Repeated injections of 131I-rituximab show patient-specific stable biodistribution and tissue kinetics.

PURPOSE: It is generally assumed that the biodistribution and pharmacokinetics of radiolabelled antibodies remain similar between dosimetric and therapeutic injections in radioimmunotherapy. However, circulation half-lives of unlabelled rituximab have been reported to increase progressively after the weekly injections of standard therapy doses. The aim of this study was to evaluate the evolution of the pharmacokinetics of repeated 131I-rituximab injections during treatment with unlabelled rituximab in patients with non-Hodgkin's lymphoma (NHL). METHODS: Patients received standard weekly therapy with rituximab (375 mg/m2) for 4 weeks and a fifth injection at 7 or 8 weeks. Each patient had three additional injections of 185 MBq 131I-rituximab in either treatment weeks 1, 3 and 7 (two patients) or weeks 2, 4 and 8 (two patients). The 12 radiolabelled antibody injections were followed by three whole-body (WB) scintigraphic studies during 1 week and blood sampling on the same occasions. Additional WB scans were performed after 2 and 4 weeks post 131I-rituximab injection prior to the second and third injections, respectively. RESULTS: A single exponential radioactivity decrease for WB, liver, spleen, kidneys and heart was observed. Biodistribution and half-lives were patient specific, and without significant change after the second or third injection compared with the first one. Blood T(1/2)beta, calculated from the sequential blood samples and fitted to a bi-exponential curve, was similar to the T(1/2) of heart and liver but shorter than that of WB and kidneys. Effective radiation dose calculated from attenuation-corrected WB scans and blood using Mirdose3.1 was 0.53+0.05 mSv/MBq (range 0.48-0.59 mSv/MBq). Radiation dose was highest for spleen and kidneys, followed by heart and liver. CONCLUSION: These results show that the biodistribution and tissue kinetics of 131I-rituximab, while specific to each patient, remained constant during unlabelled antibody therapy. RIT radiation doses can therefore be reliably extrapolated from a preceding dosimetry study.

Dynamic simulation of regulatory networks using SQUAD.

BACKGROUND: The ambition of most molecular biologists is the understanding of the intricate network of molecular interactions that control biological systems. As scientists uncover the components and the connectivity of these networks, it becomes possible to study their dynamical behavior as a whole and discover what is the specific role of each of their components. Since the behavior of a network is by no means intuitive, it becomes necessary to use computational models to understand its behavior and to be able to make predictions about it. Unfortunately, most current computational models describe small networks due to the scarcity of kinetic data available. To overcome this problem, we previously published a methodology to convert a signaling network into a dynamical system, even in the total absence of kinetic information. In this paper we present a software implementation of such methodology. RESULTS: We developed SQUAD, a software for the dynamic simulation of signaling networks using the standardized qualitative dynamical systems approach. SQUAD converts the network into a discrete dynamical system, and it uses a binary decision diagram algorithm to identify all the steady states of the system. Then, the software creates a continuous dynamical system and localizes its steady states which are located near the steady states of the discrete system. The software permits to make simulations on the continuous system, allowing for the modification of several parameters. Importantly, SQUAD includes a framework for perturbing networks in a manner similar to what is performed in experimental laboratory protocols, for example by activating receptors or knocking out molecular components. Using this software we have been able to successfully reproduce the behavior of the regulatory network implicated in T-helper cell differentiation. CONCLUSION: The simulation of regulatory networks aims at predicting the behavior of a whole system when subject to stimuli, such as drugs, or determine the role of specific components within the network. The predictions can then be used to interpret and/or drive laboratory experiments. SQUAD provides a user-friendly graphical interface, accessible to both computational and experimental biologists for the fast qualitative simulation of large regulatory networks for which kinetic data is not necessarily available.

Ambulatory measurement of ankle kinetics for clinical applications.

This study aimed to design and validate the measurement of ankle kinetics (force, moment, and power) during consecutive gait cycles and in the field using an ambulatory system. An ambulatory system consisting of plantar pressure insole and inertial sensors (3D gyroscopes and 3D accelerometers) on foot and shank was used. To test this system, 12 patients and 10 healthy elderly subjects wore shoes embedding this system and walked many times across a gait lab including a force-plate surrounded by seven cameras considered as the reference system. Then, the participants walked two 50-meter trials where only the ambulatory system was used. Ankle force components and sagittal moment of ankle measured by ambulatory system showed correlation coefficient (R) and normalized RMS error (NRMSE) of more than 0.94 and less than 13% in comparison with the references system for both patients and healthy subjects. Transverse moment of ankle and ankle power showed R>0.85 and NRMSE<23%. These parameters also showed high repeatability (CMC>0.7). In contrast, the ankle coronal moment of ankle demonstrated high error and lower repeatability. Except for ankle coronal moment, the kinetic features obtained by the ambulatory system could distinguish the patients with ankle osteoarthritis from healthy subjects when measured in 50-meter trials. The proposed ambulatory system can be easily accessible in most clinics and could assess main ankle kinetics quantities with acceptable error and repeatability for clinical evaluations. This system is therefore suggested for field measurement in clinical applications.

Imaging of Anorectal Malformations: Finding the Way out of the Labyrinth

Purpose/Aim: To review the embryological basis of a wide spectrum of anorectal malformations (ARM), to provide anatomical schemas showing the possiblelocations of fistulas in boys and girls and to present the typical imaging findings of these complex anomalies using various imaging methods with emphasis on3T-MRI.Content Organization: 1. Embryology. 2. Imaging techniques. 3. Normal 3T-MRI pelvic anatomy. 4. Ano-rectal malformations in boys: - Classification -Anatomic schemas of location of fistulas. - Imaging studies. 5. Ano-rectal malformations in girls: - Classification - Anatomic schemas of location of fistulas. -Imaging studies. 6. Imaging of Currarino syndrome. 7. Imaging of Vacterl syndrome.Summary: ARM are a group of complex anatomical alterations characterized by an abnormal separation of genitourinary system from hindgut. The major teachingpoints of this pictorial essay are to show: - The normal anatomy of the pelvis floor and the sphincter muscle complex in 3T-MRI. - Anatomic schemas of thedifferent types of ARM in boys and girls. - Imaging findings of a wide spectrum of ARM using a multimodality approach. including colostogramm, voidingcystourethrogramm and MRI of the pelvis.

Are oxygen uptake kinetics modified when using a respiratory snorkel?

PURPOSE: The aim of this study was to compare VO2 kinetics during constant power cycle exercise measured using a conventional facemask (CM) or a respiratory snorkel (RS) designed for breath-by-breath analysis in swimming. METHODS: VO2 kinetics parameters-obtained using CM or RS, in randomized counterbalanced order-were compared in 10 trained triathletes performing two submaximal heavy-intensity cycling square-wave transitions. These VO2 kinetics parameters (ie, time delay: td1, td2; time constant: τ1, τ2; amplitude: A1, A2, for the primary phase and slow component, respectively) were modeled using a double exponential function. In the case of the RS data, this model incorporated an individually determined snorkel delay (ISD). RESULTS: Only td1 (8.9 ± 3.0 vs 13.8 ± 1.8 s, P < .01) differed between CM and RS, whereas all other parameters were not different (τ1 = 24.7 ± 7.6 vs 21.1 ± 6.3 s; A1 = 39.4 ± 5.3 vs 36.8 ± 5.1 mL x min(-1) x kg(-1); td2 = 107.5 ± 87.4 vs 183.5 ± 75.9 s; A2' (relevant slow component amplitude) = 2.6 ± 2.4 vs 3.1 ± 2.6 mL x min(-1) x kg(-1) for CM and RS, respectively). CONCLUSIONS: Although there can be a small mixture of breaths allowed by the volume of the snorkel in the transition to exercise, this does not appear to significantly influence the results. Therefore, given the use of an ISD, the RS is a valid instrument for the determination of VO2 kinetics within submaximal exercise.

Differences in whole-body fat oxidation kinetics between cycling and running.

This study aimed to quantitatively describe and compare whole-body fat oxidation kinetics in cycling and running using a sinusoidal mathematical model (SIN). Thirteen moderately trained individuals (7 men and 6 women) performed two graded exercise tests, with 3-min stages and 1 km h(-1) (or 20 W) increment, on a treadmill and on a cycle ergometer. Fat oxidation rates were determined using indirect calorimetry and plotted as a function of exercise intensity. The SIN model, which includes three independent variables (dilatation, symmetry and translation) that account for main quantitative characteristics of kinetics, provided a mathematical description of fat oxidation kinetics and allowed for determination of the intensity (Fat(max)) that elicits maximal fat oxidation (MFO). While the mean fat oxidation kinetics in cycling formed a symmetric parabolic curve, the mean kinetics during running was characterized by a greater dilatation (i.e., widening of the curve, P < 0.001) and a rightward asymmetry (i.e., shift of the peak of the curve to higher intensities, P = 0.01). Fat(max) was significantly higher in running compared with cycling (P < 0.001), whereas MFO was not significantly different between modes of exercise (P = 0.36). This study showed that the whole-body fat oxidation kinetics during running was characterized by a greater dilatation and a rightward asymmetry compared with cycling. The greater dilatation may be mainly related to the larger muscle mass involved in running while the rightward asymmetry may be induced by the specific type of muscle contraction.

A simple way to decompress the left ventricle during venoarterial bypass

OBJECTIVE: The aim of this investigation was to improve the hemodynamics during venoarterial bypass by remote decompression of the left ventricle (LV). METHODS: Venoarterial bypass was established in 5 bovine experiments (69+/-10 kg) by the transjugular insertion of a self-expanding cannula (smartcanula) with return through a carotid artery. Cardiogenic shock was simulated with ventricular fibrillation induced by an external stimulator. Left ventricular decompression was achieved by switching to transfemoral drainage of the pulmonary artery (PA) with a long self-expanding cannula. RESULTS: Initial pump flow was 4.7+/-0.9 l/min and the aortic pressure accounted for 75+/-21 mmHg. After induction of ventricular fibrillation, the pump flow dropped after 11+/-8 min to 2.5+/-0.1 l/min. Transfemoral decompression increased the pump flow to 5.6+/-0.7 l/min, while the RV pressure decreased from 27+/-9 to 3+/-5 mmHg, the PA pressure decreased from 29+/-7 to 5+/-4 mmHg, the LV pressure decreased from 29+/-6 to 7+/-2 mmHg, and the aortic pressure increased from 31+/-3 to 47+/-11 mmHg. CONCLUSIONS: Remote drainage of the pulmonary artery during venoarterial bypass allows for effective decompression of the left ventricle and provides superior hemodynamics.

Version brève du DISCERN, une voie d'amélioration de la recherche d'information médicale sur le net [Brief-DISCERN, a possible way to improve patient's search on the health-related web]

Internet is increasingly used as a source of information on health issues and is probably a major source of patients' empowerment. This process is however limited by the frequently poor quality of web-based health information designed for consumers. A better diffusion of information about criteria defining the quality of the content of websites, and about useful methods designed for searching such needed information, could be particularly useful to patients and their relatives. A brief, six-items DISCERN version, characterized by a high specificity for detecting websites with good or very good content quality was recently developed. This tool could facilitate the identification of high-quality information on the web by patients and may improve the empowerment process initiated by the development of the health-related web.

Gender differences in whole-body fat oxidation kinetics during exercise.

Discrepancies appear in studies comparing fat oxidation between men and women. Therefore, this study aimed to quantitatively describe and compare whole-body fat oxidation kinetics between genders during exercise, using a sinusoidal (SIN) model. Twelve men and 11 women matched for age, body mass index, and aerobic fitness (maximal oxygen uptake and maximal power output per kilogram of fat-free mass (FFM)) performed submaximal incremental tests (Incr) with 5-min stages and a 7.5% maximal power output increment on a cycle ergometer. Fat oxidation rates were determined using indirect calorimetry, and plotted as a function of exercise intensity. The SIN model, which includes 3 independent variables (dilatation, symmetry, translation) that account for the main quantitative characteristics of kinetics, was used to mathematically describe fat oxidation kinetics and to determine the intensity (Fatmax) eliciting the maximal fat oxidation (MFO). During Incr, women exhibited greater fat oxidation rates from 35% to 85% maximal oxygen uptake, MFO (6.6 ± 0.9 vs. 4.5 ± 0.3 mg·kg FFM-1·min-1), and Fatmax (58.1% ± 1.9% vs. 50.0% ± 2.7% maximal oxygen uptake) than men (p < 0.05). While men and women showed similar global shapes of fat oxidation kinetics in terms of dilatation and symmetry (p > 0.05), the fat oxidation curve tended to be shifted toward higher exercise intensities in women (rightward translation, p = 0.08). These results support the idea that women have a greater reliance on fat oxidation than men during submaximal exercise, but also indicate that this greater fat oxidation is shifted toward higher exercise intensities in women than in men.

Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients.

BACKGROUND: Inter-individual variability in plasma concentration-time profiles might contribute to differences in anti-malarial treatment response. This study investigated the pharmacokinetics of three different forms of artemisinin combination therapy (ACT) in Tanzania and Cambodia to quantify and identify potential sources of variability. METHODS: Drug concentrations were measured in 143 patients in Tanzania (artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine), and in 63 (artesunate, dihydroartemisinin and mefloquine) and 60 (dihydroartemisinin and piperaquine) patients in Cambodia. Inter- and intra-individual variabilities in the pharmacokinetic parameters were assessed and the contribution of demographic and other covariates was quantified using a nonlinear mixed-effects modelling approach (NONMEM®). RESULTS: A one-compartment model with first-order absorption from the gastrointestinal tract fitted the data for all drugs except piperaquine (two-compartment). Inter-individual variability in concentration exposure was about 40% and 12% for mefloquine. From all the covariates tested, only body weight (for all antimalarials) and concomitant treatment (for artemether only) showed a significant influence on these drugs' pharmacokinetic profiles. Artesunate and dihydroartemisinin could not be studied in the Cambodian patients due to insufficient data-points. Modeled lumefantrine kinetics showed that the target day 7 concentrations may not be achieved in a substantial proportion of patients. CONCLUSION: The marked variability in the disposition of different forms of ACT remained largely unexplained by the available covariates. Dosing on body weight appears justified. The concomitance of unregulated drug use (residual levels found on admission) and sub-optimal exposure (variability) could generate low plasma levels that contribute to selecting for drug-resistant parasites.

Effect of acute and chronic exercise on fat oxidation and hormonal and plasma metabolite kinetics in obese and severely obese men

Acute exercise increases energy expenditure (EE) during exercise and post-exercise recovery [excess post-exercise oxygen consumption (EPOC)] and therefore may be recommended as part of the multidisciplinary management of obesity. Moreover, chronic exercise (training) effectively promotes an increase in insulin sensitivity, which seems to be associated with increased fat oxidation rates (FORs). The main purpose of this thesis is to investigate 1) FORs and extra-muscular factors (hormones and plasma metabolites) that regulate fat metabolism during acute and chronic exercise; and 2) EPOC during acute post-exercise recovery in obese and severely obese men (class II and III). In the first study, we showed that obese and severely obese men present a lower exercise intensity (Fatmax) eliciting maximal fat oxidation and a lower reliance on fat oxidation at high, but not at low and moderate, exercise intensities compared to lean men. This was most likely related to an impaired muscular capacity to oxidize non-esterified fatty acids (NEFA) rather than decreased plasma NEFA availability or a change in the hormonal milieu during exercise. In the second study, we developed an accurate maximal incremental test to correctly and simultaneously evaluate aerobic fitness and fat oxidation kinetics during exercise in this population. This test may be used for the prescription of an appropriate exercise training intensity. In the third study, we demonstrated that only 2 wk of exercise training [continuous training at Fatmax and adapted high-intensity interval training (HIIT)], matched with respect to mechanical work, may be effective to improve aerobic fitness, FORs during exercise and insulin sensitivity, which suggest that FORs might be rapidly improved and that adapted HIIT is feasible in this population. The increased FORs concomitant with the lack of changes in lipolysis during exercise suggest an improvement in the mismatching between NEFA availability and oxidation, highlighting the importance of muscular (oxidative capacity) rather than extra-muscular (hormones and plasma metabolites) factors in the regulation of fat metabolism after a training program. In the fourth study, we observed a positive correlation between EE during exercise and EPOC, suggesting that a chronic increase in the volume or intensity of exercise may increase EE during exercise and during recovery. This may have an impact in weight management in obesity. In conclusion, these findings might have practical implications for exercise training prescriptions in order to improve the therapeutic approaches in obesity and severe obesity. -- L'exercice aigu augmente la dépense énergétique (DE) pendant l'exercice et la récupération post-exercice [excès de consommation d'oxygène post-exercise (EPOC)] et peut être utilisé dans la gestion multidisciplinaire de l'obésité. Quant à l'exercice chronique (entraînement), il est efficace pour augmenter la sensibilité à l'insuline, ce qui semble être associé à une amélioration du débit d'oxydation lipidique (DOL). Le but de cette thèse est d'étudier 1) le DOL et les facteurs extra-musculaires (hormones et métabolites plasmatiques) qui régulent le métabolisme lipidique pendant l'exercice aigu et chronique et 2) l'EPOC lors de la récupération aiguë post-exercice chez des hommes obèses et sévèrement obèses (classe II et III). Dans la première étude nous avons montré que les hommes obèses et sévèrement obèses présentent une plus basse intensité d'exercice (Fatmax) correspondant au débit d'oxydation lipidique maximale et un plus bas DOL à hautes, mais pas à faibles et modérées, intensités d'exercice comparé aux sujets normo-poids, ce qui est probablement lié à une incapacité musculaire à oxyder les acides gras non-estérifiés (AGNE) plutôt qu'à une diminution de leur disponibilité ou à un changement du milieu hormonal pendant l'exercice. Dans la deuxième étude nous avons développé un test maximal incrémental pour évaluer simultanément l'aptitude physique aérobie et la cinétique d'oxydation des lipides pendant l'exercice chez cette population. Dans la troisième étude nous avons montré que seulement deux semaines d'entraînement (continu à Fatmax et intermittent à haute intensité), appariés par la charge de travail, sont efficaces pour améliorer l'aptitude physique aérobie, le DOL pendant l'exercice et la sensibilité à l'insuline, ce qui suggère que le DOL peut être rapidement amélioré chez cette population. Ceci, en absence de changements de la lipolyse pendant l'exercice, suggère une amélioration de la balance entre la disponibilité et l'oxydation des AGNE, ce qui souligne l'importance des facteurs musculaires (capacité oxydative) plutôt que extra-musculaires (hormones et métabolites plasmatiques) dans la régulation du métabolisme lipidique après un entraînement. Dans la quatrième étude nous avons observé une corrélation positive entre la DE pendant l'exercice et l'EPOC, ce qui suggère qu'une augmentation chronique du volume ou de l'intensité de l'exercice pourrait augmenter la DE lors de l'exercice et lors de la récupération post-exercice. Ceci pourrait avoir un impact sur la gestion du poids chez cette population. En conclusion, ces résultats pourraient avoir des implications pratiques lors de la prescription des entraînements dans le but d'améliorer les approches thérapeutiques de l'obésité et de l'obésité sévère.