Quantitative Ultrasound of the Heel and Fracture Risk Assessment: an Updated Meta-Analysis

Objectives: Quantitative ultrasound (QUS) is an attractive method for assessing fracture risk because it is portable, inexpensive, without ionizing radiation, and available in areas of the world where DXA is not readily accessible or affordable. However, the diversity of QUS scanners and variability of fracture outcomes measured in different studies is an important obstacle to widespread utilisation of QUS for fracture risk assessment. We aimed in this review to assess the predictive power of heel QUS for fractures considering different characteristics of the association (QUS parameters and fracture outcomes measured, QUS devices, study populations, and independence from DXA-measured bone density).Materials/Methods : We conducted an inverse-variance randomeffects meta-analysis of prospective studies with heel QUS measures at baseline and fracture outcomes in their follow-up. Relative risks (RR) per standard deviation (SD) of different QUS parameters (broadband ultrasound attenuation [BUA], speed of sound &SOS;, stiffness index &SI;, and quantitative ultrasound index [QUI]) for various fracture outcomes (hip, vertebral, any clinical, any osteoporotic, and major osteoporotic fractures) were reported based on study questions.Results : 21 studies including 55,164 women and 13,742 men were included with a total follow-up of 279,124 person-years. All four QUS parameters were associated with risk of different fractures. For instance, RR of hip fracture for 1 SD decrease of BUA was 1.69 (95% CI 1.43-2.00), SOS was 1.96 (95% CI 1.64-2.34), SI was 2.26 (95%CI 1.71-2.99), and QUI was 1.99 (95% CI 1.49-2.67). Validated devices from different manufacturers predicted fracture risks with a similar performance (meta-regression p-values>0.05 for difference of devices). There was no sign of publication bias among the studies. QUS measures predicted fracture with a similar performance in men and women. Meta-analysis of studies with QUS measures adjusted for hip DXA showed a significant and independent association with fracture risk (RR/SD for BUA =1.34 [95%CI 1.22-1.49]).Conclusions : This study confirms that QUS of the heel using validated devices predicts risk of different fracture outcomes in elderly men and women. Further research and international collaborations are needed for standardisation of QUS parameters across various manufacturers and inclusion of QUS in fracture risk assessment tools. Disclosure of Interest : None declared.

Interpretation of lesions of the cardiac conduction system in cocaine-related fatalities.

This study examines cases of chronic drug users who died suddenly after drug administration. Victims were young subjects, aged from 19 to 35 from Switzerland and known to the police as long-term drug users. The circumstances of death suggested the occurrence of a sudden, unexpected death. Some victims were undergoing methadone treatment. In each case, a forensic autopsy and toxicological analyses were performed at the Institute of Forensic Medicine in Lausanne in Switzerland between 2002 and 2004, including hair analysis as a means to establish chronic drug use in general, and cocaine use in particular. The conduction system was examined histologically and cases showing potentially lethal changes were chosen for this report. The most frequent lesions found were severe thickening of the atrioventricular node artery, intranodal and perinodal fibrosis, and microscopic foci of chronic inflammatory infiltration. The authors conclude that pathological lesions in the conduction tissue may play a role in the occurrence of death attributed to intoxication consecutive to cocaine ingestion.

Quantitative morphometry analysis of the fetal brain using clinical MR imaging

In vivo fetal magnetic resonance imaging provides aunique approach for the study of early human braindevelopment [1]. In utero cerebral morphometry couldpotentially be used as a marker of the cerebralmaturation and help to distinguish between normal andabnormal development in ambiguous situations. However,this quantitative approach is a major challenge becauseof the movement of the fetus inside the amniotic cavity,the poor spatial resolution provided by very fast MRIsequences and the partial volume effect. Extensiveefforts are made to deal with the reconstruction ofhigh-resolution 3D fetal volumes based on severalacquisitions with lower resolution [2,3,4]. Frameworkswere developed for the segmentation of specific regionsof the fetal brain such as posterior fossa, brainstem orgerminal matrix [5,6], or for the entire brain tissue[7,8], applying the Expectation-Maximization MarkovRandom Field (EM-MRF) framework. However, many of theseprevious works focused on the young fetus (i.e. before 24weeks) and use anatomical atlas priors to segment thedifferent tissue or regions. As most of the gyraldevelopment takes place after the 24th week, acomprehensive and clinically meaningful study of thefetal brain should not dismiss the third trimester ofgestation. To cope with the rapidly changing appearanceof the developing brain, some authors proposed a dynamicatlas [8]. To our opinion, this approach however faces arisk of circularity: each brain will be analyzed /deformed using the template of its biological age,potentially biasing the effective developmental delay.Here, we expand our previous work [9] to proposepost-processing pipeline without prior that allow acomprehensive set of morphometric measurement devoted toclinical application. Data set & Methods: Prenatal MRimaging was performed with a 1-T system (GE MedicalSystems, Milwaukee) using single shot fast spin echo(ssFSE) sequences (TR 7000 ms, TE 180 ms, FOV 40 x 40 cm,slice thickness 5.4mm, in plane spatial resolution1.09mm). For each fetus, 6 axial volumes shifted by 1 mmwere acquired under motherâeuro?s sedation (about 1min pervolume). First, each volume is segmentedsemi-automatically using region-growing algorithms toextract fetal brain from surrounding maternal tissues.Inhomogeneity intensity correction [10] and linearintensity normalization are then performed. Brain tissues(CSF, GM and WM) are then segmented based on thelow-resolution volumes as presented in [9]. Ahigh-resolution image with isotropic voxel size of 1.09mm is created as proposed in [2] and using B-splines forthe scattered data interpolation [11]. Basal gangliasegmentation is performed using a levet setimplementation on the high-resolution volume [12]. Theresulting white matter image is then binarized and givenas an input in FreeSurfer software(http://surfer.nmr.mgh.harvard.edu) to providetopologically accurate three-dimensional reconstructionsof the fetal brain according to the local intensitygradient. References: [1] Guibaud, Prenatal Diagnosis29(4) (2009). [2] Rousseau, Acad. Rad. 13(9), 2006. [3]Jiang, IEEE TMI 2007. [4] Warfield IADB, MICCAI 2009. [5]Claude, IEEE Trans. Bio. Eng. 51(4) 2004. [6] Habas,MICCAI 2008. [7] Bertelsen, ISMRM 2009. [8] Habas,Neuroimage 53(2) 2010. [9] Bach Cuadra, IADB, MICCAI2009. [10] Styner, IEEE TMI 19(39 (2000). [11] Lee, IEEETrans. Visual. And Comp. Graph. 3(3), 1997. [12] BachCuadra, ISMRM 2010.

Quantitative multiparameter assays to measure the effect of adjuvants on human antigen-specific CD8 T-cell responses.

Large numbers and functionally competent T cells are required to protect from diseases for which antibody-based vaccines have consistently failed (1), which is the case for many chronic viral infections and solid tumors. Therefore, therapeutic vaccines aim at the induction of strong antigen-specific T-cell responses. Novel adjuvants have considerably improved the capacity of synthetic vaccines to activate T cells, but more research is necessary to identify optimal compositions of potent vaccine formulations. Consequently, there is a great need to develop accurate methods for the efficient identification of antigen-specific T cells and the assessment of their functional characteristics directly ex vivo. In this regard, hundreds of clinical vaccination trials have been implemented during the last 15 years, and monitoring techniques become more and more standardized.

Prediction of hip fracture risk by quantitative ultrasound in more than 7000 Swiss women > or =70 years of age: comparison of three technologically different bone ultrasound devices in the SEMOF study.

To compare the prediction of hip fracture risk of several bone ultrasounds (QUS), 7062 Swiss women > or =70 years of age were measured with three QUSs (two of the heel, one of the phalanges). Heel QUSs were both predictive of hip fracture risk, whereas the phalanges QUS was not. INTRODUCTION: As the number of hip fracture is expected to increase during these next decades, it is important to develop strategies to detect subjects at risk. Quantitative bone ultrasound (QUS), an ionizing radiation-free method, which is transportable, could be interesting for this purpose. MATERIALS AND METHODS: The Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk (SEMOF) study is a multicenter cohort study, which compared three QUSs for the assessment of hip fracture risk in a sample of 7609 elderly ambulatory women > or =70 years of age. Two QUSs measured the heel (Achilles+; GE-Lunar and Sahara; Hologic), and one measured the heel (DBM Sonic 1200; IGEA). The Cox proportional hazards regression was used to estimate the hazard of the first hip fracture, adjusted for age, BMI, and center, and the area under the ROC curves were calculated to compare the devices and their parameters. RESULTS: From the 7609 women who were included in the study, 7062 women 75.2 +/- 3.1 (SD) years of age were prospectively followed for 2.9 +/- 0.8 years. Eighty women reported a hip fracture. A decrease by 1 SD of the QUS variables corresponded to an increase of the hip fracture risk from 2.3 (95% CI, 1.7, 3.1) to 2.6 (95% CI, 1.9, 3.4) for the three variables of Achilles+ and from 2.2 (95% CI, 1.7, 3.0) to 2.4 (95% CI, 1.8, 3.2) for the three variables of Sahara. Risk gradients did not differ significantly among the variables of the two heel QUS devices. On the other hand, the phalanges QUS (DBM Sonic 1200) was not predictive of hip fracture risk, with an adjusted hazard risk of 1.2 (95% CI, 0.9, 1.5), even after reanalysis of the digitalized data and using different cut-off levels (1700 or 1570 m/s). CONCLUSIONS: In this elderly women population, heel QUS devices were both predictive of hip fracture risk, whereas the phalanges QUS device was not.

Evolutionary aspects of population structure for molecular and quantitative traits in the freshwater snail Radix balthica.

Detecting the action of selection in natural populations can be achieved using the QST-FST comparison that relies on the estimation of FST with neutral markers, and QST using quantitative traits potentially under selection. QST higher than FST suggests the action of directional selection and thus potential local adaptation. In this article, we apply the QST-FST comparison to four populations of the hermaphroditic freshwater snail Radix balthica located in a floodplain habitat. In contrast to most studies published so far, we did not detect evidence of directional selection for local optima for any of the traits we measured: QST calculated using three different methods was never higher than FST. A strong inbreeding depression was also detected, indicating that outcrossing is probably predominant over selfing in the studied populations. Our results suggest that in this floodplain habitat, local adaptation of R. balthica populations may be hindered by genetic drift, and possibly altered by uneven gene flow linked to flood frequency.

Equilibration and disequilibration between monazite and garnet: indication from phase-composition and quantitative texture analysis

The integration of information which can be gained from accessory [i.e. age (t)] and rock-forming minerals [i.e. temperature (T) and pressure (P)] requires a more profound understanding of the equilibration kinetics during metamorphic processes. This paper presents an approach comparing conventional P-T estimate from equilibrated assemblages of rock-forming minerals with temperature data derived from yttrium-garnet-monazite (YGM) and yttrium-garnet-xenotime (YGX) geothermometry. Such a comparison provides an initial indication on differences between equilibration of major and trace elements. Regarding this purpose, two migmatites, two polycyclic and one monocyclic gneiss from the Central Alps (Switzerland, northern Italy) were investigated. While the polycyclic samples exhibit trace-element equilibration between monazite and garnet grains assigned to the same metamorphic event, there are relics of monazite and garnet obviously surviving independent of their textural position. These observations suggest that surface processes dominate transport processes during equilibration of those samples. The monocyclic gneiss, on the contrary, displays rare isolated monazite with equilibration of all elements, despite comparably large transport distances. With a nearly linear crystal-size distribution of the garnet grain population, growth kinetics, related to the major elements, were likely surface-controlled in this sample. In contrast to these completely equilibrated examples, the migmatites indicate disequilibrium between garnet and monazite with a change in REE patterns on garnet transects. The cause for this disequilibrium may be related to a potential disequilibrium initiated by a changing bulk chemistry during melt segregation. While migmatite environments are expected to support high transport rates (i.e. high temperatures and melt presence), the evolution of equilibration in migmatites is additionaly related to change in chemistry. As a key finding, surface-controlled equilibration kinetics seem to dominate transport-controlled processes in the investigated samples. This may be decisive information towards the understanding of age data derived from monazite.

Analytical methods for the quantitative determination of selective serotonin reuptake inhibitors for therapeutic drug monitoring purposes in patients.

Five selective serotonin reuptake inhibitors (SSRIs) have been introduced recently: citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Although no therapeutic window has been defined for SSRIs, in contrast to tricyclic antidepressants, analytical methods for therapeutic drug monitoring of SSRIs are useful in several instances. SSRIs differ widely in their chemical structure and in their metabolism. The fact that some of them have N-demethylated metabolites, which are also SSRIs, requires that methods be available which allow therapeutic drug monitoring of the parent compounds and of these active metabolites. most procedures are based on prepurification of the SSRIs by liquid-liquid extraction before they are submitted to separation by chromatographic procedures (high-performance liquid chromatography, gas chromatography, thin layer chromatography) and detection by various detectors (UV, fluorescence, electrochemical detector, nitrogen-phosphorus detector, mass spectrometry). This literature review shows that most methods allow quantitative determination of SSRIs in plasma, in the lower ng/ml range, and that they are, therefore, suitable for therapeutic drug monitoring purposes of this category of drugs.

"Soap-Bubble" visualization and quantitative analysis of 3D coronary magnetic resonance angiograms.

In order to compare coronary magnetic resonance angiography (MRA) data obtained with different scanning methodologies, adequate visualization and presentation of the coronary MRA data need to be ensured. Furthermore, an objective quantitative comparison between images acquired with different scanning methods is desirable. To address this need, a software tool ("Soap-Bubble") that facilitates visualization and quantitative comparison of 3D volume targeted coronary MRA data was developed. In the present implementation, the user interactively specifies a curved subvolume (enclosed in the 3D coronary MRA data set) that closely encompasses the coronary arterial segments. With a 3D Delaunay triangulation and a parallel projection, this enables the simultaneous display of multiple coronary segments in one 2D representation. For objective quantitative analysis, frequently explored quantitative parameters such as signal-to-noise ratio (SNR); contrast-to-noise ratio (CNR); and vessel length, sharpness, and diameter can be assessed. The present tool supports visualization and objective, quantitative comparisons of coronary MRA data obtained with different scanning methods. The first results obtained in healthy adults and in patients with coronary artery disease are presented.

Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes.

Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases. Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies. It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios. Thus far, dozens of methods have been proposed to quantify cell death-related parameters. However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate. Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls. These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise. Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells.

Natural aphrodisiacs: studies of commercially-available herbal recipes, and phytochemical investigation of "Erythroxylum vacciniifolium" Mart. (Erythroxylaceae) from Brazil

De tout temps, hommes et femmes ont cherché par tous les moyens à développer, préserver ou recouvrer leurs propres capacités sexuelles mais également à stimuler le désir du partenaire. L?utilisation d?aphrodisiaques naturels a été l?un des recours les plus répandus. De nos jours, la commercialisation de nouvelles "love drugs" de synthèse, e.g. Viagra®, Cialis®, Levitra®, a remis au goût du jour les aphrodisiaques classiques et à relancer la recherche sur des molécules nouvelles. La pratique croissante de l?automédication, le matraquage publicitaire sur les aphrodisiaques naturels, la prolifération sur le marché de compléments alimentaires non contrôlés et l?absence de véritable législation accroissent les risques qui pèsent sur la santé publique. Dans le but d?évaluer les risques potentiels sur le consommateur de produits aphrodisiaques commercialisés, le développement et la validation d?une méthode rapide d?analyse qualitative et quantitative de la yohimbine dans ces préparations du marché sont exposés dans la première partie de ce travail. La yohimbine est un antagoniste ?2-adrénocepteur du système nerveux central et périphérique, elle est employée depuis plus d?un siècle dans le traitement des dysfonctionnements érectiles. Cette méthode analytique utilise la chromatographie liquide couplée à l?ultraviolet et à la spectrométrie de masse (LC-UV-MS) et au total, vingt préparations aphrodisiaques ont été étudiées. La dose journalière de yohimbine mesurée s?est révélée très variable selon les produits puisqu?elle varie de 1.32 à 23.16 mg. La seconde partie de ce travail concerne l?étude phytochimique et pharmacologique d?Erythroxylum vacciniifolium Mart. (Erythroxylaceae), une plante, appelée localement catuaba, utilisée dans la médecine traditionnelle brésilienne comme tonique et aphrodisiaque. Dans un premier temps, l?extrait alcaloïdique a été analysé par chromatographie liquide haute performance (HPLC) couplée soit à un détecteur UV à barrette d?iode (LC-UV-DAD), soit à un spectromètre de masse (LC-MS), ou soit à un spectromètre de résonance magnétique nucléaire (LC-RMN). L?interprétation de ces données spectrales enregistrées en ligne a permis d?obtenir des informations structurales et d?identifier partiellement près de 24 alcaloïdes appartenant à la classe des tropanes et potentiellement originaux. Par des méthodes classiques de chromatographie liquide sur l?extrait alcaloïdique de la plante, dix sept tropanes nouveaux ont ensuite été isolés dont les catuabines et leurs dérivés, et les vaccinines. Tous ces composés sont des tropane-diols ou triols estérifiés par au moins un groupe acide 1-méthyl-1H-pyrrole-2-carboxylique. Un de ces composés a été identifié comme un tropane N-oxyde. Toutes les structures ont été déterminées par spectrométrie de masse haute résolution et spectroscopie RMN multi-dimensionnelle. Parmi les nombreux tests biologiques réalisés sur ces tropanes, seuls les tests de cytotoxicité se sont révélés faiblement positifs pour certains de ces composés.<br/><br/>Throughout the ages, men and women have incessantly pursued every means to increase, preserve or recapture their sexual capacity, or to stimulate the sexual desire of selected individuals. One of the most recurrent methods has been the use of natural aphrodisiacs. Nowadays, the commercialization of new synthetic "love drugs", e.g. Viagra®, Cialis® and Levitra®, has fascinated the public interest and has led to a reassessment of classical aphrodisiacs and to the search for new ones. The practice of self-medication by an increasing number of patients, the incessant aggressive advertising of these herbal aphrodisiacs, the invasion of the medicinal market with uncontrolled dietary supplements and the absence of real directives amplifies the potential health hazards to the community. In order to evaluate the possible risks of commercialized aphrodisiac products on consumer health, the development and validation of a rapid qualitative and quantitative method for the analysis of yohimbine in these products, is reported in the first part of the present work. Yohimbine, a pharmacologically well-characterized ?2-adrenoceptor antagonist with activity in the central and peripheral nervous system, has been used for over a century in the treatment of erectile dysfunction. The analytical method is based on liquid chromatography coupled with ultraviolet and mass spectrometry (LC-UV-MS) and in total, 20 commercially-available aphrodisiac preparations were analyzed. The amount of yohimbine measured and expressed as the maximal dose per day suggested on product labels ranged from 1.32 to 23.16 mg. The second part of this work involved the phytochemical and pharmacological investigation of Erythroxylum vacciniifolium Mart. (Erythroxylaceae), a plant used in Brazilian traditional medicine as an aphrodisiac and tonic, and locally known as catuaba. With the aim of obtaining preliminary structure information on-line, the alkaloid extract was analyzed by high performance liquid chromatography (HPLC) coupled to diode array UV detection (LC-UVDAD), to mass spectrometry (LC-MS) and to nuclear magnetic resonance spectroscopy (LCNMR). Interpretation of on-line spectroscopic data led to structure elucidation and partial identification of 24 potentially original alkaloids bearing the same tropane skeleton. Seventeen new tropane alkaloids were then isolated from the alkaloid extract of the plant, including catuabines D to I, their derivatives and vaccinines A and B. All compounds were elucidated as tropane-diol or -triol alkaloids esterified by at least one 1-methyl-1H-pyrrole-2-carboxylic acid. One of the isolated compounds was identified as a tropane alkaloid N-oxide. Their structures were determined by high resolution mass spectrometry and multi-dimensional NMR spectroscopy. Among the numerous bioassays undertaken, only the cytotoxicity tests exhibited a weak positive activity of certain compounds.