Recombinant erythropoietin in acute chemotherapy-induced anemia of children with cancer.

Chemotherapy-induced anemia in children with cancer is usually of acute onset. To investigate an alternate treatment to transfusion (Tx), we undertook a phase I-II clinical trial of daily administrations of recombinant erythropoietin (rHuEPO). Patients with a hemoglobin (Hgb) value < 75 g/l were treated for 14 days in cohorts of 3 at escalating daily doses of 25, 50, 70, 80, 90, and 100 U/kg respectively. The maximum-tolerated dose was not encountered. Of 18 courses given to 15 children aged 0.5-18 years, 7 (39%) were associated with increased or stable Hgb levels (courses without Tx), while 11 (61%) were terminated by a Tx, without evidence of a dose-response relationship. Changes in mean Hgb levels and absolute reticulocyte counts were paralleled by those of mean white blood cell, platelet, and absolute neutrophil counts during the first 7 days and when the end-points of the study were reached. Numbers of circulating burst-forming units-erythroid remained low throughout courses without Tx. No cumulative increase of serially determined serum EPO levels was observed and serum ferritin levels were elevated in both groups of courses. We conclude that daily administration of rHuEPO were safe but ineffective in our trial. Recovery of chemotherapy-induced myelosuppression appeared to be the rate-limiting factor for the outcome, without evidence of an enhanced stimulation of erythropoiesis. The lack of a proliferative response of specific progenitor cells suggested a mechanism of transient primary resistance to rHuEPO.

Social mobility in 20th century, Switzerland

The study of social mobility enables us to assess the extent to which a given society is "open". Addressing this issue is particularly crucial in our democratic societies, where it is expected that the place of individuals in society should no longer be determined at birth, but rather by individual quality. The present inquiry investigates this issue in the context of Switzerland, a country characterised by specific institutional settings, notably through the close association its educational system shares with the labour market. Through a detailed empirical analysis based on robust statistical analyses carried out from a unique tailor-made dataset, I demonstrate that Swiss society has not become more open throughout the twentieth century. Although some barriers have lost some salience, Swiss society has overall remained extremely rigid. In particular, because it channels individuals into highly segmented tracks very early on, the Swiss educational system does not attenuate social background differences. Thus, Switzerland is found in a particular configuration where an individual's place in society is highly determined not only by his or her educational attainment, but also by his or her social background. In other words, Switzerland constitutes a sort of "non-meritocratic meritocracy". - L'étude de la mobilité sociale permet d'évaluer dans quelle mesure une société donnée est « ouverte ». S'intéresser à cette question est particulièrement crucial dans nos sociétés démocratiques, où il est attendu que la place des individus ne soit plus déterminée à la naissance, mais plutôt par les qualités individuelles. La présente étude examine cette question dans le cadre de la Suisse, un pays aux caractéristiques institutionnelles spécifiques, particulièrement de part le lien étroit que son système éducatif entretien avec le marché du travail. A travers une analyse empirique détaillée fondée sur des analyses statistiques robustes menées à partir d'un jeu de données unique construit sur-mesure, je démontre que la société suisse n'est pas devenue plus ouverte au cours du 20ème siècle. Même si certaines barrières ont perdu de l'importance, dans son ensemble, la société suisse est restée extrêmement rigide. En particulier, parce qu'il oriente très tôt les individus dans des filières fortement segmentées, le système éducatif suisse n'atténue pas les différences entre milieux sociaux. Ainsi, la Suisse se trouve dans une configuration particulière où, d'une part, la place d'un individu dans la société est hautement déterminée par son niveau d'étude et, d'autre part, par son origine sociale. En d'autres termes, la Suisse apparaît comme une sorte de « méritocratie non-méritocratique ».

Serum-Mediane von Placentaprotein-Markern: Relevanz der Unterschiede zwischen spontanen und nach-in-vitro-Fertilisation eingetretenen Schwangerschaften für das fetale Trisomie-Screening.

Trisomy-21 (Down syndrome) is the most frequent chromosomal abnorm- ality but only one third of cases would be detected by amniocentesis based on maternal age alone. Serum screening tests in the early second trimester increase the detec- tion rate to 60-65%, and more recently it was found that such screening was also possible in the first trimester by quantifying a diffe- rent panel of markers. The concen- trations of these placental proteins are strongly dependent on gestatio- nal age; thus control medians must be established and precise dating is essential. Serum chorionic gonado- trophin (HCG) levels were recently found to be increased in IVF preg- nancies compared to spontaneous gestations, leading to a falsely ele- vated trisomy screening risk. The aim of this preliminary study was to find out whether, in the first-trime- ster screening, the markers similarly differed between IVF and spontane- ous pregnancies which would call for the establishment of separate normal medians for IVF patients. We compared 24 pregnancies ob- tained after ovarian stimulation and IVF with six women after thawed embryo transfer (unstimulated cycle) and 63 gestation- and maternal-age matched spontaneously pregnant controls. A single serum was ob- tained between 6 and 16 weeks of gestation and various placental protein levels determined by im- munometric assays. Serum levels of pregnancy-associated plasma protein A (PAPP-A), which is the major marker in the first-trimes- ter screening test, were reduced in IVF pregnancies: after 9 weeks of gestation, multiples of median (MoMs) ranged between 0.23 and 3.58 (logarithmic mean 0.743). For the frozen/thawed transfers, this value was 1.08. In the 9-12 week group containing 6 cases of IVF, three thawed transfers and 25 con- trols, PAPP-A was significantly redu- ced in the stimulated compared to the nonstimulated cycles. In the late first and early second trimester the difference was not significant in our small group but the trend persisted. Pregnancies after IVF will thus show an increased incidence of false positive results in fetal trisomy-21 screening, and special medians should be established for these pati- ents.

Exhaled nitric oxide in high-altitude pulmonary edema: role in the regulation of pulmonary vascular tone and evidence for a role against inflammation.

High-altitude pulmonary edema (HAPE) is a life-threatening condition occurring in predisposed subjects at altitudes above 2,500 m. It is not clear whether, in addition to hemodynamic factors and defective alveolar fluid clearance, inflammation plays a pathogenic role in HAPE. We therefore made serial measurements of exhaled pulmonary nitric oxide (NO), a marker of airway inflammation, in 28 HAPE-prone and 24 control subjects during high-altitude exposure (4,559 m). To examine the relationship between pulmonary NO synthesis and pulmonary vascular tone, we also measured systolic pulmonary artery pressure (Ppa). In the 13 subjects who developed HAPE, exhaled NO did not show any tendency to increase during the development of lung edema. Throughout the entire sojourn at high altitude, pulmonary exhaled NO was roughly 30% lower in HAPE-prone than in control subjects, and there existed an inverse relationship between Ppa and exhaled NO (r = -0.51, p < 0.001). These findings suggest that HAPE is not preceded by airway inflammation. Reduced exhaled NO may be related to altered pulmonary NO synthesis and/or transport and clearance, and the data in our study could be consistent with the novel concept that in HAPE-prone subjects, a defect in pulmonary epithelial NO synthesis may contribute to exaggerated hypoxic pulmonary vasoconstriction and in turn to pulmonary edema.

Change in individual growth rate and its link to gill-net fishing in two sympatric whitefish species

Size-selective fishing is expected to affect traits such as individual growth rate, but the relationship between the fishery-linked selection differentials and the corresponding phenotypic changes is not well understood. We analysed a 25-year monitoring survey of sympatric populations of the two Alpine whitefish Coregonus albellus and C. fatioi. We determined the fishing-induced selection differentials on growth rates, the actual change of growth rates over time, and potential indicators of reproductive strategies that may change over time. We found marked declines in adult growth rate and significant selection differentials that may partly explain the observed declines. However, when comparing the two sympatric species, the selection differentials on adult growth were stronger in C. albellus while the decline in adult growth rate seemed more pronounced in C. fatioi. Moreover, the selection differential on juvenile growth was significant in C. albellus but not in C. fatioi, while a significant reduction in juvenile growth over the last 25 years was only found in C. fatioi. Our results suggest that size-selective fishing affects the genetics for individual growth in these whitefish, and that the link between selection differentials and phenotypic changes is influenced by species-specific factors.

Voriconazole-Induced Inhibition of the Fungicidal Activity of Amphotericin B in Candida Strains with Reduced Susceptibility to Voriconazole: an Effect Not Predicted by the MIC Value Alone.

An antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicans strains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in Candida strains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole-resistant strains, C. albicans strains with characterized mechanisms of resistance against voriconazole, as well as Candida glabrata and Candida krusei strains with differences in their degrees of susceptibility to voriconazole were exposed to voriconazole or amphotericin B alone, to both drugs simultaneously, or to voriconazole followed by amphotericin B in an in vitro kinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced (median reduction, 61%; range, 9 to 94%). Levels of voriconazole-dependent inhibition of amphotericin B activity differed significantly among the strains but were not correlated with the MIC values (correlation coefficient, -0.19; P = 0.65). Inhibition was found in C. albicans strains with increases in CDR1 and CDR2 expression but not in the strain with an increase in MDR1 expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole-resistant Candida strains. The degree of interaction could not be predicted by the MIC value alone.

Density-dependent pollen limitation and reproductive assurance in a wind-pollinated herb with contrasting sexual systems

1. Wind pollination is thought to have evolved in response to selection for mechanisms to promote pollination success, when animal pollinators become scarce or unreliable. We might thus expect wind-pollinated plants to be less prone to pollen limitation than their insect-pollinated counterparts. Yet, if pollen loads on stigmas of wind-pollinated species decline with distance from pollen donors, seed set might nevertheless be pollen-limited in populations of plants that cannot self-fertilize their progeny, but not in self-compatible hermaphroditic populations.2. Here, we test this hypothesis by comparing pollen limitation between dioecious and hermaphroditic (monoecious) populations of the wind-pollinated herb Mercurialis annua.3. In natural populations, seed set was pollen-limited in low-density patches of dioecious, but not hermaphroditic, M. annua, a finding consistent with patterns of distance-dependent seed set by females in an experimental array. Nevertheless, seed set was incomplete in both dioecious and hermaphroditic populations, even at high local densities. Further, both factors limited the seed set of females and hermaphrodites, after we manipulated pollen and resource availability in a common garden experiment.4. Synthesis. Our results are consistent with the idea that pollen limitation plays a role in the evolution of combined vs. separate sexes in M. annua. Taken together, they point to the potential importance of pollen transfer between flowers on the same plant (geitonogamy) by wind as a mechanism of reproductive assurance and to the dual roles played by pollen and resource availability in limiting seed set. Thus, seed set can be pollen-limited in sparse populations of a wind-pollinated species, where mates are rare or absent, having potentially important demographic and evolutionary implications.

Habitat, breeding performance, diet and individual age in Swiss barn owls (Tyto alba)

Intensification of farming over the past 50 years has homogenised the landscape structure and contributed to the decline of bird populations in Europe. To better target the conservation of the Barn Owl Tyto alba, we assessed the influence of the landscape structure on breeding performance in western Switzerland. The analyses considered a 23-year data set of breeding parameters collected in an area dominated by intensive agriculture. Using a Geographic Information System approach, landscape characteristics were described around 194 nest sites. Our analyses showed that nest-box occupancy, laying date, clutch and brood size, egg volume and probability of producing a second annual clutch were not significantly associated with any of the eight principal landscape variables (agricultural land, woodland, urban area, hedgerows, cereals, sugar beet, maize and meadow). Nevertheless, the probability that a breeding pair occupied a nest-box decreased the more roads there were surrounding the nest-box. The absence of strong associations between habitat features and breeding parameters suggests that prey availability may be relatively similar between the different breeding sites. In our study area Barn Owls can always find suitable foraging habitats around most nest-boxes.

Encoding dysfunctions in a dynamic-static paradigm for visuospatial working memory in first-episode psychosis patients: a 2-year follow-up study.

Aim: To investigate static and dynamic visuospatial working memory (VSWM) processes in first-episode psychosis (FEP) patients and explore the validity of such measures as specific trait markers of schizophrenia. Methods: Twenty FEP patients and 20 age-, sex-, laterality- and education-matched controls carried out a dynamic and static VSWM paradigm. At 2-year follow up 13 patients met Diagnostic and Statistical Manual (of Mental Health Disorders) - Fourth Edition (DSM-IV) criteria for schizophrenia, 1 for bipolar disorder, 1 for brief psychotic episode and 5 for schizotypal personality disorder. Results: Compared with controls, the 20 FEP patients showed severe impairment in the dynamic VSWM condition but much less impairment in the static condition. No specific bias in stimulus selection was detected in the two tasks. Two-year follow-up evaluations suggested poorer baseline scores on the dynamic task clearly differentiated the 13 FEP patients who developed schizophrenia from the seven who did not. Conclusions: Results suggest deficits in VSWM in FEP patients. Specific exploratory analyses further suggest that deficit in monitoring-manipulation VSWM processes, especially involved in our dynamic VSWM task, can be a reliable marker of schizophrenia.

Trabecular Bone Score Helps Classifying Women At Riskof Fracture Prospectively In The Ofely Study

Objectives: Trabecular Bone Score (TBS, Med-Imaps, France) is an index of bone microarchitecture calculated from antero-posterior spine DXA scan and reported to be associated with fracture in prior case-control studies and in a large prospective study with the Prodigy DXA device. Our aim was to assess the ability of TBS to predict incident fracture and improve the classification of fracture prospectively in the OFELY study.Materials/Methods: TBS was assessed in 564 postmenopausal women (66±8 years old) from the OFELY cohort, who had a spine DXA scan (QDR 4500A, Hologic, USA) between year 2000 and 2001. During a mean follow up of 7.8±1.3 years, 94 women sustained a fragility fracture.Results: At the time of baseline DXA scan, women with incident fracture were significantly older (70±9 vs. 65± 8 years), had a lower spine BMD (T-score: −1.9±1.2 vs. −1.3±1.3, p<0.001) and spine TBS (−3.1%, p<0.001) than women without incident fracture. After adjustment for age, BMI and the presence of prevalent fracture, the magnitude of fracture prediction was similar for spine BMD (OR=1.42 [1.11;1.82] per SD decrease [95% CI]) and TBS (OR=1.34 [1.04;1.74]) but the combination of TBS and spine BMD did not improve fracture prediction. Spine BMD and TBS were both correlated with age (respectively r=−0.17 and −0.49, p<0.001) and correlated together with 39% of TBS explained by spine BMD (r=0.63, p<0.001). When using the WHO classification, 38% of the fractures occurred in osteoporotic (fracture rate=29%), 47% in osteopenic (fracture rate=16%) and 15% in women with T-score >−1 (fracture rate=9%). By classifying our population in tertiles of TBS, we found that 47% of the fractures occurred in the lowest tertile of TBS (fracture rate=23%) and 39% of the fracture that occurred in osteopenic women were in the lowest tertile of TBS.Conclusions: Spine BMD and TBS predicted fractures equally well. The addition of TBS to spine BMD added only limited information on fracture risk prediction in our cohort when considering the all range of BMD. Nevertheless combining the osteopenic T-score and the lowest TBS helped defining a subset of osteopenic women at higher risk of fracture.Disclosure of Interest: None declared.

Pale and dark reddish melanic tawny owls differentially regulate the level of blood circulating POMC prohormone in relation to environmental conditions.

Knowledge of the hormonal pathway controlling genotype-specific norms of reaction would shed light on the ecological factors to which each genotype is adapted. Environmentally mediated changes in the sign and magnitude of covariations between heritable melanin-based colouration and fitness components are frequent, revealing that extreme melanin-based phenotypes can display different physiological states depending on the environment. Yet, the hormonal mechanism underlying this phenomenon is poorly understood. One novel hypothesis proposes that these covariations stem from pleiotropic effects of the melanocortin system. Melanocortins are post-translationally modified bioactive peptides derived from the POMC prohormone that are involved in melanogenesis, anti-inflammation, energy homeostasis and stress responses. Thus, differential regulation of fitness components in relation to environmental factors by pale and dark melanic individuals may be due to colour-specific regulation of the POMC prohormone. Accordingly, we found that the degree of reddish melanic colouration was negatively correlated with blood circulating levels of the POMC prohormone in female tawny owls (Strix aluco) rearing a brood for which the size was experimentally reduced, but not when enlarged, and in females located in rich but not in poor territories. Our findings support the hypothesis that the widespread links between melanin-based colouration and fitness components may be mediated, at least in part, by the melanocortin system.

Visual stimulus-dependent changes in interhemispheric EEG coherence in humans.

We analyzed the coherence of electroencephalographic (EEG) signals recorded symmetrically from the two hemispheres, while subjects (n = 9) were viewing visual stimuli. Considering the many common features of the callosal connectivity in mammals, we expected that, as in our animal studies, interhemispheric coherence (ICoh) would increase only with bilateral iso-oriented gratings located close to the vertical meridian of the visual field, or extending across it. Indeed, a single grating that extended across the vertical meridian significantly increased the EEG ICoh in normal adult subjects. These ICoh responses were obtained from occipital and parietal derivations and were restricted to the gamma frequency band. They were detectable with different EEG references and were robust across and within subjects. Other unilateral and bilateral stimuli, including identical gratings that were effective in anesthetized animals, did not affect ICoh in humans. This fact suggests the existence of regulatory influences, possibly of a top-down kind, on the pattern of callosal activation in conscious human subjects. In addition to establishing the validity of EEG coherence analysis for assaying cortico-cortical connectivity, this study extends to the human brain the finding that visual stimuli cause interhemispheric synchronization, particularly in frequencies of the gamma band. It also indicates that the synchronization is carried out by cortico-cortical connection and suggests similarities in the organization of visual callosal connections in animals and in man.

Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts.

Major depressive disorder (MDD) is a highly prevalent disorder with substantial heritability. Heritability has been shown to be substantial and higher in the variant of MDD characterized by recurrent episodes of depression. Genetic studies have thus far failed to identify clear and consistent evidence of genetic risk factors for MDD. We conducted a genome-wide association study (GWAS) in two independent datasets. The first GWAS was performed on 1022 recurrent MDD patients and 1000 controls genotyped on the Illumina 550 platform. The second was conducted on 492 recurrent MDD patients and 1052 controls selected from a population-based collection, genotyped on the Affymetrix 5.0 platform. Neither GWAS identified any SNP that achieved GWAS significance. We obtained imputed genotypes at the Illumina loci for the individuals genotyped on the Affymetrix platform, and performed a meta-analysis of the two GWASs for this common set of approximately half a million SNPs. The meta-analysis did not yield genome-wide significant results either. The results from our study suggest that SNPs with substantial odds ratio are unlikely to exist for MDD, at least in our datasets and among the relatively common SNPs genotyped or tagged by the half-million-loci arrays. Meta-analysis of larger datasets is warranted to identify SNPs with smaller effects or with rarer allele frequencies that contribute to the risk of MDD.

Oxygen consumption in offspring tawny owls Strix aluco is associated with colour morph of foster mother

In several colour polymorphic species, morphs differ in thermoregulation either because dark and pale surfaces absorb solar radiation to a different extent and/or because morphs differ in key metabolic processes. Morph-specific thermoregulation may potentially account for the observation that differently coloured individuals are frequently not randomly distributed among habitats, and differ in many respects, including behaviour, morphology, survival and reproductive success. In a wild population of the colour polymorphic tawny owl Strix aluco, a recent cross-fostering experiment showed that offspring raised and born from red mothers were heavier than those from grey mothers. In the present study, we tested in the same individuals whether these morph-specific offspring growth patterns were associated with a difference in metabolic rate between offspring of red and grey mothers. For this purpose, we measured nestling oxygen consumption under two different temperatures (laboratory measurements: 4 and 20 degrees C), and examined the relationships between these data sets and the colour morph of foster and biological mothers. After controlling for nestling body mass, oxygen consumption at 20 degrees C was greater in foster offspring raised by grey foster mothers. No relationship was found between nestling oxygen consumption and coloration of their biological mother. Therefore, our study indicates that in our experiment offspring raised by grey foster mothers showed not only a lower body mass than offspring raised by red foster mothers, but also consumed more oxygen under warm temperature. This further indicates that rearing conditions in nests of grey mothers were more stressful than in nests of red mothers.

Nest-box design for the study of diurnal raptors and owls is still an overlooked point in ecological, evolutionary and conservation studies: a review

The use of artificial nest-boxes has led to significant progress in bird conservation and in our understanding of the functional and evolutionary ecology of free-ranging birds that exploit cavities for roosting and reproduction. Nest-boxes and their improved accessibility have made it easier to perform comparative and experimental field investigations. However, concerns about the generality and applicability of scientific studies involving birds breeding in nest-boxes have been raised because the occupants of boxes may differ from conspecifics occupying other nest sites. Here we review the existing evidence demonstrating the importance of nest-box design to individual life-history traits in three falcon (Falconiformes) and seven owl (Strigiformes) species, as well as the extent to which publications on these birds describe the characteristics of exploited artificial nest-boxes in their 'methods' sections. More than 60% of recent publications did not provide any details on nest-box design (e.g. size, shape, material), despite several calls >15 years ago to increase the reporting of such information. We exemplify and discuss how variation in nest-box characteristics can affect or confound conclusions from nest-box studies and conclude that it is of overall importance to present details of nest-box characteristics in scientific publications.