Evaluation of oral versus intravenous dose of vinorelbine to achieve equivalent blood exposures in patients with solid tumours.

Patient's preference is for oral chemotherapy when both oral and i.v. are available, provided that efficacy is equivalent. Reliable switch from oral to i.v. is possible if correspondence between respective doses has been established. Vinorelbine oral was developed as a line extension of VRL i.v. on the basis that similar AUCs result in similar activities. From a first crossover study on 24 patients receiving VRL 25 mg/m2 i.v. and 80 mg/m2 oral data extrapolation concluded on AUCs bioequivalence between Vinorelbine 30 mg/m2 i.v. and 80 mg/m2 oral. A new trial was performed to support this calculation. In a crossover design study on patients (PS 0-1) with advanced solid tumours (44% breast carcinoma), VRL was administered (30 mg/m2 i.v., 80 mg/m2 oral) with a standard meal and 5-HT3 antagonists, at 2 weeks interval. Pharmacokinetics was performed over 168 h and VRL was measured by LC-MS/MS. Statistics included bioequivalence tests. Forty-eight patients were evaluable for PK: median age 58 years (25-71), PS0/PS1: 20/28, M/F: 11/37. Mean AUCs were 1,230 +/- 290 and 1,216 +/- 521 ng/ml for i.v. and oral, respectively. The confidence interval of the AUC ratio (0.83-1.03) was within the required regulatory range (0.8-1.25) and proved the bioequivalence between the two doses. The absolute bioavailability was 37.8 +/- 16.0%, and close to the value from the first study (40%). Patient tolerability was globally comparable between both forms with no significant difference on either haematological or non-haematological toxicities (grade 3-4). This new study, conducted on a larger population, confirmed the reliable dose correspondence previously established between vinorelbine 80 mg/m2 oral and 30 mg/m2 i.v.

Is the absence of spiritual well-being at the facit-sp equivalent to spiritual distress in older patients?

Objective: Although initially developed to assess spiritual well-being,the FACIT-Sp is increasingly used to assess the other end of the spectrum,i.e. spiritual distress. This study intends to investigate whether theFACIT-Sp could really contribute to this aim in older patients. Method:Patients (N=135, 81.47.1 years, 68.3% women) aged 65 years and over,with MMSE score>19, admitted consecutively in post-acute rehabilitationwere enrolled. The FACIT-Sp (12 items, score 0 to 48, high spiritualwell-being defined as score_36) was administered and commentswere systematically retrieved. Results: Overall, 32(23.7%) patients hadhigh spiritual well-being. FACIT-Sp internal consistency was good(Cronbach's 0.85) and a confirmatory factorial analysis was consistentwith Meaning and Faith proposed subscales. Qualitative analysisshowed that negative answers (score=0) to "My illness has strengthenedmy faith or spiritual beliefs" (N=76/135) could equally reflect theabsence of impact (49/76, 64.5%) or a negative impact (religious struggle,27/76, 35.5%) of illness on faith. However, former patients had significantlyhigher FACIT-Sp scores than the latter (30.35.6 vs 20.97.9,P<.001). Similarly, among patients (N=73/135) with negative answers(score<3) to "I feel a sense of purpose in my life" those mentioning their"old age" to explain their answer (N=34/73, 46.6%) had higher FACITSpscores than those who did not (26.47.7 vs 22.58.1,P=.02). Conclusion:The FACIT-Sp identifies older people with high spiritual wellbeingbut could underestimate well-being in some older patients. Lowscores on some items could have very different meanings and interpretationof FACIT-Sp global scores below the usual cut-off should becautious.

Diffusion spectrum imaging shows the structural basis of functional cerebellar circuits in the human cerebellum in vivo.

BACKGROUND: The cerebellum is a complex structure that can be affected by several congenital and acquired diseases leading to alteration of its function and neuronal circuits. Identifying the structural bases of cerebellar neuronal networks in humans in vivo may provide biomarkers for diagnosis and management of cerebellar diseases. OBJECTIVES: To define the anatomy of intrinsic and extrinsic cerebellar circuits using high-angular resolution diffusion spectrum imaging (DSI). METHODS: We acquired high-resolution structural MRI and DSI of the cerebellum in four healthy female subjects at 3T. DSI tractography based on a streamline algorithm was performed to identify the circuits connecting the cerebellar cortex with the deep cerebellar nuclei, selected brainstem nuclei, and the thalamus. RESULTS: Using in-vivo DSI in humans we were able to demonstrate the structure of the following cerebellar neuronal circuits: (1) connections of the inferior olivary nucleus with the cerebellar cortex, and with the deep cerebellar nuclei (2) connections between the cerebellar cortex and the deep cerebellar nuclei, (3) connections of the deep cerebellar nuclei conveyed in the superior (SCP), middle (MCP) and inferior (ICP) cerebellar peduncles, (4) complex intersections of fibers in the SCP, MCP and ICP, and (5) connections between the deep cerebellar nuclei and the red nucleus and the thalamus. CONCLUSION: For the first time, we show that DSI tractography in humans in vivo is capable of revealing the structural bases of complex cerebellar networks. DSI thus appears to be a promising imaging method for characterizing anatomical disruptions that occur in cerebellar diseases, and for monitoring response to therapeutic interventions.

Secretory IgA-mediated neutralization of Shigella flexneri prevents intestinal tissue destruction by down-regulating inflammatory circuits.

Shigella, a Gram-negative invasive enteropathogenic bacterium responsible for bacillary dysentery, causes the rupture, invasion, and inflammatory destruction of the human colonic mucosa. We explored the mechanisms of protection mediated by Shigella LPS-specific secretory IgA (SIgA), the major mucosal Ab induced upon natural infection. Bacteria, SIgA, or SIgA-S. flexneri immune complexes were administered into rabbit ligated intestinal loops containing a Peyer's patch. After 8 h, localizations of bacteria, SIgA, and SIgA-S. flexneri immune complexes were examined by immunohistochemistry and confocal microscopy imaging. We found that anti-Shigella LPS SIgA, mainly via immune exclusion, prevented Shigella-induced inflammation responsible for the destruction of the intestinal barrier. Besides this luminal trapping, a small proportion of SIgA-S. flexneri immune complexes were shown to enter the rabbit Peyer's patch and were internalized by dendritic cells of the subepithelial dome region. Local inflammatory status was analyzed by quantitative RT-PCR using newly designed primers for rabbit pro- and anti-inflammatory mediator genes. In Peyer's patches exposed to immune complexes, limited up-regulation of the expression of proinflammatory genes, including TNF-alpha, IL-6, Cox-2, and IFN-gamma, was observed, consistent with preserved morphology. In contrast, in Peyer's patches exposed to Shigella alone, high expression of the same mediators was measured, indicating that neutralizing SIgA dampens the proinflammatory properties of Shigella. These results show that in the form of immune complexes, SIgA guarantees both immune exclusion and neutralization of translocated bacteria, thus preserving the intestinal barrier integrity by preventing bacterial-induced inflammation. These findings add to the multiple facets of the noninflammatory properties of SIgA.

Distinct neuronal circuits underlying the bahavioral and physiological components of the fear response

Abstract : Expression of fear involves changes in a number of behavioral and physiological parameters that are triggered by the central amygdala (CeA). The fear circuit also includes a series of brain stem nuclei that are the final effectors of the changes induced by the fear reaction. The CeA expresses many different neuropeptide receptors that can modulate fear responses. Today, the precise organization and the modulation of projections from the amygdala to the brain stem are still poorly understood. The aim of this project was to better understand the organization and the modulation of the fear circuit. To investigate this we first determined whether the CeA is composed of separate neuronal populations, where each one projects to specific brain stem nuclei, or whether single CeA neurons project to several nuclei. For this purpose, we first selected two brain stem nuclei implicated in the modulation of different components of the fear reactions, the periaqueductal gray (implicated in freezing) and the nucleus of solitary tract (implicated in heart rate modulation). We then performed double injections of two different retrograde tracers in these two nuclei and we quantified the subsequent presence of co-labelling in the CeA. We found that neurons projecting to the PAG and to the NTS are organized in separate populations. Subsequent electrophysiological recordings of the two populations revealed that PAG and NTS projecting neurons also have different electrophysiological characteristics. We then verified in vitro whether the neurons projecting to different brain stem nuclei express specific combinations of neuropeptide receptors, and whether a neuropeptide acting pre-synaptically (oxytocin) specifically modulates one of these two projections. We did not find differences at the level of expression of neurópeptide receptors, but we observed that oxytocin, a neuropeptide with anxiolytic properties, modulates PAG projecting neurons without affecting NTS projecting neurons. As oxytocin appeared to specifically modulate projections to the PAG, involved in the modulation of the freezing reaction, but did not affect the projections to the NTS, implicated in the modulation of cardiovascular parameters, we verified how this modulation translates in living animals. We investigated the effects of infra-amygdala injection of oxytocin on cardiovascular and behavioral changes induced by contextual fear conditioning. We found that oxytocin decreased the freezing response without affecting the cardiovascular system. Finally, as neuropeptides are considered potential future anxiolytics, we investigated whether diazepam and oxytocin, acting on the same circuit, had additive effects. This question was addressed exclusively with an in vitro electrophysiological approach. We obtained that oxytocin and diazepam, when co-applied, had an additive effect on both synaptic transmission and neuronal activity. These results open new perspectives for the possible clinical applications of oxytocin. Résumé : L'expression de la peur est accompagnée par de nombreux changements physiologiques et comportementaux qui sont déclenchés par l'amygdale centrale (CeA). Le circuit inclue aussi une série de noyaux du tronc cérébrale qui sont les effecteurs des différentes composantes de la réaction de peur. On sait que CeA envoie des projections aux noyaux du tronc cérébral et que ces neurones expriment une grande variété de récepteurs aux neuropeptides. Par contre, l'organisation des projections, ainsi que la modulation de ces projections par les neuropeptides reste encore peu connue. Avec ce projet, on premièrement voulu déterminer si CeA est composée de populations neuronales séparées qui projettent vers un noyau spécifique, ou bien si chaque neurones envoie des projections vers plusieurs noyaux. A ce propos, on a effectué des doubles injections de deux traceurs rétrogrades différentes dans deux noyaux du tronc cérébral impliqués dans des différentes composantes des réactions de peur. On a injecté la substance grise périaqueducale (PAG), qui est impliquée dans la réponse d'immobilisation, ainsi que le noyau du tractus solitaire (NTS) qui est responsable des changements cardiovasculaires. On a ensuite quantifié la présence de neurones contenant les deux traceurs dans CeA. On a trouvé que la plupart des neurones de l'amygdale centrale projettent vers un noyau spécifique, et on peut donc dire que l'amygdale semble être composée de populations neuronales séparées. On a ensuite mesuré les caractéristiques électrophysiologiques de ces deux projections et on a trouvé des différences substantielles concernant la résistance membranaire, la capacitance, le potentiel membranaire de repos ainsi que la fréquence des potentiels d'action spontanés. Puis, comme beaucoup de neuropéptides dans l'amygdale exercent un effet modulatoire sûr les réactions de peur et sur l'anxiété, on a étudié les effets directs et indirects d'une série de neuropeptides sur les différentes projections pour évaluer s'il y a des neuropeptides qui agissent spécifiquement sur une. On n'a pas trouvé de différences entre neurones qui projettent vers le PAG et neurones qui projettent vers le NTS concernant les effets de neuropeptides qui agissent directement sur ces cellules. Par contre, on a trouvé que l'ocytocine, un neuropeptide qui se lie à des récepteurs dans la partie latérale de l'amygdale centrale et inhibe de façon indirecte les neurones de l'amygdala centrale médiale, module les projections vers le PAG sans affecter celles qui vont vers le NTS. Comme le PAG est impliqué dans la réponse d'immobilisation, alors que le NTS est impliqué dans la modulation cardiovasculaire, on a ensuite étudié les effets de l'ocytocine injectée dans l'amygdale de rat vivants sur les réactions de peur conditionnées. On a trouvé que l'ocytocine diminue la réponse d'immobilisation sans par contre affecter la réponse cardiovasculaire. Pour terminer, on a vérifié si l'ocytocine potentialise les effets d'un médicament anxiolytique, le diazeparn. Avec une étude in vitro on a trouvé qu'une co-application d'ocytocine et diazeparn résulte en un effet additionnel à la fois sur la transmission synaptique ainsi que sur l'activité neuronale des neurones de l'amygdale centrale médiale. Ces résultats ouvrent des nouvelles perspectives pour une potentielle utilisation clinique de l'ocytocine.

Metabolic equivalent: one size does not fit all.

The metabolic equivalent (MET) is a widely used physiological concept that represents a simple procedure for expressing energy cost of physical activities as multiples of resting metabolic rate (RMR). The value equating 1 MET (3.5 ml O2 x kg(-1) x min(-1) or 1 kcal x kg(-1) x h(-1)) was first derived from the resting O2 consumption (VO2) of one person, a 70-kg, 40-yr-old man. Given the extensive use of MET levels to quantify physical activity level or work output, we investigated the adequacy of this scientific convention. Subjects consisted of 642 women and 127 men, 18-74 yr of age, 35-186 kg in weight, who were weight stable and healthy, albeit obese in some cases. RMR was measured by indirect calorimetry using a ventilated hood system, and the energy cost of walking on a treadmill at 5.6 km/h was measured in a subsample of 49 men and 49 women (26-45 kg/m2; 29-47 yr). Average VO2 and energy cost corresponding with rest (2.6 +/- 0.4 ml O2 x kg(-1) x min(-1) and 0.84 +/- 0.16 kcal x kg(-1) x h(-1), respectively) were significantly lower than the commonly accepted 1-MET values of 3.5 ml O2 x kg(-1) x min(-1) and 1 kcal x kg(-1) x h(-1), respectively. Body composition (fat mass and fat-free mass) accounted for 62% of the variance in resting VO2 compared with age, which accounted for only 14%. For a large heterogeneous sample, the 1-MET value of 3.5 ml O2 x kg(-1) x min(-1) overestimates the actual resting VO2 value on average by 35%, and the 1-MET of 1 kcal/h overestimates resting energy expenditure by 20%. Using measured or predicted RMR (ml O2 x kg(-1) x min(-1) or kcal x kg(-1) x h(-1)) as a correction factor can appropriately adjust for individual differences when estimating the energy cost of moderate intensity walking (5.6 km/h).

Brain tissue properties differentiate between motor and limbic basal ganglia circuits.

Despite advances in understanding basic organizational principles of the human basal ganglia, accurate in vivo assessment of their anatomical properties is essential to improve early diagnosis in disorders with corticosubcortical pathology and optimize target planning in deep brain stimulation. Main goal of this study was the detailed topological characterization of limbic, associative, and motor subdivisions of the subthalamic nucleus (STN) in relation to corresponding corticosubcortical circuits. To this aim, we used magnetic resonance imaging and investigated independently anatomical connectivity via white matter tracts next to brain tissue properties. On the basis of probabilistic diffusion tractography we identified STN subregions with predominantly motor, associative, and limbic connectivity. We then computed for each of the nonoverlapping STN subregions the covariance between local brain tissue properties and the rest of the brain using high-resolution maps of magnetization transfer (MT) saturation and longitudinal (R1) and transverse relaxation rate (R2*). The demonstrated spatial distribution pattern of covariance between brain tissue properties linked to myelin (R1 and MT) and iron (R2*) content clearly segregates between motor and limbic basal ganglia circuits. We interpret the demonstrated covariance pattern as evidence for shared tissue properties within a functional circuit, which is closely linked to its function. Our findings open new possibilities for investigation of changes in the established covariance pattern aiming at accurate diagnosis of basal ganglia disorders and prediction of treatment outcome.

Towards equivalent health care of prisoners: European soft law and public health policy in Geneva.

Prisoners have a right to health care and to be protected against inhumane and degrading treatment. Health care personnel and public policy makers play a central role in the protection of these rights and in the pursuit of public health goals. This article examines the legal framework for prison medicine in the canton of Geneva, Switzerland and provides examples of this framework that has shaped prisoners' medical care, including preventive measures. Geneva constitutes an intriguing example of how the Council of Europe standards concerning prison medicine have acquired a legal role in a Swiss canton. Learning how these factors have influenced implementation of prison medicine standards in Geneva may be helpful to public health managers elsewhere and encourage the use of similar strategies.

Quantitative comparison of simulations of seismic wave propagation in heterogeneous poro-elastic media involving fluid-solid interfaces and in equivalent visco-elastic solids

There is increasing evidence to suggest that the presence of mesoscopic heterogeneities constitutes the predominant attenuation mechanism at seismic frequencies. As a consequence, centimeter-scale perturbations of the subsurface physical properties should be taken into account for seismic modeling whenever detailed and accurate responses of the target structures are desired. This is, however, computationally prohibitive since extremely small grid spacings would be necessary. A convenient way to circumvent this problem is to use an upscaling procedure to replace the heterogeneous porous media by equivalent visco-elastic solids. In this work, we solve Biot's equations of motion to perform numerical simulations of seismic wave propagation through porous media containing mesoscopic heterogeneities. We then use an upscaling procedure to replace the heterogeneous poro-elastic regions by homogeneous equivalent visco-elastic solids and repeat the simulations using visco-elastic equations of motion. We find that, despite the equivalent attenuation behavior of the heterogeneous poro-elastic medium and the equivalent visco-elastic solid, the seismograms may differ due to diverging boundary conditions at fluid-solid interfaces, where there exist additional options for the poro-elastic case. In particular, we observe that the seismograms agree for closed-pore boundary conditions, but differ significantly for open-pore boundary conditions. This is an interesting result, which has potentially important implications for wave-equation-based algorithms in exploration geophysics involving fluid-solid interfaces, such as, for example, wave field decomposition.

Le marché des footballeurs. Réseaux et circuits dans l'économie globale

Fin assemblage entre démarches théoriques et empiriques, l'ouvrage illustre les logiques sous-jacentes à la mondialisation du marché des footballeurs. Il présente des informations de première main sur le fonctionnement des réseaux de transfert, collectées par l'auteur au cours de dix années de recherches menées en Europe et en Afrique. Des données statistiques inédites, élaborées par l'Observatoire des footballeurs professionnels, et de nombreuses illustrations cartographiques rendent la lecture particulièrement agréable. L'analyse des réseaux et circuits migratoires des footballeurs permet de saisir le rôle décisif joué par de nombreux intermédiaires dans le développement d'un marché global de talents. L'ouvrage dévoile la manière dont agents, dirigeants de clubs et spéculateurs privés investissent sur des joueurs dans l'optique de mettre en place des chaînes de transferts à valeur ajoutée. Ce processus est exemplifié à travers l'étude du cas des footballeurs africains