Wild bids. Gambling for resurrection in procurement contracts

This paper analyzes the problem of abnormally low tenders in theprocurement process. Limited liability causes firms in a bad financialsituation to bid more aggressively than good firms in the procurementauction. Therefore, it is more likely that the winning firm is a firm infinancial difficulties with a high risk of bankruptcy. The paper analyzesthe different regulatory practices to face this problem with a specialemphasis on surety bonds used e.g. in the US. We characterize the optimalsurety bond and show that it does not coincide with the current USregulation. In particular we show that under a natural assumption the USregulation is too expensive and provides overinsurance to the problem ofabnormally low tenders.

A process approach to the utility for gambling

This paper argues that any specific utility or disutility for gamblingmust be excluded from expected utility because such a theory is consequentialwhile a pleasure or displeasure for gambling is a matter of process, notof consequences. A (dis)utility for gambling is modeled as a process utilitywhich monotonically combines with expected utility restricted to consequences.This allows for a process (dis)utility for gambling to be revealed. Asan illustration, the model shows how empirical observations in the Allaisparadox can reveal a process disutility of gambling. A more general modelof rational behavior combining processes and consequences is then proposedand discussed.

Atlas-based segmentation of pathological MR brain images using a model of lesion growth.

We propose a method for brain atlas deformation in the presence of large space-occupying tumors, based on an a priori model of lesion growth that assumes radial expansion of the lesion from its starting point. Our approach involves three steps. First, an affine registration brings the atlas and the patient into global correspondence. Then, the seeding of a synthetic tumor into the brain atlas provides a template for the lesion. The last step is the deformation of the seeded atlas, combining a method derived from optical flow principles and a model of lesion growth. Results show that a good registration is performed and that the method can be applied to automatic segmentation of structures and substructures in brains with gross deformation, with important medical applications in neurosurgery, radiosurgery, and radiotherapy.

Dense deformation field estimation for atlas-based segmentation of pathological MR brain images.

Atlas registration is a recognized paradigm for the automatic segmentation of normal MR brain images. Unfortunately, atlas-based segmentation has been of limited use in presence of large space-occupying lesions. In fact, brain deformations induced by such lesions are added to normal anatomical variability and they may dramatically shift and deform anatomically or functionally important brain structures. In this work, we chose to focus on the problem of inter-subject registration of MR images with large tumors, inducing a significant shift of surrounding anatomical structures. First, a brief survey of the existing methods that have been proposed to deal with this problem is presented. This introduces the discussion about the requirements and desirable properties that we consider necessary to be fulfilled by a registration method in this context: To have a dense and smooth deformation field and a model of lesion growth, to model different deformability for some structures, to introduce more prior knowledge, and to use voxel-based features with a similarity measure robust to intensity differences. In a second part of this work, we propose a new approach that overcomes some of the main limitations of the existing techniques while complying with most of the desired requirements above. Our algorithm combines the mathematical framework for computing a variational flow proposed by Hermosillo et al. [G. Hermosillo, C. Chefd'Hotel, O. Faugeras, A variational approach to multi-modal image matching, Tech. Rep., INRIA (February 2001).] with the radial lesion growth pattern presented by Bach et al. [M. Bach Cuadra, C. Pollo, A. Bardera, O. Cuisenaire, J.-G. Villemure, J.-Ph. Thiran, Atlas-based segmentation of pathological MR brain images using a model of lesion growth, IEEE Trans. Med. Imag. 23 (10) (2004) 1301-1314.]. Results on patients with a meningioma are visually assessed and compared to those obtained with the most similar method from the state-of-the-art.

Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features.

BACKGROUND: Differences exist between the proximal and distal colon in terms of developmental origin, exposure to patterning genes, environmental mutagens, and gut flora. Little is known on how these differences may affect mechanisms of tumorigenesis, side-specific therapy response or prognosis. We explored systematic differences in pathway activation and their clinical implications. MATERIALS AND METHODS: Detailed clinicopathological data for 3045 colon carcinoma patients enrolled in the PETACC3 adjuvant chemotherapy trial were available for analysis. A subset of 1404 samples had molecular data, including gene expression and DNA copy number profiles for 589 and 199 samples, respectively. In addition, 413 colon adenocarcinoma from TCGA collection were also analyzed. Tumor side-effect on anti-epidermal growth factor receptor (EGFR) therapy was assessed in a cohort of 325 metastatic patients. Outcome variables considered were relapse-free survival and survival after relapse (SAR). RESULTS: Proximal carcinomas were more often mucinous, microsatellite instable (MSI)-high, mutated in key tumorigenic pathways, expressed a B-Raf proto-oncogene, serine/threonine kinase (BRAF)-like and a serrated pathway signature, regardless of histological type. Distal carcinomas were more often chromosome instable and EGFR or human epidermal growth factor receptor 2 (HER2) amplified, and more frequently overexpressed epiregulin. While risk of relapse was not different per side, SAR was much poorer for proximal than for distal stage III carcinomas in a multivariable model including BRAF mutation status [N = 285; HR 1.95, 95% CI (1.6-2.4), P < 0.001]. Only patients with metastases from a distal carcinoma responded to anti-EGFR therapy, in line with the predictions of our pathway enrichment analysis. CONCLUSIONS: Colorectal carcinoma side is associated with differences in key molecular features, some immediately druggable, with important prognostic effects which are maintained in metastatic lesions. Although within side significant molecular heterogeneity remains, our findings justify stratification of patients by side for retrospective and prospective analyses of drug efficacy and prognosis.

Expression of E-Selectin and Vascular Cell Adhesion Molecule-1 in So-Called 'Negative' Appendices: First Results to Support the Pathological Diagnosis in Borderline Cases.

Background: Since the rate of histologically 'negative' appendices still ranges between 15 and 20%, appendicitis in 'borderline' cases remains a challenging disease. As previously described, cell adhesion molecule expression correlates with different stages of appendicitis. Therefore, it was of interest to determine whether the 'negative' appendix correlated with the absence of E-selectin or vascular cell adhesion molecule-1 (VCAM-1). Methods: Nineteen grossly normal appendices from a series of 120 appendectomy specimens from patients with suspected appendicitis were analysed in frozen sections for the expression of E-selectin and VCAM-1. As control, 5 normal appendices were stained. Results: This study showed a coexpression of E-selectin and VCAM-1 in endothelial cells in early and recurrent appendicitis. In patients with symptoms for less than 6 h, only E-selectin was detected. Cases with fibrosis and luminal obliteration were only positive for VCAM-1. In cases of early appendicitis with symptoms of less than 6 h duration, a discordance between histological and immunohistochemical results was found. Conclusions: This report indicates that E-selectin and VCAM-1 expression could be useful parameters in the diagnosis of appendicitis in borderline cases.

Reelin controls progenitor cell migration in the healty and pathological adult brain

Understanding the signals that control migration of neural progenitor cells in the adult brain may provide new therapeutic opportunities. Reelin is best known for its role in regulating cell migration during brain development, but we now demonstrate a novel function for reelin in the injured adult brain. First, we show that Reelin is upregulated around lesions. Second, experimentally increasing Reelin expression levels in healthy mouse brain leads to a change in the migratory behavior of subventricular zone-derived progenitors, triggering them to leave the rostral migratory stream (RMS) to which they are normally restricted during their migration to the olfactory bulb. Third, we reveal that Reelin increases endogenous progenitor cell dispersal in periventricular structures independently of any chemoattraction but via cell detachment and chemokinetic action, and thereby potentiates spontaneous cell recruitment to demyelination lesions in the corpus callosum. Conversely, animals lacking Reelin signaling exhibit reduced endogenous progenitor recruitment at the lesion site. Altogether, these results demonstrate that beyond its known role during brain development, Reelin is a key player in post-lesional cell migration in the adult brain. Finally our findings provide proof of concept that allowing progenitors to escape from the RMS is a potential therapeutic approach to promote myelin repair.

Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

Background Brain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington's disease (HD), but its conditional administration is one of its most challenging problems. Results Here we used transgenic mice that over-express BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter (pGFAP-BDNF mice) to test whether up-regulation and release of BDNF, dependent on astrogliosis, could be protective in HD. Thus, we cross-mated pGFAP-BDNF mice with R6/2 mice to generate a double-mutant mouse with mutant huntingtin protein and with a conditional over-expression of BDNF, only under pathological conditions. In these R6/2:pGFAP-BDNF animals, the decrease in striatal BDNF levels induced by mutant huntingtin was prevented in comparison to R6/2 animals at 12 weeks of age. The recovery of the neurotrophin levels in R6/2:pGFAP-BDNF mice correlated with an improvement in several motor coordination tasks and with a significant delay in anxiety and clasping alterations. Therefore, we next examined a possible improvement in cortico-striatal connectivity in R62:pGFAP-BDNF mice. Interestingly, we found that the over-expression of BDNF prevented the decrease of cortico-striatal presynaptic (VGLUT1) and postsynaptic (PSD-95) markers in the R6/2:pGFAP-BDNF striatum. Electrophysiological studies also showed that basal synaptic transmission and synaptic fatigue both improved in R6/2:pGAP-BDNF mice. Conclusions These results indicate that the conditional administration of BDNF under the GFAP promoter could become a therapeutic strategy for HD due to its positive effects on synaptic plasticity.

An Adeno-Associated Virus-Based Intracellular Sensor of Pathological Nuclear Factor-κB Activation for Disease-Inducible Gene Transfer.

Stimulation of resident cells by NF-κB activating cytokines is a central element of inflammatory and degenerative disorders of the central nervous system (CNS). This disease-mediated NF-κB activation could be used to drive transgene expression selectively in affected cells, using adeno-associated virus (AAV)-mediated gene transfer. We have constructed a series of AAV vectors expressing GFP under the control of different promoters including NF-κB -responsive elements. As an initial screen, the vectors were tested in vitro in HEK-293T cells treated with TNF-α. The best profile of GFP induction was obtained with a promoter containing two blocks of four NF-κB -responsive sequences from the human JCV neurotropic polyoma virus promoter, fused to a new tight minimal CMV promoter, optimally distant from each other. A therapeutical gene, glial cell line-derived neurotrophic factor (GDNF) cDNA under the control of serotype 1-encapsidated NF-κB -responsive AAV vector (AAV-NF) was protective in senescent cultures of mouse cortical neurons. AAV-NF was then evaluated in vivo in the kainic acid (KA)-induced status epilepticus rat model for temporal lobe epilepsy, a major neurological disorder with a central pathophysiological role for NF-κB activation. We demonstrate that AAV-NF, injected in the hippocampus, responded to disease induction by mediating GFP expression, preferentially in CA1 and CA3 neurons and astrocytes, specifically in regions where inflammatory markers were also induced. Altogether, these data demonstrate the feasibility to use disease-activated transcription factor-responsive elements in order to drive transgene expression specifically in affected cells in inflammatory CNS disorders using AAV-mediated gene transfer.

Report on a special investigation of the Eastern Iowa Center for Problem Gambling for the period May 1, 2007 through April 30, 2009

Report on a special investigation of the Eastern Iowa Center for Problem Gambling for the period May 1, 2007 through April 30, 2009

Genetics of normal and pathological sleep in humans.

The complexity of sleep-wake regulation, in addition to the many environmental influences, includes genetic predisposing factors, which begin to be discovered. Most of the current progress in the study of sleep genetics comes from animal models (dogs, mice, and drosophila). Multiple approaches using both animal models and different genetic techniques are needed to follow the segregation and ultimately to identify 'sleep genes' and molecular bases of sleep disorders. Recent progress in molecular genetics and the development of detailed human genome map have already led to the identification of genetic factors in several complex disorders. Only a few genes are known for which a mutation causes a sleep disorder. However, single gene disorders are rare and most common disorders are complex in terms of their genetic susceptibility, environmental factors, gene-gene, and gene-environment interactions. We review here the current progress in the genetics of normal and pathological sleep and suggest a few future perspectives.

Regulated exocytosis from astrocytes physiological and pathological related aspects.

Astrocytes have traditionally been considered ancillary, satellite cells of the nervous system. However, it is a very recent acquisition that glial cells generate signaling loops which are integral to the brain circuitry and participate, interactively with neuronal networks, in the processing of information. Such a conceptual breakthrough makes this field of investigation one of the hottest in neuroscience, as it calls for a revision of past theories of brain function as well as for new strategies of experimental exploration of brain function. Glial cells are electrically not excitable, and it was only the use of optical recording techniques together with calcium sensitive dyes, that allowed the chemical excitability of glial cells to become apparent. Studies using these new techniques have shown for the first time that glial cells are activated by surrounding synaptic activity and translate neuronal signals into their own calcium code. Intracellular calcium concentration([Ca2+]i) elevations in glial cells have then shown to underlie spatial transfer of information in the glial network, accompanied by release of chemical transmitters (gliotransmitters) such as glutamate and back-signaling to neurons. As a consequence, optical imaging techniques applied to cell cultures or intact tissue have become a state-of-the-art technology for studying glial cell signaling. The molecular mechanisms leading to release of "gliotransmitters," especially glutamate, from glia are under debate. Accumulating evidence clearly indicates that astrocytes secrete numerous transmitters by Ca(2+)-dependent exocytosis. This review will discuss the mechanisms underlying the release of chemical transmitters from astrocytes with a particular emphasis to the regulated exocytosis processes.

Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial.

BACKGROUND: Pathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes. PATIENTS AND METHODS: Patients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses. RESULTS: Sufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1). CONCLUSIONS: pCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis. CLINICALTRIALSGOV: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.