Clinical outcome following combination of cutting balloon angioplasty and coronary β-radiation for in-stent restenosis : a report from the RENO registry

RESUME : Actuellement la brachythérapie endovasculaire reste le seul traitement efficace pour la resténose intrastent. Malgré ceci, la limitation majeure de cette technique est la resténose aux extrémités du stent (effet de bord) due à une couverture incomplète par la source radioactive (geographical miss). Le ballon coupant et qui ne glisse pas pourrait limiter le barotraumatisme engendré par la dilatation et qui avec la diminution de la radiation aux extrémités de la source radioactive, est à la base du geographical miss. Cette étude prospective a pour but d'examiner l'efficacité du traitement de la resténose intrastent par la combinaison d'angioplastie avec cutting ballon et β - irradiation. Le registre « Radiation in Europe NOvoste » (RENO) inclut tous les patients traités par β - irradiation coronaire avec le système Beta-CathTM System (Novoste Corporation, Brussels, Belgium) n'ayant pas été inclus dans une autre étude randomisée. Un premier sous-groupe de ces patients (groupe 1, n=166), représente les patients traités par cutting ballon et β - irradiation intra coronaire. Ce groupe a été défini d'une manière prospective et les résultats cliniques à 6 mois ont été comparés par rapport aux autres patients qui ont reçu un traitement par dilatation coronaire conventionnelle et β - irradiation (groupe 2, n=712). A 6 mois de suivi, on a retrouvé une différence significative entre les 2 groupes par rapport à la nécessité d'une nouvelle revascularisation du vaisseau préalablement traité (10,2% de récidive dans le groupe 1 contre 16,6 % dans le groupe 2 , p=0,04). Le nombre d'événements cardiaques majeurs (mortalité, infarctus du myocarde et revascularisation) a également été diminué de manière significative (10,8% contre 19,2% ; />=0,01). Cette observation a été confirmée par une analyse multivariée qui indique un risque diminué pour les événements cardiaques majeurs à 6 mois, (rapport de côtes : 0,49 ; intervalle de confiance 0,27-0,88 ; p=0,02). Comparé à l'angioplastie coronarienne avec ballon conventionnel, l'utilisation de cutting ballon avant la β - irradiation dans le traitement de la resténose intrastent démontre une meilleure évolution clinique à 6 mois. ABSTRACT: At present, vascular brachytherapy is the only efficient therapy for in-stent restenosis. Nevertheless edge restenosis often relat¬ed to geographical miss has been identified as a major limitation of the technique. The non-slippery cutting balloon has the potential to limit vascular barotraumas which, together with low-dose irradiation at both ends of the radioactive source, are the prerequisite for geographical miss. This prospective study aimed to examine the efficacy of combining cut¬ting balloon angioplasty and brachytherapy for in-stent restenosis. The Radiation in Europe NOvoste (RENO) registry prospectively tracked all patients who had been treated by coronary β-radiation with the Beta-CathTM System (Novoste Corporation. Brussels, Belgium) but were not included in a randomized radiation trial, A subgroup of patients with in-stent restenosis treated by cutting balloon angioplasty and coronary β-radiation (group 1, n = 166) was prospectively defined, and clinical outcomes of patients at 6 months were compared with those of patients treated by conventional angioplasty and coronary β -radiation (group 2, n = 712). At 6-month follow-up, there was a significant difference between groups 1 and 2 in- target vessel revascularization (10.2% versus 16.6% respectively; p = 0.04) and in the incidence of major adverse clinical events (MACE) including, death, myocardial infarction, and revascularization (10.8% versus 19.2%; p= 0.01). This observation was confirmed by a multivariate analysis indicating a. lower risk for MACE at 6 months (odds ratio: 0.49; confidence intervals: 0.27-0.88; p = 0.02). Compared to conventional angioplasty, cutting balloon angio¬plasty prior to coronary beta-radiation with the Beta-CathTM System seems to improve the 6-month clinical outcome in patients with in-stent restenosis.

Cutting edge: thymic NK cells develop independently from T cell precursors.

Although NK cells in the mouse are thought to develop in the bone marrow, a small population of NK cells in the thymus has been shown to derive from a GATA3-dependent pathway. Characteristically, thymic NK cells express CD127 and few Ly49 molecules and lack CD11b. Because these NK cells develop in the thymus, the question of their relationship to the T cell lineage has been raised. Using several different mouse models, we find that unlike T cells, thymic NK cells are not the progeny of Rorc-expressing progenitors and do not express Rag2 or rearrange the TCRγ locus. We further demonstrate that thymic NK cells develop independently of the Notch signaling pathway, supporting the idea that thymic NK cells represent bona fide NK cells that can develop independently of all T cell precursors.

The genome of the leaf-cutting ant Acromyrmex echinatior suggests key adaptations to advanced social life and fungus farming.

We present a high-quality (>100× depth) Illumina genome sequence of the leaf-cutting ant Acromyrmex echinatior, a model species for symbiosis and reproductive conflict studies. We compare this genome with three previously sequenced genomes of ants from different subfamilies and focus our analyses on aspects of the genome likely to be associated with known evolutionary changes. The first is the specialized fungal diet of A. echinatior, where we find gene loss in the ant's arginine synthesis pathway, loss of detoxification genes, and expansion of a group of peptidase proteins. One of these is a unique ant-derived contribution to the fecal fluid, which otherwise consists of "garden manuring" fungal enzymes that are unaffected by ant digestion. The second is multiple mating of queens and ejaculate competition, which may be associated with a greatly expanded nardilysin-like peptidase gene family. The third is sex determination, where we could identify only a single homolog of the feminizer gene. As other ants and the honeybee have duplications of this gene, we hypothesize that this may partly explain the frequent production of diploid male larvae in A. echinatior. The fourth is the evolution of eusociality, where we find a highly conserved ant-specific profile of neuropeptide genes that may be related to caste determination. These first analyses of the A. echinatior genome indicate that considerable genetic changes are likely to have accompanied the transition from hunter-gathering to agricultural food production 50 million years ago, and the transition from single to multiple queen mating 10 million years ago.

Cutting edge: cyclic polypeptide and aminoglycoside antibiotics trigger IL-1β secretion by activating the NLRP3 inflammasome.

Clinical use of antibiotics is based on their capacity to inhibit bacterial growth via bacteriostatic or bacteriocidal effects. In this article, we show that the aminoglycoside antibiotic neomycin, the cyclic lipopeptide antibiotic polymyxin B, and the cyclic peptide antibiotics gramicidin and tyrothricin can induce IL-1β secretion in bone marrow dendritic cells and macrophages. LPS priming was required to trigger the transcription and translation of pro-IL-1β but was independent of TNFR or IL-1R signaling. All four antibiotics required the NLRP3 inflammasome, the adaptor ASC, and caspase-1 activation to secrete IL-1β, a process that depended on potassium efflux but was independent of P2X7 receptor. All four antibiotics induced neutrophil influx into the peritoneal cavity of mice, which required NLRP3 only in the case of polymyxin B. Together, certain antibiotics have the potential to directly activate innate immunity of the host.

Glomerular filtration rate: measure creatinine and height rather than cystatin C!

AIM: Inulin clearance (Cin) is the gold standard for assessing glomerular filtration rate (GFR). Other methods are based on the plasma creatinine concentration (Pcreat), creatinine clearance (Ccreat), the Haycock-Schwartz formula and the plasma concentration of cystatin C (PcysC), a 13 kDa basic protein produced at a constant rate by all nucleated cells. The present prospective study was thus designed to evaluate the reliability of PcysC as a marker of GFR in comparison with that of Pcreat, Ccreat and the Haycock-Schwartz formula, using Cin as the gold standard. METHODS: Ninety-nine children (51 m/48 f), with a median age of 8.3 y (1.0-17.9) were studied. Using a cut-off for Cin of 100 ml/min per 1.73 m2, 54 children (54.5%) had impaired GFR. Those with normal GFR were comparable for age, height, weight and body mass index. RESULTS: Logistic regression, ROC analysis and linear regression all showed that Ccreat was the best parameter to discriminate between impaired and normal GFR, followed by the Haycock-Schwartz formula, PcysC, and finally Pcreat, each one being significantly more predictive than the next. CONCLUSION: GFR is better assessed by the Haycock-Schwartz formula than by PcysC or Pcreat alone. It is therefore concluded that when urine collection is not possible, simply measuring the child's Pcreat and height is the best, easiest and cheapest way to assess GFR.

No use for waist-for-height ratio in addition to body mass index to identify children with elevated blood pressure.

Abstract Background. In children, waist-for-height ratio (WHtR) has been proposed to identify subjects at higher risk of cardiovascular diseases. The utility of WHtR to identify children with elevated blood pressure (BP) is unclear. Design. Cross-sectional population-based study of schoolchildren. Methods. Weight, height, waist circumference and BP were measured in all sixth-grade schoolchildren of the canton de Vaud (Switzerland) in 2005/06. WHtR was computed as waist [cm]/height [cm]. Elevated BP was defined according to sex-, age- and height-specific US reference data. The area under the receiver operating characteristic curve (AUC) statistic was computed to compare the ability of body mass index (BMI) z-score and WHtR, alone or in combination, to identify children with elevated BP. Results. 5207 children participated (76% response) [2621 boys, 2586 girls; mean (± SD) age, 12.3 ± 0.5 years; range: 10.1-14.9]. The prevalence of elevated BP was 11%. Mean WHtR was 0.44 ± 0.05 (range: 0.29- 0.77) and 11% had high WHtR (> 0.5). BMI z-score and WHtR were strongly correlated (Spearman correlation coefficient r = 0.76). Both indices were positively associated with elevated BP. AUCs for elevated BP was relatively low for BMI z-score (0.62) or for WHtR (0.62), and was not substantially improved when both indices were considered together (0.63). Conclusions. The ability of BMI z-score or WHtR to identify children aged 10-14 with elevated BP was weak. Adding WHtR did not confer additional discriminative power to BMI alone. These findings do not support the measurement of WHtR in addition to BMI to identify children with elevated BP.

Trends in the association between height and socioeconomic indicators in France, 1970-2003

Average physical stature has increased dramatically during the 20th century in many populations across the world with few exceptions. It remains unclear if social inequalities in height persist despite improvements in living standards in the welfare economies of Western Europe. We examined trends in the association between height and socioeconomic indicators in adults over three decades in France. The data were drawn from the French Decennial Health Surveys: a multistage, stratified, random survey of households, representative of the population, conducted in 1970, 1980, 1991, and 2003. We categorised age into 10-year bands, 25-34, 35-44, 45-54 and 55-64 years. Education and income were the two socioeconomic measures used. The slope index of inequality (SII) was used as a summary index of absolute social inequalities in height. The results show that average height increased over this period; men and women aged 25-34 years were 171.9 and 161.2 cm tall in 1970 and 177.0 and 164.0 cm in 2003, respectively. However, education-related inequalities in height remained unchanged over this period and in men were 4.48 cm (1970), 4.71 cm (1980), 5.58 cm (1991) and 4.69 cm (2003), the corresponding figures in women were 2.41, 2.37, 3.14 and 2.96 cm. Income-related inequalities in height were smaller and much attenuated after adjustment for education. These results suggest that in France, social inequalities in adult height in absolute terms have remained unchanged across the three decades under examination.

Cutting edge: thymic crosstalk regulates delta-like 4 expression on cortical epithelial cells.

Interactions between Notch1 receptors on lymphoid progenitors and Delta-like 4 (DL4) ligands on cortical thymic epithelial cells (cTEC) are essential for T cell lineage commitment, expansion, and maturation in the thymus. Using a novel mAb against DL4, we show that DL4 levels on cTEC are very high in the fetal and neonatal thymus when thymocyte expansion is maximal but decrease dramatically in the adult when steady-state homeostasis is attained. Analysis of mutant mouse strains where thymocyte development is blocked at different stages indicates that lymphostromal interactions ("thymus crosstalk") are required for DL4 down-regulation on cTEC. Reconstitution of thymocyte development in these mutant mice further suggests that maturation of thymocytes to the CD4(+)CD8(+) stage and concomitant expansion are needed to promote DL4 down-regulation on cTEC. Collectively, our data support a model where thymic crosstalk quantitatively regulates the rate of Notch1-dependent thymopoiesis by controlling DL4 expression levels on cTEC.

Cutting edge: a novel viral TNF receptor superfamily member in virulent strains of human cytomegalovirus.

The UL144 open reading frame found in clinical isolates of human CMV (HCMV) encodes a structural homologue of the herpesvirus entry mediator, a member of the TNFR superfamily. UL144 is a type I transmembrane glycoprotein that is expressed early after infection of fibroblasts; however, it is retained intracellularly. A YXXZ motif in the highly conserved cytoplasmic tail contributes to UL144 subcellular distribution. The finding that no known ligand of the TNF family binds UL144 suggests that its mechanism of action is distinct from other known viral immune evasion genes. Specific Abs to UL144 can be detected in the serum of a subset of HCMV seropositive individuals infected with HIV. This work establishes a novel molecular link between the TNF superfamily and herpesvirus that may contribute to the ability of HCMV to escape immune clearance.

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

Hundreds of variants clustered in genomic loci and biological pathways affect human height.

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Termination of major ductile strike-slip shear and differential cooling along the Insubric line (Central Alps): U-Pb, Rb-Sr and 40Ar/39Ar ages of cross-cutting pegmatites

To constrain the age of strike-slip shear, related granitic magmatism, and cooling along the Insubric line, 29 size fractions of monazite and xenotime were dated by the U-Pb method, and a series of 25 Rb-Sr and Ar-40/Ar-39 ages were measured on different size fractions of muscovite and biotite. The three pegmatitic intrusions analyzed truncate high-grade metamorphic mylonite gneisses of the Simplon shear zone, a major Alpine structure produced in association with dextral strike-slip movements along the southern edge of the European plate, after collision with its Adriatic indenter. Pegmatites and aplites were produced between 29 and 25 Ma in direct relation to right-lateral shear along the Insubric line, by melting of continental crust having Sr-87/Sr-86 between 0.7199 and 0.7244 at the time of melting. High-temperature dextral strike-slip shear was active at 29.2 +/- 0.2 (2 sigma) Ma, and it terminated before 26.4 +/- 0.1 Ma. During dike injection, temperatures in the country rocks of the Isorno-Orselina and Monte Rosa structural units did not exceed approximate to 500 degrees C, leading to fast initial cooling, followed by slower cooling to approximate to 350 degrees C within several million years. In one case, initial cooling to approximate to 500 degrees C was significantly delayed by about 4 m.y., with final cooling to approximate to 300 degrees C at 20-19 Ma in all units. For the period between 29 and 19 Ma, cooling of the three sample localities was non-uniform in space and time, with significant variations on the kilometre scale. These differences are most likely due to strongly varying heat flow, and/or heterogeneous distribution of unroofing rates within the continuously deforming Insubric line. If entirely ascribed to differences in unroofing, corresponding rates would vary between 0.5 and 2.5 mm/y, for a thermal gradient of 30 degrees/km.