Proarrhythmic remodelling of the right ventricle in a porcine model of repaired tetralogy of Fallot

OBJECTIVE: The growing adult population with surgically corrected tetralogy of Fallot (TOF) is at risk of arrhythmias and sudden cardiac death. We sought to investigate the contribution of right ventricular (RV) structural and electrophysiological remodelling to arrhythmia generation in a preclinical animal model of repaired TOF (rTOF). METHODS AND RESULTS: Pigs mimicking rTOF underwent cardiac MRI functional characterisation and presented with pulmonary regurgitation, RV hypertrophy, dilatation and dysfunction compared with Sham-operated animals (Sham). Optical mapping of rTOF RV-perfused wedges revealed a significant prolongation of RV activation time with slower conduction velocities and regions of conduction slowing well beyond the surgical scar. A reduced protein expression and lateralisation of Connexin-43 were identified in rTOF RVs. A remodelling of extracellular matrix-related gene expression and an increase in collagen content that correlated with prolonged RV activation time were also found in these animals. RV action potential duration (APD) was prolonged in the epicardial anterior region at early and late repolarisation level, thus contributing to a greater APD heterogeneity and to altered transmural and anteroposterior APD gradients in rTOF RVs. APD remodelling involved changes in Kv4.3 and MiRP1 expression. Spontaneous arrhythmias were more frequent in rTOF wedges and more complex in the anterior than in the posterior RV. CONCLUSION: Significant remodelling of RV conduction and repolarisation properties was found in pigs with rTOF. This remodelling generates a proarrhythmic substrate likely to facilitate re-entries and to contribute to sudden cardiac death in patients with rTOF

Snipe taxonomy based on vocal and non-vocal sound displays: the South American Snipe is two species

We analysed breeding sounds of the two subspecies of South American Snipe Gallinago paraguaiae paraguaiae and Gallinago paraguaiae magellanica to determine whether they might be different species: loud vocalizations given on the ground, and the tail‐generated Winnow given in aerial display. Sounds of the two taxa differ qualitatively and quantitatively. Both taxa utter two types of ground call. In G. p. paraguaiae, the calls are bouts of identical sound elements repeated rhythmically and slowly (about five elements per second (Hz)) or rapidly (about 11 Hz). One call of G. p. magellanica is qualitatively similar to those of G. p. paraguaiae but sound elements are repeated more slowly (about 3 Hz). However, its other call type differs strikingly: it is a bout of rhythmically repeated sound couplets, each containing two kinds of sound element. The Winnow of G. p. paraguaiae is a series of sound elements that gradually increase in duration and energy; by contrast, that of G. p. magellanica has two or more kinds of sound element that roughly alternate and are repeated as sets, imparting a stuttering quality. Sounds of the related Puna Snipe (Gallinago andina) resemble but differ quantitatively from those of G. p. paraguaiae. Differences in breeding sounds of G. p. paraguaiae and G. p. magellanica are strong and hold throughout their geographical range. Therefore we suggest that the two taxa be considered different species: G. paraguaiae east of the Andes in much of South America except Patagonia, and G. magellanica in central and southern Chile, Argentina east of the Andes across Patagonia, and Falklands/Malvinas.Fil: Miller, Edward H.. Memorial University Of Newfoundland; CanadáFil: Areta, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Jaramillo, Alvaro. San Francisco Bay Bird Observatory; Estados UnidosFil: Imberti, Santiago. Asociación Ambiente Sur, Rio Gallegos; ArgentinaFil: Matus, Ricardo. Kilómetro 7 Sur; Chil

The Ontogenetic Osteohistology of Tenontosaurus tilletti

Tenontosaurus tilletti is an ornithopod dinosaur known from the Early Cretaceous (Aptian-Albian) Cloverly and Antlers formations of the Western United States. It is represented by a large number of specimens spanning a number of ontogenetic stages, and these specimens have been collected across a wide geographic range (from central Montana to southern Oklahoma). Here I describe the long bone histology of T. tilletti and discuss histological variation at the individual, ontogenetic and geographic levels. The ontogenetic pattern of bone histology in T. tilletti is similar to that of other dinosaurs, reflecting extremely rapid growth early in life, and sustained rapid growth through sub-adult ontogeny. But unlike other iguanodontians, this dinosaur shows an extended multi-year period of slow growth as skeletal maturity approached. Evidence of termination of growth (e.g., an external fundamental system) is observed in only the largest individuals, although other histological signals in only slightly smaller specimens suggest a substantial slowing of growth later in life. Histological differences in the amount of remodeling and the number of lines of arrested growth varied among elements within individuals, but bone histology was conservative across sampled individuals of the species, despite known paleoenvironmental differences between the Antlers and Cloverly formations. The bone histology of T. tilletti indicates a much slower growth trajectory than observed for other iguanodontians (e.g., hadrosaurids), suggesting that those taxa reached much larger sizes than Tenontosaurus in a shorter time

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

Variations in age, size at maturity and gestation duration among two neighbouring populations of the alpine salamander (Salamandra lanzai)

International audienceWe describe the age structures of two neighbouring terrestrial salamander populations. The skeletochronological method was also used on larvae in utero and on new-born individuals. The age of adults was 8-24 years in population A, while males reached maturity at 3-5 years old and the youngest females were 6 years old in population B. Males and females from population B were also larger than those in population A. For the first time, lines of arrested growth (LAGs) were also found in the humerus of intra-uterine larvae and new-born individuals, indicating that young can spend up to 3 years in utero (population B) and up to 4 years (population A) before hatching. Growth of adults (fitted by the Bertalanffy model) also exhibited differences in growth coefficient (k) and mean asymptotic length (SVLmax) between sexes and populations. Local climatic conditions differed between the two areas of these populations and we hypothesize that the number of rainy days directly influences foraging during the short period of activity (< 3 months), leading to a delay in age at maturity, smaller length and growth rate, and increased gestation duration in the drier environment. The discussion is focused on proximate environmental influences on the variation of length and associated life-history traits in ectotherms, especially in terrestrial salamanders