Multimodal non-rigid image registration methods for therapy and surgery planning

La planificación pre-operatoria se ha convertido en una tarea esencial en cirugías y terapias de marcada complejidad, especialmente aquellas relacionadas con órgano blando. Un ejemplo donde la planificación preoperatoria tiene gran interés es la cirugía hepática. Dicha planificación comprende la detección e identificación precisa de las lesiones individuales y vasos así como la correcta segmentación y estimación volumétrica del hígado funcional. Este proceso es muy importante porque determina tanto si el paciente es un candidato adecuado para terapia quirúrgica como la definición del abordaje a seguir en el procedimiento. La radioterapia de órgano blando es un segundo ejemplo donde la planificación se requiere tanto para la radioterapia externa convencional como para la radioterapia intraoperatoria. La planificación comprende la segmentación de tumor y órganos vulnerables y la estimación de la dosimetría. La segmentación de hígado funcional y la estimación volumétrica para planificación de la cirugía se estiman habitualmente a partir de imágenes de tomografía computarizada (TC). De igual modo, en la planificación de radioterapia, los objetivos de la radiación se delinean normalmente sobre TC. Sin embargo, los avances en las tecnologías de imagen de resonancia magnética (RM) están ofreciendo progresivamente ventajas adicionales. Por ejemplo, se ha visto que el ratio de detección de metástasis hepáticas es significativamente superior en RM con contraste Gd–EOB–DTPA que en TC. Por tanto, recientes estudios han destacado la importancia de combinar la información de TC y RM para conseguir el mayor nivel posible de precisión en radioterapia y para facilitar una descripción precisa de las lesiones del hígado. Con el objetivo de mejorar la planificación preoperatoria en ambos escenarios se precisa claramente de un algoritmo de registro no rígido de imagen. Sin embargo, la gran mayoría de sistemas comerciales solo proporcionan métodos de registro rígido. Las medidas de intensidad de voxel han demostrado ser criterios de similitud de imágenes robustos, y, entre ellas, la Información Mutua (IM) es siempre la primera elegida en registros multimodales. Sin embargo, uno de los principales problemas de la IM es la ausencia de información espacial y la asunción de que las relaciones estadísticas entre las imágenes son homogéneas a lo largo de su domino completo. La hipótesis de esta tesis es que la incorporación de información espacial de órganos al proceso de registro puede mejorar la robustez y calidad del mismo, beneficiándose de la disponibilidad de las segmentaciones clínicas. En este trabajo, se propone y valida un esquema de registro multimodal no rígido 3D usando una nueva métrica llamada Información Mutua Centrada en el Órgano (Organ-Focused Mutual Information metric (OF-MI)) y se compara con la formulación clásica de la Información Mutua. Esto permite mejorar los resultados del registro en áreas problemáticas incorporando información regional al criterio de similitud, beneficiándose de la disponibilidad real de segmentaciones en protocolos estándares clínicos, y permitiendo que la dependencia estadística entre las dos modalidades de imagen difiera entre órganos o regiones. El método propuesto se ha aplicado al registro de TC y RM con contraste Gd–EOB–DTPA así como al registro de imágenes de TC y MR para planificación de radioterapia intraoperatoria rectal. Adicionalmente, se ha desarrollado un algoritmo de apoyo de segmentación 3D basado en Level-Sets para la incorporación de la información de órgano en el registro. El algoritmo de segmentación se ha diseñado específicamente para la estimación volumétrica de hígado sano funcional y ha demostrado un buen funcionamiento en un conjunto de imágenes de TC abdominales. Los resultados muestran una mejora estadísticamente significativa de OF-MI comparada con la Información Mutua clásica en las medidas de calidad de los registros; tanto con datos simulados (p<0.001) como con datos reales en registro hepático de TC y RM con contraste Gd– EOB–DTPA y en registro para planificación de radioterapia rectal usando OF-MI multi-órgano (p<0.05). Adicionalmente, OF-MI presenta resultados más estables con menor dispersión que la Información Mutua y un comportamiento más robusto con respecto a cambios en la relación señal-ruido y a la variación de parámetros. La métrica OF-MI propuesta en esta tesis presenta siempre igual o mayor precisión que la clásica Información Mutua y consecuentemente puede ser una muy buena alternativa en aplicaciones donde la robustez del método y la facilidad en la elección de parámetros sean particularmente importantes. Abstract Pre-operative planning has become an essential task in complex surgeries and therapies, especially for those affecting soft tissue. One example where soft tissue preoperative planning is of high interest is liver surgery. It involves the accurate detection and identification of individual liver lesions and vessels as well as the proper functional liver segmentation and volume estimation. This process is very important because it determines whether the patient is a suitable candidate for surgical therapy and the type of procedure. Soft tissue radiation therapy is a second example where planning is required for both conventional external and intraoperative radiotherapy. It involves the segmentation of the tumor target and vulnerable organs and the estimation of the planned dose. Functional liver segmentations and volume estimations for surgery planning are commonly estimated from computed tomography (CT) images. Similarly, in radiation therapy planning, targets to be irradiated and healthy and vulnerable tissues to be protected from irradiation are commonly delineated on CT scans. However, developments in magnetic resonance imaging (MRI) technology are progressively offering advantages. For instance, the hepatic metastasis detection rate has been found to be significantly higher in Gd–EOB–DTPAenhanced MRI than in CT. Therefore, recent studies highlight the importance of combining the information from CT and MRI to achieve the highest level of accuracy in radiotherapy and to facilitate accurate liver lesion description. In order to improve those two soft tissue pre operative planning scenarios, an accurate nonrigid image registration algorithm is clearly required. However, the vast majority of commercial systems only provide rigid registration. Voxel intensity measures have been shown to be robust measures of image similarity, and among them, Mutual Information (MI) is always the first candidate in multimodal registrations. However, one of the main drawbacks of Mutual Information is the absence of spatial information and the assumption that statistical relationships between images are the same over the whole domain of the image. The hypothesis of the present thesis is that incorporating spatial organ information into the registration process may improve the registration robustness and quality, taking advantage of the clinical segmentations availability. In this work, a multimodal nonrigid 3D registration framework using a new Organ- Focused Mutual Information metric (OF-MI) is proposed, validated and compared to the classical formulation of the Mutual Information (MI). It allows improving registration results in problematic areas by adding regional information into the similitude criterion taking advantage of actual segmentations availability in standard clinical protocols and allowing the statistical dependence between the two modalities differ among organs or regions. The proposed method is applied to CT and T1 weighted delayed Gd–EOB–DTPA-enhanced MRI registration as well as to register CT and MRI images in rectal intraoperative radiotherapy planning. Additionally, a 3D support segmentation algorithm based on Level-Sets has been developed for the incorporation of the organ information into the registration. The segmentation algorithm has been specifically designed for the healthy and functional liver volume estimation demonstrating good performance in a set of abdominal CT studies. Results show a statistical significant improvement of registration quality measures with OF-MI compared to MI with both simulated data (p<0.001) and real data in liver applications registering CT and Gd–EOB–DTPA-enhanced MRI and in registration for rectal radiotherapy planning using multi-organ OF-MI (p<0.05). Additionally, OF-MI presents more stable results with smaller dispersion than MI and a more robust behavior with respect to SNR changes and parameters variation. The proposed OF-MI always presents equal or better accuracy than the classical MI and consequently can be a very convenient alternative within applications where the robustness of the method and the facility to choose the parameters are particularly important.

Proprioceptive force estimation and control for teleoperation in radioactive environments

A medida que se incrementa la energía de los aceleradores de partículas o iones pesados como el CERN o GSI, de los reactores de fusión como JET o ITER, u otros experimentos científicos, se va haciendo cada vez más imprescindible el uso de técnicas de manipulación remota para la interacción con el entorno sujeto a la radiación. Hasta ahora la tasa de dosis radioactiva en el CERN podía tomar valores cercanos a algunos mSv para tiempos de enfriamiento de horas, que permitían la intervención humana para tareas de mantenimiento. Durante los primeros ensayos con plasma en JET, se alcanzaban valores cercanos a los 200 μSv después de un tiempo de enfriamiento de 4 meses y ya se hacía extensivo el uso de técnicas de manipulación remota. Hay una clara tendencia al incremento de los niveles de radioactividad en el futuro en este tipo de instalaciones. Un claro ejemplo es ITER, donde se esperan valores de 450 Sv/h en el centro del toroide a los 11 días de enfriamiento o los nuevos niveles energéticos del CERN que harán necesario una apuesta por niveles de mantenimiento remotos. En estas circunstancias se enmarca esta tesis, que estudia un sistema de control bilateral basado en fuerza-posición, tratando de evitar el uso de sensores de fuerza/par, cuyo contenido electrónico los hace especialmente sensitivos en estos ambientes. El contenido de este trabajo se centra en la teleoperación de robots industriales, que debido a su reconocida solvencia y facilidad para ser adaptados a estos entornos, unido al bajo coste y alta disponibilidad, les convierte en una alternativa interesante para tareas de manipulación remota frente a costosas soluciones a medida. En primer lugar se considera el problema cinemático de teleoperación maestro-esclavo de cinemática disimilar y se desarrolla un método general para la solución del problema en el que se incluye el uso de fuerzas asistivas para guiar al operador. A continuación se explican con detalle los experimentos realizados con un robot ABB y que muestran las dificultades encontradas y recomendaciones para solventarlas. Se concluye el estudio cinemático con un método para el encaje de espacios de trabajo entre maestro y esclavo disimilares. Posteriormente se mira hacia la dinámica, estudiándose el modelado de robots con vistas a obtener un método que permita estimar las fuerzas externas que actúan sobre los mismos. Durante la caracterización del modelo dinámico, se realizan varios ensayos para tratar de encontrar un compromiso entre complejidad de cálculo y error de estimación. También se dan las claves para modelar y caracterizar robots con estructura en forma de paralelogramo y se presenta la arquitectura de control deseada. Una vez obtenido el modelo completo del esclavo, se investigan diferentes alternativas que permitan una estimación de fuerzas externas en tiempo real, minimizando las derivadas de la posición para minimizar el ruido. Se comienza utilizando observadores clásicos del estado para ir evolucionando hasta llegar al desarrollo de un observador de tipo Luenberger-Sliding cuya implementación es relativamente sencilla y sus resultados contundentes. También se analiza el uso del observador propuesto durante un control bilateral simulado en el que se compara la realimentación de fuerzas obtenida con las técnicas clásicas basadas en error de posición frente a un control basado en fuerza-posición donde la fuerza es estimada y no medida. Se comprueba como la solución propuesta da resultados comparables con las arquitecturas clásicas y sin embargo introduce una alternativa para la teleoperación de robots industriales cuya teleoperación en entornos radioactivos sería imposible de otra manera. Finalmente se analizan los problemas derivados de la aplicación práctica de la teleoperación en los escenarios mencionados anteriormente. Debido a las condiciones prohibitivas para todo equipo electrónico, los sistemas de control se deben colocar a gran distancia de los manipuladores, dando lugar a longitudes de cable de centenares de metros. En estas condiciones se crean sobretensiones en controladores basados en PWM que pueden ser destructivas para el sistema formado por control, cableado y actuador, y por tanto, han de ser eliminadas. En este trabajo se propone una solución basada en un filtro LC comercial y se prueba de forma extensiva que su inclusión no produce efectos negativos sobre el control del actuador. ABSTRACT As the energy on the particle accelerators or heavy ion accelerators such as CERN or GSI, fusion reactors such as JET or ITER, or other scientific experiments is increased, it is becoming increasingly necessary to use remote handling techniques to interact with the remote and radioactive environment. So far, the dose rate at CERN could present values near several mSv for cooling times on the range of hours, which allowed human intervention for maintenance tasks. At JET, they measured values close to 200 μSv after a cooling time of 4 months and since then, the remote handling techniques became usual. There is a clear tendency to increase the radiation levels in the future. A clear example is ITER, where values of 450 Sv/h are expected in the centre of the torus after 11 days of cooling. Also, the new energetic levels of CERN are expected to lead to a more advanced remote handling means. In these circumstances this thesis is framed, studying a bilateral control system based on force-position, trying to avoid the use of force/torque sensors, whose electronic content makes them very sensitive in these environments. The contents of this work are focused on teleoperating industrial robots, which due its well-known reliability, easiness to be adapted to these environments, cost-effectiveness and high availability, are considered as an interesting alternative to expensive custom-made solutions for remote handling tasks. Firstly, the kinematic problem of teloperating master and slave with dissimilar kinematics is analysed and a new general approach for solving this issue is presented. The solution includes using assistive forces in order to guide the human operator. Coming up next, I explain with detail the experiments accomplished with an ABB robot that show the difficulties encountered and the proposed solutions. This section is concluded with a method to match the master’s and slave’s workspaces when they present dissimilar kinematics. Later on, the research studies the dynamics, with special focus on robot modelling with the purpose of obtaining a method that allows to estimate external forces acting on them. During the characterisation of the model’s parameters, a set of tests are performed in order to get to a compromise between computational complexity and estimation error. Key points for modelling and characterising robots with a parallelogram structure are also given, and the desired control architecture is presented. Once a complete model of the slave is obtained, different alternatives for external force estimation are review to be able to predict forces in real time, minimizing the position differentiation to minimize the estimation noise. The research starts by implementing classic state observers and then it evolves towards the use of Luenberger- Sliding observers whose implementation is relatively easy and the results are convincing. I also analyse the use of proposed observer during a simulated bilateral control on which the force feedback obtained with the classic techniques based on the position error is compared versus a control architecture based on force-position, where the force is estimated instead of measured. I t is checked how the proposed solution gives results comparable with the classical techniques and however introduces an alternative method for teleoperating industrial robots whose teleoperation in radioactive environments would have been impossible in a different way. Finally, the problems originated by the practical application of teleoperation in the before mentioned scenarios are analysed. Due the prohibitive conditions for every electronic equipment, the control systems should be placed far from the manipulators. This provokes that the power cables that fed the slaves devices can present lengths of hundreds of meters. In these circumstances, overvoltage waves are developed when implementing drives based on PWM technique. The occurrence of overvoltage is very dangerous for the system composed by drive, wiring and actuator, and has to be eliminated. During this work, a solution based on commercial LC filters is proposed and it is extensively proved that its inclusion does not introduce adverse effects into the actuator’s control.

The cell wall components peptidoglycan and lipoteichoic acid from Staphylococcus aureus act in synergy to cause shock and multiple organ failure.

Although the incidence of Gram-positive sepsis has risen strongly, it is unclear how Gram-positive organisms (without endotoxin) initiate septic shock. We investigated whether two cell wall components from Staphylococcus aureus, peptidoglycan (PepG) and lipoteichoic acid (LTA), can induce the inflammatory response and multiple organ dysfunction syndrome (MODS) associated with septic shock caused by Gram-positive organisms. In cultured macrophages, LTA (10 micrograms/ml), but not PepG (100 micrograms/ml), induces the release of nitric oxide measured as nitrite. PepG, however, caused a 4-fold increase in the production of nitrite elicited by LTA. Furthermore, PepG antibodies inhibited the release of nitrite elicited by killed S. aureus. Administration of both PepG (10 mg/kg; i.v.) and LTA (3 mg/kg; i.v.) in anesthetized rats resulted in the release of tumor necrosis factor alpha and interferon gamma and MODS, as indicated by a decrease in arterial oxygen pressure (lung) and an increase in plasma concentrations of bilirubin and alanine aminotransferase (liver), creatinine and urea (kidney), lipase (pancreas), and creatine kinase (heart or skeletal muscle). There was also the expression of inducible nitric oxide synthase in these organs, circulatory failure, and 50% mortality. These effects were not observed after administration of PepG or LTA alone. Even a high dose of LTA (10 mg/kg) causes only circulatory failure but no MODS. Thus, our results demonstrate that the two bacterial wall components, PepG and LTA, work together to cause systemic inflammation and multiple systems failure associated with Gram-positive organisms.

Avaliação da inervação entérica e análise proteômica do intestino delgado de ratos expostos à dose aguda ou crônica de fluoreto

O trato gastrointestinal (TGI) é a principal rota de exposição ao fluoreto (F) e o seu mais importante sítio de absorção. Acredita-se que a toxicidade do F comprometa a fisiologia do intestino, devido à relevante sintomatologia gastrointestinal relatada em consequência da exposição excessiva ao F. A função intestinal é controlada por uma complexa rede neuronal interligada e incorporada à parede deste órgão, denominada Sistema Nervoso Entérico (SNE). Embora os efeitos tóxicos do F sobre o Sistema Nervoso Central sejam descritos na literatura, não há estudos relacionados à sua toxicidade sobre o SNE. Neste estudo realizado em ratos, foi avaliado o efeito da exposição aguda ou crônica ao F, sobre a população geral de neurônios entéricos e sobre as subpopulações que expressam os principais neurotransmissores entéricos: Acetilcolina (ACh), Óxido Nítrico (NO), Peptídeo Vasoativo Intestinal (VIP), Peptídeo Relacionado ao Gene da Calcitonina (CGRP) e Substância P (SP). Os animais foram divididos em 5 grupos: 3 destinados à exposição crônica (0 ppm, 10 ppm ou 50 ppm de F na água de beber) e 2 à exposição aguda (0 ou 25 mgF/Kg por gavagem gástrica). Foram coletados os 3 segmentos do intestino delgado (duodeno, jejuno e íleo) e processados para a detecção da HuC/D, ChAT, nNOS, VIP, CGRP e SP, através de técnicas de imunofluorescência, no plexo mioentérico. Foram obtidas imagens para a realização da análise quantitativa dos neurônios da população geral (HuC/D) e nitrérgicos (imunorreativos à nNOS); e morfométrica dos neurônios imunorreativos à HuC/D ou nNOS; e das varicosidades imunorreativas à ChAT, VIP, CGRP ou SP. Amostras dos 3 segmentos intestinais foram preparadas e coradas em Hematoxilina e Eosina para análise histológica da morfologia básica. O segmento intestinal considerado mais afetado na análise morfométrica da população geral de neurônios, o duodeno, foi selecionado para a realização da análise proteômica, com o objetivo de oferecer o seu perfil proteico e determinar diferenças na expressão proteica em decorrência da exposição crônica ou aguda ao F. A análise da concentração de F no plasma sanguíneo foi realizada para a confirmação da exposição. Na análise quantitativa, o grupo de 50 ppm F, apresentou uma diminuição significativa na densidade da população geral de neurônios do jejuno e do íleo e na densidade dos neurônios imunorreativos à nNOS no duodeno e no jejuno. Quanto à análise morfométrica, a população geral e as subpopulações neuronais entéricas avaliadas apresentaram alterações morfológicas significativas, tanto após a exposição crônica quanto a aguda. Para a análise proteômica do duodeno, verificou-se que da associação de seus genes a um termo, e assim classificadas de acordo com diferentes processos biológicos. No caso do grupo da dose aguda, o processo biológico com a maior porcentagem de genes associados foi a geração de metabólitos precursores e energia (27% das proteínas); enquanto para os grupos de 10 e 50 ppm F foram o processo metabólico da piridina (41%) e a polimerização proteica (33%), respectivamente.

Nocardia infection in solid organ transplant recipients: a multicenter European case-control study.

BACKGROUND  Nocardiosis is a rare, life-threatening opportunistic infection, affecting 0.04% to 3.5% of patients after solid organ transplantation (SOT). The aim of this study was to identify risk factors for Nocardia infection after SOT and to describe the presentation of nocardiosis in these patients. METHODS  We performed a retrospective case-control study of adult patients diagnosed with nocardiosis after SOT between 2000 and 2014 in 36 European (France, Belgium, Switzerland, Netherlands, Spain) centers. Two control subjects per case were matched by institution, transplant date and transplanted organ. A multivariable analysis was performed using conditional logistic regression to identify risk factors for nocardiosis. RESULTS  One hundred and seventeen cases of nocardiosis and 234 control patients were included. Nocardiosis occurred at a median of 17.5 [range 2-244] months after transplantation. In multivariable analysis, high calcineurin inhibitor trough levels in the month before diagnosis (OR=6.11 [2.58-14.51]), use of tacrolimus (OR=2.65 [1.17-6.00]) and corticosteroid dose (OR=1.12 [1.03-1.22]) at the time of diagnosis, patient age (OR=1.04 [1.02-1.07]) and length of stay in intensive care unit after SOT (OR=1.04 [1.00-1.09]) were independently associated with development of nocardiosis; low-dose cotrimoxazole prophylaxis was not found to prevent nocardiosis. Nocardia farcinica was more frequently associated with brain, skin and subcutaneous tissue infections than were other Nocardia species. Among the 30 cases with central nervous system nocardiosis, 13 (43.3%) had no neurological symptoms. CONCLUSIONS  We identified five risk factors for nocardiosis after SOT. Low-dose cotrimoxazole was not found to prevent Nocardia infection. These findings may help improve management of transplant recipients.

Prospective evaluation of a D-optimal designed population pharmacokinetic study

Recently, methods for computing D-optimal designs for population pharmacokinetic studies have become available. However there are few publications that have prospectively evaluated the benefits of D-optimality in population or single-subject settings. This study compared a population optimal design with an empirical design for estimating the base pharmacokinetic model for enoxaparin in a stratified randomized setting. The population pharmacokinetic D-optimal design for enoxaparin was estimated using the PFIM function (MATLAB version 6.0.0.88). The optimal design was based on a one-compartment model with lognormal between subject variability and proportional residual variability and consisted of a single design with three sampling windows (0-30 min, 1.5-5 hr and 11 - 12 hr post-dose) for all patients. The empirical design consisted of three sample time windows per patient from a total of nine windows that collectively represented the entire dose interval. Each patient was assigned to have one blood sample taken from three different windows. Windows for blood sampling times were also provided for the optimal design. Ninety six patients were recruited into the study who were currently receiving enoxaparin therapy. Patients were randomly assigned to either the optimal or empirical sampling design, stratified for body mass index. The exact times of blood samples and doses were recorded. Analysis was undertaken using NONMEM (version 5). The empirical design supported a one compartment linear model with additive residual error, while the optimal design supported a two compartment linear model with additive residual error as did the model derived from the full data set. A posterior predictive check was performed where the models arising from the empirical and optimal designs were used to predict into the full data set. This revealed the optimal'' design derived model was superior to the empirical design model in terms of precision and was similar to the model developed from the full dataset. This study suggests optimal design techniques may be useful, even when the optimized design was based on a model that was misspecified in terms of the structural and statistical models and when the implementation of the optimal designed study deviated from the nominal design.

A prospective trial of short-fractionation radiotherapy for the palliation of liver metastases

The purpose of this study was to prospectively examine the effectiveness and tolerability of a simple radiotherapy technique for the palliation of symptomatic liver metastases. Twenty-eight patients with symptomatic liver metastases were enrolled from seven centres, and received targeted (partial or whole) liver irradiation consisting of 10 Gy in two fractions over 2 days. Symptoms at baseline were hepatic pain (27 patients), abdominal distension (19), night sweats (12), nausea (18) and vomiting (eight). Twenty-two patients (76%) had failed previous treatment with chemotherapy, hormonal therapy and/or high-dose steroids. Symptoms and potential toxicities were prospectively assessed at the time of treatment, then 2, 6 and 10 weeks later. Individual symptom response rates were 53−66% at 2 weeks. Partial or complete global symptomatic responses were noted in 15 patients (54%) overall. The treatment was well tolerated with two patients (7%) experiencing grade 3 toxicity (one vomiting and one diarrhoea); however, four patients reported temporary worsening of pain shortly after treatment. This simple and well-tolerated treatment achieves useful palliation.

Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti-epileptic drugs in pregnancy

To compare the incidence of foetal malformations (FMs) in pregnant women with epilepsy treated with different anti-epileptic drugs (AED) and doses, and the influence of seizures, family and personal history, and environmental factors. A prospective, observational, community-based cohort study. Methods. A voluntary, Australia-wide, telephone-interview-based register prospectively enrolling three groups of pregnant women: taking AEDs for epilepsy; with epilepsy not taking AEDs; taking AEDs for a non-epileptic indication. Four hundred and fifty eligible women were enrolled over 40 months. Three hundred and ninety six pregnancies had been completed, with 7 sets of twins, for a total of 403 pregnancy outcomes. Results. 354 (87.8%) pregnancy outcomes resulted in a healthy live birth, 26 (6.5%) had a FM, 4 (1%) a death in utero, 1 (0.2%) a premature labour with stillbirth, 14 (3.5%) a spontaneous abortion and 4 lost to follow-up. The FM rate was greater in pregnancies exposed to sodium valproate (VPA) in the first trimester (116.0%) compared with those exposed to all other AEDs (16.0% vs. 2.4%, P < 0.01) or no AEDs (16.0% vs. 3.1 %, P < 0.01). The mean daily dose of VPA taken in pregnancy with FMs was significantly greater than in those without (11975 vs: 1128 mg, P < 0.01). The incidence of FM with VPA doses greater than or equal to 1100 mg was 30.2% vs. 3.2% with doses < 1100 mg (P < 0.01). Conclusions. There is a dose-effect relationship for FM and exposure to VPA during the first trimester of pregnancy, with higher doses of VPA associated with a significantly greater risk than with lower doses or with other AEDs. These results highlight the need to limit, where possible, the dose of VPA in pregnancy. (C) 2004 Elsevier Ltd. All rights reserved.

Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation

The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients. Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates. Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 'acceptable' ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immuno suppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.

A standard weight descriptor for dose adjustment in the obese patient

Objective: To develop a standard weight descriptor that can be used for estimation of patient size for obese patients. Patients and methods: Data were available from 3849 patients: 2839 from oncology patients (index data set) and 1010 from general medical patients (validation data set). The patients had a wide range of age (16-100 years), weight (25-165kg) and body mass index (BMI) [12-52 kg/m(2)] in both data sets. From the normal-weight patients in the oncology data set, an equation for male and female patients was developed to predict their normal weight as the sum of the lean body mass and normal fat body mass. The equations were evaluated by predicting the weight of patients in the general medical data set who had a normal BMI (30 kg/m(2)).

Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet

Aims The major aims of the study were to compare the safety of a continuous low-dose estradiol-releasing vaginal ring (ESTring) to that of a vaginal estradiol tablet (Vagifem®) on the endometrium and the relief of subjective symptoms and signs of urogenital estrogen deficiency. Quality of life and acceptability of treatment delivery were also assessed. Study design A prospective, randomized study in which women were assigned in a 2: 1 ratio to ESTring and Vagifem and followed for 12 months. The primary endpoint was endometrial safety, based on the results of ultrasound measurement of endometrial thickness and a progestogen challenge test at baseline and week 48. Efficacy was determined by subjective assessment of urogenital estrogen deficiency symptoms at baseline and weeks 3, 12, 24, 36 and 48 and assessment of signs of vaginal epithelial atrophy by the clinician at baseline, 12 and 48 weeks. In addition, pelvic floor strength, vaginal cytological evaluation and pH, bacteruria and patient acceptability were assessed. Quality of life was assessed using a menopause-specific quality-of-life questionnire and a 2-day bladder diary at baseline and 12 and 48 weeks. The comparability of the two groups was assessed using ANOVA, χ(2) or Fisher's exact tests. Results A total of 126 women were randomized to ESTring and 59 to Vagifem. There was no statistical difference between the groups in the alleviation of symptoms and signs of urogenital estrogen deficiency. Maturation indices increased in both groups, from generally atrophic at baseline to proliferative or highly proliferative at 48 weeks. After 48 weeks of treatment, there was no statistically significant difference in endometrial thickness between the two groups. A statistically smaller proportion of bleeding/spotting occurred in the ESTring group (n = 0) compared to the Vagifem users (n = 4). Estradiol and total estrone serum levels increased during treatment in both groups but remained within the normal postmenopausal range. General health status in both groups was unchanged but the urogenital component of health burden was significantly improved in both groups. Bladder diary variables showed no differences between treatment groups. Conclusion Equivalent endometrial safety and efficacy in the relief of the symptoms and signs of urogenital estrogen deficiency were demonstrated for the 12 months' use of a low-dose estradiol-releasing vaginal ring and a vaginal estradiol tablet.

Prospective study of physical activity and depressive symptoms in middle-aged women

Background: Although many studies support an inverse association between physical activity (PA) and depressive symptoms, prospective relationships between these variables have been confounded by pre-existing psychological and physical health problems. Methods: This study examined the dose-response relationships between self-reported PA and depressive symptoms, using cross-sectional and prospective data from a population-based cohort of middle-aged women who participated in the Australian Longitudinal Study on Women's Health (ALSWH) between 1996 and 2001. Participants completed three mailed surveys (SI, 1996; S2, 1998; S3, 2001), which included questions about time spent in walking, moderate- and vigorous-intensity PA, and measures of psychological health (Center for Epidemiologic Studies Depression scale [CESD-10], and Mental health [MH] subscale of the Short Form 36 survey). Relationships between previous (SI, S2), current (S3), and habitual (S1, S2, S3) PA and depressive symptoms were examined, adjusting for sociodemographic and health-related variables (n = 9207). Results: Mean CESD-10 scores decreased, and MH scores increased with increasing levels of previous, current, and habitual activity. Odds ratios for CESD-10 scores >= 10 or MH scores = 60 minutes of moderate-intensity PA per week, compared with those who reported less PA than this. Women who were in the lowest PA category at SI, but who subsequently reported >= 240 metabolic equivalent minutes (MET.mins) per week had lower odds of CESD-10 scores of >= 10 or MH scores

The effect of St John's wort extracts on CYP3A: a systematic review of prospective clinical trials

Aim The aim of this systematic review was to assess the quality and outcomes of clinical trials investigating the effect of St John's wort extracts on the metabolism of drugs by CYP3A. Methods Prospective clinical trials assessing the effect of St John's wort (SJW) extracts on metabolism by CYP3A were identified through computer-based searches (from their inception to May 2005) of Medline, Cinahl, PsycINFO, AMED, Current Contents and Embase, hand-searches of bibliographies of relevant papers and consultation with manufacturers and researchers in the field. Two reviewers selected trials for inclusion, independently extracted data and recorded details on study design. Results Thirty-one studies met the eligibility criteria. More than two-thirds of the studies employed a before-and-after design, less than one-third of the studies used a crossover design, and only three studies were double-blind and placebo controlled. In 12 studies the SJW extract had been assayed, and 14 studies stated the specific SJW extract used. Results from 26 studies, including all of the 19 studies that used high-dose hyperforin extracts (> 10 mg day(-1)), had outcomes consistent with CYP3A induction. The three studies using low-dose hyperforin extracts (< 4 mg day(-1)) demonstrated no significant effect on CYP3A. Conclusion There is reasonable evidence to suggest that high-dose hyperforin SJW extracts induce CYP3A. More studies are required to determine whether decreased CYP3A induction occurs after low-dose hyperforin extracts. Future studies should adopt study designs with a control phase or control group, identify the specific SJW extract employed and provide quantitative analyses of key constituents.

Improved estimation of postmortem interval with Cardiac Troponin T and improved analytical methods

Accurate knowledge of the time since death, or postmortem interval (PMI), has enormous legal, criminological, and psychological impact. In this study, an investigation was made to determine whether the relationship between the degradation of the human cardiac structure protein Cardiac Troponin T and PMI could be used as an indicator of time since death, thus providing a rapid, high resolution, sensitive, and automated methodology for the determination of PMI. ^ The use of Cardiac Troponin T (cTnT), a protein found in heart tissue, as a selective marker for cardiac muscle damage has shown great promise in the determination of PMI. An optimized conventional immunoassay method was developed to quantify intact and fragmented cTnT. A small sample of cardiac tissue, which is less affected than other tissues by external factors, was taken, homogenized, extracted with magnetic microparticles, separated by SDS-PAGE, and visualized with Western blot by probing with monoclonal antibody against cTnT. This step was followed by labeling and available scanners. This conventional immunoassay provides a proper detection and quantitation of cTnT protein in cardiac tissue as a complex matrix; however, this method does not provide the analyst with immediate results. Therefore, a competitive separation method using capillary electrophoresis with laser-induced fluorescence (CE-LIF) was developed to study the interaction between human cTnT protein and monoclonal anti-TroponinT antibody. ^ Analysis of the results revealed a linear relationship between the percent of degraded cTnT and the log of the PMI, indicating that intact cTnT could be detected in human heart tissue up to 10 days postmortem at room temperature and beyond two weeks at 4C. The data presented demonstrates that this technique can provide an extended time range during which PMI can be more accurately estimated as compared to currently used methods. The data demonstrates that this technique represents a major advance in time of death determination through a fast and reliable, semi-quantitative measurement of a biochemical marker from an organ protected from outside factors. ^