Quantification of brain glycogen concentration and turnover through localized 13C NMR of both the C1 and C6 resonances.

We have recently shown that at isotopic steady state (13)C NMR can provide a direct measurement of glycogen concentration changes, but that the turnover of glycogen was not accessible with this protocol. The aim of the present study was to design, implement and apply a novel dual-tracer infusion protocol to simultaneously measure glycogen concentration and turnover. After reaching isotopic steady state for glycogen C1 using [1-(13)C] glucose administration, [1,6-(13)C(2)] glucose was infused such that isotopic steady state was maintained at the C1 position, but the C6 position reflected (13)C label incorporation. To overcome the large chemical shift displacement error between the C1 and C6 resonances of glycogen, we implemented 2D gradient based localization using the Fourier series window approach, in conjunction with time-domain analysis of the resulting FIDs using jMRUI. The glycogen concentration of 5.1 +/- 1.6 mM measured from the C1 position was in excellent agreement with concomitant biochemical determinations. Glycogen turnover measured from the rate of label incorporation into the C6 position of glycogen in the alpha-chloralose anesthetized rat was 0.7 micromol/g/h.

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.

PURPOSE: This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM). METHODS: Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). RESULTS: Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml). CONCLUSIONS: This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.

Nanosized Nb-TiO2 gas sensors derived from alkoxides hydrolization

Nanocrystalline TiO2 modified with Nb has been produced through the sol-gel technique. Nanopowders have been obtained by means of the hydrolysis of pure alkoxides with deionized water and peptization of the resulting hydrolysate with diluted acid nitric at 100 C. The addition of Nb stabilizes the anatase phase to higher temperatures. XRD spectra of the undoped and the Nb-doped samples show that the undoped sample has been almost totally converted to rutile at 600 C, meanwhile the doped samples present still a low percentage of rutile phase. Nanocrystalline powders stabilized at 600 C with grain sizes of about 17 nm have successfully been synthesized by the addition of Nb with a concentration of 2% at., which appears to be an adequate additive concentration to improve the gas sensor performances, such as it is suggested by the catalytic conversion efficiency experiments performed from FTIR measurements. FTIR absorbance spectra show that catalytic conversion of CO occurs at lower temperatures when niobium is introduced. The electrical response of the films to different concentrations of CO and ethanol has been monitored in dry and wet environments in order to test the influence of humidity in the sensor response. The addition of Nb decreases the working temperature and increases the stability of the layers. Also, large enhancement of the response time is obtained even with lower working temperatures. Moreover, humidity effects on the gas sensor response toward CO and ethanol are less important in Nb-doped samples than in the undoped ones.

Développement d'un outil de gestion graduée des risques spécifique au cas des nanomatériaux : rapport d'appui scientifique et technique

L' évaluation quantitative des dangers et des expositions aux nanomatériaux se heurte à de nombreuses incertitudes qui ne seront levées qu'à mesure de la progression des connaissances scientifiques de leurs propriétés. L' une des conséquences de ces incertitudes est que les valeurs limites d'exposition professionnelle définies actuellement pour les poussières ne sont pas nécessairement pertinentes aux nanomatériaux. En l'absence de référentiel quantitatif et, à la demande de la DGS pour éclairer les réflexions de l' AFNOR et de l'ISO sur le sujet, une démarche de gestion graduée des risques (control banding) a été élaborée au sein de l' Anses. Ce développement a été réalisé à l'aide d'un groupe d'experts rapporteurs rattaché au Comité d'experts spécialisés évaluation des risques liés aux agents physiques, aux nouvelles technologies et aux grands aménagements. La mise en oeuvre de la démarche de gestion graduée des risques proposée repose sur quatre grandes étapes: 1. Le recueil des informations. Cette étape consiste à réunir les informations disponibles sur les dangers du nanomatériau manufacturé considéré ; ainsi que sur l'exposition potentielle des personnes aux postes de travail (observation sur le terrain, mesures, etc.). 2. L'attribution d'une bande de danger. Le danger potentiel du nanomatériau manufacturé présent, qu'il soit brut où incorporé dans une matrice (liquide ou solide) est évalué dans cette étape. La bande danger attribuée tient compte de la dangerosité du produit bulk ou de sa substance analogue à l'échelle non-nanométrique, de la bio-persistance du matériau (pour les matériaux fibreux), de sa solubilité et de son éventuelle réactivité. 3. Attribution d'une bande d'exposition. La bande d'exposition du nanomatériau manufacturé considéré ou du produit en contenant est définie par le niveau de potentiel d'émission du produit. Elle tient compte de sa forme physique (solide, liquide, poudre aérosol), de sa pulvérulence et de sa volatilité. Le nombre de travailleurs, la fréquence, la durée d'exposition ainsi que la quantité mise en oeuvre ne sont pas pris en compte, contrairement à une évaluation classique des risques chimiques. 4. Obtention d'une bande de maîtrise des risques. Le croisement des bandes de dangers et d'exposition préalablement attribuées permet de défi nir le niveau de maîtrise du risque. Il fait correspondre les moyens techniques et organisationnels à mettre en oeuvre pour maintenir le risque au niveau le plus faible possible. Un plan d'action est ensuite défi ni pour garantir l'effi cacité de la prévention recommandée par le niveau de maîtrise déterminé. Il tient compte des mesures de prévention déjà existantes et les renforce si nécessaire. Si les mesures indiquées par le niveau de maîtrise de risque ne sont pas réalisables, par exemple, pour des raisons techniques ou budgétaires, une évaluation de risque approfondie devra être réalisée par un expert. La gestion graduée des risques est une méthode alternative pour réaliser une évaluation qualitative de risques et mettre en place des moyens de prévention sans recourir à une évaluation quantitative des risques. Son utilisation semble particulièrement adaptée au contexte des nanomatériaux manufacturés, pour lequel les choix de valeurs de référence (Valeurs limites d'exposition en milieu professionnel) et des techniques de mesurage appropriées souffrent d'une grande incertitude. La démarche proposée repose sur des critères simples, accessibles dans la littérature scientifi que ou via les données techniques relatives aux produits utilisés. Pour autant, sa mise en oeuvre requiert des compétences minimales dans les domaines de la prévention des risques chimiques (chimie, toxicologie, etc.), des nanosciences et des nanotechnologies.

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: Results from the randomized controlled I-COME Trial

Introduction: Imatinib trough plasma concentrations (Cmin) have been correlated with treatment response in chronic myeloid leukemia (CML) patients. The use of Cmin monitoring for optimizing imatinib dosage (therapeutic drug monitoring [TDM]) is therefore proposed for patients with unsatisfying response or tolerance ("rescue TDM"). A cycle of "routine TDM" for dosage individualization could also be beneficial to prevent unfavorable events, yet its clinical usefulness has not been evaluated. We aimed to assess prospectively whether a "routine TDM" intervention targeting imatinib Cmin of 1000 ng/mL (tolerance, 750-1500 ng/mL) could improve efficacy, tolerance, and persistence on treatment compared with "rescue TDM" use only. Patients (or Materials) and Methods: The Swiss Imatinib COncentration Monitoring Evaluation (I-COME) study was a multicenter randomized controlled trial (ISRCTN31181395). Adult patients in chronic or accelerated phase CML receiving imatinib ≤5 years were eligible. Patients were randomly (1:1) allocated to receive "routine TDM" intervention or to serve as controls with access only to "rescue TDM". All had 1-year follow-up. The primary endpoint was a combined efficacy-safety outcome (failure- and toxicity-free survival without imatinib discontinuation), analyzed in intention-to-treat. Results: Among 56 CML recruited patients, 55 had their molecular and cytogenetic response measured. 14/27 of patients receiving "routine TDM" (52% [33%-71%]) remained event-free versus 16/28 of control patients with "rescue TDM" only (57% [39%-75%]; P=0.69). In the "routine TDM" group, dosage recommendations were adopted entirely in 50% of patients (median Cmin at study end, 895 ng/mL; CV = 33%). These patients had fewer unfavorable events (28% [5%-52%]) compared with patients not receiving the advised dosage (77% [54%-99%]; P = 0.03; median Cmin at study end, 648 ng/mL; CV = 38%). Conclusion: This first prospective target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" of imatinib, especially due to a small patient number and limited prescriber's adherence to dosage recommendations. Nevertheless, the patients receiving the advised dosage more often met target concentrations and the combined outcome (efficacy, tolerance, and persistence). A cycle of routine TDM could thus be favorable, at least in patients eligible for dosage adjustment. Its usefulness should, however, be further confirmed in larger trials.

The geographical concentration of industry across Spanish Regions, 1856-1995

New economic geography models show that there may be a strong relationship between economic integration and the geographical concentration of industries. Nevertheless, this relationship is neither unique nor stable, and may follow a ?-shaped pattern in the long term. The aim of the present paper is to analyze the evolution of the geographical concentration of manufacturing across Spanish regions during the period 1856-1995. We construct several geographical concentration indices for different points in time over these 140 years. The analysis is carried out at two levels of aggregation, in regions corresponding to the NUTS-II and NUTS-III classifications. We confirm that the process of economic integration stimulated the geographical concentration of industrial activity. Nevertheless, the localization coefficients only started to fall after the beginning of the integration of the Spanish Economy into the international markets in the mid-70s, and this new path was not interrupted by Spain¿s entry in the European Union some years later

Vacancy and interstitial depth profiles in ion-implanted silicon

An experimental method of studying shifts between concentration-versus-depth profiles of vacancy- and interstitial-type defects in ion-implanted silicon is demonstrated. The concept is based on deep level transient spectroscopy measurements utilizing the filling pulse variation technique. The vacancy profile, represented by the vacancy¿oxygen center, and the interstitial profile, represented by the interstitial carbon¿substitutional carbon pair, are obtained at the same sample temperature by varying the duration of the filling pulse. The effect of the capture in the Debye tail has been extensively studied and taken into account. Thus, the two profiles can be recorded with a high relative depth resolution. Using low doses, point defects have been introduced in lightly doped float zone n-type silicon by implantation with 6.8 MeV boron ions and 680 keV and 1.3 MeV protons at room temperature. The effect of the angle of ion incidence has also been investigated. For all implantation conditions the peak of the interstitial profile is displaced towards larger depths compared to that of the vacancy profile. The amplitude of this displacement increases as the width of the initial point defect distribution increases. This behavior is explained by a simple model where the preferential forward momentum of recoiling silicon atoms and the highly efficient direct recombination of primary point defects are taken into account.

Majority carrier capture cross section determination in the large deep trap concentration cases

A method to determine the thermal cross section of a deep level from capacitance measurements is reported. The results enable us to explain the nonexponential behavior of the capacitance versus capture time when the trap concentration is not negligible with respect to that of the shallow one, and the Debye tail effects are taken into account. A figure of merit for the nonexponential behavior of the capture process is shown and discussed for different situations of doping and applied bias. We have also considered the influence of the position of the trap level"s energy on the nonexponentiality of the capture transient. The experimental results are given for the gold acceptor level in silicon and for the DX center in Al0.55 Ga0.45As, which are in good agreement with the developed theory.

Nanosized Nb-TiO2 gas sensors derived from alkoxides hydrolization

Nanocrystalline TiO2 modified with Nb has been produced through the sol-gel technique. Nanopowders have been obtained by means of the hydrolysis of pure alkoxides with deionized water and peptization of the resulting hydrolysate with diluted acid nitric at 100 C. The addition of Nb stabilizes the anatase phase to higher temperatures. XRD spectra of the undoped and the Nb-doped samples show that the undoped sample has been almost totally converted to rutile at 600 C, meanwhile the doped samples present still a low percentage of rutile phase. Nanocrystalline powders stabilized at 600 C with grain sizes of about 17 nm have successfully been synthesized by the addition of Nb with a concentration of 2% at., which appears to be an adequate additive concentration to improve the gas sensor performances, such as it is suggested by the catalytic conversion efficiency experiments performed from FTIR measurements. FTIR absorbance spectra show that catalytic conversion of CO occurs at lower temperatures when niobium is introduced. The electrical response of the films to different concentrations of CO and ethanol has been monitored in dry and wet environments in order to test the influence of humidity in the sensor response. The addition of Nb decreases the working temperature and increases the stability of the layers. Also, large enhancement of the response time is obtained even with lower working temperatures. Moreover, humidity effects on the gas sensor response toward CO and ethanol are less important in Nb-doped samples than in the undoped ones.

Extraction and concentration of biogenic calcium oxalate from plant leaves

The objective of this study was to extract and concentrate calcium oxalate (CaOx) crystals from plant leaves that form the above mentioned crystals. The chemical and physical studies of CaOx from plant to be performed depend on an adequate amount of the crystals. The plant used in this study was croton (Codiaeum variegatum). The leaves were ground in a heavy duty blender and sieved through a 0.20 mm sieve. The suspension obtained was suspended in distilled water. The crystals were concentrated at the bottom of a test tube. The supernatant must be washed until it is free of plant pigments and other organic substances. Biogenic CaOx crystals have well-defined and sharp peaks, indicating very high crystallinity. Moreover, the CaOx crystals were not damaged during the extraction procedure, as can be seen on the scanning electron microscope images. The porposed method can be considered efficient to extract and concentrate biogenic calcium oxalate.

Transfer insensitive labeling technique (TILT): application to multislice functional perfusion imaging.

Cerebral blood flow can be studied in a multislice mode with a recently proposed perfusion sequence using inversion of water spins as an endogenous tracer without magnetization transfer artifacts. The magnetization transfer insensitive labeling technique (TILT) has been used for mapping blood flow changes at a microvascular level under motor activation in a multislice mode. In TILT, perfusion mapping is achieved by subtraction of a perfusion-sensitized image from a control image. Perfusion weighting is accomplished by proximal blood labeling using two 90 degrees radiofrequency excitation pulses. For control preparation the labeling pulses are modified such that they have no net effect on blood water magnetization. The percentage of blood flow change, as well as its spatial extent, has been studied in single and multislice modes with varying delays between labeling and imaging. The average perfusion signal change due to activation was 36.9 +/- 9.1% in the single-slice experiments and 38.1 +/- 7.9% in the multislice experiments. The volume of activated brain areas amounted to 1.51 +/- 0.95 cm3 in the contralateral primary motor (M1) area, 0.90 +/- 0.72 cc in the ipsilateral M1 area, 1.27 +/- 0.39 cm3 in the contralateral and 1.42 +/- 0.75 cm3 in the ipsilateral premotor areas, and 0.71 +/- 0.19 cm3 in the supplementary motor area.