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While aortic valve repair remains the ideal intervention to restore normal valvular function, the optimal aortic valve substitute for patients with a non-repairable aortic valve remains an ongoing subject for debate. In particular, younger patients with a non-repairable valve represent a unique challenge because of their active lifestyle and long life expectancy, which carries a higher cumulative risk of prosthesis-related complications. The Ross procedure, unlike prosthetic or homograft aortic valve replacement (AVR), provides an expected survival equivalent to that of the age and gender-matched general population. Contemporary data has shown that the Ross procedure can be performed safely in centers with expertise, and is associated with improved valvular durability, hemodynamics and quality of life., Competing Interests: Conflicts of Interest: MWAC has received speaker’s honorarium from Medtronic, Edwards Lifesciences, Terumo Aortic, Abbott Vascular and Boston Scientific. The other authors have no conflicts of interest to declare., (2021 Annals of Cardiothoracic Surgery. All rights reserved.)

As a setting where children and adolescents live and learn, linked to the family and embedded within the wider community, schools have an important influence on every student's health. Many health interventions have used schools as a platform, often for standalone programmatic initiatives to reduce health risks, and sometimes for more comprehensive approaches, but the interventions, uptake, and sustainability are generally disappointing. Evidence shows that, to improve health and to reduce inequality, all students must attend school from a young age and for as long as possible, and their educational success therein must be maximised. Thus, beyond educational benefits, schools are also important for health. Coherence between each school's policies, structures and systems, human resources, and practices is required to advance both academic and health outcomes. Beyond simply implementing ready-made programmes into schools, health professionals can position themselves as catalysts for structural change as they have many opportunities to advocate for, and participate in, the intersectoral implementation of reforms and innovations in school systems to promote the health of all students., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Maize feeding value is strongly linked to plant digestibility. Cell wall composition and structure can partly explain cell wall digestibility variations, and we recently showed that tissue lignification and lignin spatial distribution also contribute to cell wall digestibility variations. Although the genetic determinism of digestibility and cell wall composition has been studied for more than 20 years, little is available concerning that of tissue lignification. Moreover, maize yield is negatively impacted by water deficit, and we newly highlighted the impact of water deficit on cell wall digestibility and composition together with tissue lignification. Consequently, the aim of this study was to explore the genetic mechanisms of lignin distribution in link with cell wall composition and digestibility under contrasted water regimes. Maize internodes from a recombinant inbred line (RIL) population grown in field trials with contrasting irrigation scenarios were biochemically and histologically quantified. Results obtained showed that biochemical and histological traits have different response thresholds to water deficit. Histological profiles were therefore only modified under pronounced water deficit, while most of the biochemical traits responded whatever the strength of the water deficit. Three main clusters of quantitative trait locus (QTL) for histological traits were detected. Interestingly, overlap between the biochemical and histological clusters is rare, and one noted especially colocalizations between histological QTL/clusters and QTL for p -coumaric acid content. These findings reinforce the suspected role of tissue p-coumaroylation for both the agronomic properties of plants as well as their digestibility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 El Hage, Virlouvet, Lopez-Marnet, Griveau, Jacquemot, Coursol, Méchin and Reymond.)

The decarboxylative Giese-type reaction offers a versatile methodology for the radical alkylation of electron-deficient alkenes. Photo-mediated variants often require a pre-activation of carboxylic acids and/or employment of costly transition-metal photocatalysts. Herein, we present a metal-free photocatalyzed decarboxylative Giese-type addition to electron-deficient alkenes using pyrimidopteridine N -oxides as organic photoredox-active catalysts. This protocol comprises mono-, di-, and trisubstituted aliphatic, α-amino, and α-oxy acids as well as a variety of electron-deficient alkenes. Moreover, post-synthetic derivatization and applications are presented.

Iatrogenic coronary injury after mitral repair is related to blind annuloplasty suture ligation or kinking of the circumflex artery (CxA) and can present with early ST segment changes, malignant ventricular arrhythmias, and segmental wall motion abnormalities. Corrective treatment is imperative to avoid myocardial infarction and can include removal of the annuloplasty ring or CxA bypass. We present a novel hybrid approach for the rapid diagnosis and management of iatrogenic CxA injury after mitral repair., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To compare the masticatory efficiency of an All-on-4 prosthesis with complete dentures on a Class I ridge with a color-mixing analysis test., Materials and Methods: Ten patients with fixed complete dentures on implants and an additional 10 patients with conventional complete dentures on a Class I ridge (Atwood) chewed a bicolor chewing gum (Hubba Bubba) for different numbers of cycles (5, 10, 15, and 20). The chewed gum was retrieved, scanned, and weighted to quantify masticatory efficiency., Results: This study showed higher values for implant-supported fixed complete dentures than conventional complete dentures. These findings were significant with the color-mixing test in cycles 5 and 10 between both groups. The reduction in weight was not significantly different between the two groups but was noteworthy in intercycle comparison., Conclusion: Implant-supported fixed complete dentures showed superior masticatory efficiency compared with conventional complete dentures constructed over well-formed ridges in the early chewing cycles.

Background: The fate of unrepaired tricuspid regurgitation (TR) after mitral valve repair for degenerative mitral regurgitation remains highly debated. The objective of this study was to examine the progress of unrepaired TR after mitral valve repair for degenerative mitral regurgitation, with a particular focus on comparing patients with moderate preoperative TR with those having none or mild preoperative TR., Methods: Between 2008 and 2018, 183 consecutive patients (mean age, 61 years [SD, 14]) with severe degenerative mitral regurgitation and less-than-severe TR underwent mitral valve repair alone without concomitant TR repair. They were prospectively followed for a median duration of 3.1 years (interquartile range, 1.6-5.5; maximal duration of 9.4 years)., Results: At baseline 146 patients (80%) had none or mild TR; 37 patients (20%) had moderate TR. At follow-up 51 patients (30%) had improved TR compared with 28 patients (17%) who had worse TR. At 3 years postoperatively echocardiographic data were available for 82 of 183 patients: 70 (85%) had none or mild TR, 11 (13%) had moderate TR, and 1 (1.2%) had moderate to severe TR. In an exploratory multivariable analysis with limited statistical power, patients with moderate preoperative TR (vs those with none or mild TR) had an association with higher mortality (hazard ratio, 2.8; 95% confidence interval, 0.81-9.4; P = .11)., Conclusions: After mitral valve repair but without concomitant tricuspid valve repair, a number of patients had progression in their TR. There was a signal of harm in patients having moderate preoperative TR in terms of mortality, but this finding is exploratory and requires investigation., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: We set out to compare in a prospective cohort study the mid-term clinical and echocardiographic outcomes of mini-mitral repair for simple (posterior prolapse) vs complex regurgitation (anterior/bileaflet prolapse)., Methods: A total of 245 consecutive patients underwent mini-mitral repair for severe degenerative mitral regurgitation through a right, endoscopic approach (n = 145 simple, n = 100 complex). The most common repair technique was annuloplasty + artificial chordae (84%, n = 121 for simple vs 88%, n = 88 for complex, P  = 0.3). Patients were prospectively followed for a maximal duration of 9 years. Patients' characteristics were well balanced between groups., Results: The 30-day/in-hospital mortality was similar (0%, n = 0 simple vs 1%, n = 1 complex, P  = 0.2). Both groups had similar rates of early postoperative complications: myocardial infarction (1.4%, n = 2 vs 0%, n = 0, P  = 0.2), neurologic complications (1.4%, n = 2 vs 0%, n = 0, P  = 0.2), reoperation for bleeding (0.7%, n = 1 vs 3%, n = 3, P  = 0.2), intensive care unit length of stay (1 interquartile range, 1-1 days vs 1 interquartile range, 1-1 days, P  = 0.7). Late survival (88% for simple vs 92% for complex, P  = 0.4) was similar between groups. Cumulative incidence of late reoperation at 6 years is 0% for both groups (subdistribution hazard ratio = 1, P  = 1). There was no difference in recurrent mitral regurgitation greater than 2+ at each year after surgery up to 6 years postoperatively., Conclusion: Mitral repair using an endoscopic, minimally invasive approach yields excellent mid-term outcomes regardless of disease complexity., (© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.)

Both surgical and percutaneous mitral repair remain contraindicated in patients with severe degenerative mitral regurgitation (DMR) with severe left ventricular (LV) dysfunction because of inadequate LV reserve and increased LV work with a competent mitral valve. We report a 55-year-old gentleman who presented in cardiogenic shock with missed severe DMR and severe LV dysfunction, in whom we performed a high-risk mitral repair and insertion of a prophylactic CentriMag LV assist device. This innovative approach was found to be successful with significant patient improvement in both LV function and clinical symptoms with a competent mitral valve.

Objectives: Degenerative mitral valve (MV) regurgitation (MR) is associated with left ventricular (LV) dilatation. Surgical treatment of MR has been shown to favorably affect LV remodeling. We prospectively compared the long-term echocardiographic outcomes of LV remodeling following mini-mitral repair for simple versus complex MV disease., Methods: We prospectively followed up 203 consecutive patients who underwent mini-MV repair for severe degenerative MR over a 9-year period. Simple disease (n = 122 patients: posterior leaflet prolapse) was compared to complex disease (n = 81 patients: anterior, bilateral or commissural prolapse). Baseline demographics were similar between simple and complex groups (age: 63 ± 13 years vs 60 ± 15 years; p = .2; sex: 71% male vs 72% male, p = 1; preoperative MR grade ≥ 3+: 100%; n = 122; vs 100%; n = 81; p = 1), respectively., Results: Preoperative left ventricular ejection fraction (LVEF) was significantly lower in the complex group as compared to the simple group (57.2% simple vs 56.0% complex; p = .04). Preoperative LV end-systolic diameter (LVESD: 35 mm simple vs 36 mm complex, p < .05) and LV end-diastolic diameter (LVEDD: 50 mm simple vs 51 mm complex; p < .05), as well as LV mass index (99.5 g/m 2 vs 102.4 g/m 2 ; p = .06) were larger in the complex group. Despite different baseline characteristics of LV function and geometry, both groups had similar remodeling of LV after MV repair., Conclusions: Patients with complex MV disease are referred late for surgical repair, causing LV function and dimensions to never fully recover. This suggests that earlier referral (before LV changes and potentially before symptoms) may be the preferred approach in those with complex disease., (© 2019 Wiley Periodicals, Inc.)

The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins. The fraction of protein passing through the ER represents a large proportion of the total protein in the cell. Protein folding, glycosylation, sorting and transport are essential tasks of the ER and a compromised ER folding network has been recognized to be a key component in the disease pathogenicity of common neurodegenerative, metabolic and malignant diseases. On the other hand, the ER protein folding machinery also holds significant potential for therapeutic interventions. Many causes can lead to ER stress. A disturbed calcium homeostasis, the generation of reactive oxygen species (ROS) and a persistent overload of misfolded proteins within the ER can drive the course of adisease. In this review the role of ER-stress in diseases of the liver and pancreas will be examined using pancreatitis and Wilson´s disease as examples. Potential therapeutic targets in ER-stress pathways will also be discussed., (Copyright © 2019 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Plant cell walls development is an integrated process during which several components are deposited successively. In the cell walls in grass, the accessibility of structural polysaccharides is limited by the cell walls structure and composition mainly as a result of phenolic compounds. Here, we studied the patterns of cell walls establishment in the internode supporting the ear in three distinct maize genotypes. The developmental patterns observed in the internode cell walls in terms of its composition are reported with an emphasis on lignification, p-coumaroylation and feruloylation. We combined biochemical and histological approaches and revealed that internode cell walls development in maize before flowering is characterized by the rapid deposition of secondary cell walls components and robust lignification in both the pith and the rind. After flowering and until silage maturity, the slow deposition of secondary walls components occurs in the cortical region, and the deposited lignins are rich in β-O-4 bonds and are highly p-coumaroylated. We conclude the paper by proposing a revised spatiotemporal model based on that proposed by Terashima et al. (1993) for cell walls development in grass., Competing Interests: The authors have declared that no competing interests exist.

The use of lignocellulosic biomass for animal feed or biorefinery requires the optimization of its degradability. Moreover, biomass crops need to be better adapted to the changing climate and in particular to periods of drought. Although the negative impact of water deficit on biomass yield has often been mentioned, its impact on biomass quality has only been recently reported in a few species. In the present study, we combined the mapping power of a maize recombinant inbred line population with robust near infrared spectroscopy predictive equations to track the response to water deficit of traits associated with biomass quality. The population was cultivated under two contrasted water regimes over 3 consecutive years in the south of France and harvested at silage stage. We showed that cell wall degradability and β-O-4-linked H lignin subunits were increased in response to water deficit, while lignin and p -coumaric acid contents were reduced. A mixed linear model was fitted to map quantitative trait loci (QTLs) for agronomical and cell wall-related traits. These QTLs were categorized as "constitutive" (QTL with an effect whatever the irrigation condition) or "responsive" (QTL involved in the response to water deficit) QTLs. Fifteen clusters of QTLs encompassed more than two third of the 213 constitutive QTLs and 13 clusters encompassed more than 60% of the 149 responsive QTLs. Interestingly, we showed that only half of the responsive QTLs co-localized with constitutive and yield QTLs, suggesting that specific genetic factors support biomass quality response to water deficit. Overall, our results demonstrate that water deficit favors cell wall degradability and that breeding of varieties that reconcile improved drought-tolerance and biomass degradability is possible.

Purpose of Review: The review explores the recent findings surrounding the evaluation and the treatment of patients with heart failure and coronary artery disease. It also shed the light on the gaps in this area., Recent Findings: Surgical revascularization in patients with ischemic cardiomyopathy has the potential to offer symptomatic and survival benefits., Summary: Patients with heart failure and coronary artery disease should be considered candidates for revascularization on the basis of their symptoms, extent of the disease, and comorbidities. Surgical revascularization in these patients provides a symptomatic relief, and a survival benefit.

Background: Crop species are of increasing interest both for cattle feeding and for bioethanol production. The degradability of the plant material largely depends on the lignification of the tissues, but it also depends on histological features such as the cellular morphology or the relative amount of each tissue fraction. There is therefore a need for high-throughput phenotyping systems that quantify the histology of plant sections., Results: We developed custom image processing and an analysis procedure for quantifying the histology of maize stem sections coloured with FASGA staining and digitalised with whole microscopy slide scanners. The procedure results in an automated segmentation of the input images into distinct tissue regions. The size and the fraction area of each tissue region can be quantified, as well as the average coloration within each region. The measured features can discriminate contrasted genotypes and identify changes in histology induced by environmental factors such as water deficit., Conclusions: The simplicity and the availability of the software will facilitate the elucidation of the relationships between the chemical composition of the tissues and changes in plant histology. The tool is expected to be useful for the study of large genetic populations, and to better understand the impact of environmental factors on plant histology.

A 75-year-old male with a previous orthotopic heart transplantation performed 28 years ago was incidentally discovered to have an asymptomatic chronic type A aortic dissection. Catheter-induced dissection during coronary angiography was believed to be the culprit factor. Aortic root replacement and aortic valve reconstruction were successfully performed., (© 2017 Wiley Periodicals, Inc.)

Background: Although the trans-radial approach (TR) has been applied to various subsets of patients in percutaneous coronary intervention, the feasibility, efficacy, acute procedural and long-term outcomes of TR versus trans-femoral approach (TF) for alcohol septal ablation (ASA) have not yet been determined., Objectives: The aim of this study was to compare the short and long-term outcomes of ASA with the TR approach compared to the TF approach., Methods: We retrospectively analyzed 240 patients who underwent an ASA procedure at our institution from November 1999 to November 2015. The TR approach was performed in 172 cases and the TF approach in the remaining 68 cases., Results: The use of TR approach progressively increased from 62% in 1999-2005 to 91% in 2011-2015 (p=0.0001). The TF and TR group had similar age, baseline NYHA class (NYHA 3 or 4) and mean left ventricular outflow tract peak gradient before ASA. Total contrast used (TR: 73.2±47.2ml; TF: 88.7±49.3ml, p=0.11), total radiation Air kerma area product (TR: 43.7±48.0Gycm(-2); TF: 55.9±48.2Gycm(-2); p=0.39) and peak left ventricular outflow tract gradient immediately after ASA (TR: 19.1±19.6mmHg; TF: 20.4±18.0mmHg, p=0.63) were similar in both groups. Procedural success was 91.9% and 91.2% in the TR and TF groups, respectively (p=0.53). At 30days, there was 2 intra-hospital death (1 in TF and 1 in TR), 1 major stroke in the TF group and 1 coronary artery dissection in the TR group. Vascular complications were less frequent in the TR group (0.58% vs. 7.3%; p=0.002). The mean length of follow-up was 4.56±4.34years (IQR 0.69-8.2; median 2.92years; maximum: 15.5years). By Kaplan-Meier estimate, the observed survival in the overall cohort was comparable to the expected survival for a sex and age-matched comparable general French population at 10years (86.9 vs. 83.6%, p=0.88). Survival was similar between the TR and TF group (92.1% vs. 89.7% at 6years, respectively; p=0.71)., Conclusions: Alcohol septal ablation from the radial approach can be performed with similar acute and long-term success, but with lower vascular complications compared to the femoral approach., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

A quick glance at selected topics in this issue aims to highlight selected articles and provide a quick review to the reader.

Interleukin-8 (IL8) is highly expressed by injured arteries in a variety of diseases and is a chemoattractant for neutrophils which express IL8 receptors IL8RA and RB (IL8RA/B) on their membranes. Neutrophils interact with the damaged endothelium and initiate an inflammatory cascade at the site of injury. We have generated a novel translational targeted cell therapy for acute vascular injury using adenoviral vectors to overexpress IL8RA/B and green fluorescent protein (GFP) on the surface of endothelial cells (ECs) derived from human induced pluripotent stem cells (HiPS-IL8RA/B-ECs). We hypothesize that HiPS-IL8RA/B-ECs transfused intravenously into rats with balloon injury of the carotid artery will target to the injured site and compete with neutrophils, thus inhibiting inflammation and neointima formation. Young adult male Sprague-Dawley rats underwent balloon injury of the right carotid artery and received intravenous transfusion of saline vehicle, 1.5 × 10(6) HiPS-ECs, 1.5 × 10(6) HiPS-Null-ECs, or 1.5 × 10(6) HiPS-IL8RA/B-ECs immediately after endoluminal injury. Tissue distribution of HiPS-IL8RA/B-ECs was analyzed by a novel GFP DNA qPCR method. Cytokine and chemokine expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 h postinjury by ELISA and immunohistochemistry, respectively. Neointimal, medial areas, and reendothelialization were measured 14 days postinjury. HiPS-IL8RA/B-ECs homed to injured arteries, inhibited inflammatory mediator expression and inflammatory cell infiltration, accelerated reendothelialization, and attenuated neointima formation after endoluminal injury while control HiPS-ECs and HiPS-Null-ECs did not. HiPS-IL8RA/B-ECs transfused into rats with endoluminal carotid artery injury target to the injured artery and provide a novel strategy to treat vascular injury.

Objective: MCTD is a chronic, immune-mediated disorder defined by the combined presence of serum anti-RNP antibodies and distinct clinical features, including progressive lung fibrosis. The aim of the study was to evaluate the potential impact of anti-SSA (i.e. Ro52 and Ro60) and anti-SSB autoantibodies as markers for disease outcomes in MCTD., Methods: Stored serum samples from 113 patients included in the cross-sectional, nationwide Norwegian MCTD cohort were screened for the presence of anti-Ro52, anti-Ro60 and anti-SSB by a commercial line immunoassay. Correlation analyses were carried out with clinical parameters, including quantitative lung fibrosis scores by high-resolution CT. Lung fibrosis was defined by reticular pattern changes according to the Fleischner Society CT criteria for interstitial lung disease., Results: Anti-Ro52 antibodies were present in 29%, anti-Ro60 in 19% and anti-SSB in 6% of the MCTD sera. High-resolution CT scoring identified lung fibrosis in 38 of 113 (34%) MCTD patients. Anti-Ro52 antibodies were detected in 50% (19 of 38) of the MCTD patients with lung fibrosis and in 19% (14 of 75) without lung fibrosis (P < 0.001). The odds ratio for the presence of anti-Ro52 antibodies in lung fibrosis was 4.4 (95% CI 1.8, 10.3). Anti-Ro52 antibodies were equally frequent in patients with mild to moderate (eight of 17; 44%) and severe fibrosis (11 of 21; 52%). Anti-Ro52 was not associated with any of the other clinical parameters assessed, nor was anti-Ro60 or anti-SSB., Conclusion: Our cross-sectional data suggest that anti-Ro52 antibodies may serve as a potential marker for lung fibrosis in MCTD., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Although Li- and Mn-rich transition metal oxides have been extensively studied as high-capacity cathode materials for Li-ion batteries, the crystal structure of these materials in their pristine state is not yet fully understood. Here we apply complementary electron microscopy and spectroscopy techniques at multi-length scale on well-formed Li1.2(Ni0.13Mn0.54Co0.13)O2 crystals with two different morphologies as well as two commercially available materials with similar compositions, and unambiguously describe the structural make-up of these samples. Systematically observing the entire primary particles along multiple zone axes reveals that they are consistently made up of a single phase, save for rare localized defects and a thin surface layer on certain crystallographic facets. More specifically, we show the bulk of the oxides can be described as an aperiodic crystal consisting of randomly stacked domains that correspond to three variants of monoclinic structure, while the surface is composed of a Co- and/or Ni-rich spinel with antisite defects.

Controlling the growth of eutectic Si and thereby modifying the eutectic Si from flake-like to fibrous is a key factor in improving the properties of Al-Si alloys. To date, it is generally accepted that the impurity-induced twinning (IIT) mechanism and the twin plane re-entrant edge (TPRE) mechanism as well as poisoning of the TPRE mechanism are valid under certain conditions. However, IIT, TPRE or poisoning of the TPRE mechanism cannot be used to interpret all observations. Here, we report an atomic-scale experimental and theoretical investigation on the roles of Eu during the growth of eutectic Si in Al-Si alloys. Both experimental and theoretical investigations reveal three different roles: (i) the adsorption at the intersection of Si facets, inducing IIT mechanism, (ii) the adsorption at the twin plane re-entrant edge, inducing TPRE mechanism or poisoning of the TPRE mechanism, and (iii) the segregation ahead of the growing Si twins, inducing a solute entrainment within eutectic Si. This investigation not only demonstrates a direct experimental support to the well-accepted poisoning of the TPRE and IIT mechanisms, but also provides a full picture about the roles of Eu atoms during the growth of eutectic Si, including the solute entrainment within eutectic Si.

Objectives: This study investigated the feasibility and the safety of using a 6.5-French sheathless guide catheter in patients with small radial arteries., Background: The small size of radial arteries is a limitation of transradial coronary intervention. A new sheathless guiding catheter with a diameter almost 2-Fr smaller than conventional sheaths and a full-length hydrophilic coating has been introduced., Methods: A total of 148 patients from three French hospitals were consecutively enrolled from March 2009 to February 2012. They underwent transradial approach (TRA) for percutaneous coronary interventions (PCI) using the 6.5-F ASAHI sheathless Eaucath guiding catheter system., Results: Among the 148 patients enrolled, 95 were females (64%), and 183 lesions were treated. Procedural success rate was 100%. Thirteen patients (9%) underwent same-procedure multivessel interventions for the right and left coronary artery. Among the group of 46 patients undergoing bifurcation PCI, 35 (76%) bifurcated lesions were treated with a kissing balloon technique, one patient had a saphenous vein bypass graft lesion requiring filter wire placement prior to intervention, nine (6.1%) patients required rotational atherectomy, thrombus-aspiration catheters were used in 19 (12.8%) patients, fractional flow reserve (FFR)-guided PCI in 10 (6.7%) patients, alcohol septal ablation in three (2%) patients. Ten (6.7%) cases of chronic total occlusion were successfully treated in nine (6.1%) patients using the hydrophilic catheter. No radial artery site complications was noted., Conclusion: The use of sheathless guiding catheters is a safe, effective method for PCI via TRA in small radial arteries without catheter-related complications., (© 2015 Wiley Periodicals, Inc.)

A shift in the balance between Th17-cells and regulatory T-cells (Treg) is an important feature of systemic autoimmune diseases (SAID), and may also contribute to their development. Hereby, we assessed the distribution of peripheral Th17 and Treg-cells in patients with undifferentiated connective tissue disease (UCTD), the forerunner of SAIDs and followed these parameters during the development towards definitive SAIDs. Fifty-one UCTD patients were investigated and followed-up for 3 years. Flow cytometry was used to identify and follow three cell-populations: Th17-cells (CD4+IL-17+ T-cells), natural regulatory T-cells (CD4(+)CD25(bright)FoxP3(+); nTregs) and IL-10 producing Type-1 regulatory T-cells (CD4+IL-10+ T-cells; Tr1). Altogether 37.3% of these patients progressed into SAIDs. Th17-cells were increased in UCTD vs. controls, which further increased in those, whom developed SAIDs eventually. The Th17/nTreg ratio gradually increased from controls through UCTD patients, reaching the highest values in SAID-progressed patients. Regarding the Th17/Tr1 ratios, a similar tendency was observed moreover Th17/Tr1 could distinguish between UCTD patients with, or without subsequent SAID progression in a very early UCTD stage. Various immunoserological markers showed association with Th17 and Th17/nTreg at baseline, indicating the consecutive development of a distinct SAID. The derailed Th17/Treg balance may contribute to disease progression therefore could function as a prognostic marker., (Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

We identified that the antigen preprocalcitonin (ppCT) is recognized on a human lung carcinoma by a cytotoxic T lymphocyte clone derived from autologous tumor-infiltrating lymphocytes. The antigenic peptide ppCT(16-25) is encoded by the gene calcitonin-related polypeptide alpha (CALCA), which codes for CT and is overexpressed in several lung carcinomas compared with normal tissues. The ppCT peptide is derived from the C-terminal region of the signal peptide and is processed independently of proteasomes and the transporter associated with antigen processing (TAP)1/TAP2 heterodimeric complexes. Instead, processing occurs within the endoplasmic reticulum by a novel mechanism involving signal pepsidase (SP) and signal peptide peptidase (SPP). Although lung cancer cells bearing the ppCT(16-25) epitope displayed low levels of TAP, restoration of TAP expression by interferon (IFN)-γ treatment or by TAP1/TAP2 gene transfer inhibited ppCT antigen presentation. Thus, the ppCT(16-25) human tumor epitope requires low TAP expression for efficient presentation. These results indicate that emerging SP-generated peptides represent alternative T cell targets that permit cytotoxic T lymphocytes to destroy TAP-impaired tumors, a process that helps to overcome tumor escape from CD8(+) T cell immunity. Additionally, our data suggest that ppCT is a promising candidate for cancer immunotherapy., (© 2013 The New York Academy of Sciences.)

School programs are defined to promote the health of the pupils and to develop their competencies so that they can adopt behaviors favorable to their health. With the European project FP6 Biohead-Citizen (2004-2007), we analyzed the conceptions of teachers as regards health education, in France, Lebanon, Morocco and Tunisia, in reference to the biomedical model and the social health model. These four countries were selected because their school curricula represented different models of health education. Lebanon and Tunisia addressed health education with the biomedical model. In Morocco, the curriculum was also primarily based on the biomedical model and enclosed a few instructions issued from the social health model. In France, the health education curriculum declared an approach based on the health promotion model. Our study was based on multivariate statistical analyses of questionnaires filled out by 2537 in-service and pre-service teachers. Our analysis showed that the conceptions of the teachers concerning health education were not structured and related to a specific model. We also found that the dominating factors of influence on the choices expressed with regards to health education were, among different sociocultural variables, the religion, the home country, and, to a lesser extent, the level of training. Thus, the conceptions of the teachers were not integrated into comprehensive approaches but related to individual characteristics. Consequently health education implementation would require thorough training for pre-service and in-service teachers and should also explicitly take into account their conceptions and values.

Decreased antigenicity of cancer cells is a major problem in tumor immunology. This is often acquired by an expression defect in the TAP. However, it has been reported that certain murine Ags appear on the target cell surface upon impairment of TAP expression. In this study, we identified a human CTL epitope belonging to this Ag category. This epitope is derived from preprocalcitonin (ppCT) signal peptide and is generated within the endoplasmic reticulum by signal peptidase and signal peptide peptidase. Lung cancer cells bearing this antigenic peptide displayed low levels of TAP, but restoration of their expression by IFN-γ treatment or TAP1 and TAP2 gene transfer abrogated ppCT Ag presentation. In contrast, TAP upregulation in the same tumor cells increased their recognition by proteasome/TAP-dependent peptide-specific CTLs. Thus, to our knowledge, ppCT(16-25) is the first human tumor epitope whose surface expression requires loss or downregulation of TAP. Lung tumors frequently display low levels of TAP molecules and might thus be ignored by the immune system. Our results suggest that emerging signal peptidase-generated peptides represent alternative T cell targets, which permit CTLs to destroy TAP-impaired tumors and thus overcome tumor escape from CD8(+) T cell immunity.

This study utilized a transgenic mouse model that expresses an inducible dominant-negative mutation of the transforming growth factor (TGF)-beta type II receptor (DnTGFbetaRII) to define the structural and functional responses of the left ventricle (LV) to pressure-overload stress in the absence of an intact TGF-beta signaling cascade. DnTGFbetaRII and nontransgenic (NTG) control mice (male, 8-10 wk) were randomized to receive Zn(2+) (25 mM ZnSO(4) in drinking H(2)O to induce DnTGFbetaRII gene expression) or control tap H(2)O and then further randomized to undergo transverse aortic constriction (TAC) or sham surgery. At 7 days post-TAC, interstitial nonmyocyte proliferation (Ki67 staining) was greatly reduced in LV of DnTGFbetaRII+Zn(2+) mice compared with the other TAC groups. At 28 and 120 days post-TAC, collagen deposition (picrosirius-red staining) in LV was attenuated in DnTGFbetaRII+Zn(2+) mice compared with the other TAC groups. LV end systolic diameter and end systolic and end diastolic volumes were markedly increased, while ejection fraction and fractional shortening were significantly decreased in TAC-DnTGFbetaRII+Zn(2+) mice compared with the other groups at 120 days post-TAC. These data indicate that interruption of TGF-beta signaling attenuates pressure-overload-induced interstitial nonmyocyte proliferation and collagen deposition and promotes LV dilation and dysfunction in the pressure-overloaded heart, thus creating a novel model of dilated cardiomyopathy.

Regadenoson is a selective A(2A) receptor agonist that was recently approved by the Food and Drug Administration for vasodilator stress myocardial perfusion imaging. Because the drug is cleared by renal excretion, its safety in patients with end-stage renal disease (ESRD) needs to be determined. We studied 277 consecutive patients with ESRD who had undergone regadenoson stress gated single photon emission computed tomography myocardial perfusion imaging and compared their side effect profile and safety outcome to those of 134 patients with normal kidney function. The ESRD group included 164 men (59%) and the control group included 73 men (54%; p = NS). The patients with ESRD were younger than the controls (52 +/- 11 years vs 61 +/- 12 years; p <0.001). The myocardial perfusion imaging findings were abnormal in 53 patients (19%) with ESRD and in 24 patients in the control group (18%; p = NS). The left ventricular ejection fraction was 57 +/- 12% in the ESRD group and 64 +/- 12% in the control group (p <0.001). The changes in heart rate and systolic blood pressure (from baseline to peak stress) were 20 +/- 12 beats/min versus 22 +/- 13 beats/min and -11 +/- 24 mm Hg versus -12 +/- 23 mm Hg in the ESRD and control groups, respectively (p = NS for both). Very few patients in either group reported symptoms during the stress test. No medication-related hospitalizations, serious events, or death occurred in either group within 30 days of the study. In conclusion, this is the first study to document the safety of regadenoson in a large number of patients with ESRD. The drug was well tolerated, and the hemodynamic and side effect profiles were similar to those of patients with normal renal function.

Hypoxia is an essential component of tumor microenvironment. In this study, we investigated the influence of hypoxia (1% PO(2)) on CTL-mediated tumor cell lysis. We demonstrate that exposure of target tumor cells to hypoxia has an inhibitory effect on the CTL clone (Heu171)-induced autologous target cell lysis. Such inhibition correlates with hypoxia-inducible factor-1alpha (HIF-1alpha) induction but is not associated with an alteration of CTL reactivity as revealed by granzyme B polarization or morphological change. Western blot analysis indicates that although hypoxia had no effect on p53 accumulation, it induced the phosphorylation of STAT3 in tumor cells by a mechanism at least in part involving vascular endothelial growth factor secretion. We additionally show that a simultaneous nuclear translocation of HIF-1alpha and phospho-STAT3 was observed. Interestingly, gene silencing of STAT3 by small interfering RNA resulted in HIF-1alpha inhibition and a significant restoration of target cell susceptibility to CTL-induced killing under hypoxic conditions by a mechanism involving at least in part down-regulation of AKT phosphorylation. Moreover, knockdown of HIF-1alpha resulted in the restoration of target cell lysis under hypoxic conditions. This was further supported by DNA microarray analysis where STAT3 inhibition resulted in a partly reversal of the hypoxia-induced gene expression profile. The present study demonstrates that the concomitant hypoxic induction of phospho-STAT3 and HIF-1alpha are functionally linked to the alteration of non-small cell lung carcinoma target susceptibility to CTL-mediated killing. Considering the eminent functions of STAT3 and HIF-1alpha in the tumor microenvironment, their targeting may represent novel strategies for immunotherapeutic intervention.

Estrogen has antiinflammatory and vasoprotective effects when administered to young women or experimental animals that appear to be converted to proinflammatory and vasotoxic effects in older subjects, particularly those that have been hormone free for long periods. Clinical studies have raised many important questions about the vascular effects of estrogen that cannot easily be answered in human subjects. Here we review cellular/molecular mechanisms by which estrogen modulates injury-induced inflammation, growth factor expression, and oxidative stress in arteries and isolated vascular smooth muscle cells, with emphasis on the role of estrogen receptors and the nuclear factor-kappaB (NFkappaB) signaling pathway, as well as evidence that these protective mechanisms are lost in aging subjects.

Objectives: We hypothesized that the prophylactic administration of sodium nitroprusside (NTP) during saphenous vein graft (SVG) PCI would ameliorate the detrimental effects of distal embolization and reduce the frequency and magnitude of post-procedural myonecrosis., Methods: Sixty-four consecutive patients with normal preprocedural cardiac enzymes underwent SVG PCI without embolic protection devices and received prophylactic intragraft NTP before initial device activation. For each case, 2 control patients were selected in reverse chronologic order and were matched for stent use, thromboatherectomy device use, clinical presentation, presence of thrombus and pre-PCI thrombolysis in myocardial infarction (TIMI) flow., Results: Mean patient age was 66 +/- 10 years, 78% of whom were males. Stent and thromboatherectomy use was 95.3% and 3.1%, respectively in both groups (p = ns). Prior to intervention, TIMI < 3 flow was present in 26.6% of cases and in 24.2% of control patients (p = ns). Thrombus was present in 20.3% of cases and in 19.5% of controls (p = ns). Post-PCI creatinine kinase (CK)-MB elevation > 3 x the upper limit of normal (ULN) occurred in 6.3% of cases vs. 16.4% of controls (p = 0.049) and > 5 x ULN in 1.6% of cases vs.10.9% of controls (p = 0.022). In a multivariate regression model that included stent use, in-stent restenosis, thrombus presence, preprocedural TIMI 3 flow, MI as procedural indication, NTP and glycoprotein IIb/IIIa use, NTP was the only independent and significant predictor of reduced post-procedural CK-MB elevation > 5 x ULN., Conclusion: Prophylactic administration of intragraft NTP during SVG PCIs results in a lower frequency and magnitude of post-procedural cardiac enzyme elevation.

Nowadays, sex education contributes to public health not only with regard to the prevention of HIV/AIDS, other sexually transmitted infections and sex abuse, but it is also concerned with addressing aspects such as interpersonal relationships and psychosocial implications. The school setting has emerged as a unique environment for access to information and scientific knowledge that contribute to better understanding of the various dimensions of sexuality. Teachers' and future teachers' conceptions about sex education are analysed in this paper. Data were obtained from a questionnaire designed by the European Biohead-Citizen research project. Responses were received from 2 537 teachers from four Mediterranean countries (Tunisia, Lebanon, Morocco and France) who completed the questionnaire. The methodology is based upon analyses of core components that support the discovery of teachers' conceptions. Following that exercise, standardised factorial scores were calculated. Results for in-service and pre-service teachers show high correlations between their conceptions and national culture, religious beliefs, and level of academic training. Detailed results are presented and discussed.

Background: Coronary angiography is limited by its inability to assess the hemodynamic significance of a coronary artery stenosis. The assessment of the physiological significance of saphenous vein graft (SVG) lesions with a pressure wire to determine the fractional flow reserve (FFR) is lacking., Methods: FFR was determined in 10 SVG lesions of 10 males who had stress myocardial perfusion imaging (MPI) prior to referral for percutaneous coronary intervention for clinical indications., Results: All SVGs had a diameter stenosis (DS) > 50% and 30% had a DS > or = 70%. A significant FFR was present in 30% of patients. Ischemia along the territory of the SVG was present in 20% of patients. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FFR < 0.75 for the detection of ischemia on stress MPI were 50, 75, 33, 85, and 70%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FFR < 0.75 for detecting > or = 70% DS on angiography were 33, 71, 33, 71, and 60%, respectively. There was no significant correlation between FFR and % DS (R(2) = 0.1, P = 0.35)., Conclusion: The use of FFR to assess the physiological significance of SVG lesions is feasible and provides an acceptable specificity and negative predictive value compared to stress MPI., (2008 Wiley-Liss, Inc.)

We identified an antigen recognized on a human non-small-cell lung carcinoma by a cytotoxic T lymphocyte clone derived from autologous tumor-infiltrating lymphocytes. The antigenic peptide is presented by HLA-A2 and is encoded by the CALCA gene, which codes for calcitonin and for the alpha-calcitonin gene-related peptide. The peptide is derived from the carboxy-terminal region of the preprocalcitonin signal peptide and is processed independently of proteasomes and the transporter associated with antigen processing. Processing occurs within the endoplasmic reticulum of all tumoral and normal cells tested, including dendritic cells, and it involves signal peptidase and the aspartic protease, signal peptide peptidase. The CALCA gene is overexpressed in medullary thyroid carcinomas and in several lung carcinomas compared with normal tissues, leading to recognition by the T cell clone. This new epitope is, therefore, a promising candidate for cancer immunotherapy.

Objectives: To test the feasibility, safety, and in-hospital outcomes of utilizing the FilterWire EZ to extract clot prior to percutaneous coronary intervention (PCI) in patients presenting with acute myocardial infarction (MI)., Background: PCI in patients with acute MI is associated with a higher incidence of distal embolization, no-reflow, or slow flow partly due to the presence of clot burden., Methods: The authors describe the feasibility, safety, and outcomes of using a FilterWire EZ distal protection device as a clot extraction device in patients who presented with acute MI and documented clot on coronary angiography., Results: Fifteen consecutive male patients with a mean age of 54 +/- 8 years presented with acute MI (60% ST elevation MI). MI involved left anterior descending artery (n = 4), circumflex artery (n = 3), and right coronary artery (n = 8). Clot extraction followed by PCI reduced the percent diameter stenosis from 94 +/- 12 to 65 +/- 11 (P < 0.001) and restored TIMI 3 flow in all patients without distal embolization. The angiographic, procedural, and clinical success rates were 100%. The mean left ventricular ejection fraction (LVEF) was 52 +/- 8% (range 30-62%) with only three patients (15%) who had an LVEF <50% and five patients (33%) without apparent wall motion abnormalities on echocardiography., Conclusions: Clot extraction before PCI during acute MI in native coronaries is feasible, safe, and effective in restoring TIMI 3 flow without distal embolization. Whether this approach results in better outcomes and improved LV function compared with standard therapy alone requires further investigation., (2008 Wiley-Liss, Inc.)

Cellular transformation is initiated by genetic and epigenetic mutations that activate oncogenes and inactivate tumor suppressor pathways. Cancers thus arise when somatic cells escape intrinsic and extrinsic tumor suppressor mechanisms in the context of their cellular microenvironment. Given the well established importance of the immune system at controlling and shaping developing tumors, pointing the different strategies of tumor escape may provide important insights for the development of effective cancer therapies. In respect, a better understanding of the molecular interactions between tumors and the host immune system may thus allow the development of novel integrated approaches based on the simultaneous control of tumor escape pathways and the activation of anti-cancer immune responses. We hereafter review the currently known escape strategies developed by tumors and discuss the very limited success of trials using active immunization with vaccines or adoptive immunotherapy conducted to date, with a focus on potential therapeutic avenues. We believe that the induction of clinically relevant anti-cancer immunity and tumor rejection require an orchestrated set of events that are thus far impossible to activate by a single approach. Therefore, combining immunotherapy with conventional therapies may help in breaking down the existing barriers.

We previously characterized several tumor-specific T cell clones from PBL and tumor-infiltrating lymphocytes of a lung cancer patient with identical TCR rearrangements and similar lytic potential, but with different antitumor response. A role of the TCR inhibitory molecule CD5 to impair reactivity of peripheral T cells against the tumor was found to be involved in this process. In this report, we demonstrate that CD5 also controls the susceptibility of specific T cells to activation-induced cell death (AICD) triggered by the tumor. Using a panel of tumor-infiltrating lymphocytes and PBL-derived clones expressing different levels of CD5, our results indicate that T lymphocyte AICD in response to the cognate tumor is inversely proportional to the surface expression level of CD5. They also suggest a direct involvement of CD5 in this process, as revealed by an increase in tumor-mediated T lymphocyte AICD following neutralization of the molecule with specific mAb. Mechanistically, our data indicate that down-regulation of FasL expression and subsequent inhibition of caspase-8 activation are involved in CD5-induced T cell survival. These results provide evidence for a role of CD5 in the fate of peripheral tumor-specific T cells and further suggest its contribution to regulate the extension of CTL response against tumor.

The notion that the immune system regulates cancer development is now well established. An overwhelming amount of data from animal models, together with compelling data from human patients, indicate that the immune system is instrumental in scanning and irradicating tumors. Analysis of individuals with congenital or acquired immunodeficiencies or patients undergoing immunosuppressive therapy has documented a highly elevated incidence of virally induced malignancies and cancers compared with immunocompetent individuals [1-3]. During the last decade, thanks to the breakthoughts in understanding the molecular mechanisms responsible for immune activation, the tumor antigen identification, the dendritic cell biology, the immunogenecity of tumors, the immune escape mechanisms, the host-tumor relationship, we are facing a new area of tumor immunotherapy. The basic advances were translated in therapeutical applications and have changed the view of immunotherapy from "a dream scenario" to a clinical fourth modality to cancer treatments. Multiple cancer trials using active immunization with vaccines or adoptive immunotherapy have been conducted with only very limited success. There are still a number of issues that still need to be resolved including a better understanding of immune escape mechanisms. Cancer vaccines continue to be evaluated and may lead to the emergence of clinically useful new treatments. A comprehensive approach to define the intricate molecular program initiated by tumor cells to resist to escape and the immune system of the host may help in breaking down the barriers to a more adapted cancer immunotherapy.

We have identified an antigen recognized on a large cell carcinoma of the lung by tumor-specific cytotoxic T lymphocytes (CTL). The antigenic peptide is encoded by a mutated alpha-actinin-4 gene and presented by human leukocyte antigen (HLA)-A2. Using HLA-A2-peptide tetramers, we have derived from patient peripheral blood lymphocytes (PBL) and autologous tumor infiltrating lymphocytes (TIL) several mutated alpha-actinin-4-specific T cell clones. These clones displayed similar tetramer staining but distinct T cell receptor (TCR) usage and antitumor reactivity. Indeed, TIL clones lysed more efficiently the autologous tumor cells and released higher cytokine levels than PBL clones. Importantly, treatment of cancer cells with interferon-gamma enhanced their susceptibility to PBL clone-mediated lysis correlated with increase in HLA-class I expression. The present findings provide evidence that an immune T cell response took place in a lung cancer patient with favorable clinical evolution and suggest that CTL, recognizing a truly tumor-specific antigen, may contribute to controlling the tumor.

We have isolated from tumor-infiltrating lymphocytes (TIL) and PBL of a lung carcinoma patient several tumor-specific T cell clones displaying similar peptide-MHC tetramer staining and expressing a unique TCR. Although these clones elicited identical functional avidity and similar cytolytic potential, only T cell clones derived from TIL efficiently lysed autologous tumor cells. Interestingly, all of these clones expressed the same T cell surface markers except for the TCR inhibitory molecule CD5, which was expressed at much lower levels in TIL than in PBL. Video-imaging recordings demonstrated that, although both T cell clones could form stable conjugates with tumor cells, the Ca(2+) response occurred in TIL clones only. Significantly, analysis of a panel of circulating clones indicated that antitumor cytolytic activity was inversely proportional to CD5 expression levels. Importantly, CD5 levels in TIL appeared to parallel the signaling intensity of the TCR/peptide-MHC interaction. Thus, in situ regulation of CD5 expression may be a strategy used by CTL to adapt their sensitivity to intratumoral peptide-MHC levels.

We hypothesized that a single copy of the proatrial natriuretic peptide gene (Nppa+/-) would not be adequate to protect heterozygous mice against exaggerated cardiac hypertrophy and remodeling after pressure-overload stress. Nppa+/+, Nppa+/-, and Nppa-/- mice were subjected to sham surgery or transverse aortic constriction and fed a basal salt diet. Heart weight varied inversely with Nppa gene load by 1 week after either surgery. Fractional shortening did not differ among genotypes at baseline and fell in Nppa-/- mice only after transverse aortic constriction. There was a graded response in collagen deposition related to atrial natriuretic peptide (ANP) expression after either surgery. A robust interstitial and perivascular fibrosis was noted in Nppa-/- and Nppa+/- but not in Nppa+/+ mice after transverse aortic constriction. Our findings are consistent with a growing body of evidence that ANP is an important modulator of cardiac hypertrophy and remodeling in response to hemodynamic stress. The observation that partial ANP deficiency results in exaggerated hypertrophy and remodeling after pressure overload suggests that genetic or environmental variation in ANP levels may play a role in the development of cardiac hypertrophy, remodeling, and failure in humans.

T lymphocytes infiltrating a human lung carcinoma stimulated in vitro with autologous tumor cell line showed a TCRVbeta13.6(+) T-cell expansion. This subset was isolated using TCRVbeta-specific antibody and several T-cell clones were generated. All these clones expressed a unique Vbeta13.6-Jbeta2.7 TCR with the same junctional region strongly suggesting that they derived from the same cell. They were CD8(+)/CD28(-) and expressed the MHC class I binding killer cell Ig-like receptor (KIR)3DL2/p140, but not KIR3DL1/p70, KIR2DL1/p58.1 and KIR2DL2/3/p58.2. Sequence analysis indicated that KIR3DL2/p140 cDNA was identical to the previously reported 3DL2*002 allele except for two nucleic acid substitutions. Functional studies showed that KIR3DL2/p140(+) CTL secrete a significant level of IFNgamma and mediate an HLA-A2-restricted cytotoxicity against the autologous and some allogeneic tumor cells but not towards the autologous EBV-B cells. Strikingly, both the lytic and the cytokine secretion activities induced upon specific cell interactions were unaffected by anti-KIR3DL2/p140 antibody. In addition, crosslinking KIR3DL2/p140 molecules on CTL did not result into the modification of cytotoxicity and cytokine production triggered by anti-CD3 antibody. These results strongly suggest that, as opposed to distinct KIR expressed by CTL, the in vitro KIR3DL2/p140 engagement does not result into inhibitory (nor activatory) effects on tumor-specific CTL.