Limited sampling strategies for monitoring tacrolimus in paediatric liver transplant recipients

Ce travail de recherche a été réalisé dans le laboratoire de pharmacologie clinique, au Centre Hospitalier Universitaire Sainte-Justine, à Montréal. C'est une étude rétrospective basée sur le suivi thérapeutique du Tacrolimus prescrit chez les enfants après transplantation hépatique. Ce suivi est nécessaire car le Tacrolimus possède une importante variabilité pharmacocinétique inter et intra-individuelle ainsi qu'un index thérapeutique très étroit. Actuellement, l'individualisation des doses prescrites est basée sur la mesure de la concentration de base - du médicament dans le sang (C0), mais des études récentes montrent que cette mesure ne reflète pas précisément l'exposition du Tacrolimus dans l'organisme chez les enfants. Le meilleur reflet de cette exposition est la mesure de l'aire sous la courbe (AUC). Cependant, cette dernière implique la mesure de multiples concentrations tout au long de l'intervalle entre 2 doses de médicament (Tacrolimus: 12 heures) ce qui est long, cher et impraticable en ambulatoire. De nouvelles méthodes utilisant un nombre limité de prélèvements ont donc été développées pour prédire au mieux cette AUC. Ce sont les "Limited sampling strategies" ou LSS. La plupart de ces LSS pour le Tacrolimus ont été développées et validées chez des patients transplantés adultes et leur application directe chez les transplantés pédiatriques n'est pas possible en raison de différences importantes au niveau des paramètres pharmacocinétiques du médicament entre ces deux populations. Aussi, le but de ce travail était de développer et valider, pour la première fois, des LSS chez les enfants transplantés hépatiques. Pour cela, une analyse de 36 profils pharmacocinétiques de 28 patients transplantés hépatiques âgés de 0.4- 18.5 ans a été effectuée. Tous les profils ont été réalisés au Centre Hospitalier Universitaire Sainte-Justine entre janvier 2007 et janvier 2009. Les LSS comportant au maximum 4 mesures de concentration ont été développées en utilisant une analyse de régression multiple. Parmi tous les modèles obtenus, cinq ont été sélectionnés sur la base de critères précis puis validés selon la méthode décrite par Sheiner et Beal.¦Les résultats montrent que ces cinq modèles peuvent prédire l'AUC du Tacrolimus avec une précision cliniquement acceptable de ± 15% alors que la C0 présente la plus faible corrélation avec l'AUC.¦En conclusion, cette étude confirme que la C0 ne permet pas de prédire de manière efficace l'exposition du Tacrolimus dans l'organisme dans notre population de patients pédiatriques contrairement aux LSS analysées qui offrent une méthode pratique et fiable. Par ailleurs, en permettant d'obtenir une estimation précise et simplifiée de l'AUC complète du Tacrolimus chez les patients, ces LSS ouvrent la porte à de futures études prospectives visant à mieux définir l'AUC cible du médicament et à déterminer si le suivi basé sur la mesure de l'AUC est plus efficace et plus sûr que celui basé sur la mesure de la C0.

Development of projections from auditory to visual areas in the cat.

In newborn kittens, cortical auditory areas (including AI and AII) send transitory projections to ipsi- and contralateral visual areas 17 and 18. These projections originate mainly from neurons in supragranular layers but also from a few in infragranular layers (Innocenti and Clarke: Dev. Brain Res. 14:143-148, '84; Clarke and Innocenti: J. Comp. Neurol. 251:1-22, '86). The postnatal development of these projections was studied with injections of anterograde tracers (wheat germ agglutinin-horseradish peroxidase [WGA-HRP]) in AI and AII and of retrograde tracers (WGA-HRP, fast blue, diamidino yellow, rhodamine-labeled latex beads) in areas 17 and 18. It was found that the projections are nearly completely eliminated in development, this, by the end of the first postnatal month. Until then, most of the transitory axons seem to remain confined to the white matter and the depth of layer VI; a few enter it further but do not appear to form terminal arbors. As for other transitory cortical projections the disappearance of the transitory axons seems not to involve death of their neurons of origin. In kittens older than 1 month and in normal adult cats, retrograde tracer injections restricted to, or including, areas 17 and 18 label only a few neurons in areas AI and AII. Unlike the situation in the kitten, nearly all of these are restricted to layers V and VI. A similar distribution of neurons projecting from auditory to visual areas is found in adult cats bilaterally enucleated at birth, which suggests that the postnatal elimination of the auditory-to-visual projection is independent of visual experience and more generally of information coming from the retina.

Long-distance wolf recolonization of France and Switzerland inferred from non-invasive genetic sampling over a period of 10 years

In the early 1900s, the wolf (Canis lupus) was extirpated from France and Switzerland. There is growing evidence that the species is presently recolonizing these countries in the western Alps. By sequencing the mitochondrial DNA (mtDNA) control region of various samples mainly collected in the field (scats, hairs, regurgitates, blood or tissue; n = 292), we could (1) develop a non-invasive method enabling the unambiguous attribution of these samples to wolf, fox (Vulpes vulpes) or dog (Canis familiaris), among others; (2) demonstrate that Italian, French and Swiss wolves share the same mtDNA haplotype, a haplotype that has never been found in any other wolf population world-wide. Combined together, field and genetic data collected over 10 years corroborate the scenario of a natural expansion of wolves from the Italian source population. Furthermore, such a genetic approach is of conservation significance, since it has important consequences for management decisions. This first long-term report using non-invasive sampling demonstrates that long-distance dispersers are common, supporting the hypothesis that individuals may often attempt to colonize far from their native pack, even in the absence of suitable corridors across habitats characterized by intense human activities.

Using niche-based models to improve the sampling of rare species

Because data on rare species usually are sparse, it is important to have efficient ways to sample additional data. Traditional sampling approaches are of limited value for rare species because a very large proportion of randomly chosen sampling sites are unlikely to shelter the species. For these species, spatial predictions from niche-based distribution models can be used to stratify the sampling and increase sampling efficiency. New data sampled are then used to improve the initial model. Applying this approach repeatedly is an adaptive process that may allow increasing the number of new occurrences found. We illustrate the approach with a case study of a rare and endangered plant species in Switzerland and a simulation experiment. Our field survey confirmed that the method helps in the discovery of new populations of the target species in remote areas where the predicted habitat suitability is high. In our simulations the model-based approach provided a significant improvement (by a factor of 1.8 to 4 times, depending on the measure) over simple random sampling. In terms of cost this approach may save up to 70% of the time spent in the field.

Dyslexia in a French-Spanish bilingual girl: behavioural and neural modulations following a visual attention span intervention.

We report the case study of a French-Spanish bilingual dyslexic girl, MP, who exhibited a severe visual attention (VA) span deficit but preserved phonological skills. Behavioural investigation showed a severe reduction of reading speed for both single items (words and pseudo-words) and texts in the two languages. However, performance was more affected in French than in Spanish. MP was administered an intensive VA span intervention programme. Pre-post intervention comparison revealed a positive effect of intervention on her VA span abilities. The intervention further transferred to reading. It primarily resulted in faster identification of the regular and irregular words in French. The effect of intervention was rather modest in Spanish that only showed a tendency for faster word reading. Text reading improved in the two languages with a stronger effect in French but pseudo-word reading did not improve in either French or Spanish. The overall results suggest that VA span intervention may primarily enhance the fast global reading procedure, with stronger effects in French than in Spanish. MP underwent two fMRI sessions to explore her brain activations before and after VA span training. Prior to the intervention, fMRI assessment showed that the striate and extrastriate visual cortices alone were activated but none of the regions typically involved in VA span. Post-training fMRI revealed increased activation of the superior and inferior parietal cortices. Comparison of pre- and post-training activations revealed significant activation increase of the superior parietal lobes (BA 7) bilaterally. Thus, we show that a specific VA span intervention not only modulates reading performance but further results in increased brain activity within the superior parietal lobes known to housing VA span abilities. Furthermore, positive effects of VA span intervention on reading suggest that the ability to process multiple visual elements simultaneously is one cause of successful reading acquisition.

Visual cortex in Alzheimer's disease: occurrence of neuronal death and glial proliferation, and correlation with pathological hallmarks.

Visual areas 17 and 18 were studied with morphometric methods for numbers of neurons, glia, senile plaques (SP), and neurofibrillary tangles (NFT) in 13 cases of Alzheimer's disease (AD) as compared to 11 controls. In AD cases, the mean neuronal density was significantly decreased by about 30% in both areas 17 and 18, while the glial density was increased significantly only in area 17. The volume of area 17 was unchanged in AD cases but its total number of neurons was decreased by 33% and its total number of glia increased by 45% compared to controls. In AD the number of SP was similar in areas 17 and 18, while that of NFT was significantly higher in area 18. The number of neurons with NFT was only 2% in area 17 and about 10% in area 18. The discrepancy between the loss of neurons and the amount of NFT suggests that neuronal loss can occur without passing through NFT degeneration. The deposition of SP was correlated with glial proliferation, but not with neuronal loss or neurofibrillary degeneration.

Remaining rod activity mediates visual behavior in adult Rpe65-/- mice.

Purpose: C57/Bl6, Cpfl1-/- (Cone photoreceptors function loss 1; pure rod function), Gnat1alpha-/- (rod alpha-transducin; pure cone function) and Rpe65-/-;Rho-/- double knock-out mice were studied in order to distinguish the respective contributions of the different photoreceptor (PR) systems that enable light perception and mediate a visual reflex in adult Rpe65-/- mice using a simple behavioural procedure. Methods: Visual function was estimated using a rotating automatized optomotor drum covered with vertical black and white stripes at spatial frequencies of 0.025 to 0.5 cycles per degree (cpd) in both photopic and scotopic conditions. To evaluate the contribution as well as the light intensity threshold of each PR system, we tested the mouse strains with different luminances. Results: Stripe rotation elicits head movements in wild-type (WT) animals in photopic and scotopic conditions depending on the spatial frequency, whereas Cpfl1-/- mice show a reduced activity in the photopic condition and Gnat1alpha-/- mice an almost absent response in the scotopic condition. Interestingly, a robust visual response is obtained with Rpe65-/- knockout mice at 0.075 cpd and 0.1 cpd in the photopic condition. The residual rod function in the Rpe65-/- animals was demonstrated by testing Rpe65-/-;Rho-/- mice that present no response in photopic conditions. Conclusions: The optomotor test is a simple method to estimate the visual function, and to evaluate the respective contributions of rod and cone systems. Using this test, we demonstrate that in Rpe65-/- mice, devoid of functional cones and of detectable 11-cis-retinal protein, rods mimic in part the cone function by mediating vision in photopic conditions.

Visuospatial working memory deficits and visual pursuit impairments are not directly related in schizophrenia.

OBJECTIVE: Patients with schizophrenia show deficits in visuospatial working memory and visual pursuit processes. It is currently unclear, however, whether both impairments are related to a common neuropathological origin. The purpose of the present study was therefore to examine the possible relations between the encoding and the discrimination of dynamic visuospatial stimuli in schizophrenia. METHOD: Sixteen outpatients with schizophrenia and 16 control subjects were asked to encode complex disc displacements presented on a screen. After a delay, participants had to identify the previously presented disc trajectory from a choice of six static linear paths, among which were five incorrect paths. The precision of visual pursuit eye movements during the initial presentation of the dynamic stimulus was assessed. The fixations and scanning time in definite regions of the six paths presented during the discrimination phase were investigated. RESULTS: In comparison with controls, patients showed poorer task performance, reduced pursuit accuracy during incorrect trials and less time scanning the correct stimulus or the incorrect paths approximating its global structure. Patients also spent less time scanning the leftmost portion of the correct path even when making a correct choice. The accuracy of visual pursuit and head movements, however, was not correlated with task performance. CONCLUSIONS: The present study provides direct support for the hypothesis that active integration of visuospatial information within working memory is deficient in schizophrenia. In contrast, a general impairment of oculomotor mechanisms involved in smooth pursuit did not appear to be directly related to lower visuospatial working memory performance in schizophrenia.