New generation vaccine induces effective melanoma-specific CD8+ T cells in the circulation but not in the tumor site.

Although increasing evidence suggests that CTL are important to fight the development of some cancers, the frequency of detectable tumor-specific T cells is low in cancer patients, and these cells have generally poor functional capacities, compared with virus-specific CD8(+) T cells. The generation with a vaccine of potent CTL responses against tumor Ags therefore remains a major challenge. In the present study, ex vivo analyses of Melan-A-specific CD8(+) T cells following vaccination with Melan-A peptide and CpG oligodeoxynucleotides revealed the successful induction in the circulation of effective melanoma-specific T cells, i.e., with phenotypic and functional characteristics similar to those of CTL specific for immunodominant viral Ags. Nonetheless, the eventual impact on tumor development in vaccinated melanoma donors remained limited. The comprehensive study of vaccinated patient metastasis shows that vaccine-driven tumor-infiltrating lymphocytes, although activated, still differed in functional capacities compared with blood counterparts. This coincided with a significant increase of FoxP3(+) regulatory T cell activity within the tumor. The consistent induction of effective tumor-specific CD8(+) T cells in the circulation with a vaccine represents a major achievement; however, clinical benefit may not be achieved unless the tumor environment can be altered to enable CD8(+) T cell efficacy.

Torasemide is an effective diuretic in the newborn rabbit.

The effect of intravenous (i.v.) torasemide on diuresis and renal function was evaluated in three groups of normoxemic, 5- to 10-day-old, newborn New Zealand White rabbits. The animals of group 1 received 0.2 mg/kg of torasemide i.v., whereas in group 2 an i.v. dose of 1.0 mg/kg was given. The third group of animals received a bolus i.v. dose of 1.0 mg/kg torasemide with continuous i.v. replacement of estimated urinary fluid and electrolyte losses. Torasemide proved to be an effective, potassium-sparing diuretic, without significant effect on glomerular filtration rate (GFR). Renal blood flow (RBF) fell and the renal vascular resistance (RVR) rose in all three groups of animals, although the rise in RVR in group 3 was not significant. These changes in renal hemodynamics were most pronounced in the animals of group 2 and are probably secondary to torasemide-induced hypovolemia (2.8% loss of body weight) and accompanying humoral reactions, such as an increase in angiotensin II (not measured). When the latter is prevented by simultaneous re-infusion of an electrolyte solution (group 3), replacing urinary losses, GFR increases and the changes in RBF and RVR are blunted. We conclude that torasemide is an effective, potassium-sparing diuretic in newborn rabbits. No evidence was found for a vasodilatory action of the drug.

A rapid and effective vignetting correction for quantitative microscopy

Images acquired using optical microscopes are inherently subject to vignetting effects due to imperfect illumination and image acquisition. However, such vignetting effects hamper accurate extraction of quantitative information from biological images, leading to less effective image segmentation and increased noise in the measurements. Here, we describe a rapid and effective method for vignetting correction, which generates an estimate for a correction function from the background fluorescence without the need to acquire additional calibration images. We validate the usefulness of this algorithm using artificially distorted images as a gold standard for assessing the accuracy of the applied correction and then demonstrate that this correction method enables the reliable detection of biologically relevant variation in cell populations. A simple user interface called FlattifY was developed and integrated into the image analysis platform YeastQuant to facilitate easy application of vignetting correction to a wide range of images.

Safe and effective variability-a criterion for dose individualization.

BACKGROUND: : A primary goal of clinical pharmacology is to understand the factors that determine the dose-effect relationship and to use this knowledge to individualize drug dose. METHODS: : A principle-based criterion is proposed for deciding among alternative individualization methods. RESULTS: : Safe and effective variability defines the maximum acceptable population variability in drug concentration around the population average. CONCLUSIONS: : A decision on whether patient covariates alone are sufficient, or whether therapeutic drug monitoring in combination with target concentration intervention is needed, can be made by comparing the remaining population variability after a particular dosing method with the safe and effective variability.

The Island of Drive. Representations, somatic states and the origin of drive

Freud defined the drive as "a concept on the frontier between the mental and the somatic". Today this view that was based on clinical observations interpreted within the psychoanalytical framework, can be revisited in light of the current neuroscientific notions of neuronal plasticity and somatic states. Indeed, through the mechanisms of plasticity experience leaves a trace that forms the neural basis of a representation of the experience. Such a representation R is associated with a somatic state S in the sense taken from the "somatic marker" model of Damasio. Thus, the internal reality of the subject, particularly the unconscious one, is constituted by such connected R's and S's. In the model that we discuss, the posterior insula represents the primary interoceptive cortex where information about somatic states S converges, while in the anterior insula the connection between R and S can take place and establish a neurobiological correlate for the notion of drive. We posit that the re-representations of S associated with R in the anterior insula may correspond to the Vorstellungsrepräsentanz postulated by Freud. We further propose that the tension between R and S established in the anterior insula is discharged according to the notion of drive through the motor arm of the limbic system, namely the anterior cingulate cortex which is heavily connected with the anterior insula.

Cefuroxime prophylaxis is effective in noninstrumented spine surgery: a double-blind, placebo-controlled study.

STUDY DESIGN: Double-blind, placebo-controlled randomized clinical trial. OBJECTIVE: To assess the efficacy of 1 preoperative 1.5 g dose of cefuroxime in preventing surgical site infection after surgery for herniated disc. SUMMARY OF BACKGROUND DATA: Antibiotic prophylaxis was only tested in nonconclusive trials in this setting. METHODS: The study was conducted in 2 university hospitals in Switzerland. Patients were assessed for occurrence of surgical site infection (defined by the criteria of the Centers for Diseases Control and Prevention), other infections, or adverse events up to 6 months after surgery. Outcome measures were compared in a univariate, per-protocol analysis. RESULTS: Baseline characteristics were similar in patients allocated to cefuroxime (n = 613) or placebo (n = 624). Eight (1.3%) patients in the cefuroxime group and 18 patients (2.8%) in the placebo group developed a surgical site infection (P = 0.073). A diagnosis of spondylodiscitis or epidural abscess was made in 9 patients in the placebo group, but none in the cefuroxime group (P < 0.01), which corresponded to a number necessary to treat of 69 patients to prevent one of these infections. There were no significant adverse events attributed to either cefuroxime or placebo. CONCLUSION: A single, preoperative dose of cefuroxime significantly reduces the risk of organ-space infection, most notably spondylodiscitis, after surgery for herniated disc.

Auction theory, sequential local service privatization, and the effects of geographical scale economies on effective competition

A sequential weakly efficient two-auction game with entry costs, interdependence between objects, two potential bidders and IPV assumption is presented here in order to give some theoretical predictions on the effects of geographical scale economies on local service privatization performance. It is shown that the first object seller takes profit of this interdependence. The interdependence externality rises effective competition for the first object, expressed as the probability of having more than one final bidder. Besides, if there is more than one final bidder in the first auction, seller extracts the entire bidder¿s expected future surplus differential between having won the first auction and having lost. Consequences for second object seller are less clear, reflecting the contradictory nature of the two main effects of object interdependence. On the one hand, first auction winner becomes ¿stronger¿, so that expected payments rise in a competitive environment. On the other hand, first auction loser becomes relatively ¿weaker¿, hence (probably) reducing effective competition for the second object. Additionally, some contributions to static auction theory with entry cost and asymmetric bidders are presented in the appendix

Origin of a restraining bend in an evolving strike-slip system: The Cenozoic As Pontes basin (NW Spain)

The As Pontes basin (12 km2), NW Iberian Peninsula, is bounded by a double restraining bend of a dextral strike-slip fault, which is related to the western onshore end of the Pyrenean belt. Surface and subsurface data obtained from intensive coal exploration and mining in the basin since the 1960s together with additional structural and stratigraphic sequence analysis allowed us to determine the geometric relationships between tectonic structures and stratigraphic markers. The small size of the basin and the large amount of quality data make the As Pontes basin a unique natural laboratory for improving our understanding of the origin and evolution of restraining bends. The double restraining bend is the end stage of the structural evolution of a compressive underlapping stepover, where the basin was formed. During the first stage (stepover stage), which began ca. 30 Ma ago (latest Rupelian) and lasted 3.4 My, two small isolated basins bounded by thrusts and normal faults were formed. For 1.3 My, the strike-slip faults, which defined the stepover, grew towards each other until joining and forming the double restraining bend, which bounds one large As Pontes basin (transition stage). The history of the basin was controlled by the activity of the double restraining bend for a further 3.4 My (restraining bend stage) and ended in mid-Aquitanian times (ca. 22 Ma).

Genomics and the origin of species.

Speciation is a fundamental evolutionary process, the knowledge of which is crucial for understanding the origins of biodiversity. Genomic approaches are an increasingly important aspect of this research field. We review current understanding of genome-wide effects of accumulating reproductive isolation and of genomic properties that influence the process of speciation. Building on this work, we identify emergent trends and gaps in our understanding, propose new approaches to more fully integrate genomics into speciation research, translate speciation theory into hypotheses that are testable using genomic tools and provide an integrative definition of the field of speciation genomics.

Effective one-dimensional square well for two-dimensional quantum wires

The symmetrical two-dimensional quantum wire with two straight leads joined to an arbitrarily shaped interior cavity is studied with emphasis on the single-mode approximation. It is found that for both transmission and bound-state problems the solution is equivalent to that for an energy-dependent one-dimensional square well. Quantum wires with a circular bend, and with single and double right-angle bends, are examined as examples. We also indicate a possible way to detect bound states in a double bend based on the experimental setup of Wu et al.

Effective eigenvalue for the intensity correlations of single-mode and two-mode lasers

Exact formulas for the effective eigenvalue characterizing the initial decay of intensity correlation functions are given in terms of stationary moments of the intensity. Spontaneous emission noise and nonwhite pump noise are considered. Our results are discussed in connection with earlier calculations, simulations, and experimental results for single-mode dye lasers, two-mode inhomogeneously broadened lasers, and two-mode dye ring lasers. The effective eigenvalue is seen to depend sensitively on noise characteristics and symmetry properties of the system. In particular, the effective eigenvalue associated with cross correlations of two-mode lasers is seen to vanish in the absence of pump noise as a consequence of detailed balance. In the presence of pump noise, the vanishing of this eigenvalue requires equal pump parameters for the two modes and statistical independence of spontaneous emission noise acting on each mode.