrates, possibly stabilizing the enzyme–substrate complexes in yeast. After screening a mouse embryo cDNA expression library by using the bait plasmid for caspase-3, we obtained 13 clones that encoded proteins binding to caspase-3, and showed that 10 clones including gelsolin, an actin-regulatory protein implicated in apoptosis, were cleaved by recombinant caspase-3 in vitro . Using the same bait, we also isolated human gelsolin cDNA from a human thymus cDNA expression library. We showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at D 352 of DQTD 352 G, findings consistent with previous observations on murine gelsolin. In addition, we ascribed the antiapoptotic activity of gelsolin (which we previously reported) to prevention of a step leading to cytochrome c release from the mitochondria into the cytosol. Our results indicate that this cloning method is useful for identification of the substrates of caspases and possibly also of other enzymes.

Proteases of the caspase family, especially caspase-1 (ICE)(-like), caspase-3 (CPP32/Yama/apopain)(-like) and caspase-8 (MACH/FLICE/Mch5) proteases, are implicated in Fas (APO-1/CD95)-mediated apoptosis. Here, we show that the caspase-4 (TX/ICH-2/ICE(rel)II)(-like) protease, another member of the caspase family, is also involved in Fas-mediated apoptosis, based upon the observations: (i) caspase-4 is processed in response to an agonistic anti-Fas antibody treatment, (ii) overexpression of a mutant caspase-4 with active site mutations in both p20 and p10 subunits delays Fas-mediated apoptosis, (iii) microinjected anti-caspase-4 antibodies inhibit Fas-mediated apoptosis. Together with our observations that the mutant caspase-4 inhibits the Fas-mediated activation of caspase-3(-like) proteases and purified caspase-4 cleaves pro-caspase-3 to generate a subunit of active form, these results suggest that Fas-mediated apoptosis is driven by a caspase cascade in which the caspase-4(-like) protease transmits a death signal from caspase-8 to caspase-3(-like) proteases probably through directly cleaving pro-caspase-3(-like) proteases.

Electrolysis of the ethylene acetal of β-formylpropionic acid with butyric acid gave caproaldehyde ethylene acetal as a result of crossed coupling. Crossed electrolysis with monoesters of succinic, adipic and sebacic acid were then studied. The expected products, adipinaldehydic, suberinal dehydic and ω-formylundecylic acid, were obtained as their ethylene acetal ester respectively. As ω-aldehydic acids are usually inaccessible compounds, these electrolytic reactions may provide a new convenient synthetic route. Furthermore, it has been found that the tetramer of β-formylpropionic acid underwent the normal electrolytic reaction in the presence of fatty acids and the corresponding aliphatic aldehydes were obtained in relatively good yields.