Food availability affects the maternal transfer of androgens and antibodies into eggs of a colonial seabird.

Mothers can improve the quality of their offspring by increasing the level of certain components in their eggs. To examine whether or not mothers increase deposition of such components in eggs as a function of food availability, we food-supplemented black-legged kittiwake females (Rissa tridactyla) before and during egg laying and compared deposition of androgens and antibodies into eggs of first and experimentally induced replacement clutches. Food-supplemented females transferred lower amounts of androgens and antibodies into eggs of induced replacement clutches than did non-food-supplemented mothers, whereas first clutches presented no differences between treatments. Our results suggest that when females are in lower condition, they transfer more androgens and antibodies into eggs to facilitate chick development despite potential long-term costs for juveniles. Females in prime condition may avoid these potential long-term costs because they can provide their chicks with more and higher quality resources.

Transfer of ultrasmall iron oxide nanoparticles from human brain-derived endothelial cells to human glioblastoma cells.

Nanoparticles (NPs) are being used or explored for the development of biomedical applications in diagnosis and therapy, including imaging and drug delivery. Therefore, reliable tools are needed to study the behavior of NPs in biological environment, in particular the transport of NPs across biological barriers, including the blood-brain tumor barrier (BBTB), a challenging question. Previous studies have addressed the translocation of NPs of various compositions across cell layers, mostly using only one type of cells. Using a coculture model of the human BBTB, consisting in human cerebral endothelial cells preloaded with ultrasmall superparamagnetic iron oxide nanoparticles (USPIO NPs) and unloaded human glioblastoma cells grown on each side of newly developed ultrathin permeable silicon nitride supports as a model of the human BBTB, we demonstrate for the first time the transfer of USPIO NPs from human brain-derived endothelial cells to glioblastoma cells. The reduced thickness of the permeable mechanical support compares better than commercially available polymeric supports to the thickness of the basement membrane of the cerebral vascular system. These results are the first report supporting the possibility that USPIO NPs could be directly transferred from endothelial cells to glioblastoma cells across a BBTB. Thus, the use of such ultrathin porous supports provides a new in vitro approach to study the delivery of nanotherapeutics to brain cancers. Our results also suggest a novel possibility for nanoparticles to deliver therapeutics to the brain using endothelial to neural cells transfer.

Multinational Firms’ Heterogeneity in Tax Responsiveness: the Role of Transfer Pricing

In this paper we show that the ability of multinational firms to manipulate transfer prices affects the tax sensitivity of foreign direct investment (FDI). We offer a model of international capital allocation where firms are heterogeneous in their ability to manipulate transfer prices. Perhaps paradoxically, we show that the ability to shift profits can make parent companies' investment more sensitive to host-country tax rates, as long as investors expect fisscal authorities to use price and profit detection methods. We then offer a comprehensive empirical study to test our predictions in the case of Japanese FDI. We exploit the finding that the unobservable ability to manipulate transfer prices is correlated with whole ownership of a±liates and R&D expenditure. Based on country, parent firm and sector characteristics, we estimate an investment equation on a sample of 3614 Japanese affiliates in 49 emerging countries. We obtain a greater semi-elasticity of investment to the statutory tax rate in a±liates that are wholly-owned and that have R&D intensive parents. We interpret these results as indirect evidence that abusive transfer pricing is one of the determinants of FDI activity.

Directed integration of new insulated lentiviral vectors to heterochromatin towards safer gene transfer to stem cells

The need for better gene transfer systems towards improved risk=benefit balance for patients remains a major challenge in the clinical translation of gene therapy (GT). We have investigated the improvement of integrating vectors safety in combining (i) new short synthetic genetic insulator elements (GIE) and (ii) directing genetic integration to heterochromatin. We have designed SIN-insulated retrovectors with two candidate GIEs and could identify a specific combination of insulator 2 repeats which translates into best functional activity, high titers and boundary effect in both gammaretro (p20) and lentivectors (DCaro4) (see Duros et al, abstract ibid). Since GIEs are believed to shield the transgenic cassette from inhibitory effects and silencing, DCaro4 has been further tested with chimeric HIV-1 derived integrases which comprise C-ter chromodomains targeting heterochromatin through either histone H3 (ML6chimera) or methylatedCpGislands (ML10). With DCaro4 only and both chimeras, a homogeneous expression is evidenced in over 20% of the cells which is sustained over time. With control lentivectors, less than 2% of cells express GFP as compared to background using a control double-mutant in both catalytic and ledgf binding-sites; in addition, a two-times increase of expression can be induced with histone deacetylase inhibitors. Our approach could significantly reduce integration into open chromatin sensitive sites in stem cells at the time of transduction, a feature which might significantly decrease subsequent genotoxicity, according to X-SCIDs patients data.Work performed with the support of EC-DG research within the FP6-Network of Excellence, CLINIGENE: LSHB-CT-2006-018933

Programme de remédiation cognitive pour patients présentant une schizophrénie ou un trouble associé (Recos) : résultats préliminaires [Cognitive remediation program for individuals living with schizophrenia (Recos): preliminary results].

BACKGROUND: Nowadays, cognitive remediation is widely accepted as an effective treatment for patients with schizophrenia. In French-speaking countries, techniques used in cognitive remediation for patients with schizophrenia have been applied from those used for patients with cerebral injury. As cognitive impairment is a core feature of schizophrenia, the Département de psychiatrie du CHUV in Lausanne (DP-CHUV) intended to develop a cognitive remediation program for patients with a schizophrenia spectrum disease (Recos-Vianin, 2007). Numerous studies show that the specific cognitive deficits greatly differ from one patient to another. Consequently, Recos aims at providing individualized cognitive remediation therapy. In this feasibility trial, we measured the benefits of this individualized therapy for patients with schizophrenia. Before treatment, the patients were evaluated with a large battery of cognitive tests in order to determine which of the five specific training modules - Verbal memory, visuospatial memory and attention, working memory, selective attention, reasoning - could provide the best benefit depending on their deficit. OBJECTIVES: The study was designed to evaluate the benefits of the Recos program by comparing cognitive functioning before and after treatment. METHOD: Twenty-eight patients with schizophrenia spectrum disorders (schizophrenia [n=18], schizoaffective disorder [n=5], schizotypal disorder [n=4], schizophreniform disorder [n=1], DSM-IV-TR) participated in between one and three of the cognitive modules. The choice of the training module was based on the results of the cognitive tests obtained during the first evaluation. The patients participated in 20 training sessions per module (one session per week). At the end of the training period, the cognitive functioning of each patient was reevaluated by using the same neuropsychological battery. RESULTS: The results showed a greater improvement in the cognitive functions, which were specifically trained, compared to the cognitive functions, which were not trained. However, an improvement was also observed in both types of cognitive functions, suggesting an indirect cognitive gain. CONCLUSION: In our view, the great heterogeneity of the observed cognitive deficits in schizophrenia necessitates a detailed neuropsychological investigation as well as an individualized cognitive remediation therapy. These preliminary results need to be confirmed with a more extended sample of patients.

Long-term effect of a school-based physical activity program (KISS) on fitness and adiposity in children: a cluster-randomized controlled trial.

BACKGROUND: School-based intervention studies promoting a healthy lifestyle have shown favorable immediate health effects. However, there is a striking paucity on long-term follow-ups. The aim of this study was therefore to assess the 3 yr-follow-up of a cluster-randomized controlled school-based physical activity program over nine month with beneficial immediate effects on body fat, aerobic fitness and physical activity. METHODS AND FINDINGS: Initially, 28 classes from 15 elementary schools in Switzerland were grouped into an intervention (16 classes from 9 schools, n = 297 children) and a control arm (12 classes from 6 schools, n = 205 children) after stratification for grade (1st and 5th graders). Three years after the end of the multi-component physical activity program of nine months including daily physical education (i.e. two additional lessons per week on top of three regular lessons), short physical activity breaks during academic lessons, and daily physical activity homework, 289 (58%) participated in the follow-up. Primary outcome measures included body fat (sum of four skinfolds), aerobic fitness (shuttle run test), physical activity (accelerometry), and quality of life (questionnaires). After adjustment for grade, gender, baseline value and clustering within classes, children in the intervention arm compared with controls had a significantly higher average level of aerobic fitness at follow-up (0.373 z-score units [95%-CI: 0.157 to 0.59, p = 0.001] corresponding to a shift from the 50th to the 65th percentile between baseline and follow-up), while the immediate beneficial effects on the other primary outcomes were not sustained. CONCLUSIONS: Apart from aerobic fitness, beneficial effects seen after one year were not maintained when the intervention was stopped. A continuous intervention seems necessary to maintain overall beneficial health effects as reached at the end of the intervention. TRIAL REGISTRATION: ControlledTrials.com ISRCTN15360785.

The Electoral Determinants of Collective Remittances: The Mexican 3x1 Program for Migrants

The 3x1 Program for Migrants is a matching grant scheme that seeks to direct the money sent by migrant organizations abroad to the provision of public and social infrastructure, and to productive projects in migrants’ communities of origin. To do so, the municipal, state, and federal administrations match the amount sent by hometown associations by 3 to 1. This opens the door to the political manipulation of the program. We explore the impact of a particular facet of Mexican political life on the operation of the 3x1: its recent democratization and the increasing political competition at the municipal level. Relying on the literature on redistributive politics, we posit that an increasing number of effective parties in elections may have two different effects. On the one hand, the need to cater to more heterogeneous constituencies may increase the provision of public projects. On the other hand, since smaller coalitions are needed to win elections under tighter competition, fewer public and more private (clientelistic) projects could be awarded. Using a unique dataset on the 3x1 Program for Migrants for over 2,400 municipalities in the period 2002 through 2007, we find a lower provision of public goods in electorally competitive jurisdictions. Thus, we remain sceptical about the program success in promoting public goods in politically competitive locations with high migration levels.

Normal kinetics of intestinal glucose absorption in the absence of GLUT2: evidence for a transport pathway requiring glucose phosphorylation and transfer into the endoplasmic reticulum.

Glucose is absorbed through the intestine by a transepithelial transport system initiated at the apical membrane by the cotransporter SGLT-1; intracellular glucose is then assumed to diffuse across the basolateral membrane through GLUT2. Here, we evaluated the impact of GLUT2 gene inactivation on this transepithelial transport process. We report that the kinetics of transepithelial glucose transport, as assessed in oral glucose tolerance tests, was identical in the presence or absence of GLUT2; that the transport was transcellular because it could be inhibited by the SGLT-1 inhibitor phlorizin, and that it could not be explained by overexpression of another known glucose transporter. By using an isolated intestine perfusion system, we demonstrated that the rate of transepithelial transport was similar in control and GLUT2(-/-) intestine and that it was increased to the same extent by cAMP in both situations. However, in the absence, but not in the presence, of GLUT2, the transport was inhibited dose-dependently by the glucose-6-phosphate translocase inhibitor S4048. Furthermore, whereas transport of [(14)C]glucose proceeded with the same kinetics in control and GLUT2(-/-) intestine, [(14)C]3-O-methylglucose was transported in intestine of control but not of mutant mice. Together our data demonstrate the existence of a transepithelial glucose transport system in GLUT2(-/-) intestine that requires glucose phosphorylation and transfer of glucose-6-phosphate into the endoplasmic reticulum. Glucose may then be released out of the cells by a membrane traffic-based pathway similar to the one we previously described in GLUT2-null hepatocytes.

The Global Diffusion of Regulatory Agencies: Channels of Transfer and Stages of Diffusion

The autonomous regulatory agency has recently become the ‘appropriate model’ of governance across countries and sectors. The dynamics of this process is captured in our data set, which covers the creation of agencies in 48 countries and 16 sectors since the 1920s. Adopting a diffusion approach to explain this broad process of institutional change, we explore the role of countries and sectors as sources of institutional transfer at different stages of the diffusion process. We demonstrate how the restructuring of national bureaucracies unfolds via four different channels of institutional transfer. Our results challenge theoretical approaches that overemphasize the national dimension in global diffusion and are insensitive to the stages of the diffusion process. Further advance in study of diffusion depends, we assert, on the ability to apply both cross-sectoral and cross-national analysis to the same research design and to incorporate channels of transfer with different causal mechanisms for different stages of the diffusion process.

Recombinant adeno-associated virus serotype 6 (rAAV2/6)-mediated gene transfer to nociceptive neurons through different routes of delivery.

BACKGROUND: Gene transfer to nociceptive neurons of the dorsal root ganglia (DRG) is a promising approach to dissect mechanisms of pain in rodents and is a potential therapeutic strategy for the treatment of persistent pain disorders such as neuropathic pain. A number of studies have demonstrated transduction of DRG neurons using herpes simplex virus, adenovirus and more recently, adeno-associated virus (AAV). Recombinant AAV are currently the gene transfer vehicles of choice for the nervous system and have several advantages over other vectors, including stable and safe gene expression. We have explored the capacity of recombinant AAV serotype 6 (rAAV2/6) to deliver genes to DRG neurons and characterized the transduction of nociceptors through five different routes of administration in mice. RESULTS: Direct injection of rAAV2/6 expressing green fluorescent protein (eGFP) into the sciatic nerve resulted in transduction of up to 30% eGFP-positive cells of L4 DRG neurons in a dose dependent manner. More than 90% of transduced cells were small and medium sized neurons (< 700 microm 2), predominantly colocalized with markers of nociceptive neurons, and had eGFP-positive central terminal fibers in the superficial lamina of the spinal cord dorsal horn. The efficiency and profile of transduction was independent of mouse genetic background. Intrathecal administration of rAAV2/6 gave the highest level of transduction (approximately 60%) and had a similar size profile and colocalization with nociceptive neurons. Intrathecal administration also transduced DRG neurons at cervical and thoracic levels and resulted in comparable levels of transduction in a mouse model for neuropathic pain. Subcutaneous and intramuscular delivery resulted in low levels of transduction in the L4 DRG. Likewise, delivery via tail vein injection resulted in relatively few eGFP-positive cells within the DRG, however, this transduction was observed at all vertebral levels and corresponded to large non-nociceptive cell types. CONCLUSION: We have found that rAAV2/6 is an efficient vector to deliver transgenes to nociceptive neurons in mice. Furthermore, the characterization of the transduction profile may facilitate gene transfer studies to dissect mechanisms behind neuropathic pain.

Colonoscopy is the preferred colorectal cancer screening method in a population-based program.

BACKGROUND AND STUDY AIMS: Various screening methods for colorectal cancer (CRC) are promoted by professional societies; however, few data are available about the factors that determine patient participation in screening, which is crucial to the success of population-based programs. This study aimed (i) to identify factors that determine acceptance of screening and preference of screening method, and (ii) to evaluate procedure success, detection of colorectal neoplasia, and patient satisfaction with screening colonoscopy. PATIENTS AND METHODS: Following a public awareness campaign, the population aged 50 - 80 years was offered CRC screening in the form of annual fecal occult blood tests, flexible sigmoidoscopy, a combination of both, or colonoscopy. RESULTS: 2731 asymptomatic persons (12.0 % of the target population) registered with and were eligible to take part in the screening program. Access to information and a positive attitude to screening were major determinants of participation. Colonoscopy was the method preferred by 74.8 % of participants. Advanced colorectal neoplasia was present in 8.5 %; its prevalence was higher in males and increased with age. Significant complications occurred in 0.5 % of those undergoing colonoscopy and were associated with polypectomy or sedation. Most patients were satisfied with colonoscopy and over 90 % would choose it again for CRC screening. CONCLUSIONS: In this population-based study, only a small proportion of the target population underwent CRC screening despite an extensive information campaign. Colonoscopy was the preferred method and was safe. The determinants of participation in screening and preference of screening method, together with the distribution of colorectal neoplasia in different demographic categories, provide a rationale for improving screening procedures.