Search

Background: Emerging digital measures and clinical outcome assessments (COAs) leveraging digital health technologies (DHTs) could address the need for objective, quantitative measures of symptoms of atopic dermatitis (AD), such as nocturnal scratching. Development of such measures needs to be supported by evidence reflecting meaningfulness to patients., Objectives: To assess nocturnal scratching as a concept of interest associated with meaningful aspects of health of patients with AD (adults and children); and to explore patient-centred considerations for novel COAs measuring nocturnal scratch using DHTs., Methods: Phase 1 evaluated disease impacts on everyday life and the lived experience with nocturnal scratching through qualitative interviews of AD patients and caregivers. Phase 2 deployed a quantitative survey to a sample of AD patients as well as caregivers., Results: Four cohorts with various AD severity levels participated in Phase 1: (1) adults with AD ( n  = 15), (2) their caregivers/spouses/partners ( n  = 6), (3) children with AD ( n  = 14), and (4) their adult caregivers ( n  = 14). Findings were used to develop a conceptual model for nocturnal scratching as a potential concept of interest. The Phase 2 survey was completed by 1349 of 27640 invited adults with AD and caregivers of children with AD. The most burdensome aspects of AD reported were itchy skin and scratching. Overall, ∼65% of participants reported nocturnal scratching ≥1 day/week, resulting in ∼1-1.4 h of sleep lost per night. In all, 85%-91% of respondents considered it at least somewhat valuable that a treatment reduces night-time scratching. About 50% reported willingness to use technology to this end and ∼25% were unsure., Conclusion: Our results represented by the conceptual model confirm that nocturnal scratch is a concept of interest related to meaningful aspects of health for patients with AD and therefore is worth being captured as a distinct outcome for clinical and research purposes. DHTs are suitable tools presenting an important measurement opportunity to assess and evaluate occurrence, frequency, and other parameters of nocturnal scratching as a disease biomarker or COA of treatment efficacy., Competing Interests: Lucia Cesnakova and Jennifer C. Goldsack are employees of the Digital Medicine Society, the sponsor of this study. The other authors are employees of their respective organizations. Carrie A. Northcott, Doina Sirbu and Jérémy Lambert are shareholders of their respective organizations., (© 2023 Digital Medicine Society (DiME). Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background High-risk pulmonary embolism is associated with a high early mortality rate. We report our experience with percutaneous mechanical thrombectomy in patients with high-risk pulmonary embolism and contraindications for thrombolytic therapy. Patients and methods This was a retrospective analysis of consecutive patients with high-risk pulmonary embolism and contraindications to thrombolytic therapy. They were treated with percutaneous mechanical thrombectomy which included thrombectomy and additional thrombus aspiration when needed. Clinical parameters and survival to discharge were measured. Results From November 2005 to September 2015 we treated 25 patients with a mean age of 62.6 ± 12.7 years, 64% were men. Mean simplified Pulmonary Embolism Severity Index was 2.9. Mean maximum lactate levels were 7.8 ± 6.6 mmol/L, vasopressors were used in 77%, and 59% needed mechanical ventilation. Mechanical treatment included thrombus fragmentation complemented with aspiration (56%) and aspiration using Aspirex®S catheter (44%). Local (5 patients; 20%) and systemic (3 patients; 12%) thrombolytics were used as a salvage therapy. We observed nonsignificant improvements in systemic blood pressure (100 ± 41 mm Hg vs 119 ± 34; p = 0.100) and heart frequency (99 ± 35 min-1 vs 87 ± 31 min-1; p = 0.326) before and after treatment, respectively. Peak systolic tricuspid pressure gradient was significantly lower after treatment (57 ± 14 mm Hg vs 31 ± 3 mm Hg; p = 0.018). Overall the procedure was technically successful in 20 patients (80%) and 17 patients (68%) survived to hospital discharge. Conclusions In patients with high-risk pulmonary embolism who cannot receive thrombolytic therapy, percutaneous mechanical thrombectomy is a promising alternative to reduce pulmonary artery pressure.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (alloSCT). By static microscopy, cutaneous GVHD lesions contain a mix of T cells and myeloid cells. We used 2-photon intravital microscopy to investigate the dynamics of CD4 + and CD8 + T cells and donor dendritic cells (DCs) in cutaneous GVHD lesions in an MHC-matched, multiple minor histocompatibility antigen-mismatched (miHA) model. The majority of CD4 and CD8 cells were stationary, and few cells entered and stopped or were stopped and left the imaged volumes. CD8 cells made TCR:MHCI-dependent interactions with CD11c + cells, as measured by the durations that CD8 cells contacted MHCI + vs MHCI - DCs. The acute deletion of Langerin + CD103 + DCs, which were relatively rare, did not affect CD8 cell motility and DC contact times, indicating that Langerin - CD103 - DCs provide stop signals to CD8 cells. CD4 cells, in contrast, had similar contact durations with MHCII + and MHCII - DCs. However, CD4 motility rapidly increased after the infusion of an MHCII-blocking antibody, indicating that TCR signaling actively suppressed CD4 movements. Many CD4 cells still were stationary after anti-MHCII antibody infusion, suggesting CD4 cell heterogeneity within the lesion. These data support a model of local GVHD maintenance within target tissues., (© 2019 by The American Society of Hematology.)

Most membrane-proteins exist in complexes rather than isolated entities. To fully understand their biological function it is essential to study the intact membrane-protein assemblies. The overexpression and purification of many essential membrane-protein complexes is still a considerable and often unsurmountable challenge. In these cases, extraction from source is the only option for many large multi-subunit cellular machines. Here, we describe recent advances in overexpression of multi-subunit membrane-protein complexes, the strategies to stabilize these complexes and highlight major achievements in membrane-protein structural research that were facilitated by the prospect of achieving subnanometer to near-atomic resolution by electron cryo-microscopy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Contrasting data have been so far reported on facilitation with glycoprotein IIb-IIIa inhibitors (GpIIbIIIa) in patients who underwent primary percutaneous coronary intervention. However, it has been demonstrated a time-dependent composition of coronary thrombus in ST-segment elevation myocardial infarction, with more platelets in the first hours. Subsequently, the benefits of early administration of GpIIbIIIa may be affected by the time from symptoms onset to GpIIbIIIa, that therefore is the aim of this study. Our population is represented by 814 patients who underwent GpIIbIIIa facilitated primary angioplasty included in the Early glycoprotein IIb-IIIa inhibitors in primary angioplasty database. Patients were divided according to quartiles of time from symptom onset to GpIIbIIIa administration (≤65 minutes; 65 to 100 minutes; 101 to 178 minutes; and >178 minutes). Myocardial perfusion was evaluated by myocardial blush grade and ST-segment resolution. Time from symptoms onset to GpIIbIIIa was linearly associated with hypertension, diabetes, hypercholesterolemia, and previous myocardial infarction but inversely associated with smoking. Abciximab was more often administrated later from symptoms onset. Time from symptoms onset to GpIIbIIIa was significantly associated with the rate of preprocedural recanalization (thrombolysis in myocardial infarction [TIMI] 2 to 3; p <0.001), postprocedural TIMI 3 flow (p <0.001), the rate of complete ST-segment resolution (p <0.001), and the rate of myocardial blush grade 2 to 3 (p <0.001) and inversely associated with the occurrence of distal embolization (p <0.001). Follow-up data were collected at a median (twenty-fifth to seventy-fifth) of 360 (30 to 1,095) days. A total of 52 patients had died. Time to GpIIbIIIa had a significant impact on mortality (hazard ratio [95% confidence interval] 1.46 [1.11 to 1.92], p = 0.007) that was confirmed after correction for baseline confounding factors (adjusted hazard ratio [95% confidence interval] 1.41 [1.02 to 2.21], p = 0.042). In conclusion, this study showed that in patients who underwent primary angioplasty with upstream GpIIbIIIa, time from symptoms onset to GpIIbIIIa strongly impacts on preprocedural recanalization, distal embolization, myocardial perfusion, and long-term survival., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are evolutionarily conserved machines that couple their folding/assembly to membrane fusion. However, it is unclear how these processes are regulated and function. To determine these mechanisms, we characterized the folding energy and kinetics of four representative SNARE complexes at a single-molecule level using high-resolution optical tweezers. We found that all SNARE complexes assemble by the same step-wise zippering mechanism: slow N-terminal domain (NTD) association, a pause in a force-dependent half-zippered intermediate, and fast C-terminal domain (CTD) zippering. The energy release from CTD zippering differs for yeast (13 kBT) and neuronal SNARE complexes (27 kBT), and is concentrated at the C-terminal part of CTD zippering. Thus, SNARE complexes share a conserved zippering pathway and polarized energy release to efficiently drive membrane fusion, but generate different amounts of zippering energy to regulate fusion kinetics.

Despite mechanical reperfusion, the outcome is still unsatisfactory in elderly patients with ST-segment elevation myocardial infarction (STEMI). The vast majority of studies have been conducted without extensive use of glycoprotein (Gp) IIb-IIIa inhibitors, which have been associated with improved perfusion and survival. Thus the aim of the current study was to evaluate the impact of age on the angiographic and clinical outcome patients with STEMI undergoing primary angioplasty with Gp IIb-IIIa inhibitors. Our population is represented by a total of 1,662 patients undergoing primary angioplasty for STEMI included in 11 randomized trials comparing early versus late administration of Gp IIb-IIIa inhibitors. Myocardial perfusion was evaluated by myocardial blush grade and ST-segment resolution. Follow-up data were collected between 30 days and 1 year after primary angioplasty. A total of 231 (13.9 %) patients were older than 75 years. Elderly patients showed a larger prevalence of female gender, hypertension, and diabetes, more advanced Killip class at presentation and longer time to treatment, but a smaller prevalence of smoking. All patients were treated with GP IIb-IIIa inhibitors. Elderly patients showed a significantly impaired postprocedural thrombolysis in myocardial infarction (TIMI) flow (TIMI 0-2: 17.7 vs 10.3 %, P = 0.002) and myocardial perfusion (myocardial blush grade 0-1: 38.3 vs 26.5 %, P = 0.001), and higher prevalence of distal embolization (19.2 vs 9.8 %, P < 0.001), whereas no difference was observed in terms of ST-segment resolution. At follow-up, elderly patients showed a significantly higher mortality (3.2 vs 11.0 %, hazard ratio (HR) (95 % confidence interval (CI)) = 3.78 (2.31-6.16), P < 0.001), which was confirmed after adjustment for baseline confounding factors (HR (95 % CI) = 5.01 (2.63-9.55), P < 0.0001). This study showed that among patients with STEMI undergoing primary angioplasty, advanced age is an independent predictor of mortality after primary angioplasty. Higher rates of distal embolization and poor myocardial perfusion, in addition to the worse risk profile, contribute toward explaining the impact of aging on mortality.

Background: Primary angioplasty has been shown to be superior to thrombolysis. However, previous reports have shown a negative impact of longer time-to-treatment on myocardial perfusion and survival even with mechanical reperfusion. However, these deleterious effects might potentially be overcome by an extensive use of glycoprotein (Gp) IIb-IIIa inhibitors. Thus, the aim of the current study was to evaluate the prognostic role of the interval from symptoms onset to reperfusion in a large cohort of patients undergoing primary angioplasty with Gp IIb-IIIa inhibitors., Methods: Our population is represented by 1560 patients undergoing primary angioplasty for ST-segment elevation myocardial infarction (STEMI) included in the EGYPT (Early Glycoprotein IIb-IIIa Inhibitors in Primary Angiography) database. Myocardial perfusion was evaluated by angiography or ST-segment resolution, whereas infarct size was estimated by using peak creatine kinase and creatine kinase-MB (CK-MB). Follow-up data were collected between 30 days and 1 year after primary angioplasty., Results: Time-to-treatment was significantly associated with age and female sex, diabetes and previous myocardial infarction (MI), but inversely related to smoking. Time-to-treatment affected the rate of postprocedural thrombolysis in myocardial infarction (TIMI) 3 flow (P < 0.0001), myocardial blush grade 2-3 (P = 0.052), complete ST-resolution (P < 0.0001) and distal embolization (P = 0.038). This relationship was confirmed after correction for baseline confounding factors for postprocedural TIMI 3 flow (P = 0.008) and complete ST-segment resolution (P = 0.003). Furthermore, time-to-treatment significantly affected enzymatic infarct size, even after correction for baseline confounding factors [odds ratio (OR) 95% confidence interval (95% CI) = 1.002 (1.001-1.003), P = 0.004]. At 208 ± 160 days follow-up, time-to-treatment was associated with a significantly higher mortality (P = 0.006). The impact was confirmed when time-to-treatment was evaluated as a continuous variable (P < 0.001), even after correction for baseline confounding factors [age, sex, diabetes, smoking, hypertension, previous myocardial infarction (MI), preprocedural TIMI 3 flow, multivessel disease, coronary stenting and early Gp IIb-IIIa inhibitors] (P = 0.001)., Conclusion: This study showed that time-to-treatment is a major determinant of mortality in ST-segment elevation myocardial infarction patients undergoing primary angioplasty. Impaired epicardial and myocardial perfusion and larger infarct size associated with longer ischemia time contribute to explain this finding.

Hypertension is a well-known risk factor for atherosclerosis. However, data on the impact of hypertension in patients with ST elevation myocardial infarction (STEMI) are inconsistent and mainly related to studies performed in the thrombolytic era, with very few data on patients undergoing primary angioplasty. The aim of the present study was to evaluate the impact of hypertension on distal embolization, myocardial perfusion, and mortality in patients with STEMI undergoing primary percutaneous coronary intervention. Our population is represented by 1,662 patients undergoing primary angioplasty for STEMI included in the Early Glycoprotein IIb-IIIa inhibitors in Primary angioplasty database. Myocardial perfusion was evaluated by myocardial blush grade and ST segment resolution. Follow-up data were collected within 1 year after primary angioplasty. Hypertension was observed in 700 patients (42.1%). Hypertension was associated with more advanced age (p <0.001), female gender (p <0.001), diabetes (p <0.001), hypercholesterolemia (p <0.001), previous revascularization (p <0.001), anterior myocardial infarction (p = 0.006), longer ischemia time (p = 0.03), more extensive coronary artery disease (p = 0.002), more often treated with abciximab (p <0.001), and less often smokers (p <0.001). Hypertension was associated with impaired postprocedural myocardial blush grade 2 to 3 (68.2% vs 74.2%, p = 0.019) and complete ST segment resolution (51.7% vs 61.1%, p = 0.001). By a mean follow-up of 206 ± 158 days, 70 patients (4.3%) had died. Hypertension was associated with a greater mortality (6.2% vs 2.9%, hazard ratio 2.31, 95% confidence interval 1.42 to 3.73, p <0.001), confirmed after correction for baseline confounding factors (hazard ratio 1.82, 95% confidence interval 1.03 to 3.22, p <0.001). In conclusion, this study showed that among patients with STEMI undergoing primary angioplasty, hypertension is associated with impaired reperfusion and independently predicts 1-year mortality., (Copyright © 2013 Elsevier Inc. All rights reserved.)

AMP-activated protein kinase (AMPK) is a cellular and whole body energy sensor with manifold functions in regulating energy homeostasis, cell morphology and proliferation in health and disease. Here we apply multiple, complementary in vitro and in vivo interaction assays to identify several isoforms of glutathione S-transferase (GST) as direct AMPK binding partners: Pi-family member rat GSTP1 and Mu-family members rat GSTM1, as well as Schistosoma japonicum GST. GST/AMPK interaction is direct and involves the N-terminal domain of the AMPK β-subunit. Complex formation of the mammalian GSTP1 and -M1 with AMPK leads to their enzymatic activation and in turn facilitates glutathionylation and activation of AMPK in vitro. GST-facilitated S-glutathionylation of AMPK may be involved in rapid, full activation of the kinase under mildly oxidative physiological conditions.

Background: Although primary angioplasty achieves thrombolysis in myocardial infarction (TIMI) 3 flow in most patients with ST-elevation myocardial infarction, epicardial recanalization does not guarantee optimal perfusion in a large proportion of patients. The influence of multivessel disease on myocardial reperfusion and survival after primary angioplasty has not been extensively investigated., Aim: To evaluate the impact of multivessel disease on myocardial perfusion and survival in a large cohort of patients with ST-elevation myocardial infarction treated with angioplasty and glycoprotein (GP) IIb/IIIa inhibitors., Methods: This analysis is based on 1494 patients undergoing primary angioplasty included in the EGYPT database. Myocardial perfusion was evaluated by angiography or ST-segment resolution, whereas infarct size was estimated by using peak creatine kinase-MB (CK-MB). Follow-up data were collected between 30 days and 1 year after primary angioplasty., Results: Multivessel disease was observed in 870 patients (58.2%). The extent of coronary artery disease was associated with age, diabetes, hypertension, previous myocardial infarction, previous revascularization, abciximab treatment and longer ischaemic time, and was independently associated with impaired angiographic myocardial perfusion (adjusted odds ratio 1.18, 95% confidence interval [CI] 1.01-1.40, P=0.049). At 208±160 days, the extent of coronary artery disease was independently associated with higher mortality (adjusted hazard ratio 1.54, 95% CI 1.06-2.24, P=0.022)., Conclusions: Among patients with ST-elevation myocardial infarction undergoing primary angioplasty with GP IIb/IIIa inhibitor treatment, the extent of coronary artery disease was independently associated with impaired myocardial perfusion and survival., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Transcription-coupled DNA repair uses components of the transcription machinery to identify DNA lesions and initiate their repair. These repair pathways are complex, so their mechanistic features remain poorly understood. Bacterial transcription-coupled repair is initiated when RNA polymerase stalled at a DNA lesion is removed by Mfd, an ATP-dependent DNA translocase. Here we use single-molecule DNA nanomanipulation to observe the dynamic interactions of Escherichia coli Mfd with RNA polymerase elongation complexes stalled by a cyclopyrimidine dimer or by nucleotide starvation. We show that Mfd acts by catalysing two irreversible, ATP-dependent transitions with different structural, kinetic and mechanistic features. Mfd remains bound to the DNA in a long-lived complex that could act as a marker for sites of DNA damage, directing assembly of subsequent DNA repair factors. These results provide a framework for considering the kinetics of transcription-coupled repair in vivo, and open the way to reconstruction of complete DNA repair pathways at single-molecule resolution.

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins drive membrane fusion by assembling into a four-helix bundle in a zippering process. Here, we used optical tweezers to observe in a cell-free reconstitution experiment in real time a long-sought SNARE assembly intermediate in which only the membrane-distal amino-terminal half of the bundle is assembled. Our findings support the zippering hypothesis, but suggest that zippering proceeds through three sequential binary switches, not continuously, in the amino- and carboxyl-terminal halves of the bundle and the linker domain. The half-zippered intermediate was stabilized by externally applied force that mimicked the repulsion between apposed membranes being forced to fuse. This intermediate then rapidly and forcefully zippered, delivering free energy of 36 k(B)T (where k(B) is Boltzmann's constant and T is temperature) to mediate fusion.

In most bacteria, the timing and synchrony of initiation of chromosomal replication are determined by the binding of the AAA(+) protein DnaA to a set of high- and low-affinity sites found within the origin of chromosomal replication (oriC). Despite the large amount of information on the role and regulation of DnaA, the actual structure of the DnaA-oriC complex and the mechanism by which it primes the origin for the initiation of replication remain unclear. In this study, we have performed magnetic tweezers experiments to investigate the structural properties of the DnaA-oriC complex. We show that the DnaA-ATP-oriC complex adopts a right-handed helical conformation involving a variable amount of DNA and protein whose features fit qualitatively as well as quantitatively with an existing model based on the crystal structure of a truncated DnaA tetramer obtained in the absence of DNA. We also investigate the topological effect of oriC's DNA unwinding element.

Aims: Considerable interest has been focused in recent years on the role of distal embolisation as a major determinant of impaired reperfusion after primary angioplasty for STEMI. The aim of the current study was to evaluate in a large cohort of STEMI patients undergoing primary angioplasty with glycoprotein (Gp) IIb-IIIa inhibitors, whether the impact of distal embolisation on myocardial perfusion and survival may depend on time-to-treatment., Methods and Results: Our population is represented by 1,182 patients undergoing primary angioplasty for STEMI included in the EGYPT database. Patients were grouped according to time-to-treatment (<3 hours, 3-6 hours, >6 hours). Distal embolisation was defined as an abrupt "cutoff" in the main vessel or one of the coronary branches of the infarct-related artery, distal to the angioplasty site. Myocardial perfusion was evaluated by angiography or ST-segment resolution, whereas infarct size was estimated by using peak creatine kinase (CK) and CK-MB. Follow-up data were collected between 30 days and one year after primary angioplasty. Distal embolisation was observed in 132 patients (11.1%) and tended to occur more frequently in late presenters (p=0.067). Patients with distal embolisation less often had post-procedural Thrombolysis In Myocardial Infarction (TIMI) 3 flow (p<0.001), post-procedural myocardial blush grade (MBG) 2-3 (p<0.001), complete ST-segment resolution (p=0.021) and larger infarct size (p=0.012). Distal embolisation was associated with a significantly higher mortality (9.2% vs. 2.7%, heart rate [HR] [95% CI]=3.41 [1.73-6.71], p<0.0001). The impact of distal embolisation on myocardial perfusion and survival persisted for all time intervals., Conclusions: This study showed that among STEMI patients treated with Gp IIb-IIIa inhibitors, the negative impact of distal embolisation on myocardial perfusion and mortality is independent of the time from symptom onset to balloon angioplasty.

Background: Despite optimal epicardial recanalization, primary angioplasty for ST-elevation myocardial infarction (STEMI) is still associated with suboptimal reperfusion in a relatively large proportion of patients. The aim of the current study was to evaluate the impact of preprocedural TIMI flow on myocardial perfusion, distal embolization, and survival among STEMI patients undergoing primary angioplasty with glycoprotein (GP) IIb/IIIa inhibitors., Methods: Our population is represented by a total of 1637 patients undergoing primary angioplasty for STEMI treated with GP IIb/IIIa inhibitors. Myocardial perfusion was evaluated by myocardial blush grade and ST-segment resolution. Follow-up data were collected between 30 days and 1 year after primary angioplasty., Results: Poor preprocedural TIMI flow (TIMI 0-1) was observed in 1039 patients (63.5%), and was associated with higher Killip class at presentation (P=.006), longer time-to-treatment (P=.03), less often with early administration of GP IIb/IIIa inhibitors (P<.001), impaired postprocedural epicardial (P=.001) and myocardial perfusion (determined by myocardial blush grade, P<.001 and/or ST-segment resolution (P<.001), and distal embolization (P=.041). At 206 ± 158 days follow-up, poor preprocedural recanalization was associated with a significantly higher mortality (adjusted odds ratio, 0.58; 95% CI, 0.34-0.96; P=.034)., Conclusion: This study shows that among patients with STEMI undergoing primary angioplasty with GP IIb/IIIa inhibitors, poor preprocedural TIMI flow is associated with higher incidence of distal embolization and impaired epicardial and myocardial perfusion, and significantly higher mortality.

AMP-activated protein kinase (AMPK) is emerging as a central cellular signaling hub involved in energy homeostasis and proliferation. The kinase is considered as a suitable target for pharmacological intervention in several energy-related pathologies like diabetes type II and cancer, although its signaling network is still incompletely understood. Here we apply an original two-dimensional in vitro screening approach for AMPK substrates that combines biophysical interaction based on surface plasmon resonance with in vitro phosphorylation. By enriching for proteins that interact with a specific AMPK isoform, we aimed to identify substrates that are also preferentially phosphorylated by this specific AMPK isoform. Application of this screen to full-length AMPK α2β2γ1 and soluble rat liver proteins identified the tumor suppressor fumarate hydratase (FH). FH was confirmed to interact with and to be preferentially phosphorylated by the AMPKα2 isoform by using yeast-two-hybrid and in vitro phosphorylation assays. AMPK-mediated phosphorylation of FH significantly increased enzyme activity in vitro and in vivo, suggesting that it is a bona fide AMPK substrate. In vivo, AMPKα2 is supposed to target the cytosolic/nuclear pools of FH, whose tumor suppressor function relies on DNA damage repair and inhibition of HIF-1α-signaling., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Even although time to treatment has been shown to be a determinant of mortality in primary angioplasty, the potential benefits are still unclear from early pharmacological reperfusion by glycoprotein (Gp) IIb-IIIa inhibitors. Therefore, the aim of this meta-analysis was to combine individual data from all randomized trials conducted on upstream as compared with late peri-procedural abciximab administration in primary angioplasty., Methods: The literature was scanned using formal searches of electronic databases (MEDLINE and EMBASE) from January 1990 to December 2010. All randomized trials on upstream abciximab administration in primary angioplasty were examined. No language restrictions were enforced., Results: We included a total of seven randomized trials enrolling 722 patients, who were randomized to early (n = 357, 49.4%) or late (n = 365, 50.6%) peri-procedural abciximab administration. No difference in baseline characteristics was observed between the two groups. Follow-up data were collected at a median (25th-75th percentiles) of 1095 days (720-1967). Early abciximab was associated with a significant reduction in mortality (primary endpoint) [20% vs. 24.6%; hazard ratio (HR) 95% confidence interval (CI) = 0.65 (0.42-0.98) P = 0.02, P(het) = 0.6]. Furthermore, early abciximab administration was associated with a significant improvement in pre-procedural thrombolysis in myocardial infarction (TIMI) 3 flow (21.6% vs. 10.1%, P < 0.0001), post-procedural TIMI 3 flow (90% vs. 84.8%, P = 0.04), an improvement in myocardial perfusion as evaluated by post-procedural myocardial blush grade (MBG) 3 (52.0% vs. 43.2%, P = 0.03) and ST-segment resolution (58.4% vs. 43.5%, P < 0.0001) and significantly less distal embolization (10.1% vs. 16.2%, P = 0.02). No difference was observed in terms of major bleeding complications between early and late abciximab administration (3.3% vs. 2.3%, P = 0.4)., Conclusions: This meta-analysis shows that early upstream administration of abciximab in patients undergoing primary angioplasty for ST-segment elevation myocardial infarction (STEMI) is associated with significant benefits in terms of pre-procedural epicardial re-canalization and ST-segment resolution, which translates in to significant mortality benefits at long-term follow-up., (© 2011 International Society on Thrombosis and Haemostasis.)

Several studies have found that among patients with ST-elevation myocardial infarction (STEMI) treated by thrombolysis, female sex is associated with a worse outcome. The aim of this study was to investigate sex-related differences in clinical and angiographic findings in patients with STEMI treated with primary angioplasty and Gp IIb-IIIa inhibitors. Our population is represented by 1662 patients undergoing primary angioplasty included in the EGYPT database. Myocardial perfusion was evaluated by myocardial blush grade and ST-segment resolution. Follow-up data were collected between 30 days and 1 year after primary angioplasty. Among 1662 patients, 379 were women (22.8%). Female sex was associated with more advanced age, higher prevalence of diabetes, hypertension, more advanced Killip class, longer ischemia time, less often smokers, with higher prevalence of preprocedural recenalization. No difference was observed in terms of postprocedural TIMI flow, myocardial perfusion and distal embolization. Similar findings were observed in terms of enzymatic infarct size and preprocedural ejection fraction. Female gender was associated with higher mortality (6.4% vs. 3.6%, HR = 1.83 [1.12-3.0], P = 0.015). However, the difference disappeared after correction for baseline confounding factors (HR = 1.01 [0.56-1.83], P = 0.98). This study shows that in patients with STEMI treated by primary angioplasty, female gender is associated with higher mortality rate in comparison with men, and this is mainly due to their higher clinical and angiographic risk profiles. In fact, female sex did not emerge as an independent predictor of mortality.

The applicability of single-molecule fluorescence assays in liquids is limited by diffusion to concentrations in the low picomolar range. Here, we demonstrate quantitative single-molecule detection at attomolar concentrations within 1 min by excitation and detection of fluorescence through a single-mode optical fiber in presence of turbulent flow. The combination of high detectability and short measurement times promises applications in ultrasensitive assays, sensors, and point-of-care medical diagnostics.

Even though primary angioplasty is able to obtain TIMI 3 flow in the vast majority of STEMI patients, epicardial recanalization does not guarantee optimal myocardial perfusion, that remain suboptimal in a relatively large proportion of patients. Large interest has been focused in recent years on the role of distal embolization as major determinant of impaired reperfusion. The aim of the current study was to investigate in a large cohort of STEMI undergoing primary angioplasty with Gp IIb-IIIa inhibitors the impact of distal embolization on myocardial perfusion and survival. Our population is represented by patients undergoing primary angioplasty for STEMI included in the EGYPT database. Distal embolization was defined as an abrupt ''cutoff'' in the main vessel or one of the coronary branches of the infarct-related artery, distal to the angioplasty site. Myocardial perfusion was evaluated by angiography or ST-segment resolution, whereas infarct size was estimated by using peak CK and CK-MB. Follow-up data were collected between 30 days and 1 year after primary angioplasty. Data on distal embolization were available in a total of 1182 patients (71% of total population). Distal embolization was observed in 132 patients (11.1%). Patients with distal embolization were older (P < 0.001), with larger prevalence of diabetes (P = 0.01), previous MI (P = 0.048) and advanced Killip class at presentation (P = 0.018), abciximab administration (P < 0.001), with a lower prevalence of smoking (P = 0.04). Patients with distal embolization had more often poor preprocedural recanalization (P = 0.061), less often postprocedural TIMI 3 flow (P < 0.001), postprocedural MBG 2-3 (P < 0.001), complete ST-segment resolution (P = 0.021) and larger infarct size (CK-MB: 328 +/- 356 U/l vs. 259 +/- 226 U/l, P = 0.012). The impact of distal embolization on myocardial perfusion was confirmed after correction for baseline confounding factors as evaluated by MBG 2-3 (adjusted OR [95% CI] = 3.14 [2.06-4.77], P < 0.0001) but not complete ST-segment resolution (adjusted OR [95% CI] = 1.23 [0.84-1.92], P = 0.26). At 208 +/- 160 days follow-up, distal embolization was associated with a significantly higher mortality (9.2% vs. 2.7%, HR [95% CI] = 3.41 [1.73-6.71], P < 0.0001), that was confirmed after correction for baseline confounding factors (adjusted HR [95% CI] = 2.23 [1.1-4.7], P = 0.026). This study showed among STEMI patients treated with Gp IIb-IIIa inhibitors, that distal embolization is independently associated with impaired myocardial perfusion and survival.

Background: It has been shown that, among patients with ST-segment elevation myocardial infarction (STEMI), diabetes is associated with a significantly higher mortality. The aim of the current study was to investigate the impact of diabetes on myocardial perfusion and mortality among STEMI patients treated with primary angioplasty and glycoprotein IIb-IIIa inhibitors., Methods: Our population is represented by a total of 1662 patients undergoing primary angioplasty for STEMI included in 11 randomized trials. Myocardial perfusion was evaluated by angiography (n=1324) or postprocedural ECG (n=1371). Distal embolization was defined as an abrupt "cutoff" in the main vessel or one of the coronary branches of the infarct-related artery, distal to the angioplasty site (data available in 1181 patients)., Results: Diabetes was observed in a total of 281 patients (16.9%). Diabetic patients were older, with a larger prevalence of female gender, hypertension, hypercholesterolemia, advanced killip class at presentation and multivessel disease. Diabetes was associated with impaired postprocedural TIMI 3 flow (82% vs 90%, p<0.001), MBG 2-3 (60.1% vs 74.2%, p<0.001), complete ST-segment resolution (43.2% vs 60%, p<0.001) and more distal embolization (16.4% vs 10.1%, p<0.0001). The association with impaired MBG and distal embolization was confirmed after correction for baseline confounding factors. Diabetes was associated with significantly impaired mortality (12.6% vs 3.9%, HR=3.0 [1.84-4.89], p<0.001), that persisted even after correction for baseline confounding factors (HR=2.6 [1.52-4.45], p=0.001)., Conclusion: This study showed that, among patients with STEMI undergoing primary angioplasty on the top of glycoprotein IIb-IIIa inhibitors, diabetes mellitus is independently associated with impaired perfusion and distal embolization, that contribute to explain the higher mortality observed in these patients.

The Early Glycoprotein IIb-IIIa inhibitors in Primary angioplasty (EGYPT) cooperation aimed at evaluating, by pooling individual patient's data of randomized trials, the benefits of pharmacological facilitation with Gp IIb-IIIa inhibitors among STEMI patients undergoing primary angioplasty. In the current study we analyze the benefits of early Gp IIb-IIIa inhibitors in diabetic patients. The literature was scanned by formal searches of electronic databases (MEDLINE, EMBASE) from January 1990 to October 2007. We examined all randomized trials on facilitation by early administration of Gp IIb-IIIa inhibitors in STEMI. No language restrictions were enforced. Individual patients' data were obtained from 11 out of 13 trials, including 1,662 patients. Diabetes was present in 281 (16.9%). Early Gp IIb-IIIa inhibitors were associated with improved preprocedural TIMI 3 flow (26.0% vs. 13.1%, P = 0.006), postprocedural TIMI 3 flow (90.1% vs. 75.0%, P = 0.18), MBG 3 (40.8% vs. 30.4%, P = 0.004), and less distal embolization (11.6% vs. 20.8%, P = 0.05). However, early Gp IIb-IIIa inhibitors did not significantly reduce mortality (8.3% vs. 9.5%, P = 0.64). This meta-analysis shows that pharmacological facilitation with early administration of Gp IIb-IIIa inhibitors in STEMI patients with diabetes undergoing primary angioplasty, is associated with significant benefits in terms of preprocedural and postprocedural TIMI flow, improved myocardial perfusion, without significant benefits in mortality.

Background: Although primary angioplasty has been shown to improve survival as compared with thrombolysis, the outcome is still unsatisfactory in subsets of patients such as those with signs of heart failure at presentation. In fact, although primary angioplasty is able to restore TIMI 3 flow in most patients, suboptimal myocardial reperfusion is observed in a relatively large proportion of patients. The aim of this study was to investigate among patients with ST-segment elevation myocardial infarction undergoing primary angioplasty the association between heart failure at presentation and myocardial perfusion and its implications in terms of survival., Methods: Our population is represented by patients undergoing primary angioplasty who are included in the EGYPT database. Congestive heart failure was defined as Killip class >1 at admission. Myocardial perfusion was evaluated by myocardial blush grade and ST-segment resolution. Follow-up data were collected between 30 days and 1 year after primary angioplasty., Results: Detailed data on Killip class at presentation were available in 1,427 of 1,662 patients (86% of the initial population) who represent the final population of this study. Killip class was associated with myocardial perfusion, distal embolization, enzymatic infarct size, predischarge ejection fraction, and 1-year mortality rate. Myocardial blush was an independent predictor of 1-year mortality (hazard ratio 7.44, 95% CI 1.82-30.4, P = .005) in patients with advanced Killip class at presentation., Conclusions: Our study shows that patients with heart failure complicating ST-segment elevation myocardial infarction have impaired myocardial perfusion, which accounts for the poor outcome observed in these patients. Further efforts should be aimed at improving myocardial perfusion, beyond epicardial recanalization, to further improve the outcome of these high-risk patients.

Background: Even though time-to-treatment has been shown to be a determinant of mortality in primary angioplasty, the potential benefits from early pharmacological reperfusion by glycoprotein (Gp) IIb-IIIa inhibitors are still unclear. The aim of this meta-analysis was to combine individual data from all randomised trials conducted on facilitated primary angioplasty by the use of early Gp IIb-IIIa inhibitors., Methods and Results: The literature was scanned by formal searches of electronic databases (MEDLINE, EMBASE) from January 1990 to October 2007. All randomised trials on facilitation by the early administration of Gp IIb-IIIa inhibitors in ST-segment elevation myocardial infarction (STEMI) were examined. No language restrictions were enforced. Individual patient data were obtained from 11 out of 13 trials, including 1662 patients (840 patients (50.5%) randomly assigned to early and 822 patients (49.5%) to late Gp IIb-IIIa inhibitor administration). Preprocedural Thrombolysis in Myocardial Infarction Study (TIMI) grade 3 flow was more frequent with early Gp IIb-IIIa inhibitors. Postprocedural TIMI 3 flow and myocardial blush grade 3 were higher with early Gp IIb-IIIa inhibitors but did not reach statistical significance except for abciximab, whereas the rate of complete ST-segment resolution was significantly higher with early Gp IIb-IIIa inhibitors. Mortality was not significantly different between groups, although early abciximab demonstrated improved survival compared with late administration, even after adjustment for clinical and angiographic confounding factors., Conclusions: This meta-analysis shows that pharmacological facilitation with the early administration of Gp IIb-IIIa inhibitors in patients undergoing primary angioplasty for STEMI is associated with significant benefits in terms of preprocedural epicardial recanalisation and ST-segment resolution, which translated into non-significant mortality benefits except for abciximab.

Primary percutaneous coronary intervention (PCI) is currently viewed as the preferred reperfusion strategy in patients with ST-elevation acute myocardial infarction (STEMI). This method was introduced in our hospital in 2000. From January 1, 2000, to December 31, 2004, a total of 2,393 consecutive patients with STEMI were admitted (27% transferred from 9 non-PCI hospitals and 31 prehospital emergency units/outpatient clinics). Of these patients, 1,666 (70%) underwent urgent coronary angiography and primary PCI. Platelet glycoprotein llb/llla inhibitors were used in 40% and stent placement, in 78%. Postprocedural Thrombolysis In Myocardial Infarction (TIMI) 3 flow was documented in 86%. Intra-aortic balloon counterpulsation was used in 6%; mechanical ventilation, in 8.6%; and inotropic drugs/vasopressors, in 15.8%. Mortality rates in patients with Killip's class I or II ranged from 1% to 4.9% without negative influence of ischemic time. In patients with Killip's class III or IV, mortality rates increased from 18% to 54% with increasing ischemic delay up to 6 hours (p = 0.06) and remained at around 40% afterward. Independent predictors of mortality were age (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.01 to 1.64, p = 0.04), resuscitated cardiac arrest (OR 2.44, 95% CI 1.18 to 5.05, p = 0.02), and postprocedural TIMI flow (OR 0.31, 95% CI 0.16 to 0.59). Overall mortality rates of patients who underwent a primary PCI strategy from 2000 to 2004 were significantly lower than in the control group of 152 consecutive patients who underwent thrombolysis from 1995 to 1996 (6.2% vs 16.4%; p <0.001). In conclusion, introduction of a primary PCI strategy significantly decreased hospital mortality in our unselected group of patients with STEMI compared with the thrombolytic era. Our study further emphasized the importance of shortening myocardial ischemic time, particularly in the presence of severe heart failure on admission.

We present an experimental study of the fingering patterns in a Hele-Shaw cell occurring when a gel-like material forms at the interface between aqueous solutions of a cationic surfactant (cetyltrimethylammonium bromide) and an organic salt (salicylic acid), two solutions known to form a highly elastic wormlike micellar fluid when mixed homogeneously. A variety of fingering instabilities are observed, depending on the velocity of the front (the injection rate), and on which fluid is injected into which. We have found a regime of nonconfined stationary or wavy fingers for which width selection seems to occur without the presence of bounding walls, unlike the Saffman-Taylor experiment. Qualitatively, some of our observations share common mechanisms with instabilities of cooling lava flows or growing biofilms.

Background: The 2004 ACC/AHA guidelines on ST-elevation myocardial infarction state that it is reasonable to start treatment with abciximab as early as possible before primary percutaneous coronary intervention (PCI). We investigated the potential benefit of early use of abciximab by pooling data from all the available studies., Methods: Six prospective studies were identified that had allocated 260 patients to receive early abciximab (either prehospital or soon after the patient arrived in hospital) and 342 to receive late abciximab (at the time of PCI)., Results: TIMI flow grade 2 or 3 was present in 42% of the early group compared with 29% in the late group (P = .001). After PCI, 59% of patients in the early group showed ST-resolution >or = 70%, compared with 41% in the late group (P = .003). The composite clinical outcomes death, new myocardial infarction, or repeat target vessel revascularization at 30 days occurred in 7.3% of the early group compared with 9.7% in the late group (odds ratio 0.73, 95% CI 0.41-1.32) and death alone occurred in 2.7% versus 4.7%, respectively (odds ratio 0.56, 95% CI 0.23-1.39)., Conclusions: Early administration of abciximab improves epicardial patency (TIMI flow) before PCI and results in better myocardial tissue perfusion (ST-resolution) after the procedure. The promising effects on clinical outcomes need to be tested in larger studies.