Monitoring detrital input and resuspension effects on sediment trap material using mineralogy and stable isotopes (δ18O and δ13C): the case of Lake Neuchatel (Switzerland)

Isotopic analyses on bulk carbonates are considered a useful tool for palaeoclimatic reconstruction assuming calcite precipitation occurring at oxygen isotope equilibrium with local water and detrital carbonate input being absent or insignificant. We present results from Lake Neuchatel (western Switzerland) that demonstrate equilibrium precipitation of calcite, except during high productivity periods, and the presence of detrital and resuspended calcite. Mineralogy, geochemistry and stable isotope values of Lake Neuchatel trap sediments and adjacent rivers suspension were studied. Mineralogy of suspended matter in the major inflowing rivers documents an important contribution of detrital carbonates, predominantly calcite with minor amounts of dolomite and ankerite. Using mineralogical data, the quantity of allochthonous calcite can be estimated by comparing the ratio ankerite + dolomite/calcite + ankerite + dolomite in the inflowing rivers and in the traps. Material taken from sediment traps shows an evolution from practically pure endogenic calcite in summer (10-20% detrital material) to higher percentages of detrital material in winter (up to 20-40%). Reflecting these mineralogical variations, delta(13)C and delta(18)O values of calcite from sediment traps are more negative in summer than in winter times. Since no significant variations in isotopic composition of lake water were detected over one year, factors controlling oxygen isotopic composition of calcite in sediment traps are the precipitation temperature, and the percentage of resuspended and detrital calcite. Samples taken close to the river inflow generally have higher delta values than the others, confirming detrital influence. SEM and isotopic studies on different size fractions (<2, 2-6, 6-20, 20-60, >60 mu m) of winter and summer samples allowed the recognition of resuspension and to separate new endogenic calcite from detrital calcite. Fractions >60 and (2 mu m have the highest percentage of detritus, Fractions 2-6 and 6-20 mu m are typical for the new endogenic calcite in summer, as given by calculations assuming isotopic equilibrium with local water. In winter such fractions show similar values than in summer, indicating resuspension. Using the isotopic composition of sediment traps material and of different size fractions, as well as the isotopic composition of lake water, the water temperature measurements and mineralogy, we re-evaluated the bulk carbonate potential for palaeoclimatic reconstruction in the presence of detrital and re-suspended calcite. This re-evaluation leads to the following conclusion: (1) the endogenic signal can be amplified by applying a particle-size separation, once the size of endogenic calcite is known from SEM study; (2) resuspended calcite does not alter the endogenic signal, but it lowers the time resolution; (3) detrital input decreases at increasing distances from the source, and it modifies the isotopic signal only when very abundant; (4) influence of detrital calcite on bulk sediment isotopic composition can be calculated. (C) 1998 Elsevier Science B.V. All rights reserved.

A new method to estimate the infilling of alluvial sediment of glacial valleys using a sloping local base level

A new method is used to estimate the volumes of sediments of glacial valleys. This method is based on the concept of sloping local base level and requires only a digital terrain model and the limits of the alluvial valleys as input data. The bedrock surface of the glacial valley is estimated by a progressive excavation of the digital elevation model (DEM) of the filled valley area. This is performed using an iterative routine that replaces the altitude of a point of the DEM by the mean value of its neighbors minus a fixed value. The result is a curved surface, quadratic in 2D. The bedrock surface of the Rhone Valley in Switzerland was estimated by this method using the free digital terrain model Shuttle Radar Topography Mission (SRTM) (~92 m resolution). The results obtained are in good agreement with the previous estimations based on seismic profiles and gravimetric modeling, with the exceptions of some particular locations. The results from the present method and those from the seismic interpretation are slightly different from the results of the gravimetric data. This discrepancy may result from the presence of large buried landslides in the bottom of the Rhone Valley.

Origin and evolution of homologous repeated sequences in the mitochondrial DNA control region of shrews.

The complete mitochondrial DNA (mtDNA) control region was amplified and directly sequenced in two species of shrew, Crocidura russula and Sorex araneus (Insectivora, Mammalia). The general organization is similar to that found in other mammals: a central conserved region surrounded by two more variable domains. However, we have found in shrews the simultaneous presence of arrays of tandem repeats in potential locations where repeats tend to occur separately in other mammalian species. These locations correspond to regions which are associated with a possible interruption of the replication processes, either at the end of the three-stranded D-loop structure or toward the end of the heavy-strand replication. In the left domain the repeated sequences (R1 repeats) are 78 bp long, whereas in the right domain the repeats are 12 bp long in C. russula and 14 bp long in S. araneus (R2 repeats). Variation in the copy number of these repeated sequences results in mtDNA control region length differences. Southern blot analysis indicates that level of heteroplasmy (more than one mtDNA form within an individual) differs between species. A comparative study of the R2 repeats in 12 additional species representing three shrew subfamilies provides useful indications for the understanding of the origin and the evolution of these homologous tandemly repeated sequences. An asymmetry in the distribution of variants within the arrays, as well as the constant occurrence of shorter repeated sequences flanking only one side of the R2 arrays, could be related to asymmetry in the replication of each strand of the mtDNA molecule. The pattern of sequence and length variation within and between species, together with the capability of the arrays to form stable secondary structures, suggests that the dominant mechanism involved in the evolution of these arrays in unidirectional replication slippage.

Photodynamic Diagnosis of Non-muscle-invasive Bladder Cancer with Hexaminolevulinate Cystoscopy: A Meta-analysis of Detection and Recurrence Based on Raw Data.

BACKGROUND: Studies on hexaminolevulinate (HAL) cystoscopy report improved detection of bladder tumours. However, recent meta-analyses report conflicting effects on recurrence. OBJECTIVE: To assess available clinical data for blue light (BL) HAL cystoscopy on the detection of Ta/T1 and carcinoma in situ (CIS) tumours, and on tumour recurrence. DESIGN, SETTING, AND PARTICIPANTS: This meta-analysis reviewed raw data from prospective studies on 1345 patients with known or suspected non-muscle-invasive bladder cancer (NMIBC). INTERVENTION: A single application of HAL cystoscopy was used as an adjunct to white light (WL) cystoscopy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We studied the detection of NMIBC (intention to treat [ITT]: n=831; six studies) and recurrence (per protocol: n=634; three studies) up to 1 yr. DerSimonian and Laird's random-effects model was used to obtain pooled relative risks (RRs) and associated 95% confidence intervals (CIs) for outcomes for detection. RESULTS AND LIMITATIONS: BL cystoscopy detected significantly more Ta tumours (14.7%; p<0.001; odds ratio [OR]: 4.898; 95% CI, 1.937-12.390) and CIS lesions (40.8%; p<0.001; OR: 12.372; 95% CI, 6.343-24.133) than WL. There were 24.9% patients with at least one additional Ta/T1 tumour seen with BL (p<0.001), significant also in patients with primary (20.7%; p<0.001) and recurrent cancer (27.7%; p<0.001), and in patients at high risk (27.0%; p<0.001) and intermediate risk (35.7%; p=0.004). In 26.7% of patients, CIS was detected only by BL (p<0.001) and was also significant in patients with primary (28.0%; p<0.001) and recurrent cancer (25.0%; p<0.001). Recurrence rates up to 12 mo were significantly lower overall with BL, 34.5% versus 45.4% (p=0.006; RR: 0.761 [0.627-0.924]), and lower in patients with T1 or CIS (p=0.052; RR: 0.696 [0.482-1.003]), Ta (p=0.040; RR: 0.804 [0.653-0.991]), and in high-risk (p=0.050) and low-risk (p=0.029) subgroups. Some subgroups had too few patients to allow statistically meaningful analysis. Heterogeneity was minimised by the statistical analysis method used. CONCLUSIONS: This meta-analysis confirms that HAL BL cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9-12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer.

Analysis of the contribution of the β-oxidation auxiliary enzymes in the degradation of the dietary conjugated linoleic acid 9-cis-11-trans-octadecadienoic acid in the peroxisomes of Saccharomyces cerevisiae

Beta-oxidation of the conjugated linoleic acid 9-cis,11-trans-octadecadienoic acid (rumenic acid) was analyzed in vivo in Saccharomyces cerevisiae by monitoring polyhydroxyalkanoate production in the peroxisome. Polyhydroxyalkanoate is synthesized by the polymerization of the beta-oxidation intermediates 3-hydroxyacyl-CoAs via a bacterial polyhydroxyalkanoate synthase targeted to the peroxisome. The amount of polyhydroxyalkanaote synthesized from the degradation of rumenic acid was found to be similar to the amount synthesized from the degradation of 10-trans,12-cis-octadecadienoic acid, oleic acid or 10-cis-heptadecenoic acid. Furthermore, the degradation of 10-cis-heptadecenoic acid was found to be unaffected by the presence of rumenic acid in the media. Efficient degradation of rumenic acid was found to be independent of the Delta(3,5),Delta(2,4)-dienoyl-CoA isomerase but instead relied on the presence of Delta(3),Delta(2)-enoyl-CoA isomerase activity. The presence of the unsaturated monomer 3-hydroxydodecenoic acid in polyhydroxyalkanoate derived from rumenic acid degradation was found to be dependent on the presence of a Delta(3),Delta(2)-enoyl-CoA isomerase activity. Together, these data indicate that rumenic acid is mainly degraded in vivo in S. cerevisiae through a pathway requiring only the participation of the auxiliary enzymes Delta(3),Delta(2)-enoyl-CoA isomerase, along with the enzyme of the core beta-oxidation cycle.

Lymphoid stroma in health and disease

Summary Secondary lymphoid organs (SLOB), such as lymph nodes and spleen, are the sites where primary immune responses are initiated. T lymphocytes patrol through the blood and SLOs on the search for pathogens which are presented to them as antigens by dendritic cells. Stromal cells in the Tzone - so called T zone fibroblastic reticular cells (TRCs) -are critical in organizing the migration of T cells and dendritic cells by producing the chemoattractants CCL19 and CCL21 and by forming a network which T cells use as a guidance system. They also form a system of small channels or conduits that allow rapid transport of small antigen molecules or cytokines from the subcapsular sinus to high endothelial venules. The phenotype and function of TRCs have otherwise remained largely unknown. We found a critical role for lymph node access in CD4+ and CD8+ T cell homeostasis and identified TRCs within these organs as the major source of interleukin-7 (IL-7). IL-7 is an essential survival factor for naïve T lymphocytes of which the cellular source in the periphery had been poorly defined. In vitro, TRC were able to prevent the death of naïve T but not of B lymphocytes by secreting IL-7 and the CCR7 ligand CCL 19. Using gene-targeted mice, we show anon-redundant function of CCL19 in T cell homeostasis. The data suggest that TRCs regulate T cell numbers by providing a limited reservoir of survival factors for which T cells have to compete. They help to maintain a diverse T cell repertoire granting full immunocompetence. To determine whether TRCs also play a role in pathology, we characterized so-called tertiary lymphoid organs (TLOs) that often develop at sites of chronic inflammation. We show that TLOs resemble lymph nodes or Peyer's patches not only with regard to lymphoid cells. TLOs formed extensive TRC networks and a functional conduit system in all three marine inflammation models tested. In one model we dissected the cells and signals leading to the formation of these structures. We showed that they critically depend on the presence of lymphotoxin and lymphoid tissue inducer cells. TRCs in TLOs also produce CCL19, GCL21 and possibly IL-7 which are all involved in the development of TLOs. Stromal cells therefore play a central role in the onset and perpetuation of chronic inflammatory diseases and could be an interesting target for therapy. Résumé Le système immunitaire est la défense de notre corps contre toutes sortes d'infections et de tumeurs. II est constitué de différentes populations de lymphocytes qui patrouillent constamment le corps à la recherche de pathogène. Parmi eux, les lymphocytes T et B passent régulièrement dans les organes lymphoïdes secondaires (SLO) qui sont les sites d'initiation de la réponse immunitaire. Les lymphocytes T sont recrutés du sang aux SLO où ils cherchent leur antigène respectif présenté par des cellules dendritiques. Des cellules stromales dans la zone T -nommées fibroblastic reticular cells' (TRC) -sécrètent des chimiokines CCL19 et CCL21 et ainsi facilitent les rencontres entre lymphocytes T et cellules dendritiques. De plus, elles forment un réseau que les lymphocytes T utilisent comme système de guidage. Ce réseau forme des petits canaux (ou conduits) qui permettent le transport rapide, d'antigène soluble ou de cytokines, de la lymphe aux veinules à endothelium épais (HEV). Le phénotype ainsi que les autres fonctions des TRCs demeurent encore à ce jour inconnus. Nous avons trouvé que l'accès des lymphocytes T CD4+ et CD8+ aux ganglions joue un rôle central pour l'homéostasie. Interleukin-7 (IL-7) est un facteur de survie essentiel pour les lymphocytes T naïfs dont la source cellulaire dans la périphérie était mal définie. Nous avons identifié les TRCs dans les ganglions comme source principale d'interleukin-7 (IL-7). In vitro, les TRCs étaient capable de prévenir la mort des lymphocytes T mais pas celle de lymphocytes B grâce à la sécrétion d'IL-7 et de CCL19. En utilisant des souris déficientes du gène CCL19, nous avons observé que l'homéostasie des lymphocytes T dépend aussi de CCL19 in vivo. Les données suggèrent que les TRCs aident à maintenir un répertoire large et diversifié de cellules T et ainsi l'immunocompétence. Pour déterminer si les TRCs pourraient jouer un rote également dans la pathologie, nous avons caractérisé des organes lymphoïdes tertiaires (TLOs) souvent associés avec l'inflammation chronique. Les TLOs ressemblent à des ganglions ou des plaques de Peyer pas seulement en ce qui concerne la présence de lymphocytes. Nous avons constaté que les TLOs forment des réseaux de TRC et un système fonctionnel de conduits. La formation de ces structures est fortement diminuée dans l'absence du signal lymphotoxin ou des cellules connues comme ymphoid tissue-inducer tells: Les TRCs dans les TLOs produisent les chimiokines CCL19, CCL21 et possiblement aussi IL-7 qui sont impliquées dans le développement des TLOs. Les cellules stromales jouent donc un rôle central dans l'initation et la perpétuation des maladies inflamatoires chroniques et pourraient être une cible intéressante pour la thérapie.

Biomedical risk assessment as an aid for smoking cessation.

BACKGROUND: A possible strategy for increasing smoking cessation rates could be to provide smokers who have contact with healthcare systems with feedback on the biomedical or potential future effects of smoking, e.g. measurement of exhaled carbon monoxide (CO), lung function, or genetic susceptibility to lung cancer. OBJECTIVES: To determine the efficacy of biomedical risk assessment provided in addition to various levels of counselling, as a contributing aid to smoking cessation. SEARCH METHODS: For the most recent update, we searched the Cochrane Collaboration Tobacco Addiction Group Specialized Register in July 2012 for studies added since the last update in 2009. SELECTION CRITERIA: Inclusion criteria were: a randomized controlled trial design; subjects participating in smoking cessation interventions; interventions based on a biomedical test to increase motivation to quit; control groups receiving all other components of intervention; an outcome of smoking cessation rate at least six months after the start of the intervention. DATA COLLECTION AND ANALYSIS: Two assessors independently conducted data extraction on each paper, with disagreements resolved by consensus. Results were expressed as a relative risk (RR) for smoking cessation with 95% confidence intervals (CI). Where appropriate, a pooled effect was estimated using a Mantel-Haenszel fixed-effect method. MAIN RESULTS: We included 15 trials using a variety of biomedical tests. Two pairs of trials had sufficiently similar recruitment, setting and interventions to calculate a pooled effect; there was no evidence that carbon monoxide (CO) measurement in primary care (RR 1.06, 95% CI 0.85 to 1.32) or spirometry in primary care (RR 1.18, 95% CI 0.77 to 1.81) increased cessation rates. We did not pool the other 11 trials due to the presence of substantial clinical heterogeneity. Of the remaining 11 trials, two trials detected statistically significant benefits: one trial in primary care detected a significant benefit of lung age feedback after spirometry (RR 2.12, 95% CI 1.24 to 3.62) and one trial that used ultrasonography of carotid and femoral arteries and photographs of plaques detected a benefit (RR 2.77, 95% CI 1.04 to 7.41) but enrolled a population of light smokers and was judged to be at unclear risk of bias in two domains. Nine further trials did not detect significant effects. One of these tested CO feedback alone and CO combined with genetic susceptibility as two different interventions; none of the three possible comparisons detected significant effects. One trial used CO measurement, one used ultrasonography of carotid arteries and two tested for genetic markers. The four remaining trials used a combination of CO and spirometry feedback in different settings. AUTHORS' CONCLUSIONS: There is little evidence about the effects of most types of biomedical tests for risk assessment on smoking cessation. Of the fifteen included studies, only two detected a significant effect of the intervention. Spirometry combined with an interpretation of the results in terms of 'lung age' had a significant effect in a single good quality trial but the evidence is not optimal. A trial of carotid plaque screening using ultrasound also detected a significant effect, but a second larger study of a similar feedback mechanism did not detect evidence of an effect. Only two pairs of studies were similar enough in terms of recruitment, setting, and intervention to allow meta-analyses; neither of these found evidence of an effect. Mixed quality evidence does not support the hypothesis that other types of biomedical risk assessment increase smoking cessation in comparison to standard treatment. There is insufficient evidence with which to evaluate the hypothesis that multiple types of assessment are more effective than single forms of assessment.

Phylogeography and Pleistocene refugia of the adder (Vipera berus) as inferred from mitochondrial DNA sequence data.

In order to contribute to the debate about southern glacial refugia used by temperate species and more northern refugia used by boreal or cold-temperate species, we examined the phylogeography of a widespread snake species (Vipera berus) inhabiting Europe up to the Arctic Circle. The analysis of the mitochondrial DNA (mtDNA) sequence variation in 1043 bp of the cytochrome b gene and in 918 bp of the noncoding control region was performed with phylogenetic approaches. Our results suggest that both the duplicated control region and cytochrome b evolve at a similar rate in this species. Phylogenetic analysis showed that V. berus is divided into three major mitochondrial lineages, probably resulting from an Italian, a Balkan and a Northern (from France to Russia) refugial area in Eastern Europe, near the Carpathian Mountains. In addition, the Northern clade presents an important substructure, suggesting two sequential colonization events in Europe. First, the continent was colonized from the three main refugial areas mentioned above during the Lower-Mid Pleistocene. Second, recolonization of most of Europe most likely originated from several refugia located outside of the Mediterranean peninsulas (Carpathian region, east of the Carpathians, France and possibly Hungary) during the Mid-Late Pleistocene, while populations within the Italian and Balkan Peninsulas fluctuated only slightly in distribution range, with larger lowland populations during glacial times and with refugial mountain populations during interglacials, as in the present time. The phylogeographical structure revealed in our study suggests complex recolonization dynamics of the European continent by V. berus, characterized by latitudinal as well as altitudinal range shifts, driven by both climatic changes and competition with related species.

Evolution of the P-type II ATPase gene family in the fungi and presence of structural genomic changes among isolates of Glomus intraradices.

BACKGROUND: The P-type II ATPase gene family encodes proteins with an important role in adaptation of the cell to variation in external K+, Ca2+ and Na2+ concentrations. The presence of P-type II gene subfamilies that are specific for certain kingdoms has been reported but was sometimes contradicted by discovery of previously unknown homologous sequences in newly sequenced genomes. Members of this gene family have been sampled in all of the fungal phyla except the arbuscular mycorrhizal fungi (AMF; phylum Glomeromycota), which are known to play a key-role in terrestrial ecosystems and to be genetically highly variable within populations. Here we used highly degenerate primers on AMF genomic DNA to increase the sampling of fungal P-Type II ATPases and to test previous predictions about their evolution. In parallel, homologous sequences of the P-type II ATPases have been used to determine the nature and amount of polymorphism that is present at these loci among isolates of Glomus intraradices harvested from the same field. RESULTS: In this study, four P-type II ATPase sub-families have been isolated from three AMF species. We show that, contrary to previous predictions, P-type IIC ATPases are present in all basal fungal taxa. Additionally, P-Type IIE ATPases should no longer be considered as exclusive to the Ascomycota and the Basidiomycota, since we also demonstrate their presence in the Zygomycota. Finally, a comparison of homologous sequences encoding P-type IID ATPases showed unexpectedly that indel mutations among coding regions, as well as specific gene duplications occur among AMF individuals within the same field. CONCLUSION: On the basis of these results we suggest that the diversification of P-Type IIC and E ATPases followed the diversification of the extant fungal phyla with independent events of gene gains and losses. Consistent with recent findings on the human genome, but at a much smaller geographic scale, we provided evidence that structural genomic changes, such as exonic indel mutations and gene duplications are less rare than previously thought and that these also occur within fungal populations.

Joint inversion of crosshole GPR and seismic traveltime data

Joint inversion of crosshole ground-penetrating radar and seismic data can improve model resolution and fidelity of the resultant individual models. Model coupling obtained by minimizing or penalizing some measure of structural dissimilarity between models appears to be the most versatile approach because only weak assumptions about petrophysical relationships are required. Nevertheless, experimental results and petrophysical arguments suggest that when porosity variations are weak in saturated unconsolidated environments, then radar wave speed is approximately linearly related to seismic wave speed. Under such circumstances, model coupling also can be achieved by incorporating cross-covariances in the model regularization. In two case studies, structural similarity is imposed by penalizing models for which the model cross-gradients are nonzero. A first case study demonstrates improvements in model resolution by comparing the resulting models with borehole information, whereas a second case study uses point-spread functions. Although radar seismic wavespeed crossplots are very similar for the two case studies, the models plot in different portions of the graph, suggesting variances in porosity. Both examples display a close, quasilinear relationship between radar seismic wave speed in unconsolidated environments that is described rather well by the corresponding lower Hashin-Shtrikman (HS) bounds. Combining crossplots of the joint inversion models with HS bounds can constrain porosity and pore structure better than individual inversion results can.

Particle exposure scenarios for research and production activities involving nanomaterials

Nanomaterials with structures in the nanoscale (1 to 100 nm) often have chemical, physical and bioactive characteristics different from those of larger entities of the same material. This is interesting for industry but raises questions about the health of exposed people. However, little is known so far about the exposure of workers to inhalable airborne nanomaterials. We investigated several activities in research laboratories and industry to learn about relevant exposure scenarios. Work process analyses were combined with measurements of airborne particle mass concentrations and number−size distributions. Background levels in research settings were mostly low, while in industrial production, levels were sometimes elevated, especially in halls near busy roads or in the presence of diesel fork lifts without particle filters. Peak levels were found in an industrial setting dealing with powders (up to 80,000 particles/cm³ and up to 15 mg/m³). Mostly low concentrations were found for activities involving liquid applications. However, centrifugation and lyophilization of nanoparticle containing solutions resulted in very high particle number concentrations (up to 300,000 particles/cm³), whereas no increases were seen for the same activities conducted with nanoparticle−free liquids. No significant increases of particle concentrations were found for processes involving nanoparticles bound to surfaces. Also no increases were observed in laboratories that were visualizing properties and structures of small amounts of nanomaterials. Conclusion: When studying exposure scenarios for airborne nanomaterials, the focus should not only be on processes involving nano−powders, but also on processes involving intensively treated nanoparticle−containing liquids. Acknowledgement: We thank Chantal Imhof, MSc and Guillaume Ferraris, MSc for their contributions.

Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer.

BACKGROUND: Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS: Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (nâeuro0/00=âeuro0/00543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS: The proportions of patients in the 4 subgroups were comparable in both treatment arms (Pâeuro0/00=âeuro0/00.77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (Pâeuro0/00=âeuro0/00.45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (Pâeuro0/00<âeuro0/00.0001) and OS (Pâeuro0/00=âeuro0/00.001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. CONCLUSIONS: Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy.

Differing trends in the association between obesity and self-reported health in Portugal and Switzerland: data from national health surveys 1992-2007.

BACKGROUND: The escalating prevalence of obesity might prompt obese subjects to consider themselves as normal, as this condition is gradually becoming as frequent as normal weight. In this study, we aimed to assess the trends in the associations between obesity and self-rated health in two countries. METHODS: Data from the Portuguese (years 1995-6, 1998-6 and 2005-6) and Swiss (1992-3, 1997, 2002 and 2007) National Health Surveys were used, corresponding to more than 130,000 adults (64,793 for Portugal and 65,829 for Switzerland). Body mass index and self-rated health were derived from self-reported data. RESULTS: Obesity levels were higher in Portugal (17.5% in 2005-6 vs. 8.9% in 2007 in Switzerland, p < 0.001) and increased in both countries. The prevalence of participants rating their health as "bad" or "very bad" was higher in Portugal than in Switzerland (21.8% in 2005-6 vs 3.9% in 2007, p < 0.001). In both countries, obese participants rated more frequently their health as "bad" or "very bad" than participants with regular weight. In Switzerland, the prevalence of "bad" or "very bad" rates among obese participants, increased from 6.5% in 1992-3 to 9.8% in 2007, while in Portugal it decreased from 41.3% to 32.3%. After multivariate adjustment, the odds ratio (OR) of stating one self's health as "bad" or "very bad" among obese relative to normal weight participants, almost doubled in Switzerland: from 1.38 (95% confidence interval, CI: 1.01-1.87) in 1992-3 to 2.64 (95% CI: 2.14-3.26) in 2007, and similar findings were obtained after sample weighting. Conversely, no such trend was found in Portugal: 1.35 (95% CI: 1.23-1.48) in 1995-6 and 1.52 (95% CI: 1.37-1.70) in 2005-6. CONCLUSION: Obesity is increasing in Switzerland and Portugal. Obesity is increasingly associated with poorer self-health ratings in Switzerland but not in Portugal.

Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators.

The nuclear peroxisome proliferator-activated receptors (PPARs) alpha, beta, and gamma activate the transcription of multiple genes involved in lipid metabolism. Several natural and synthetic ligands have been identified for each PPAR isotype but little is known about the phosphorylation state of these receptors. We show here that activators of protein kinase A (PKA) can enhance mouse PPAR activity in the absence and the presence of exogenous ligands in transient transfection experiments. Activation function 1 (AF-1) of PPARs was dispensable for transcriptional enhancement, whereas activation function 2 (AF-2) was required for this effect. We also show that several domains of PPAR can be phosphorylated by PKA in vitro. Moreover, gel retardation experiments suggest that PKA stabilizes binding of the liganded PPAR to DNA. PKA inhibitors decreased not only the kinase-dependent induction of PPARs but also their ligand-dependent induction, suggesting an interaction between both pathways that leads to maximal transcriptional induction by PPARs. Moreover, comparing PPAR alpha knockout (KO) with PPAR alpha WT mice, we show that the expression of the acyl CoA oxidase (ACO) gene can be regulated by PKA-activated PPAR alpha in liver. These data demonstrate that the PKA pathway is an important modulator of PPAR activity, and we propose a model associating this pathway in the control of fatty acid beta-oxidation under conditions of fasting, stress, and exercise.

IgG subclass switch capacity is low in switched and in IgM-only, but high in IgD+IgM+, post-germinal center (CD27+) human B cells.

Recent studies have shown that in humans the germinal center reactions produce three types of V(D)J mutated B cells in similar proportions, i.e. Ig-switched, IgD-IgM+ (IgM-only) and IgD+IgM+ cells, and that together they form the CD27+ compartment of recirculating B cells. We investigated the Ig isotype switch capacity of these cells. Peripheral blood B subsets were sorted and IgG subclass secretion in presence or absence of IL-4 was compared in B cell assays which lead to Ig secretion in all (coculture with EL-4 thymoma cells) or only in CD27+ (CD40L stimulation) B cells. Already switched IgG+ B cells showed no significant sequential switch and IgM-only cells also had a low switch capacity, but IgD+CD27+ switched as much as IgD+CD27- B cells to all IgG subclasses. Thus, in switched B cells some alterations compromising further switch options occur frequently; IgM-only cells may result from aborted switch. However, IgD+CD27+ human B cells, extensively V(D)J mutated and "naive" regarding switch, build up a repertoire of B cells combining (1) novel cross-reactive specificities, (2) increased differentiation capacity (including after T-independent stimulation by Staphylococcus aureus Cowan I) and (3) the capacity to produce appropriate isotypes when they respond to novel pathogens.