Showing papers by "University of Bordeaux published in 2003"

Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia

Abstract: Background Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML. Methods We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression. Results After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 perce...

Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization.

Abstract: Background: AD is characterized by cerebral deposition of β-amyloid plaques with amyloid β-peptide (Aβ) 42 as the major peptide constituent, along with neurofibrillary tangles and neuronal loss. In transgenic mice, active immunization against Aβ42 removes these plaques and improves cognitive function. A Phase I study in AD patients demonstrated good safety and tolerability of multiple injections of aggregated Aβ42 (AN1792) with QS-21 as adjuvant. Methods: Three hundred seventy-two patients with mild to moderate AD were randomized to receive IM injections of AN1792 or placebo (4:1) at baseline and at months 1, 3, 6, 9, and 12 in a multicenter Phase II safety, tolerability, and pilot efficacy study. Dosing was terminated after four early reports of meningoencephalitis, but follow-up continued. The study remains blinded, and further results will be reported after its termination. Results: Symptoms and laboratory findings consistent with meningoencephalitis occurred in 18 of 298 (6%) patients treated with AN1792 compared with 0 of 74 on placebo ( p = 0.020). Sixteen of the 18 had received two doses, one had received one dose, and one had received three doses of the study drug before symptoms occurred. The median latency from the first and last injections to symptoms was 75 and 40 days. No case occurred later than 6 months after the first immunization. Anti-Aβ42 antibody titers were not correlated with the occurrence or severity of symptoms or relapses. Twelve patients recovered to or close to baseline within weeks, whereas six remain with disabling cognitive or neurologic sequelae. All 18 patients remain alive to date (December 31, 2002), 6 months to >1 year after symptom onset. Conclusions: Postvaccination meningoencephalitis occurred without clear relation to serum anti-Aβ42 antibody titers. Potential mechanisms such as T-cell and microglial activation may be responsible and are under consideration to develop a safer anti-Aβ immunotherapy for AD.

Risk factors for anastomotic leakage after resection of rectal cancer

Abstract: Background The most important surgical complication following rectal resection with anastomosis is symptomatic anastomotic leakage. which is associated with a 6-22 per cent mortality rate. The aim of this retrospective study was to evaluate the risk factors for clinical anastomotic leakage after anterior resection for cancer of the rectum. Methods From 1980 to 1995, 272 consecutive anterior resections for rectal cancer were performed by the same surgical team; 131 anastomoses were situated 5 cm or less from the anal verge. The associations between clinical anastomotic leakage and 19 patient-, tumour-, surgical- and treatment-related variables were studied by univariate and multivariate analysis. Results The rate of clinical anastomotic leakage was 12 per cent (32 of 272). Multivariate analysis of the overall population showed that only male sex and level of anastomosis were independent factors for development of anastomotic leakage. The risk of leakage was 6.5 times higher for anastomoses situated less than 5 cm from the anal verge than for those situated above 5 cm; it was 2.7 times higher for men than for women. In a second analysis of low anastomoses (5 cm or less from the anal verge; = 131), obesity was statistically associated with leakage. Conclusion A protective stoma is suitable after sphincter-saving resection for rectal cancer for anastomoses situated at or less than 5 cm from the anal verge, particularly for men and obese patients.

Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice

Abstract: We targeted the locus encoding the cyclin-dependent kinase 2 (CDK2) by homologous recombination in mouse embryonic stem (ES) cells. Embryonic fibroblasts lacking CDK2 proliferate normally and become immortal after continuous passage in culture. Elimination of a conditional Cdk2 allele in immortal cells does not have a significant effect on proliferation. Cdk2-/- mice are viable and survive for up to two years, indicating that CDK2 is also dispensable for proliferation and survival of most cell types. But CDK2 is essential for completion of prophase I during meiotic cell division in male and female germ cells, an unforeseen role for this cell cycle kinase.

Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis.

Abstract: Neurogenesis occurs within the adult dentate gyrus of the hippocampal formation and it has been proposed that the newly born neurons, recruited into the preexistent neuronal circuits, might be involved in hippocampal-dependent learning processes. Age-dependent spatial memory impairments have been related to an alteration in hippocampal plasticity. The aim of the current study was to examine whether cognitive functions in aged rats are quantitatively correlated with hippocampal neurogenesis. To this end, we took advantage of the existence of spontaneous individual differences observed in aged subjects in a hippocampal-dependent task, the water maze. We expected that the spatial memory capabilities of aged rats would be related to the levels of hippocampal neurogenesis. Old rats were trained in the water maze, and, 3 weeks after training, rats were injected with 5-bromo-2′-deoxyuridine (BrdUrd, 50 or 150 mg/kg) to label dividing cells. Cell proliferation was examined one day after the last BrdUrd injection, whereas cell survival and differentiation were determined 3 weeks later. It is shown that a quantitative relationship exists between learning and the number of newly generated neurons. Animals with preserved spatial memory, i.e., the aged-unimpaired rats, exhibited a higher level of cell proliferation and a higher number of new neurons in comparison with rats with spatial memory impairments, i.e., the aged-impaired rats. In conclusion, the extent of memory dysfunction in aged rats is quantitatively related to the hippocampal neurogenesis. These data reinforce the assumption that neurogenesis is involved in memory processes and aged-related cognitive alterations.

Some general features of limited coalescence in solid-stabilized emulsions.

Abstract: We produce direct and inverse emulsions stabilized by solid mineral particles. If the total amount of particles is initially insufficient to fully cover the oil-water interfaces, the emulsion droplets coalesce such that the total interfacial area between oil and water is progressively reduced. Since it is likely that the particles are irreversibly adsorbed, the degree of surface coverage by them increases until coalescence is halted. We follow the rate of droplet coalescence from the initial fragmented state to the saturated situation. Unlike surfactant-stabilized emulsions, the coalescence frequency depends on time and particle concentration. Both the transient and final droplet size distributions are relatively narrow and we obtain a linear relation between the inverse average droplet diameter and the total amount of solid particles, with a slope that depends on the mixing intensity. The phenomenology is independent of the mixing type and of the droplet volume fraction allowing the fabrication of both direct and inverse emulsion with average droplet sizes ranging from micron to millimetre.

Archaeological Evidence for the Emergence of Language, Symbolism, and Music–An Alternative Multidisciplinary Perspective

Abstract: In recent years, there has been a tendency to correlate the origin of modern culture and language with that of anatomically modern humans. Here we discuss this correlation in the light of results provided by our first hand analysis of ancient and recently discovered relevant archaeological and paleontological material from Africa and Europe. We focus in particular on the evolutionary significance of lithic and bone technology, the emergence of symbolism, Neandertal behavioral patterns, the identification of early mortuary practices, the anatomical evidence for the acquisition of language, the development of conscious symbolic storage, the emergence of musical traditions, and the archaeological evidence for the diversification of languages during the Upper Paleolithic. This critical reappraisal contradicts the hypothesis of a symbolic revolution coinciding with the arrival of anatomically modern humans in Europe some 40,000 years ago, but also highlights inconsistencies in the anatomically–culturally modern equation and the potential contribution of anatomically “pre-modern” human populations to the emergence of these abilities. No firm evidence of conscious symbolic storage and musical traditions are found before the Upper Paleolithic. However, the oldest known European objects that testify to these practices already show a high degree of complexity and geographic variability suggestive of possible earlier, and still unrecorded, phases of development.

Software verification with BLAST

Abstract: Blast (the Berkeley Lazy Abstraction Software verification Tool) is a verification system for checking safety properties of C programs using automatic property-driven construction and model checking of software abstractions. Blast implements an abstract-model check-refine loop to check for reachability of a specified label in the program. The abstract model is built on the fly using predicate abstraction. This model is then checked for reachability. If there is no (abstract) path to the specified error label, Blast reports that the system is safe and produces a succinct proof. Otherwise, it checks if the path is feasible using symbolic execution of the program. If the path is feasible, Blast outputs the path as an error trace, otherwise, it uses the infeasibility of the path to refine the abstract model. Blast short-circuits the loop from abstraction to verification to refinement, integrating the three steps tightly through “lazy abstraction” [5]. This integration can offer significant advantages in performance by avoiding the repetition of work from one iteration of the loop to the next.

Secular trends in the performance of children and adolescents (1980-2000): an analysis of 55 studies of the 20m shuttle run test in 11 countries.

Abstract: It is widely believed that the performance of children and adolescents on aerobic fitness tests is declining. To test this hypothesis, this meta-analysis compared the results of 55 reports of the performance of children and adolescents aged 6–19 years who have used the 20m shuttle run test (20mSRT). All data were collected in the period 1981–2000. Following corrections for methodological variation, the results of all studies were expressed using the common metric of running speed (km/h) at the last completed stage. Raw data were combined with pseudodata generated from reported means and standard deviations using Monte Carlo simulation. Where data were available on children and adolescents from the same country of the same age and sex, but tested at different times, linear regression was used to calculate rates of change. This was possible for 11 (mainly developed) countries, representing a total of 129 882 children and adolescents in 151 age × sex × country slices. There has been a significant decline in performance in the 11 countries where data were available, and in most age × sex groups, with a sample-weighted mean decline of 0.43% of mean values per year. The decline was most marked in older age groups and the rate of decline was similar for boys and girls. There has been a very rapid secular decline in the 20mSRT performance of children and adolescents over the last 20 years, at least in developed countries. The rate of decline is not related to the change in the country’s relative wealth, as quantified by per capita gross domestic product (GDP).

Cyanobacterial Diversity in Natural and Artificial Microbial Mats of Lake Fryxell (McMurdo Dry Valleys, Antarctica): a Morphological and Molecular Approach

Abstract: Currently, there is no consensus concerning the geographic distribution and extent of endemism in Antarctic cyanobacteria. In this paper we describe the phenotypic and genotypic diversity of cyanobacteria in a field microbial mat sample from Lake Fryxell and in an artificial cold-adapted sample cultured in a benthic gradient chamber (BGC) by using an inoculum from the same mat. Light microscopy and molecular tools, including 16S rRNA gene clone libraries, denaturing gradient gel electrophoresis, and sequencing, were used. For the first time in the study of cyanobacterial diversity of environmental samples, internal transcribed spacer (ITS) sequences were retrieved and analyzed to complement the information obtained from the 16S rRNA gene. Microscopy allowed eight morphotypes to be identified, only one of which is likely to be an Antarctic endemic morphotype. Molecular analysis, however, revealed an entirely different pattern. A much higher number of phylotypes (15 phylotypes) was found, but no sequences from Nodularia and Hydrocoryne, as observed by microscopy, were retrieved. The 16S rRNA gene sequences determined in this study were distributed in 11 phylogenetic lineages, 3 of which were exclusively Antarctic and 2 of which were novel. Collectively, these Antarctic sequences together with all the other polar sequences were distributed in 22 lineages, 9 of which were exclusively Antarctic, including the 2 novel lineages observed in this study. The cultured BGC mat had lower diversity than the field mat. However, the two samples shared three morphotypes and three phylotypes. Moreover, the BGC mat allowed enrichment of one additional phylotype. ITS sequence analysis revealed a complex signal that was difficult to interpret. Finally, this study provided evidence of molecular diversity of cyanobacteria in Antarctica that is much greater than the diversity currently known based on traditional microscopic analysis. Furthermore, Antarctic endemic species were more abundant than was estimated on the basis of morphological features. Decisive arguments concerning the global geographic distribution of cyanobacteria should therefore incorporate data obtained with the molecular tools described here.

The role of receptor diffusion in the organization of the postsynaptic membrane

Abstract: Neurotransmitter receptor movement into and out of synapses is one of the core mechanisms for rapidly changing the number of functional receptors during synaptic plasticity. Recent data have shown that rapid gain and loss of receptors from synaptic sites are accounted for by endocytosis and exocytosis, as well as by lateral diffusion of receptors in the plane of the membrane. These events are interdependent and are regulated by neuronal activity and interactions with scaffolding proteins. Here we focus on the physical laws that govern receptor diffusion and stabilization, and how this might reshape how we think about the specific regulation of receptor accumulation at synapses.

A fast calculation method for magnetic field inhomogeneity due to an arbitrary distribution of bulk susceptibility

Abstract: A fast calculation method for the magnetic field distribution due to (dynamic) changes in susceptibility may allow real-time interventional applications. Here it is shown that a direct relationship can be obtained between the magnetic field perturbation and the susceptibility distribution inside the MR magnet using a first order perturbation approach to Maxwell's magneto-static equations, combined with the Fourier transformation technique to solve partial derivative equations. The mathematical formalism does not involve any limitation with respect to shape or homogeneity of the susceptibility field. A first order approximation is sufficient if the susceptibility range does not exceed 10−4 (or 100 ppm). The formalism allows fast numerical calculations using 3D matrices. A few seconds computation time on a PC is sufficient for a 128 × 128 × 128 matrix size. Predicted phase maps fitted both analytical and experimental data within 1% precision. © 2003 Wiley Periodicals, Inc. Concepts Magn Reson Part B (Magn Reson Engineering) 19B: 26–34, 2003.

Direct imaging of lateral movements of AMPA receptors inside synapses

Abstract: Trafficking of AMPA receptors in and out of synapses is crucial for synaptic plasticity. Previous studies have focused on the role of endo/exocytosis processes or that of lateral diffusion of extra-synaptic receptors. We have now directly imaged AMPAR movements inside and outside synapses of live neurons using single-molecule fluorescence microscopy. Inside individual synapses, we found immobile and mobile receptors, which display restricted diffusion. Extra-synaptic receptors display free diffusion. Receptors could also exchange between these membrane compartments through lateral diffusion. Glutamate application increased both receptor mobility inside synapses and the fraction of mobile receptors present in a juxtasynaptic region. Block of inhibitory transmission to favor excitatory synaptic activity induced a transient increase in the fraction of mobile receptors and a decrease in the proportion of juxtasynaptic receptors. Altogether, our data show that rapid exchange of receptors between a synaptic and extra-synaptic localization occurs through regulation of receptor diffusion inside synapses.

Opioid-induced hyperalgesia: abnormal or normal pain?

Abstract: INTRODUCTION It is well recognized that opioids are the analgesics of choice for the treatment of moderate to severe pain. However, a large number of clinical studies have reported that opioids can unexpectedly elicit hyperalgesia (enhanced responses to noxious stimulation) and allodynia (pain elicited by normal innocuous stimuli) [1–8]. Opioid-induced hyperalgesia has also been reported in animal experimental models [9–17]. This pain hypersensitivity has been classified as abnormal pain [16,18] as opposed to physiological (or normal) pain associated with nociception. Physiological pain has an important function in the preservation of an organism since it is an essential warning device that alerts the organism of impending danger from actual or potentially injurious stimuli in the environment. Does this suggest that there are good and bad pains, i.e. normal or abnormal pain? From a clinical viewpoint, the response is probably yes, if pain is only considered as a simple sensory system. However, pain is also a motivational process inducing a coordinated set of behavioral changes that serves to remember danger, some behaviors being facilitated and others inhibited. In this respect, pain sensitivity may be the result of a balance between the activity of inhibitory (antinociceptive) and facilitatory (pronociceptive) circuitries within the CNS with regard to the environmental state. If the main function of antinociceptive systems is to reduce pain during threatening situations as pain may compromise defensive behavior, it has been argued [19] that the function of pronociceptive systems might be that of motivating recuperative behaviors that would be adaptive for maintaining preservation of the organism when signals for safety succeed to threats. From an adaptive viewpoint, one hypothesis is that a pain hypersensitivity state is a normal step following defensive analgesia associated with the recruitment of endogenous antinociceptive systems. Since it is unlikely that evolution has selected mechanisms that are only activated by endogenous antinociceptive systems such as opioid systems, it might be suggested that delayed hyperalgesia following the use of exogenous opioids is a normal rather than an abnormal pain. In this review, we will first examine experimental evidences which indicate that exogenous opioids simultaneously activate both inhibitory and facilitatory pain systems leading to a long-lasting enhancement in pain sensitivity after analgesia. Second, we will assess the possible role of such an enhancement in pain sensitivity in the development of both tolerance to the analgesic effect of opioids and pain chronicisation processes.

Temperature dependence of the luminescence lifetime of single CdSe/ZnS quantum dots.

Abstract: We study the temperature dependence of the luminescence decay of single CdSe/ZnS quantum dots between 2 and 140 K. For the first time, we observe a biexponential decay which was completely hidden in ensemble measurements. We find that the long time component strongly depends on temperature. This demonstrates that the band edge luminescence arises from two thermally mixed fine structure states, the dark ground state and the lowest bright one. To interpret our results, we derive the analytical expressions for the decay using a three level model. Fitting the experimental data leads directly to the lifetime of the states as well as their energy splitting.

Logistic or additive euroscore for high-risk patients?

Abstract: Objectives: To assess whether the use of the full logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) is superior to the standard additive EuroSCORE in predicting mortality in high-risk cardiac surgical patients. Methods: Both the simple additive EuroSCORE and the full logistic EuroSCORE were applied to 14,799 cardiac surgical patients from across Europe, of whom there were 4293 high-risk patients (additive EuroSCORE of 6 or more). The systems were compared for absolute prediction and discrimination (area under the receiver operating characteristic (ROC) curve). Results: Actual mortality was 4.72%. The logistic model was closer to this than the additive model (4.84% (4.72– 4.94) versus 4.21 (4.21 –4.26)). Most of this difference was due to high-risk patients where actual mortality was 11.18% and predicted was 7.83% (additive) and 11.23% (logistic). Discrimination was similar in both systems as measured by the area under the ROC curve (additive 0.783, logistic 0.785). Conclusions: The additive EuroSCORE model remains a simple “gold standard” for risk assessment in European cardiac surgery, usable at the bedside without complex calculations or information technology. The logistic model is a better risk predictor especially in high-risk patients and may be of interest to institutions engaged in the study and development of risk stratification. q 2003 Elsevier Science B.V. All rights reserved.

Lactate is a preferential oxidative energy substrate over glucose for neurons in culture.

Abstract: The authors investigated concomitant lactate and glucose metabolism in primary neuronal cultures using 13C- and 1H-NMR spectroscopy. Neurons were incubated in a medium containing either [1-13C]glucose and different unlabeled lactate concentrations, or unlabeled glucose and different [3-13C]lactate concentrations. Overall, 13C-NMR spectra of cellular extracts showed that more 13C was incorporated into glutamate when lactate was the enriched substrate. Glutamate 13C-enrichment was also found to be much higher in lactate-labeled than in glucose-labeled conditions. When glucose and lactate concentrations were identical (5.5 mmol/L), relative contributions of glucose and lactate to neuronal oxidative metabolism amounted to 21% and 79%, respectively. Results clearly indicate that when neurons are in the presence of both glucose and lactate, they preferentially use lactate as their main oxidative substrate.

Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date

Abstract: The hippocampal formation, to which new neurons are added on a daily basis throughout life, is important in spatial learning. Surviving de novo produced cells integrate into the functional circuitry, where they can influence both normal and pathological behaviors. In this study, we examined the effect of the water-maze (a hippocampal-dependent spatial task) on neurogenesis. Learning in this task can be divided into two phases, an early phase during which performance improves rapidly, and a late phase during which asymptotic levels of performance are reached. Here we demonstrate that the late phase of learning has a multifaceted effect on neurogenesis depending on the birth date of new neurons. The number of newly born cells increased contingently with the late phase and a large proportion of these cells survived for at least 4 weeks and differentiated into neurons. In contrast, late-phase learning decreased the number of newly born cells produced during the early phase. This decline in neurogenesis was positively correlated with performance in the water-maze. Thus, rats with the highest de novo cell number were less able to acquire and use spatial information than those with low numbers of new cells. These results show that learning has a complex effect on hippocampal neurogenesis, and reveals a novel mechanism through which neurogenesis may influence normal and pathological behaviors.

Involved-field radiotherapy for advanced Hodgkin's lymphoma.

Abstract: Background The use of involved-field radiotherapy after chemotherapy for advanced Hodgkin's lymphoma is controversial. Methods We randomly assigned patients with previously untreated stage III or IV Hodgkin's lymphoma who were in complete remission after hybrid chemotherapy with mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP-ABV) to receive either no further treatment or involved-field radiotherapy. Radiotherapy consisted of 24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites. Patients in partial remission were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites. Results Of 739 patients, 421 had a complete remission; 161 of these patients were assigned to no further treatment, and 172 to involved-field radiotherapy. The median follow-up was 79 months. The five-year event-free survival rate was 84 percent in the group that did not receive radiotherapy and 79 percent in the group that ...

Electron-phonon scattering in metal clusters.

Abstract: Electron-lattice energy exchanges are investigated in gold and silver nanoparticles with sizes ranging from 30 to 2.2 nm embedded in different environments. Femtosecond pump-probe experiments performed in the low-perturbation regime demonstrate a strong increase of the intrinsic electron-phonon interaction for nanoparticles smaller than 10 nm due to a confinement effect.