Population pharmacokinetics of imatinib in CML and GIST patients under long-term treatment

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukaemia (CML) and gastro-intestinal stromal tumour (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occur in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualisation. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after latest dose, were measured in 59 patients receiving Glivec® at diverse regimens, using a validated chromatographic method (HPLC-UV) developed for this study. The results were analysed by non-linear mixed effect modelling (NONMEM). A one- compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. The MDR1 polymorphism 3435C>T appears to affect the disposition of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40%) and distribution volume (71%). Together with intra-patient variability (34%), this translates into an 8-fold width of the 90%-prediction interval of plasma concentrations expected under a fixed dosing regimen ! This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring programme for imatinib. It may help to individualise the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

A Comparative study of germination strategies of two species of genus Allium sect. Allium

Germination experiments were performed with seeds of two species of genus Allium section Allium, a rare and endangered species A. pyrenaicum and a common A. sphaerocephalon. Different pre-treatments and a photoperiod of 24 h darkness were applied in order to simulate different germination conditions. Both species showed a high percentage of viable seeds a part of which were dormant. An elevate percentage of dormant seeds could be caused by a later collection time. Low altitude populations had more mortality than the others, possibly caused by the hard summer conditions during flowering and fruiting time. Comparisons between dates of species coexistence localities only show inter-population variability and it could be caused by the detected dormancy. Darkness accelerates germination, possibly for elongation radicle stimulation. Heat-shock pre-treatments decreased germination time in seeds from localities where fire is a probable event. The rarity of A. Pyrenaicum not seems to be caused by restricted germination requirements but is attributable to distinct habitat preferences, related to his altitudinal range of distribution

Quality Assessment of Cardiac Magnetic Resonance Images at 1.5/3.0 T: Description and Validation of Standardized Criteria

PURPOSE: Cardiovascular magnetic resonance (CMR) has become a robust and important diagnostic imaging modality in cardiovascular medicine. However,insufficient image quality may compromise its diagnostic accuracy. No standardized criteria are available to assess the quality of CMR studies. We aimed todescribe and validate standardized criteria to evaluate the quality of CMR studies including: a) cine steady-state free precession, b) delayed gadoliniumenhancement, and c) adenosine stress first-pass perfusion. These criteria will serve for the assessment of the image quality in the setting of the Euro-CMR registry.METHOD AND MATERIALS: First, a total of 45 quality criteria were defined (35 qualitative criteria with a score from 0-3, and 10 quantitative criteria). Thequalitative score ranged from 0 to 105. The lower the qualitative score, the better the quality. The quantitative criteria were based on the absolute signal intensity (delayed enhancement) and on the signal increase (perfusion) of the anterior/posterior left ventricular wall after gadolinium injection. These criteria were then applied in 30 patients scanned with a 1.5T system and in 15 patients scanned with a 3.0T system. The examinations were jointly interpreted by 3 CMR experts and 1 study nurse. In these 45 patients the correlation between the results of the quality assessment obtained by the different readers was calculated.RESULTS: On the 1.5T machine, the mean quality score was 3.5. The mean difference between each pair of observers was 0.2 (5.7%) with a mean standarddeviation of 1.4. On the 3.0T machine, the mean quality score was 4.4. The mean difference between each pair of onservers was 0.3 (6.4%) with a meanstandard deviation of 1.6. The quantitative quality assessments between observers were well correlated for the 1.5T machine: R was between 0.78 and 0.99 (pCONCLUSION: The described criteria for the assessment of CMR image quality are robust and have a low inter-observer variability, especially on 1.5T systems.CLINICAL RELEVANCE/APPLICATION: These criteria will allow the standardization of CMR examinations. They will help to improve the overall quality ofexaminations and the comparison between clinical studies.

Analysis of the multi-copy gene family FAM90A as a copy number variant in different ethnic backgrounds

Copy number variants contribute extensively to inter-individual genomic differences, but little is known about their inter-population variability and diversity. In a previous study (Bosch et al., 2007; 16:2572-2582), we reported that the primate-specific gene family FAM90A, which accounts for as many as 25 members in the human reference assembly, has expanded the number of FAM90A clusters across the hominoid lineage. Here we examined the copy number variability of FAM90A genes in 260 HapMap samples of European, African, and Asian ancestry, and showed significant inter-population differences (p<0.0001). Based on the recent study of Stranger et al. (2007; 315:848-853), we also explored the correlation between copy number variability and expression levels of the FAM90A gene family. Despite the high genomic variability, we found a low correlation between FAM90A copy number and expression levels, which could be due to the action of independent trans-acting factors. Our results show that FAM90A is highly variable in copy number between individuals and between populations. However, this variability has little impact on gene expression levels, thus highlighting the importance of genomic variability for genes located in regions containing segmental duplications.

Three-dimensional morphological analysis of intracranial aneurysms: a fully automated method for aneurysm sac isolation and quantification

Morphological descriptors are practical and essential biomarkers for diagnosis andtreatment selection for intracranial aneurysm management according to the current guidelinesin use. Nevertheless, relatively little work has been dedicated to improve the three-dimensionalquanti cation of aneurysmal morphology, automate the analysis, and hence reduce the inherentintra- and inter-observer variability of manual analysis. In this paper we propose a methodologyfor the automated isolation and morphological quanti cation of saccular intracranial aneurysmsbased on a 3D representation of the vascular anatomy.

Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

Population pharmacokinetic study of memantine: effects of clinical and genetic factors.

BACKGROUND AND OBJECTIVE: Memantine, a frequently prescribed anti-dementia drug, is mainly eliminated unchanged by the kidneys, partly via tubular secretion. Considerable inter-individual variability in plasma concentrations has been reported. We aimed to investigate clinical and genetic factors influencing memantine disposition. METHODS: A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting. Patients were genotyped for common polymorphisms in renal cation transporters (SLC22A1/2/5, SLC47A1, ABCB1) and nuclear receptors (NR1I2, NR1I3, RXR, PPAR) involved in transporter expression. RESULTS: The average clearance was 5.2 L/h with a 27 % inter-individual variability (percentage coefficient of variation). Glomerular filtration rate (p = 0.007) and sex (p = 0.001) markedly influenced memantine clearance. NR1I2 rs1523130 was identified as the unique significant genetic covariate for memantine clearance (p = 0.006), with carriers of the NR1I2 rs1523130 CT/TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype. CONCLUSION: The better understanding of inter-individual variability of memantine disposition might be beneficial in the context of individual dose optimization.

Variation of the Chlorophyll a Related to Sea Surface Temperature, Wind and Geostrophic Currents in the Cape Verde Region Using Satellite Data

We present a comparative analysis of satellite derived climatologies in the Cape Verde region (CV). In order to establish chlorophyll a variability, in relation to other oceanographic phenomena, a set of, relatively long (from five to eight years), time series of chlorophyll a, sea surface temperature, wind and geostrophic currents, were ensembled for the Eastern Central Atlantic (ECA). We studied seasonal and inter-annual variability of phytoplankton concentration, in relation to the rest of the variables, with a special focus in CV. We compared the situation within the archipelago with those of the surrounding marine environments, such as the North West African Upwelling (NWAU), North Atlantic Subtropical Gyre (NASTG), North Equatorial Counter Current (NECC) and Guinea Dome (GD). At the seasonal scale, CV region behaves partly as the surrounding areas, nevertheless, some autochthonous features were also found. The maximum peak of the pigment having a positive correlation with temperature is found at the end of the year for all the points in the archipelago; a less remarkable rise with negative correlation is also detected in February for points CV2 and CV4. This is behavior that none of the surrounding environments have shown. This enrichment was found to be preceded by a drastic drop in wind intensity (SW Monsoon) during summer months. The inter-annual analysis shows a tendency for decreasing of the chlorophyll a concentration.

Variation of the Chlorophyll a Related to Sea Surface Temperature, Wind and Geostrophic Currents in the Cape Verde Region Using Satellite Data

We present a comparative analysis of satellite derived climatologies in the Cape Verde region (CV). In order to establish chlorophyll a variability, in relation to other oceanographic phenomena, a set of, relatively long (from five to eight years), time series of chlorophyll a, sea surface temperature, wind and geostrophic currents, were ensembled for the Eastern Central Atlantic (ECA). We studied seasonal and inter-annual variability of phytoplankton concentration, in relation to the rest of the variables, with a special focus in CV. We compared the situation within the archipelago with those of the surrounding marine environments, such as the North West African Upwelling (NWAU), North Atlantic Subtropical Gyre (NASTG), North Equatorial Counter Current (NECC) and Guinea Dome (GD). At the seasonal scale, CV region behaves partly as the surrounding areas, nevertheless, some autochthonous features were also found. The maximum peak of the pigment having a positive correlation with temperature is found at the end of the year for all the points in the archipelago; a less remarkable rise with negative correlation is also detected in February for points CV2 and CV4. This is behavior that none of the surrounding environments have shown. This enrichment was found to be preceded by a drastic drop in wind intensity (SW Monsoon) during summer months. The inter-annual analysis shows a tendency for decreasing of the chlorophyll a concentration.

An ultra performance liquid chromatography-tandem MS assay for tamoxifen metabolites profiling in plasma: first evidence of 4'-hydroxylated metabolites in breast cancer patients.

There is increasing evidence that the clinical efficacy of tamoxifen, the first and most widely used targeted therapy for estrogen-sensitive breast cancer, depends on the formation of the active metabolites 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen). Large inter-individual variability in endoxifen plasma concentrations has been observed and related both to genetic and environmental (i.e. drug-induced) factors altering CYP450s metabolizing enzymes activity. In this context, we have developed an ultra performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS) requiring 100 μL of plasma for the quantification of tamoxifen and three of its major metabolites in breast cancer patients. Plasma is purified by a combination of protein precipitation, evaporation at room temperature under nitrogen, and reconstitution in methanol/20 mM ammonium formate 1:1 (v/v), adjusted to pH 2.9 with formic acid. Reverse-phase chromatographic separation of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen is performed within 13 min using elution with a gradient of 10 mM ammonium formate and acetonitrile, both containing 0.1% formic acid. Analytes quantification, using matrix-matched calibration samples spiked with their respective deuterated internal standards, is performed by electrospray ionization-triple quadrupole mass spectrometry using selected reaction monitoring detection in the positive mode. The method was validated according to FDA recommendations, including assessment of relative matrix effects variability, as well as tamoxifen and metabolites short-term stability in plasma and whole blood. The method is precise (inter-day CV%: 2.5-7.8%), accurate (-1.4 to +5.8%) and sensitive (lower limits of quantification comprised between 0.4 and 2.0 ng/mL). Application of this method to patients' samples has made possible the identification of two further metabolites, 4'-hydroxy-tamoxifen and 4'-hydroxy-N-desmethyl-tamoxifen, described for the first time in breast cancer patients. This UPLC-MS/MS assay is currently applied for monitoring plasma levels of tamoxifen and its metabolites in breast cancer patients within the frame of a clinical trial aiming to assess the impact of dose increase on tamoxifen and endoxifen exposure.

Front-Crawl propulsive phase detection using inertial sensors

Front crawl is an alternating swimming stroke technique in which different phases of arm movement induce changes in acceleration of limbs and body. This study proposes a new approach to use inertial body worn sensors to estimate main temporal phases of front crawl. Distinctive features in kinematic signals are used to detect the temporal phases. These temporal phases are key information sources of qualitative and quantitative evaluation of swimming coordination, which have been assessed previously by video analysis. The present method has been evaluated upon a wide range of coordination and showed a difference of 4.9% with video based system. The results are in line with video analysis inter-operator variability yet offering an easy-to-use system for trainers.

Expression of apoptosis and survival genes in human memory T cell populations

RESUME Introduction: Les cellules T mémoires humaines sont classées en trois sous-populations sur la base de l'expression d'un marqueur de surface cellulaire, CD45RA, et du récepteur aux chimiokines, CCR7. Ces sous-populations, nommées cellules mémoires centrales (TcM), mémoires effectrices (TEM) et mémoires effectrices terminales (ITEM), ont des rôles fonctionnels distincts, ainsi que des capacités de prolifération et de régénération différentes. Cependant, la génération de ces différences reste encore mal comprise et on ignore les mécanismes moléculaires impliqués. Matériaux et Méthodes: Des cellules mononucléaires humaines du sang périphérique ont été séparées par cytométrie de flux selon leur expression de CD4, CD8, CD45RA et CCR7 en sous-populations de cellules CD4+ ou CD8+ naïves, TcM, TEM ou ITEM. Dans chacune de ces sous-populations, 14 gènes impliqués dans l'apoptose, la survie ou la capacité proliférative des cellules T ont été quantifiés par RT-PCR en temps réel, relativement à l'expression d'un gène de référence endogène. L'ARN provenant de 450 cellules T a été utilisé par gène et par sous-population. Les gènes analysés (cibles) comprenaient des gènes de survie (BAFF, APRIL, BAFF-R, BCMA, TACI, IL-15Rα, IL-7Rα), des gènes anti-apoptotiques (Bcl-2, BclxL, FLIP), des gènes pro-apoptotiques (Bad, Bax, Fast) et le gène anti-prolifératif, Tob. A l'aide de la méthode comparative delta-delta-CT, le taux d'expression des gènes cibles de chaque sous-population des cellules T mémoires CD4+ et CD8+, à été comparée à leur taux d'expression dans les cellules T naïves CD4+ et CD8+. Résultats: Dans les cellules CD8+, les gènes pro-apoptotiques Bax et Fast étaient surexprimés dans toutes les sous-populations mémoires, tandis que l'expression des facteurs anti-apoptotiques et de survie comme Bcl-2, APRIL et BAFF-R, étaient diminués. Ces deux tendances étaient particulièrement accentuées dans les sous-groupes des cellules mémoires TEM et TTEM. A noter que malgré le fait que leur expression était également diminuée dans les autres cellules mémoires, le facteur de survie IL-7Ra, était sélectivement surexprimé dans la sous-population de cellules TcM et l'expression d'IL-15Ra était sélectivement augmentée dans les TEM. Dans les cellules CD4+, le taux d'expression des gènes analysés était plus variable entre les sujets étudiés que dans les cellules CD8+, ne permettant pas de définir un profil d'expression spécifique. L'expression du gène de survie BAFF par contre, a été significativement augmentée dans toutes les sous-populations mémoire CD4+. Il en va de même pour l'expression d' APRIL et de BAFF-R, bien que dans moindre degré. A remarquer que l'expression du facteur anti-apoptotique Fast a été observée uniquement dans la souspopulation des TTEM. Discussion et Conclusions: Cette étude montre une nette différence entre les cellules CD8+ et CD4+, en ce qui concerne les profils d'expression des gènes impliqués dans la survie et l'apoptose des cellules T mémoires. Ceci pourrait impliquer une régulation cellulaire homéostatique distincte dans ces deux compartiments de cellules T mémoires. Dans les cellules CD8+ l'expression d'un nombre de gènes impliqués dans la survie et la protection de l'apoptose semblerait être diminuée dans les populations TEM et TTEM en comparaison à celle des sous-populations naïves et TEM, tandis que l'expression des gènes pro-apoptotiques semblerait être augmentée. Comme ceci paraît être plus accentué dans les TTEM, cela pourrait indiquer une plus grande disposition à l'apopotose dans les populations CCR7- (effectrices) et une perte de survie parallèlement à l'acquisition de capacités effectrices. Ceci parlerait en faveur d'un modèle de différentiation linéaire dans les cellules CD8+. De plus, l'augmentation sélective de l'expression d'IL-7Ra observée dans le sous-groupe de cellules mémoires TEM, et d'IL-15Ra dans celui des TEM, pourrait indiquer un moyen de sélection pour des réponses immunitaires mémoires à long terme par une réponse distincte à ces cytokines. Dans les cellules CD4+ par contre, aucun profil d'expression n'a pu être déterminé; les résultats suggèrent même une résistance relative à l'apoptose de la part des cellules mémoires. Ceci pourrait favoriser l'existence d'un modèle de différentiation plus flexible avec des possibilités d'interaction multiples. Ainsi, la surexpression sélective de BAFF, APRIL et BAFF-R dans les sous-populations individuelles des cellules mémoires pourrait être un indice de l'interaction de ces sous-groupes avec des cellules B. ABSTRACT Introduction: Based on their surface expression of the CD45 isoform and of the CCR7 chemokine receptor, memory T cells have been divided into the following three subsets: central memory (TAM), effector memory (TEM) and terminal effector memory (ITEM). Distinct functional roles and different proliferative and regenerative capacities have been attributed to each one of these subpopulations. The molecular mechanisms underlying these differences; however, remain poorly understood. Materials and Methods: According to their expression of CD4, CD8, CD45RA and CCR7, human peripheral blood mononuclear cells were sorted by flow-cytometry into CD4+ or CD8+ naïve, TAM, TEM and ITEM subsets. Using real-time PCR, the expression of 14 genes known to be involved in apoptotis, survival or proliferation of T cells was quantified separately in each individual subset, relative to an endogenous reference gene. The RNA equivalent of 450 T cells was used for each gene and subset. The target gene panel included the survival genes BAFF, APRIL, BAFF-R, BCMA, TACI, IL-15Rα and IL-7Rα, the anti-apoptotic genes Bcl2, Bcl-xL and FLIP, the pro-apoptotic genes Bad, Bax and Fast, as well as the antiproliferative gene Tob. Using the comparative CT-method, the expression of the target genes in the three memory T cell subsets of both CD4+ and CD8+ T cell populations was compared to their expression in the naïve T cells. Results: In CD8+ cells, the pro-apoptotic factors Bax and Fast were found to be upregulated in all memory T cell subsets, whereas the survival and anti-apoptotic factors Bcl-2, APRIL and BAFF-R were downregulated. These tendencies were most accentuated in TEM and TTEM subsets. Even though the survival factor IL-7Rα was also downregulated in these subsets, interestingly, it was selectively upregulated in the CD8+ TAM subset. Similarly, IL-15Rαexpression was shown to be selectively upregulated in the CD8+ TEM subset. In CD4+ cells, the expression levels of the analyzed genes showed a greater inter-individual variability than in CD8+ cells, thus suggesting the absence of any particular expression pattern for CD4+ memory T cells. However, the survival factor BAFF was found to be significantly upregulated in all CD4+ memory T cell subsets, as was also the expression of APRIL and BAFF-R, although to a lesser extent. Furthermore, it was noted that the pro-apoptotic gene Fast was only expressed in the TTEM CD4+ subset. Discussion and Conclusions: Genes involved in apoptosis and survival in human memory T cells have been shown to be expressed differently in CD8+ cells as compared to CD4+ cells, suggesting a distinct regulation of cell homeostasis in these two memory T cell compartments. The present study suggests that, in CD8+ T cells, the expression of various survival and antiapoptotic genes is downregulated in TEM and TTEM subsets, while the expression of proapoptotic genes is upregulated in comparison to the naïve and the TAM populations. These characteristics, potentially translating to a greater susceptibility to apoptosis in the CCR7- (effector) memory populations, are accentuated in the TTEM population, suggesting a loss of survival in parallel to the acquisition of effector capacities. This speaks in favour of a linear differentiation model in CD8+ T memory cells. Moreover, the observed selectively increased expression of IL-7Rα in CD8+ TAM cells - as that of IL-15Rα in CD8+ TEM cells -suggest that differential responsiveness to cytokines could confer a selection bias for distinct long-term memory cell responses. Relative to the results for CD8+ T cells, those for CD4+ T cells seem to indicate a certain resistance of the memory subsets to apoptosis, suggesting the possibility of a more flexible differentiation model with multiple checkpoints and potential interaction of CD4+ memory cells with other cells. Thus, the selective upregulation of BAFF, APRIL and BAFF-R in individual memory subsets could imply an interaction of these subsets with B cells.

Reliability of the image evaluation system PGMI

Purpose: Many countries used the PGMI (P=perfect, G=good, M=moderate, I=inadequate) classification system for assessing the quality of mammograms. Limits inherent to the subjectivity of this classification have been shown. Prior to introducing this system in Switzerland, we wanted to better understand the origin of this subjectivity in order to minimize it. Our study aimed at identifying the main determinants of the variability of the PGMI system and which criteria are the most subjected to subjectivity. Methods and Materials: A focus group composed of 2 experienced radiographers and 2 radiologists specified each PGMI criterion. Ten raters (6 radiographers and 4 radiologists) evaluated twice a panel of 40 randomly selected mammograms (20 analogic and 20 digital) according to these specified PGMI criteria. The PGMI classification was assessed and the intra- and inter-rater reliability was tested for each professional group (radiographer vs radiologist), image technology (analogic vs digital) and PGMI criterion. Results: Some 3,200 images were assessed. The intra-rater reliability appears to be weak, particularly in respect to inter-rater variability. Subjectivity appears to be largely independent of the professional group and image technology. Aspects of the PGMI classification criteria most subjected to variability were identified. Conclusion: Post-test discussions enabled to specify more precisely some criteria. This should reduce subjectivity when applying the PGMI classification system. A concomitant, important effort in training radiographers is also necessary.

Single Subject Finger Somatotopy Mapping at 7T.

Introduction: The primary somatosensory cortex (SI) contains Brodmann areas (BA) 1, 2, 3a, and 3b. Research in non-human primates showed that BAs 3b, 1, and 2 each contain one full representation of the hand with separate representations for each finger. This research also showed that the finger representation in BA3b has larger and clearer finger somatotopy than BA1 and 2. Although several efforts to map finger somatotopy in SI by fMRI have been made at 1.5 and 3T these studies have yielded variable results and were not able to detect single subject finger somatotopy, probably due to the limited spatial extent of the cortical areas representing a digit (close to the resolution in most fMRI experiments), complications due to acquisition of consistent maps for individual subjects (Schweizer et al 2008), or inter-individual variability in sulcal anatomy impeding group studies. Here, we used 7T fMRI to investigate finger somatotopy in SI, some of its functional characteristics, and its reproducibility. Methods: Eight right-handed male subjects were scanned on a 7T scanner (Siemens Medical, Germany) with an 8-channel Tx/Rx rf-coil (Rapid Biomedical, Germany). 1.3x1.3x1.3mm3 resolution fMRI data were acquired using a sinusoidal readout EPI sequence (Speck et al, 2008) and FOV=210mm, TE/TR=27ms/2.5s, GRAPPA=2. Each volume contained 28 transverse slices covering SI. A single EPI volume with 64 slices was acquired to aid coregistration. 1x1x1mm3 anatomical data were acquire using the MP2RAGE sequence (Marques et al, 2009; TE/TR/TI1,2/TRmprage=2.63ms/7.2ms/0.9,3.2s/5s). Subjects were positioned supine in the scanner with their right arm comfortably against the magnet bore. An experimenter was positioned at the entrance of the bore where he could easily reach and stroke successively the two distal phalanxes of each digit. The order of stroked digit was D1 (thumb)-D3-D5-D2-D4, with 20s ON, 10s OFF alternated. This sequence was repeated four times per run and two functional runs were acquired per subject. Realignment, smoothing (FWHM 2 mm), coregistration of the anatomical to the fMRI data and calculation of t-statistics were done using SPM8. An SI mask was obtained via an F-contrast (p<0.001) over all digits. Within the mask, voxels were labeled with the number of the digit demonstrating the highest t-value for that particular voxel. Results: For all subjects, areas corresponding to the five digits were identified in contralateral SI. BA3b showed the most consistent somatotopic finger representation (see an example in Fig.1). The five digits were localized in a consecutive order in the cortex, with D1 most anterior, inferior and distal and D5, most posterior, superior and medial (mean distance between centres of mass of digit representations ±stderr: 4.2±0.7mm; see Fig. 2). The analysis of average beta values within each finger representation region revealed the specificity of the somatotopic region to the tactile input for each tested finger (except digit 4 and 5). Five of these subjects also presented an orderly and consecutive representation of the five digits in BA1 and 2. Conclusions: Our data reveal that the increased BOLD sensitivity at 7T and the high spatial resolution used in this study allow consistent somatotopic mapping using human touch as a stimulus and that human SI contains at least three separate regions that contain five separate representations of all single contralateral fingers. Moreover, adjacent fingers were represented at adjacent cortical regions across the three SI regions. The spatial organization of SI as reflected in individual subject topography corresponds well with previous electrophysiological data in non-human primates. The small distance between digit representations highlights the need for the high spatial resolution available at 7T.

Assessment of changes in body water by bioimpedance in acutely ill surgical patients.

OBJECTIVE: To evaluate the relationship between changes in body bioelectrical impedance (BI) at 0.5, 50 and kHz and the changes in body weight, as an index of total body water changes, in acutely ill surgical patients during the rapid infusion of isotonic saline solution. DESIGN: Prospective clinical study. SETTING: Multidisciplinary surgical ICU in a university hospital. PATIENTS: Twelve male patients treated for acute surgical illness (multiple trauma n = 5, major surgery n = 7). Selection criteria: stable cardiovascular parameters, normal cardiac function, signs of hypovolemia (CVP < or = 5 mmHg, urine output < 1 ml/kg x h). INTERVENTIONS: After baseline measurements, a 60 min fluid challenge test was performed with normal saline solution, 0.25 ml/kg/min [corrected]. MEASUREMENTS AND RESULTS: Body weight (platform digital scale), total body impedance (four-surface electrode technique; measurements at 0.5, 50 and 100 kHz) and urine output. Fluid retention induced a progressive decrease in BI at 0.5, 50 and 100 kHz, but the changes were significant for BI 0.5 and BI 100 only, from 40 min after the beginning of the fluid therapy onwards. There was a significant negative correlation between changes in water retention and BI 0.5, with individual correlation coefficients ranging from -0.72 to 0.95 (p < 0.01-0.0001). The slopes of the regression lines indicated that for each kg of water change, there was a mean decrease in BI of 18 ohm, but a substantial inter-individual variability was noted. CONCLUSION: BI measured at low frequency can represent a valuable index of acute changes in body water in a group of surgical patients but not in a given individual.