Ten year clinical follow-up after Sirolimus-eluting stent implantation

BACKGROUND: Little is known on the "very" long-term incidence of major adverse cardiac events (MACE), target-lesion revascularization (TLR), target-vessel revascularization and stent thrombosis after sirolimus-eluting stent (SES) implantation. We present the first study to provide a 10-year clinical follow-up in an unselected patient population who underwent SES implantation. METHODS AND RESULTS: We ran a systematic 10-year clinical follow-up in a series of 200 consecutive patients treated with unrestricted SES implantation between April 2002 and April 2003 in two Swiss hospitals. Outcomes and follow-up were obtained in all 200 patients. The cumulative 10-year MACE rate was 47% with all-cause death of 20%, cardiac death of 9%, myocardial infarction of 7%, TLR and target-vessel revascularization of 8% and 11% respectively. Academic Research Consortium-defined "definite and probable" stent thrombosis-rate was 2.5%. TLR risk was maximal between 3 to 6 years. New lesion revascularization increased throughout the study period. CONCLUSION: Incidence of TLR was maximal 3 to 6 years after SES implantation and decreased thereafter. MACE and non-TLR revascularization rates steadily increased during the complete follow-up underlining the progression of coronary artery disease.

Functional proteomics and biochemsitry: working together to unravel mitochondrial phenomena of African trypansomes

Eukaryotic cells are compartmentalized into membrane-bound organelles in order to provide sheltered reaction rooms for various specific processes. Organelles are not randomly distributed in a cell or operate isolated from each other. At the contrary — some organelles are closely linked and their functions are tightly orchestrated. The most well-known example of two such organelles acting in concert are the ER and the mitochondrion that work together in order to coordinate cellular lipid biosynthesis, maintain Ca2+-homeostasis, regulate mitochondrial division and control mitochondrial/ER shape as well as to synchronize the movement of these organelles within a cell. To study the mitochondrion and its interface to the ER requires a simplified mitochondrial system. African trypanosomes represent such a system. The unicellular parasite that causes devastating diseases in humans and animals has only one large mitochondrion that does not undergo fission/fusion events except for the context of cell division. Moreover, mitochondrial functions and morphology are highly regulated throughout the life cycle of the protozoan. Central to the understanding of how mitochondria control their morphology, communicate with their surroundings and manage exchange of metabolites and transport of biopolymers (proteins, RNAs) is the mitochondrial outer membrane (MOM), as the MOM defines the boundary of the organelle. Recently, we have purified the MOM of T. brucei and characterized its proteome using label-free quantitative mass spectrometry for protein abundance profiling in combination with statistical analysis. Our results show that the trypanosomal MOM proteome consists of 82 proteins, two thirds of which have never been associated with mitochondria before. Among these, we identified novel factors required to regulate mitochondrial morphology and the long-elusive protein import machinery of T. brucei. A comparison with the MOM proteome of yeast defines a set of 17 common proteins that are likely present in the mitochondrial outer membrane of all eukaryotes. One of these is the Miro-GTPase Gem1. In yeast, this Ca2+-EF-Hand containing polypeptide is thought to be involved in a protein complex that physically tethers the mitochondrion to the ER. Interestingly, a putative tethering complex in mammalian cells was linked to the mitochondrial fusion/fission machinery. Thus, the concept of a protein complex-mediated connection seems to be a general and conserved feature. We are currently investigating, if such a protein complex exists in T. brucei and if the trypanosomal Gem1 protein is involved. This ER-subdomain associated with mitochondria has been termed mitochondria-associated ER-membranes or MAM. The MAM has recently been implicated to play a key role in Alzheimer’s disease. It is therefore of broad and general interest to establish other eukaryotic model systems in order to investigate the MAM-MOM connection in more detail.

Functional proteomics and biochemsitry: working together to unravel mitochondrial phenomena of African trypansomes

Central to the understanding of how mitochondria control their morphology, communicate with their surroundings and manage exchange of metabolites and transport of biopolymers (proteins, RNAs) is the mitochondrial outer membrane (MOM), as the MOM defines the boundary of the organelle. Recently, we have purified the MOM of the mitochondrial model organism T. brucei and characterized its proteome. Our results show that the trypanosomal MOM proteome consists of 82 proteins. Among these, we identified novel factors required to regulate mitochondrial morphology and the long-elusive protein import machinery of T. brucei. A comparison with the MOM proteome of yeast defines a set of 17 common proteins that are likely present in the mitochondrial outer membrane of all eukaryotes. One of these is the Miro-GTPase Gem1. In yeast, this Ca2+-EF-Hand containing polypeptide is thought to be involved in a protein complex that physically tethers the mitochondrion to the ER. In mammalian cells, a putative tethering complex was linked to the mitochondrial fusion/fission machinery. Thus, the concept of a protein complex-mediated connection seems to be a general and conserved feature. We are currently investigating if such a protein complex exists in T. brucei and if the trypanosomal Gem1 protein is involved.

Three-year outcomes of percutaneous coronary intervention with next-generation zotarolimus-eluting stents for de novo coronary bifurcation lesions.

AIMS To investigate the outcomes of percutaneous coronary intervention (PCI) in bifurcation versus non-bifurcation lesions using the next-generation Resolute zotarolimus-eluting stent (R-ZES). METHODS AND RESULTS We analyzed 3-year pooled data from the RESOLUTE All-Comers trial and the RESOLUTE International registry. The R-ZES was used in 2772 non-bifurcation lesion patients and 703 bifurcation lesion patients, of which 482 were treated with a simple-stent technique (1 stent used to treat the bifurcation lesion) and 221 with a complex bifurcation technique (2 or more stents used). The primary endpoint was 3-year target lesion failure (TLF, defined as the composite of death from cardiac causes, target vessel myocardial infarction, or clinically-indicated target lesion revascularization [TLR]), and was 13.3% in bifurcation vs 11.3% in non-bifurcation lesion patients (adjusted P=.06). Landmark analysis revealed that this difference was driven by differences in the first 30 days between bifurcation vs non-bifurcation lesions (TLF, 6.6% vs 2.7%, respectively; adjusted P<.001), which included significant differences in each component of TLF and in-stent thrombosis. Between 31 days and 3 years, TLF, its components, and stent thrombosis did not differ significantly between bifurcation lesions and non-bifurcation lesions (TLF, 7.7% vs 9.0%, respectively; adjusted P=.50). CONCLUSION The 3-year risk of TLF following PCI with R-ZES in bifurcation lesions was not significantly different from non-bifurcation lesions. However, there was an increased risk associated with bifurcation lesions during the first 30 days; beyond 30 days, bifurcation lesions and non-bifurcation lesions yielded similar 3-year outcomes.

Transcatheter Aortic Valve Replacement in Bicuspid Aortic Valve Disease.

BACKGROUND Limited information exists describing the results of transcatheter aortic valve (TAV) replacement in patients with bicuspid aortic valve (BAV) disease (TAV-in-BAV). OBJECTIVES This study sought to evaluate clinical outcomes of a large cohort of patients undergoing TAV-in-BAV. METHODS We retrospectively collected baseline characteristics, procedural data, and clinical follow-up findings from 12 centers in Europe and Canada that had performed TAV-in-BAV. RESULTS A total of 139 patients underwent TAV-in-BAV with the balloon-expandable transcatheter heart valve (THV) (n = 48) or self-expandable THV (n = 91) systems. Patient mean age and Society of Thoracic Surgeons predicted risk of mortality scores were 78.0 ± 8.9 years and 4.9 ± 3.4%, respectively. BAV stenosis occurred in 65.5%, regurgitation in 0.7%, and mixed disease in 33.8% of patients. Incidence of type 0 BAV was 26.7%; type 1 BAV was 68.3%; and type 2 BAV was 5.0%. Multislice computed tomography (MSCT)-based TAV sizing was used in 63.5% of patients (77.1% balloon-expandable THV vs. 56.0% self-expandable THV, p = 0.02). Procedural mortality was 3.6%, with TAV embolization in 2.2% and conversion to surgery in 2.2%. The mean aortic gradient decreased from 48.7 ± 16.5 mm Hg to 11.4 ± 9.9 mm Hg (p < 0.0001). Post-implantation aortic regurgitation (AR) grade ≥2 occurred in 28.4% (19.6% balloon-expandable THV vs. 32.2% self-expandable THV, p = 0.11) but was prevalent in only 17.4% when MSCT-based TAV sizing was performed (16.7% balloon-expandable THV vs. 17.6% self-expandable THV, p = 0.99). MSCT sizing was associated with reduced AR on multivariate analysis (odds ratio [OR]: 0.19, 95% confidence intervals [CI]: 0.08 to 0.45; p < 0.0001). Thirty-day device safety, success, and efficacy were noted in 79.1%, 89.9%, and 84.9% of patients, respectively. One-year mortality was 17.5%. Major vascular complications were associated with increased 1-year mortality (OR: 5.66, 95% CI: 1.21 to 26.43; p = 0.03). CONCLUSIONS TAV-in-BAV is feasible with encouraging short- and intermediate-term clinical outcomes. Importantly, a high incidence of post-implantation AR is observed, which appears to be mitigated by MSCT-based TAV sizing. Given the suboptimal echocardiographic results, further study is required to evaluate long-term efficacy.

Transcatheter aortic valve implantation in failed bioprosthetic surgical valves.

IMPORTANCE Owing to a considerable shift toward bioprosthesis implantation rather than mechanical valves, it is expected that patients will increasingly present with degenerated bioprostheses in the next few years. Transcatheter aortic valve-in-valve implantation is a less invasive approach for patients with structural valve deterioration; however, a comprehensive evaluation of survival after the procedure has not yet been performed. OBJECTIVE To determine the survival of patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves. DESIGN, SETTING, AND PARTICIPANTS Correlates for survival were evaluated using a multinational valve-in-valve registry that included 459 patients with degenerated bioprosthetic valves undergoing valve-in-valve implantation between 2007 and May 2013 in 55 centers (mean age, 77.6 [SD, 9.8] years; 56% men; median Society of Thoracic Surgeons mortality prediction score, 9.8% [interquartile range, 7.7%-16%]). Surgical valves were classified as small (≤21 mm; 29.7%), intermediate (>21 and <25 mm; 39.3%), and large (≥25 mm; 31%). Implanted devices included both balloon- and self-expandable valves. MAIN OUTCOMES AND MEASURES Survival, stroke, and New York Heart Association functional class. RESULTS Modes of bioprosthesis failure were stenosis (n = 181 [39.4%]), regurgitation (n = 139 [30.3%]), and combined (n = 139 [30.3%]). The stenosis group had a higher percentage of small valves (37% vs 20.9% and 26.6% in the regurgitation and combined groups, respectively; P = .005). Within 1 month following valve-in-valve implantation, 35 (7.6%) patients died, 8 (1.7%) had major stroke, and 313 (92.6%) of surviving patients had good functional status (New York Heart Association class I/II). The overall 1-year Kaplan-Meier survival rate was 83.2% (95% CI, 80.8%-84.7%; 62 death events; 228 survivors). Patients in the stenosis group had worse 1-year survival (76.6%; 95% CI, 68.9%-83.1%; 34 deaths; 86 survivors) in comparison with the regurgitation group (91.2%; 95% CI, 85.7%-96.7%; 10 deaths; 76 survivors) and the combined group (83.9%; 95% CI, 76.8%-91%; 18 deaths; 66 survivors) (P = .01). Similarly, patients with small valves had worse 1-year survival (74.8% [95% CI, 66.2%-83.4%]; 27 deaths; 57 survivors) vs with intermediate-sized valves (81.8%; 95% CI, 75.3%-88.3%; 26 deaths; 92 survivors) and with large valves (93.3%; 95% CI, 85.7%-96.7%; 7 deaths; 73 survivors) (P = .001). Factors associated with mortality within 1 year included having small surgical bioprosthesis (≤21 mm; hazard ratio, 2.04; 95% CI, 1.14-3.67; P = .02) and baseline stenosis (vs regurgitation; hazard ratio, 3.07; 95% CI, 1.33-7.08; P = .008). CONCLUSIONS AND RELEVANCE In this registry of patients who underwent transcatheter valve-in-valve implantation for degenerated bioprosthetic aortic valves, overall 1-year survival was 83.2%. Survival was lower among patients with small bioprostheses and those with predominant surgical valve stenosis.

Reperfusion therapy for ST elevation acute myocardial infarction 2010/2011: current status in 37 ESC countries

AIMS Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion therapy in ST-elevation myocardial infarction (STEMI). We conducted this study to evaluate the contemporary status on the use and type of reperfusion therapy in patients admitted with STEMI in the European Society of Cardiology (ESC) member countries. METHODS AND RESULTS A cross-sectional descriptive study based on aggregated country-level data on the use of reperfusion therapy in patients admitted with STEMI during 2010 or 2011. Thirty-seven ESC countries were able to provide data from existing national or regional registries. In countries where no such registries exist, data were based on best expert estimates. Data were collected on the use of STEMI reperfusion treatment and mortality, the numbers of cardiologists, and the availability of PPCI facilities in each country. Our survey provides a brief data summary of the degree of variation in reperfusion therapy across Europe. The number of PPCI procedures varied between countries, ranging from 23 to 884 per million inhabitants. Primary percutaneous coronary intervention and thrombolysis were the dominant reperfusion strategy in 33 and 4 countries, respectively. The mean population served by a single PPCI centre with a 24-h service 7 days a week ranged from 31 300 inhabitants per centre to 6 533 000 inhabitants per centre. Twenty-seven of the total 37 countries participated in a former survey from 2007, and major increases in PPCI utilization were observed in 13 of these countries. CONCLUSION Large variations in reperfusion treatment are still present across Europe. Countries in Eastern and Southern Europe reported that a substantial number of STEMI patients are not receiving any reperfusion therapy. Implementation of the best reperfusion therapy as recommended in the guidelines should be encouraged.

Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis.

BACKGROUND & AIMS Unhealthy lifestyles predispose to non-alcoholic steatohepatitis (NASH), which may further result in the development of hepatocellular carcinoma (HCC). Although NASH patients benefit from physical activity, it is unknown whether regular exercise reduces the risk of developing HCC. Therefore, we studied the effect of regular exercise on the development of HCC in male hepatocyte-specific PTEN-deficient mice (AlbCrePten(flox/flox)), which develop steatohepatitis and HCC spontaneously. METHODS Mice were fed a standardized 10% fat diet and were randomly divided into exercise or sedentary groups. The exercise group ran on a motorized treadmill for 60 minutes/day, 5 days/week during 32 weeks. RESULTS After 32 weeks of regular exercise, 71% of exercised mice developed nodules larger than 15 mm(3) vs 100% of mice in the sedentary group. The mean number of tumors per liver was reduced by exercise, as well as the total tumoral volume per liver. Exercise did not affect steatosis and had no effect on the Non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS). Exercise decreased tumor cell proliferation. Mechanistically, exercise stimulated the phosphorylation of AMPK and its substrate raptor, which decreased the kinase activity of mTOR. CONCLUSIONS These data show a benefit of regular exercise on the development of HCC in an experimental model of NASH and offer a rationale for encouraging predisposed patients to increase their physical activity for the prevention of HCC.

Critical Issues of Centralized and Cloudified LTE-FDD Radio Access Networks

Cloudification of the Centralized-Radio Access Network (C-RAN) in which signal processing runs on general purpose processors inside virtual machines has lately received significant attention. Due to short deadlines in the LTE Frequency Division Duplex access method, processing time fluctuations introduced by the virtualization process have a deep impact on C-RAN performance. This paper evaluates bottlenecks of the OpenAirInterface (OAI is an open-source software-based implementation of LTE) cloud performance, provides feasibility studies on C-RAN execution, and introduces a cloud architecture that significantly reduces the encountered execution problems. In typical cloud environments, the OAI processing time deadlines cannot be guaranteed. Our proposed cloud architecture shows good characteristics for the OAI cloud execution. As an example, in our setup more than 99.5% processed LTE subframes reach reasonable processing deadlines close to performance of a dedicated machine.

Role of a ribosomal RNA phosphate oxygen during the EF-G–triggered GTP hydrolysis

Elongation factor-catalyzed GTP hydrolysis is a key reaction during the ribosomal elongation cycle. Recent crystal structures of G proteins, such as elongation factor G (EF-G) bound to the ribosome, as well as many biochemical studies, provide evidence that the direct interaction of translational GTPases (trGTPases) with the sarcin-ricin loop (SRL) of ribosomal RNA (rRNA) is pivotal for hydrolysis. However, the precise mechanism remains elusive and is intensively debated. Based on the close proximity of the phosphate oxygen of A2662 of the SRL to the supposedly catalytic histidine of EF-G (His87), we probed this interaction by an atomic mutagenesis approach. We individually replaced either of the two nonbridging phosphate oxygens at A2662 with a methyl group by the introduction of a methylphosphonate instead of the natural phosphate in fully functional, reconstituted bacterial ribosomes. Our major finding was that only one of the two resulting diastereomers, the SP methylphosphonate, was compatible with efficient GTPase activation on EF-G. The same trend was observed for a second trGTPase, namely EF4 (LepA). In addition, we provide evidence that the negative charge of the A2662 phosphate group must be retained for uncompromised activity in GTP hydrolysis. In summary, our data strongly corroborate that the nonbridging proSP phosphate oxygen at the A2662 of the SRL is critically involved in the activation of GTP hydrolysis. A mechanistic scenario is supported in which positioning of the catalytically active, protonated His87 through electrostatic interactions with the A2662 phosphate group and H-bond networks are key features of ribosome-triggered activation of trGTPases.

Prioritizing plant defence over growth through WRKY regulation facilitates infestation by non-target herbivores

Plants generally respond to herbivore attack by increasing resistance and decreasing growth. This prioritization is achieved through the regulation of phytohormonal signaling networks. However, it remains unknown how this prioritization affects resistance against non-target herbivores. In this study, we identify WRKY70 as a specific herbivore-induced, mitogen-activated protein kinase-regulated rice transcription factor that physically interacts with W-box motifs and prioritizes defence over growth by positively regulating jasmonic acid (JA) and negatively regulating gibberellin (GA) biosynthesis upon attack by the chewing herbivore Chilo suppressalis. WRKY70-dependent JA biosynthesis is required for proteinase inhibitor activation and resistance against C. suppressalis. In contrast, WRKY70 induction increases plant susceptibility against the rice brown planthopper Nilaparvata lugens. Experiments with GA-deficient rice lines identify WRKY70-dependent GA signaling as the causal factor in N. lugens susceptibility. Our study shows that prioritizing defence over growth leads to a significant resistance trade-off with important implications for the evolution and agricultural exploitation of plant immunity.

Untangling a Holocene pollen record with forest model simulations and independent climate data

Adaptation potential of forests to rapid climatic changes can be assessed from vegetation dynamics during past climatic changes as preserved in fossil pollen data. However, pollen data reflect the integrated effects of climate and biotic processes, such as establishment, survival, competition, and migration. To disentangle these processes, we compared an annually laminated late Würm and Holocene pollen record from the Central Swiss Plateau with simulations of a dynamic forest patch model. All input data used in the simulations were largely independent from pollen data; i.e. the presented analysis is non-circular. Temperature and precipitation scenarios were based on reconstructions from pollen-independent sources. The earliest arrival times of the species at the study site after the last glacial were inferred from pollen maps. We ran a series of simulations under different combinations of climate and immigration scenarios. In addition, the sensitivity of the simulated presence/absence of four major species to changes in the climate scenario was examined. The pattern of the pollen record could partly be explained by the used climate scenario, mostly by temperature. However, some features, in particular the absence of most species during the late Würm could only be simulated if the winter temperature anomalies of the used scenario were decreased considerably. Consequently, we had to assume in the simulations, that most species immigrated during or after the Younger Dryas (12 000 years BP), Abies and Fagus even later. Given the timing of tree species immigration, the vegetation was in equilibrium with climate during long periods, but responded with lags at the time-scale of centuries to millennia caused by a secondary succession after rapid climatic changes such as at the end of Younger Dryas, or immigration of dominant taxa. Climate influenced the tree taxa both directly and indirectly by changing inter-specific competition. We concluded, that also during the present fast climatic change, species migration might be an important process, particularly if geographic barriers, such as the Alps are in the migrational path.

Functional proteomics and biochemistry: working together to unravel mitochondrial phenomena of African trypanosomes

Eukaryotic cells are compartmentalized into membrane-bound organelles in order to provide sheltered reaction rooms for various specific processes. Organelles are not randomly distributed in a cell or operate isolated from each other. At the contrary — some organelles are closely linked and their functions are tightly orchestrated. The most well-known example of two such organelles acting in concert are the ER and the mitochondrion that work together in order to coordinate cellular lipid biosynthesis, maintain Ca2+-homeostasis, regulate mitochondrial division and control mitochondrial/ER shape as well as to synchronize the movement of these organelles within a cell. To study the mitochondrion and its interface to the ER requires a simplified mitochondrial system. African trypanosomes represent such a system. The unicellular parasite that causes devastating diseases in humans and animals has only one large mitochondrion that does not undergo fission/fusion events except for the context of cell division. Moreover, mitochondrial functions and morphology are highly regulated throughout the life cycle of the protozoan. Central to the understanding of how mitochondria control their morphology, communicate with their surroundings and manage exchange of metabolites and transport of biopolymers (proteins, RNAs) is the mitochondrial outer membrane (MOM), as the MOM defines the boundary of the organelle. Recently, we have purified the MOM of T. brucei and characterized its proteome using label-free quantitative mass spectrometry for protein abundance profiling in combination with statistical analysis. Our results show that the trypanosomal MOM proteome consists of 82 proteins, two thirds of which have never been associated with mitochondria before. Among these, we identified novel factors required to regulate mitochondrial morphology and the long-elusive protein import machinery of T. brucei. A comparison with the MOM proteome of yeast defines a set of 17 common proteins that are likely present in the mitochondrial outer membrane of all eukaryotes. One of these is the Miro-GTPase Gem1. In yeast, this Ca2+-EF-Hand containing polypeptide is thought to be involved in a protein complex that physically tethers the mitochondrion to the ER. Interestingly, a putative tethering complex in mammalian cells was linked to the mitochondrial fusion/fission machinery. Thus, the concept of a protein complex-mediated connection seems to be a general and conserved feature. We are currently investigating, if such a protein complex exists in T. brucei and if the trypanosomal Gem1 protein is involved. This ER-subdomain associated with mitochondria has been termed mitochondria-associated ER-membranes or MAM. The MAM has recently been implicated to play a key role in Alzheimer’s disease. It is therefore of broad and general interest to establish other eukaryotic model systems in order to investigate the MAM-MOM connection in more detail.