Chimioradiothérapie postopératoire des cancers des voies aérodigestives : vers un nouveau standard [Post-operative radiochemotherapy of the head and neck: Towards new standards?]

Head and neck squamous cell carcinomas are frequently diagnosed at an advanced stage. Their treatment remains controversial, and has to be multidisciplinary. External beam radiotherapy is a recognized treatment option after radical curative surgery in order to improve local control. Different adjuvant treatment options have been studied in order to improve the outcome of these patients. We review in this paper the different prognostic factors indicating an adjuvant treatment and the interest of treatment intensification in bad prognostic patients.

The course of inflammatory bowel disease during pregnancy and postpartum: a prospective European ECCO-EpiCom Study of 209 pregnant women.

BACKGROUND: The impact of pregnancy on the course of IBD is still controversial. AIM: To investigate the impact of pregnancy on IBD and to search for factors with potential impact on remission. METHODS: Pregnant IBD women from 12 European countries were enrolled between January 2003 and December 2006 and compared at conception (1:1) with nonpregnant IBD women. Data on disease course were prospectively collected at each trimester during pregnancy and in the postpartum (6 months) using a standardised questionnaire. RESULTS: A total of 209 pregnant IBD women were included: 92 with Crohn's disease (CD; median age 31 years, range 17-40) and 117 with ulcerative colitis (UC; median age 32 years, range 19-42). No statistically significant difference in disease course during pregnancy and postpartum was observed between pregnant and nonpregnant CD women. Longer disease duration in CD and immunosuppressive therapy were found to be risk factors for activity during pregnancy. Pregnant UC women were more likely than nonpregnant UC women to relapse both during pregnancy (RR 2.19; 95% CI: 1.25-3.97, 0.004) and postpartum (RR 6.22; 95% CI: 2.05-79.3, P = 0.0004). During pregnancy, relapse was mainly observed in the first (RR 8.80; 95% CI 2.05-79.3, P < 0.0004) and the second trimester (RR 2.84, 95% CI 1.2-7.45, P = 0.0098). CONCLUSIONS: Pregnant women with Crohn's disease had a similar disease course both during pregnancy and after delivery as the nonpregnant women. In contrast, pregnant women with ulcerative colitis were at higher risk of relapse during pregnancy and in the postpartum than nonpregnant ulcerative colitis women.

The role of biotic interactions in shaping distributions and realised assemblages of species: implications for species distribution modelling.

Predicting which species will occur together in the future, and where, remains one of the greatest challenges in ecology, and requires a sound understanding of how the abiotic and biotic environments interact with dispersal processes and history across scales. Biotic interactions and their dynamics influence species' relationships to climate, and this also has important implications for predicting future distributions of species. It is already well accepted that biotic interactions shape species' spatial distributions at local spatial extents, but the role of these interactions beyond local extents (e.g. 10 km(2) to global extents) are usually dismissed as unimportant. In this review we consolidate evidence for how biotic interactions shape species distributions beyond local extents and review methods for integrating biotic interactions into species distribution modelling tools. Drawing upon evidence from contemporary and palaeoecological studies of individual species ranges, functional groups, and species richness patterns, we show that biotic interactions have clearly left their mark on species distributions and realised assemblages of species across all spatial extents. We demonstrate this with examples from within and across trophic groups. A range of species distribution modelling tools is available to quantify species environmental relationships and predict species occurrence, such as: (i) integrating pairwise dependencies, (ii) using integrative predictors, and (iii) hybridising species distribution models (SDMs) with dynamic models. These methods have typically only been applied to interacting pairs of species at a single time, require a priori ecological knowledge about which species interact, and due to data paucity must assume that biotic interactions are constant in space and time. To better inform the future development of these models across spatial scales, we call for accelerated collection of spatially and temporally explicit species data. Ideally, these data should be sampled to reflect variation in the underlying environment across large spatial extents, and at fine spatial resolution. Simplified ecosystems where there are relatively few interacting species and sometimes a wealth of existing ecosystem monitoring data (e.g. arctic, alpine or island habitats) offer settings where the development of modelling tools that account for biotic interactions may be less difficult than elsewhere.

Generation and characterization of function-blocking anti-ectodysplasin A (EDA) monoclonal antibodies that induce ectodermal dysplasia.

Development of ectodermal appendages, such as hair, teeth, sweat glands, sebaceous glands, and mammary glands, requires the action of the TNF family ligand ectodysplasin A (EDA). Mutations of the X-linked EDA gene cause reduction or absence of many ectodermal appendages and have been identified as a cause of ectodermal dysplasia in humans, mice, dogs, and cattle. We have generated blocking antibodies, raised in Eda-deficient mice, against the conserved, receptor-binding domain of EDA. These antibodies recognize epitopes overlapping the receptor-binding site and prevent EDA from binding and activating EDAR at close to stoichiometric ratios in in vitro binding and activity assays. The antibodies block EDA1 and EDA2 of both mammalian and avian origin and, in vivo, suppress the ability of recombinant Fc-EDA1 to rescue ectodermal dysplasia in Eda-deficient Tabby mice. Moreover, administration of EDA blocking antibodies to pregnant wild type mice induced in developing wild type fetuses a marked and permanent ectodermal dysplasia. These function-blocking anti-EDA antibodies with wide cross-species reactivity will enable study of the developmental and postdevelopmental roles of EDA in a variety of organisms and open the route to therapeutic intervention in conditions in which EDA may be implicated.

A novel family of dehydrin-like proteins is involved in stress response in the human fungal pathogen Aspergillus fumigatus.

 During a search for genes controlling conidial dormancy in Aspergillus fumigatus, two dehydrin-like genes, DprA and DprB, were identified. The deduced proteins had repeated stretches of 23 amino acids that contained a conserved dehydrin-like protein (DPR) motif. Disrupted DprAΔ mutants were hypersensitive to oxidative stress and to phagocytic killing, whereas DprBΔ mutants were impaired in osmotic and pH stress responses. However, no effect was observed on their pathogenicity in our experimental models of invasive aspergillosis. Molecular dissection of the signaling pathways acting upstream showed that expression of DprA was dependent on the stress-activated kinase SakA and the cyclic AMP-protein kinase A (cAMP-PKA) pathways, which activate the bZIP transcription factor AtfA, while expression of DprB was dependent on the SakA mitogen-activated protein kinase (MAPK) pathway, and the zinc finger transcription factor PacC. Fluorescent protein fusions showed that both proteins were associated with peroxisomes and the cytosol. Accordingly, DprA and DprB were important for peroxisome function. Our findings reveal a novel family of stress-protective proteins in A. fumigatus and, potentially, in filamentous ascomycetes.

Postoperative management of adult central neurosurgical patients: systemic and neuro-monitoring.

Postoperative neurosurgical patients are at risk of developing complications. Systemic and neuro-monitoring are used to identify patients who deteriorate in order to treat the underlying cause and minimize the impact on outcome. Hypotension and hypoxia are likely to be the most frequent insults and can be detected easily with blood pressure monitoring and pulse oximetry. Repeated clinical examination, however, is probably the most important monitor in the postoperative setting. Clinical scores such as the Glasgow Coma Score and the more recently introduced FOUR Score are important tools to standardize the clinical assessment. Intracranial pressure monitoring, cerebral blood flow monitoring, electroencephalography, and brain imaging are often used postoperatively. Despite the numerous publications on this topic only few studies address the impact of postoperative monitoring on outcome. Accordingly, in most patients the decision on which monitors are to be used must be based on the patient's presentation and clinical judgment.

The CaMV 35S promoter has a weak expression activity in dark grown tissues of moss Physcomitrella patens.

The constitutive Cauliflower Mosaic Virus 35S promoter (CaMV 35S) is widely used as a tool to express recombinant proteins in plants, but with different success. We previously showed that the expression of an F-actin marker, GFP-talin, in Physcomitrella patens using the CaMV 35S promoter failed to homogenously label moss tissues. Here, we show a significant diminution of the GFP fluorescence in dark grown old moss cells and complete lack of labelling in newly differentiated cells. Furthermore, we demonstrate that stable moss lines harbouring a resistance cassette driven by the CaMV 35S are unable to grow in darkness in the presence of the antibiotic. In contrast to the CaMV 35S, the heat inducible promoter, hsp17.3B showed uniform expression pattern in all cells and tissues following a mild heat shock.

Toward improved immunocompetence of adoptively transferred CD8+ T cells.

Adoptive transfer of autologous or allogenic T cells to patients is being used with increased frequency as a therapy for infectious diseases and cancer. However, many questions remain with regard to defining optimized procedures for preparation and selection of T cell populations for transfer. In a new study in this issue of the JCI, Gattinoni and colleagues used a TCR transgenic mouse model to examine in vitro-generated tumor antigen-specific CD8+ T cells at various stages of differentiation for their efficacy in adoptive immunotherapy against transplantable melanoma. The results confirm that CD8+ T cells progressively lose immunocompetence with prolonged in vitro cultivation and suggest that effector CD8+ T cells alone may be considerably less potent at protecting hosts with advanced tumors than are less differentiated T cells.

Teichoic acids are not required for Streptococcus pneumoniae and Staphylococcus aureus cell walls to trigger the release of tumor necrosis factor by peripheral blood monocytes.

In gram-negative bacteria, the outer membrane lipopolysaccharide is the main component triggering cytokine release from peripheral blood mononuclear cells (PBMCs). In gram-positive bacteria, purified walls also induce cytokine release, but stimulation requires 100 times more material. Gram-positive walls are complex megamolecules reassembling distinct structures. Only some of them might be inflammatory, whereas others are not. Teichoic acids (TA) are an important portion (&gt; or =50%) of gram-positive walls. TA directly interact with C3b of complement and the cellular receptor for platelet-activating factor. However, their contribution to wall-induced cytokine-release by PBMCs has not been studied in much detail. In contrast, their membrane-bound lipoteichoic acids (LTA) counterparts were shown to trigger inflammation and synergize with peptidoglycan (PGN) for releasing nitric oxide (NO). This raised the question as to whether TA are also inflammatory. We determined the release of tumor necrosis factor (TNF) by PBMCs exposed to a variety of TA-rich and TA-free wall fragments from Streptococcus pneumoniae and Staphylococcus aureus. TA-rich walls from both organisms induced measurable TNF release at concentrations of 1 microg/ml. Removal of wall-attached TA did not alter this activity. Moreover, purified pneumococcal and staphylococcal TA did not trigger TNF release at concentrations as high as &gt; or =100 microg/ml. In contrast, purified LTA triggered TNF release at 1 microg/ml. PGN-stem peptide oligomers lacking TA or amino-sugars were highly active and triggered TNF release at concentrations as low as 0.01 microg/ml (P. A. Majcherczyk, H. Langen, et al., J. Biol. Chem. 274:12537-12543,1999). Thus, although TA is an important part of gram-positive walls, it did not participate to the TNF-releasing activity of PGN.

Low estimates of dietary acid load are positively associated with bone ultrasound in women older than 75 years of age with a lifetime fracture

Dietary acid load from Western diets may be a risk factor for osteoporosis. It can be estimated by net endogenous acid production (NEAP). No data currently exists for NEAP estimates and bone indices in the very elderly (i.e. > or = 75 y). The aim of this study was to determine the association between NEAP estimates by using the potential renal acid load (PRAL) equation and quantitative bone ultrasound (QUS) measurements at the heel [broadband ultrasound attenuation (BUA)] in Caucasian women. We assessed NEAP and QUS in 401 very elderly Swiss ambulatory women. We evaluated dietary intake and NEAP estimates with a validated FFQ. QUS was measured using Achilles (Lunar). We identified 2 subgroups: 256 women (80.6 y +/- 3; BUA, 96.8 dB/MHz) with a fracture history and the remaining 145 (79.9 y SD 2.9; BUA, 101.7 dB/MHz) without. Women who reported having suffered a fracture had lower BUA (P < 0.001) than nonfractured women but did not differ in nutrient intakes and NEAP. Lower NEAP (P = 0.023) and higher potassium intake (P = 0.033) were correlated with higher BUA, which remained significant even after adjustment for age, BMI, and osteoporosis treatment. BUA was positively correlated with calcium (P = 0.016) and BMI (P < 0.001). Women who reported no fractures had no significant correlations between nutrient intake, NEAP, and BUA. Low nutritional acid load was correlated with higher BUA in very elderly women with a fracture history. Although relatively weak compared with age and BMI, this association was significant and may be an important additional risk factor that might be particularly relevant in frail patients with an already high fracture risk.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Detection of Optimal Models in Parameter Space with Support Vector Machines

The paper proposes an approach aimed at detecting optimal model parameter combinations to achieve the most representative description of uncertainty in the model performance. A classification problem is posed to find the regions of good fitting models according to the values of a cost function. Support Vector Machine (SVM) classification in the parameter space is applied to decide if a forward model simulation is to be computed for a particular generated model. SVM is particularly designed to tackle classification problems in high-dimensional space in a non-parametric and non-linear way. SVM decision boundaries determine the regions that are subject to the largest uncertainty in the cost function classification, and, therefore, provide guidelines for further iterative exploration of the model space. The proposed approach is illustrated by a synthetic example of fluid flow through porous media, which features highly variable response due to the parameter values' combination.