Rapid prototyping of compliant human aortic roots for assessment of valved stents.

Adequate in-vitro training in valved stents deployment as well as testing of the latter devices requires compliant real-size models of the human aortic root. The casting methods utilized up to now are multi-step, time consuming and complicated. We pursued a goal of building a flexible 3D model in a single-step procedure. We created a precise 3D CAD model of a human aortic root using previously published anatomical and geometrical data and printed it using a novel rapid prototyping system developed by the Fab@Home project. As a material for 3D fabrication we used common house-hold silicone and afterwards dip-coated several models with dispersion silicone one or two times. To assess the production precision we compared the size of the final product with the CAD model. Compliance of the models was measured and compared with native porcine aortic root. Total fabrication time was 3 h and 20 min. Dip-coating one or two times with dispersion silicone if applied took one or two extra days, respectively. The error in dimensions of non-coated aortic root model compared to the CAD design was <3.0% along X, Y-axes and 4.1% along Z-axis. Compliance of a non-coated model as judged by the changes of radius values in the radial direction by 16.39% is significantly different (P<0.001) from native aortic tissue--23.54% at the pressure of 80-100 mmHg. Rapid prototyping of compliant, life-size anatomical models with the Fab@Home 3D printer is feasible--it is very quick compared to previous casting methods.

Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial.

BACKGROUND: We aimed to compare panitumumab, a fully human monoclonal antibody against EGFR, plus radiotherapy with chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS: In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (two cycles of cisplatin 100 mg/m(2) during radiotherapy) or to radiotherapy plus panitumumab (three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy) using a stratified randomisation with a block size of five. All patients received 70-72 Gy to gross tumour and 54 Gy to areas of subclinical disease with accelerated fractionation radiotherapy. The primary endpoint was local-regional control at 2 years, analysed in all randomly assigned patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This study is registered with ClinicalTrials.gov, number NCT00547157. FINDINGS: Between Nov 30, 2007, and Nov 16, 2009, 152 patients were enrolled, and 151 received treatment (61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group). Local-regional control at 2 years was 61% (95% CI 47-72) in the chemoradiotherapy group and 51% (40-62) in the radiotherapy plus panitumumab group. The most frequent grade 3-4 adverse events were mucosal inflammation (25 [40%] of 62 patients in the chemoradiotherapy group vs 37 [42%] of 89 patients in the radiotherapy plus panitumumab group), dysphagia (20 [32%] vs 36 [40%]), and radiation skin injury (seven [11%] vs 21 [24%]). Serious adverse events were reported in 25 (40%) of 62 patients in the chemoradiotherapy group and in 30 (34%) of 89 patients in the radiotherapy plus panitumumab group. INTERPRETATION: Panitumumab cannot replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck, and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed. FUNDING: Amgen.

Tawny Owl Strix aluco as a bioindicator of Barn Owl Tyto alba breeding and the effect of winter severity on Barn Owl reproduction

In the temperate zone, food availability and winter weather place serious constraints on European Barn Owl Tyto alba populations. Using data collected over 22years in a Swiss population, we analysed the influence of early pre-breeding food conditions and winter severity on between-year variations in population size and reproductive performance. To estimate pre-breeding food conditions, we attempted a novel approach based on an index that combines Tawny Owl Strix aluco reproductive parameters and the occurrence of wood mice Apodemus sp. in their diet. Tawny Owls breed earlier in the season than Barn Owls and are strongly dependent on the abundance of wood mice for breeding. This index was strongly positively associated with the number of breeding pairs and early breeding in the Barn Owl. Winter severity, measured by snow cover and low temperatures, had a pronounced negative influence on the size of the breeding population and clutch size. Food conditions early in the breeding season and winter severity differentially affect the Barn Owl life cycle. We were able to use aspects of the ecology and demography of the Tawny Owl as an indicator of the quality of the environment for a related species of similar ecology, in this case the Barn Owl.

Traitement chirurgical des tumeurs palpebrales. [Surgical treatment of eyelid tumors]

After reviewing the general principles of eyelid reconstruction, the authors present reconstruction techniques with regard to the location and size of the eyelid defect. When the defect is less than one-quarter of lid length, direct suture is possible. When the defect is larger, reconstruction techniques differ for the upper and lower lid.

Rescue of the mature B cell compartment in BAFF-deficient mice by treatment with recombinant Fc-BAFF.

BAFF deficiency in mice impairs B cell development beyond the transitional stage 1 in the spleen and thus severely reduces the size of follicular and marginal zone B cell compartments. Moreover, humoral immune responses in these mice are dramatically impaired. We now addressed the question whether the decrease in mature B cell numbers and the reduced humoral immune responses in BAFF-deficient mice could be overcome by the injection of recombinant BAFF. We therefore engineered a recombinant protein containing the human IgG1 Fc moiety fused to receptor-binding domain of human BAFF (Fc-BAFF). At 1 week after the second injection of this fusion protein a complete rescue of the marginal zone B cell compartment and a 50% rescue of the follicular B cell compartment was observed. Moreover these mice mounted a T cell-dependent humoral immune response indistinguishable from wild-type mice. By day 14 upon arrest of Fc-BAFF treatment mature B cell numbers in the blood dropped by 50%, indicating that the life span of mature B cells in the absence of BAFF is 14 days or less. Collectively these findings demonstrate that injection of Fc-BAFF in BAFF-deficient mice results in a temporary rescue of a functional mature B cell compartment.

'Good-genes' and 'compatible-genes' effects in an Alpine whitefish and the information content of breeding tubercles over the course of the spawning season.

Some models of sexual selection predict that individuals vary in their genetic quality and reveal some of this variation in their secondary sexual characteristics. Alpine whitefish (Coregonus sp.) develop breeding tubercles shortly before their spawning season. These tubercles are epidermal structures that are distributed regularly along the body sides of both males and females. There is still much unexplained variation in the size of breeding tubercles within both sexes and with much overlap between the sexes. It has been suggested that breeding tubercles function to maintain body contact between the mating partners during spawning, act as weapons for defence of spawning territories, or are sexual signals that reveal aspects of genetic quality. We took two samples of whitefish from their spawning place, one at the beginning and one around the peak of spawning season. We found that females have on average smaller breeding tubercles than males, and that tubercle size partly reveals the stage of gonad maturation. Two independent full-factorial breeding experiments revealed that embryo mortality was significantly influenced by male and female effects. This finding demonstrates that the males differed in their genetic quality (because offspring get nothing but genes from their fathers). Tubercle size was negatively linked to some aspects of embryo mortality in the first breeding experiment but not significantly so in the second. This lack of consistency adds to inconsistent results that were reported before and suggests that (i) some aspects of genetic quality are not revealed in breeding tubercles while others are, or (ii) individuals vary in their signaling strategies and the information content of breeding tubercles is not always reliable. Moreover, the fact that female whitefish have breeding tubercles of significant size while males seem to have few reasons to be choosy suggests that the tubercles might also serve some functions that are not linked to sexual signaling.

Multi-modal assessment of long-term erythropoietin treatment after neonatal hypoxic-ischemic injury in rat brain.

Erythropoietin (EPO) has been recognized as a neuroprotective agent. In animal models of neonatal brain injury, exogenous EPO has been shown to reduce lesion size, improve structure and function. Experimental studies have focused on short course treatment after injury. Timing, dose and length of treatment in preterm brain damage remain to be defined. We have evaluated the effects of high dose and long-term EPO treatment in hypoxic-ischemic (HI) injury in 3 days old (P3) rat pups using histopathology, magnetic resonance imaging (MRI) and spectroscopy (MRS) as well as functional assessment with somatosensory-evoked potentials (SEP). After HI, rat pups were assessed by MRI for initial damage and were randomized to receive EPO or vehicle. At the end of treatment period (P25) the size of resulting cortical damage and white matter (WM) microstructure integrity were assessed by MRI and cortical metabolism by MRS. Whisker elicited SEP were recorded to evaluate somatosensory function. Brains were collected for neuropathological assessment. The EPO treated animals did not show significant decrease of the HI induced cortical loss at P25. WM microstructure measured by diffusion tensor imaging was improved and SEP response in the injured cortex was recovered in the EPO treated animals compared to vehicle treated animals. In addition, the metabolic profile was less altered in the EPO group. Long-term treatment with high dose EPO after HI injury in the very immature rat brain induced recovery of WM microstructure and connectivity as well as somatosensory cortical function despite no effects on volume of cortical damage. This indicates that long-term high-dose EPO induces recovery of structural and functional connectivity despite persisting gross anatomical cortical alteration resulting from HI.

The stationary distribution of a continuously varying strategy in a class-structured population under mutation-selection-drift balance.

Many traits and/or strategies expressed by organisms are quantitative phenotypes. Because populations are of finite size and genomes are subject to mutations, these continuously varying phenotypes are under the joint pressure of mutation, natural selection and random genetic drift. This article derives the stationary distribution for such a phenotype under a mutation-selection-drift balance in a class-structured population allowing for demographically varying class sizes and/or changing environmental conditions. The salient feature of the stationary distribution is that it can be entirely characterized in terms of the average size of the gene pool and Hamilton's inclusive fitness effect. The exploration of the phenotypic space varies exponentially with the cumulative inclusive fitness effect over state space, which determines an adaptive landscape. The peaks of the landscapes are those phenotypes that are candidate evolutionary stable strategies and can be determined by standard phenotypic selection gradient methods (e.g. evolutionary game theory, kin selection theory, adaptive dynamics). The curvature of the stationary distribution provides a measure of the stability by convergence of candidate evolutionary stable strategies, and it is evaluated explicitly for two biological scenarios: first, a coordination game, which illustrates that, for a multipeaked adaptive landscape, stochastically stable strategies can be singled out by letting the size of the gene pool grow large; second, a sex-allocation game for diploids and haplo-diploids, which suggests that the equilibrium sex ratio follows a Beta distribution with parameters depending on the features of the genetic system.

Rate and processes of river network rearrangement during incipient faulting: The case of the Cahabon river, Guatemala

Deeply incised river networks are generally regarded as robust features that are not easily modified by erosion or tectonics. Although the reorganization of deeply incised drainage systems has been documented, the corresponding importance with regard to the overall landscape evolution of mountain ranges and the factors that permit such reorganizations are poorly understood. To address this problem, we have explored the rapid drainage reorganization that affected the Cahabon River in Guatemala during the Quaternary. Sediment-provenance analysis, field mapping, and electrical resistivity tomography (ERT) imaging are used to reconstruct the geometry of the valley before the river was captured. Dating of the abandoned valley sediments by the Be-10-Al-26 burial method and geomagnetic polarity analysis allow us to determine the age of the capture events and then to quantify several processes, such as the rate of tectonic deformation of the paleovalley, the rate of propagation of post-capture drainage reversal, and the rate at which canyons that formed at the capture sites have propagated along the paleovalley. Transtensional faulting started 1 to 3 million years ago, produced ground tilting and ground faulting along the Cahabon River, and thus generated differential uplift rate of 0.3 +/- 0.1 up to 0.7 +/- 0.4 mm . y(-1) along the river's course. The river responded to faulting by incising the areas of relative uplift and depositing a few tens of meters of sediment above the areas of relative subsidence. Then, the river experienced two captures and one avulsion between 700 ky and 100 ky. The captures breached high-standing ridges that separate the Cahabon River from its captors. Captures occurred at specific points where ridges are made permeable by fault damage zones and/or soluble rocks. Groundwater flow from the Cahabon River down to its captors likely increased the erosive power of the captors thus promoting focused erosion of the ridges. Valley-fill formation and capture occurred in close temporal succession, suggesting a genetic link between the two. We suggest that the aquifers accumulated within the valley-fills, increased the head along the subterraneous system connecting the Cahabon River to its captors, and promoted their development. Upon capture, the breached valley experienced widespread drainage reversal toward the capture sites. We attribute the generalized reversal to combined effects of groundwater sapping in the valley-fill, axial drainage obstruction by lateral fans, and tectonic tilting. Drainage reversal increased the size of the captured areas by a factor of 4 to 6. At the capture sites, 500 m deep canyons have been incised into the bedrock and are propagating upstream at a rate of 3 to 11 mm . y(-1) deepening at a rate of 0.7 to 1 5 mm . y(-1). At this rate, 1 to 2 million years will be necessary for headward erosion to completely erase the topographic expression of the paleovalley. It is concluded that the rapid reorganization of this drainage system was made possible by the way the river adjusted to the new tectonic strain field, which involved transient sedimentation along the river's course. If the river had escaped its early reorganization and had been given the time necessary to reach a new dynamic equilibrium, then the transient conditions that promoted capture would have vanished and its vulnerability to capture would have been strongly reduced.

Clutch size and malarial parasites in female great tits.

Life-history models predict an evolutionary trade-off in the allocation of resources to current versus future reproduction. This corresponds, at the physiological level, to a trade-off in the allocation of resources to current reproduction or to the immune system, which will enhance survival and therefore future reproduction. For clutch size, life-history models predict a positive correlation between current measurement in eggs and the subsequent parasite load. Tn a population of great tits, we analyzed the correlation between natural clutch size of females and the subsequent prevalence of Plasmodium spp., a potentially harmful blood parasite. Females that showed, 14 days after hatching of the nestlings, an infection with Plasmodium had a significantly larger clutch (9.3 eggs +/- 0.5 SE, n = 18) than uninfected females (8.0 eggs +/- 0.2 SE, n = 80), as predicted by the allocation trade-off. Clutch size was positively correlated with tile prevalence of Plasmodium, but brood size 14 days after hatching was not. This suggests that females incur higher costs during laying the clutch than during rearing nestlings. Infection status of some females changed between years, and these changes were significantly correlated with a change in clutch size as predicted by die trade-off. The link between reproductive effort and parasitism may represent a possible mechanism by which the cost of egg production is mediated into future survival and may thereby be an important selective force in the shaping of clutch size.

Dpp signaling activity requires Pentagone to scale with tissue size in the growing Drosophila wing imaginal disc.

The wing of the fruit fly, Drosophila melanogaster, with its simple, two-dimensional structure, is a model organ well suited for a systems biology approach. The wing arises from an epithelial sac referred to as the wing imaginal disc, which undergoes a phase of massive growth and concomitant patterning during larval stages. The Decapentaplegic (Dpp) morphogen plays a central role in wing formation with its ability to co-coordinately regulate patterning and growth. Here, we asked whether the Dpp signaling activity scales, i.e. expands proportionally, with the growing wing imaginal disc. Using new methods for spatial and temporal quantification of Dpp activity and its scaling properties, we found that the Dpp response scales with the size of the growing tissue. Notably, scaling is not perfect at all positions in the field and the scaling of target gene domains is ensured specifically where they define vein positions. We also found that the target gene domains are not defined at constant concentration thresholds of the downstream Dpp activity gradients P-Mad and Brinker. Most interestingly, Pentagone, an important secreted feedback regulator of the pathway, plays a central role in scaling and acts as an expander of the Dpp gradient during disc growth.

On the Definition of Public Goods. Assessing Richard A. Musgrave's contribution

This paper provides an explanation of the emergence of the standard textbook definition of public goods in the middle of the 20th century. It focuses on Richard Musgrave's contribution in defining public goods as non-rival and non-excludable - from 1939 to 1969. Although Samuelson's mathematical definition is generally used in models of public goods, the qualitative understanding of the specificity of pure public goods owes more to Musgrave's emphasis on the impossibility of exclusion. This paper also highlights the importance of the size of the group to which benefits of a public good accrue. This analysis allow for a reassessment of the Summary table of goods which first appeared in Musgrave and Musgrave (1973) textbook.

Evaluation of prenatal diagnosis of congenital heart diseases by ultrasound: experience from 20 European registries.

OBJECTIVES: To evaluate prenatal diagnosis of congenital heart diseases by ultrasound investigation in well-defined European populations. DESIGN: Data from 20 registries of congenital malformations in 12 European countries were included. The prenatal ultrasound screening programs in the countries ranged from no routine screening to three ultrasound investigations per patient routinely performed. RESULTS: There were 2454 cases with congenital heart disease with an overall prenatal detection rate of 25%. Termination of pregnancy was performed in 293 cases (12%). There was considerable variation in prenatal detection rate between regions, with the lowest detection rates being in countries without ultrasound screening (11%) and in Eastern European countries (Croatia, Lithuania and Ukraine; 8%). In Western European countries with ultrasound screening, detection rate ranged from 19-48%. There was a significant difference in prenatal detection rate and proportion of induced abortions between isolated congenital heart disease and congenital heart disease associated with chromosome anomalies, multiple malformations and syndromes (P < 0.0001). There were 1694 cases with isolated congenital heart disease of which 16% were diagnosed prenatally. Malformations affecting the size of the ventricles were detected prenatally in half of the cases. CONCLUSIONS: Prenatal detection rate of congenital heart disease varies significantly between countries even with the same screening recommendations. The presence of associated malformations significantly increases the prenatal detection rate.

The adjustment of energy expenditure and oxidation to energy intake: the role of carbohydrate and fat balance.

Evidence is accumulating that total body mass and its relative composition influence the rate of fat utilization in man. This effect can be explained by two factors operating in concert: (i) the effect of the size of the tissue mass and (ii) the nature of the fuel mix oxidized, i.e. the proportion of energy derived from fat vs. carbohydrate. In a cross-sectional study of 307 women with increasing degrees of obesity, we observed that the respiratory quotient (RQ) in post-absorptive conditions became progressively lower with increased body fatness, indicating a shift in substrate utilization. However, the RQ is known to be also influenced by the diet commonly ingested by the subjects. A short-term mixed diet overfeeding in lean and obese women has also demonstrated the high sensitivity of RQ to changes in energy balance. Following a one-day overfeeding (2500 kcal/day in excess of the previous 24 h energy expenditure), the magnitude of increase in RQ was identical in lean and obese subjects and the net efficiency of substrate utilization and storage was not influenced by the state of obesity.

Circadian variations of ischemic burden among patients with myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND: Several parameters of cardiovascular physiology and pathophysiology exhibit circadian rhythms. Recently, a relation between infarct size and the time of day at which it occurs has been suggested in experimental models of myocardial infarction. The aim of this study is to investigate whether circadian rhythms could cause differences in ischemic burden in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI).¦METHODS: In 353 consecutive patients with STEMI treated by PPCI, time of symptom onset, peak creatine kinase (CK), and follow-up at 30 days were obtained. We divided 24 hours into 4 time groups based on time of symptom onset (00:00-05:59, 06:00-11:59, 12:00-17:59, and 18:00-23:59).¦RESULTS: There was no difference between the groups regarding baseline patients and management's characteristics. At multivariable analysis, there was a statistically significant difference between peak CK levels among patients with symptom onset between 00:00 and 05:59 when compared with peak CK levels of patients with symptom onset in any other time group (mean increase 38.4%, P < .05). Thirty-day mortality for STEMI patients with symptom onset occurring between 00:00 and 05:59 was significantly higher than any other time group (P < .05).¦CONCLUSION: This study demonstrates an independent correlation between the infarct size of STEMI patients treated by PPCI and the time of the day at which symptoms occurred. These results suggest that time of the day should be a critical issue to look at when assessing prognosis of patients with myocardial infarction.