Correspondence model-based 4D VMAT dose simulation for analysis of local metastasis recurrence after extracranial SBRT.

The purpose of this study is to introduce a novel approach to incorporate patient-specific breathing variability information into 4D dose simulation of volumetric arc therapy (VMAT)-based stereotactic body radiotherapy (SBRT) of extracranial metastases. Feasibility of the approach is illustrated by application to treatment planning and motion data of lung and liver metastasis patients. The novel 4D dose simulation approach makes use of a regression-based correspondence model that allows representing patient motion variability by breathing signal-steered interpolation and extrapolation of deformable image registration motion fields. To predict the internal patient motion during treatment with only external breathing signal measurements being available, the patients' internal motion information and external breathing signals acquired during 4D CT imaging were correlated. Combining the correspondence model, patient-specific breathing signal measurements during treatment and time-resolved information about dose delivery, reconstruction of a motion variability-affected dose becomes possible. As a proof of concept, the proposed approach is illustrated by a retrospective 4D simulation of VMAT-based SBRT treatment of ten patients with 15 treated lung and liver metastases and known clinical endpoints for the individual metastases (local metastasis recurrence yes/no). Resulting 4D-simulated dose distributions were compared to motion-affected dose distributions estimated by standard 4D CT-only dose accumulation and the originally (i.e. statically) planned dose distributions by means of GTV [Formula: see text] indices (dose to 98% of the GTV volume). A potential linkage of metastasis-specific endpoints to differences between GTV [Formula: see text] indices of planned and 4D-simulated dose distributions was analyzed.

Simulation of range imaging-based estimation of respiratory lung motion. Influence of noise, signal dimensionality and sampling patterns.

OBJECTIVES: A major problem associated with the irradiation of thoracic and abdominal tumors is respiratory motion. In clinical practice, motion compensation approaches are frequently steered by low-dimensional breathing signals (e.g., spirometry) and patient-specific correspondence models, which are used to estimate the sought internal motion given a signal measurement. Recently, the use of multidimensional signals derived from range images of the moving skin surface has been proposed to better account for complex motion patterns. In this work, a simulation study is carried out to investigate the motion estimation accuracy of such multidimensional signals and the influence of noise, the signal dimensionality, and different sampling patterns (points, lines, regions). METHODS: A diffeomorphic correspondence modeling framework is employed to relate multidimensional breathing signals derived from simulated range images to internal motion patterns represented by diffeomorphic non-linear transformations. Furthermore, an automatic approach for the selection of optimal signal combinations/patterns within this framework is presented. RESULTS: This simulation study focuses on lung motion estimation and is based on 28 4D CT data sets. The results show that the use of multidimensional signals instead of one-dimensional signals significantly improves the motion estimation accuracy, which is, however, highly affected by noise. Only small differences exist between different multidimensional sampling patterns (lines and regions). Automatically determined optimal combinations of points and lines do not lead to accuracy improvements compared to results obtained by using all points or lines. CONCLUSIONS: Our results show the potential of multidimensional breathing signals derived from range images for the model-based estimation of respiratory motion in radiation therapy.

Multivariate regression approaches for surrogate-based diffeomorphic estimation of respiratory motion in radiation therapy.

Breathing-induced location uncertainties of internal structures are still a relevant issue in the radiation therapy of thoracic and abdominal tumours. Motion compensation approaches like gating or tumour tracking are usually driven by low-dimensional breathing signals, which are acquired in real-time during the treatment. These signals are only surrogates of the internal motion of target structures and organs at risk, and, consequently, appropriate models are needed to establish correspondence between the acquired signals and the sought internal motion patterns. In this work, we present a diffeomorphic framework for correspondence modelling based on the Log-Euclidean framework and multivariate regression. Within the framework, we systematically compare standard and subspace regression approaches (principal component regression, partial least squares, canonical correlation analysis) for different types of common breathing signals (1D: spirometry, abdominal belt, diaphragm tracking; multi-dimensional: skin surface tracking). Experiments are based on 4D CT and 4D MRI data sets and cover intra- and inter-cycle as well as intra- and inter-session motion variations. Only small differences in internal motion estimation accuracy are observed between the 1D surrogates. Increasing the surrogate dimensionality, however, improved the accuracy significantly; this is shown for both 2D signals, which consist of a common 1D signal and its time derivative, and high-dimensional signals containing the motion of many skin surface points. Eventually, comparing the standard and subspace regression variants when applied to the high-dimensional breathing signals, only small differences in terms of motion estimation accuracy are found.

Natural course of autoimmune thyroiditis in type 1 diabetes: association with gender, age, diabetes duration, and puberty.

AIMS: To investigate the natural history and incidence of autoimmune thyroiditis (AIT) in paediatric patients with type 1 diabetes (T1D). METHODS: Since 1990, annual screening for thyroid disease has been performed in children and adolescents with T1D. Antibodies against thyroperoxidase (anti-TPO) and thyroglobulin (anti-TG) as well as TSH were measured in 659 patients (54.3% boys). In 126 patients, anti-TPO and anti-TG levels were followed at yearly intervals from onset up to five years of T1D. Anti-TPO above 30 U/ml and anti-TG above 20 U/ml were considered positive, values above 100 U/ml as significantly raised and indicative of AIT. L-thyroxine treatment was started if TSH was higher than 4.5 microU/ml and/or thyroid gland enlargement on thyroid ultrasound was present. RESULTS: At initial screening, 15.4% of patients had raised anti-TPO and 14.4% anti-TG. Girls had more frequently raised antibodies than boys. Sixty two patients (9.4%, 61% girls) required treatment with L-thyroxine. The cumulative incidence (SE) of AIT after 10 years of diabetes was 0.14 (0.02), being significantly higher in females (0.18 (0.03)), particularly after the age of 12 years. At T1D onset, positive anti-TPO and anti-TG were present in 21 of 126 patients (16.7%), each. All patients with significantly increased values of anti-TPO (n = 17, 148-5340 U/ml) and anti-TG (n = 11, 140-2000 U/ml) at T1D onset remained positive during the following five years. CONCLUSIONS: For early detection of autoimmune thyroiditis in children with T1D, measurement of anti-TPO and TSH at T1D onset and in yearly intervals after the age of 12 years is recommended.

[Physiological functional evaluation of retinal implants in animal models]. / Physiologische Funktionsprüfungen von Retinaimplantaten an Tiermodellen.

Retinal implants can--by electrical stimulation--create visual impressions in people with certain kinds of degenerative retinal diseases (e.g. Retinitis Pigmentosa). Electrically evoked potentials in the retina must be transferred into the visual cortex in an orderly manner, a prerequisite for any kind of form- and movement-perception. In the current developmental stage the difficult investigations are performed in various animal models: isolated retinae of intact chicken and of RCS-rats (a model for Retinitis Pigmentosa), as well as in anesthetised rabbits, pigs and cats with intact retinae. Our investigations show that spatially selective ganglion-cell responses can be recorded following focal electrical stimulation, in healthy and as well in degenerated retinae. Registration of activities in area 17 of the visual cortex demonstrate that electrical retinal stimulation can indeed activate it.

Implantation of retina stimulation electrodes and recording of electrical stimulation responses in the visual cortex of the cat.

BACKGROUND: Simple basic visual perception may be restored by epiretinal electrical stimulation in patients that are blind due to photoreceptor loss. To stimulate ganglion cells, epiretinally flat platinum microelectrodes embedded in thin polyimide film were developed and tested in the cat. METHODS: After removal of the lens and the vitreous body a thin microfilm electrode array was implanted through a corneoscleral incision in the cat eye (n = 4). In two eyes no further attempt was made to fixate the tip of the electrode, which was pressed onto the retinal surface due to the tension of the curved polyimide film. In two eyes the tip of the electrode was fixed with cyanoacrylate adhesive. The exterior part of the microelectrode film was directed under the skin towards the forehead which allowed fixation of the microplug to a head fixation bolt. Retinal stimulation experiments were performed within 1 week after implantation. Success of stimulation was assessed by recording neuronal activities from areas 17 and 18. Retinal microelectrodes were removed 2 weeks or longer after implantation. RESULTS: Intraocular inflammation or retinal detachment were not observed after implantation of the microelectrode film. In two eyes the tip of the microelectrodes dislocated spontaneously within the first few days. The lowest threshold of electrical stimulation was 35 microA, corresponding to a charge transfer of 14 nC per phase. These values were ten times higher than those obtained by needle electrodes used in prior experiments. CONCLUSIONS: Intraocular implanted flat microelectrodes made of platinum and polyimide were well tolerated. Because of the flat configuration of the microelectrodes higher stimulation thresholds than for needle electrodes were found, indicating insufficient contact to the retinal surface. An alternative shape and fixation technique is required to minimise electrodes' threshold of stimulation.

[Pharmacokinetics of etomidate in man (author's transl)]. / Pharmakokinetische Untersuchungen über Etomidat beim Menschen.

The pharmacokinetic behaviour of etomidate was investigated in 7 patients. A method for the analysis of etomidate is described using gas-liquid chromatography for separation and alkali flame ionization detection. The lower limit of detection for etomidate in plasma was 0.005 microgram/ml. The pharmacokinetic behaviour of etomidate after an intravenous bolus injection of 20 mg may be described in terms of an open two-compartment model. The plasma half-life of etomidate was in the alpha-phase about 3 minutes, the biological half-life of the beta-phase was about 70 minutes. The total volume of distribution was calculated at 165 litres. The total plasma clearance amounted to 1600 ml/min. These pharmacokinetic data were used to establish an intravenous infusion scheme for etomidate.

[Infusion model for etomidate (author's transl)]. / Ein pharmakokinetisch begründetes Infusionsmodell für Etomidat zur Aufrechterhaltung von Steady State-Plasmaspiegeln.

An intravenous infusion scheme was established in five healthy volunteers on the basis of pharmacokinetic analysis as described by J.G. Wagner. Concentrations of etomidate in plasma were measured by gas chromatography after solvent extraction. The monitoring of EEG background activity was used for the correlation to the pharmacodynamic effect. The minimal plasma level producing an hypnotic effect was about 0.3 microgram/ml) etomidate. An infusion model was developed for a therapeutic plasma concentration of 0.5 microgram/ml etomidate. An initial fast constant-rate infusion (8 mg/min) was followed by an infusion with 0.8 mg/min for the entire duration of the application. The measured plasma levels coincided fairly well with the predicted steady state plasma levels and were accompanied by a distinct hypnotic effect in all volunteers.

Flash photometric experiments on the photochemical cycle of bacteriorhodopsin.

The photochemical reaction cycle of bacteriorhodopsin was investigated by means of flash photometric methods. Three different intermediates with absorption maxima at about 630 nm, 411 nm, and 646 nm could be detected. Kinetic data of the occurrence of these intermediates were obtained from isolated purple membrane in different mediums and from intact halobacteria. An activation energy of 14.1 +/- 0.4 kcal-mol-1 and of about 19 kcal-mol-1 for formation of bacteriorhodopsin 411 and of bacteriorhodopsin 565, resp., was calculated. pH-changes in the medium caused by the reaction cycle of bacteriorhodopsin were detected by use of the pH-indicator bromocresol green.