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Biosynthesis of the vasopressin (VP) prohormone in magnocellular neurones of the hypothalamo-neurohypophysial system comprises endoplasmic reticulum (ER) transit, sorting into the regulated secretory pathway and subsequent processing in the individual proteins VP, neurophysin and a glycoprotein. These processes are severely disrupted in the homozygous diabetes insipidus (di/di) Brattleboro rat, which expresses a mutant VP precursor due to a single nucleotide deletion in the neurophysin region of the VP gene resulting in VP deficiency. Previous studies have shown the presence of additional frameshift mutations in VP transcripts, in solitary magnocellular neurones of the di/di rat due to a GA dinucleotide deletion resulting in two different mutant VP precursors with partly restored reading frame. Frameshifted VP precursors are also expressed in several magnocellular neurones in wild-type rats. In this study, we determined if the +1 frameshifted precursors from di/di and wild-type rats can lead to biosynthesis of the hormone VP. Therefore, eukaryotic expression plasmids containing the frameshifted VP cDNAs were transiently expressed in peptidergic tumour cell lines, and cells were analysed by reversed phase high-performance liquid chromatography and specific radioimmunoassays, and by immunofluoresence. Neuro2A neuroblastoma cells expressing the +1 frameshifted precursors of di/di rats retained products in the cell body. Only precursor or insignificant quantities of neurophysin-immunoreactive products were detected. In contrast, in AtT20 cells, frameshifted VP precursors were at least partly processed to yield the VP peptide, indicating that they have access to the regulated secretory pathway. Comparison between the two cell lines showed a very slow ER transit of the wild-type prohormone combined with inefficient processing in Neuro2A cells. The results show that mutant precursors can reach the regulated secretory pathway if ER transport is sufficiently rapid as in the case of AtT20 cells. This suggests that the di/di rat may regain the capacity to biosynthesize authentic VP through these +1 frameshifted precursors in magnocellular neurones.

In this study we present a design for a multi-frequency microwave radiometer aimed at prolonged monitoring of deep brain temperature in newborn infants and suitable for use during hypothermic neural rescue therapy. We identify appropriate hardware to measure brightness temperature and evaluate the accuracy of the measurements. We describe a method to estimate the tissue temperature distribution from measured brightness temperatures which uses the results of numerical simulations of the tissue temperature as well as the propagation of the microwaves in a realistic detailed three-dimensional infant head model. The temperature retrieval method is then used to evaluate how the statistical fluctuations in the measured brightness temperatures limit the confidence interval for the estimated temperature: for an 18 degrees C temperature differential between cooled surface and deep brain we found a standard error in the estimated central brain temperature of 0.75 degrees C. Evaluation of the systematic errors arising from inaccuracies in model parameters showed that realistic deviations in tissue parameters have little impact compared to uncertainty in the thickness of the bolus between the receiving antenna and the infant's head or in the skull thickness. This highlights the need to pay particular attention to these latter parameters in future practical implementation of the technique.

Introduction of hypothermia therapy as a neuroprotection therapy after hypoxia-ischemia in newborn infants requires appraisal of cooling methods. In this numerical study thermal simulations were performed to test the hypothesis that cooling of the surface of the cranium by the application of a cooling bonnet significantly reduces deep brain temperature and produces a temperature differential between the deep brain and the body core. A realistic three-dimensional (3-D) computer model of infant head anatomy was used, derived from magnetic resonance data from a newborn infant. Temperature distributions were calculated using the Pennes heatsink model. The cooling bonnet was at a constant temperature of 10 degrees C. When modeling head cooling only, a constant body core temperature of 37 degrees C was imposed. The computed result showed no significant cooling of the deep brain regions, only the very superficial regions of the brain are cooled to temperatures of 33-34 degrees C. Poor efficacy of head cooling was still found after a considerable increase in the modeled thermal conductivities of the skin and skull, or after a decrease in perfusion. The results for the heatsink thermal model of the infant head were confirmed by comparison of results computed for a scaled down adult head, using both the heatsink description and a discrete vessel thermal model with both anatomy and vasculature obtained from MR data. The results indicate that significant reduction in brain temperature will only be achieved if the infant's core temperature is lowered.

We have developed a thermal model in which blood vessels are described as geometrical objects, 3D curves with associated diameters. Here the behaviour of the model is examined for low resolutions compared with the vessel diameter and for strongly curved vessels. The tests include a single straight vessel and vessels describing the path of a helix embedded in square tissue blocks. The tests show the excellent behaviour of our discrete vessel implementation.

We have developed a thermal model, for use in hyperthermia treatment planning, in which blood vessels are described as geometrical objects; 3D curves with associated diameters. For the calculation of the heat exchange with the tissue an analytic result is used. To arrive at this result some assumptions were made. One of these assumptions is a cylindrically symmetric temperature distribution. In this paper the behaviour of the model is examined for counter-current vessel geometries for which this assumption is not valid. Counter-current vessel pairs intersecting a circular tissue slice are tested. For these 2D geometries vessel spacing, tissue radius and resolution are varied, as well as the position of the vessel pair with respect to the discretized tissue grid. The simulation results are evaluated by comparison of the different heat flow rates with analytical predictions. The tests show that for a fixed vessel configuration the accuracy is not a simple decreasing function of the voxel dimensions, but is also sensitive to the position of the configuration with respect to the discretized tissue grid.

The quality of temperature distributions that can be generated with the Multi Electrode Current Source (MECS) interstitial hyperthermia (IHT) system, which allows 3D control of the temperature distribution, has been investigated. For the investigations, computer models of idealised anatomies containing discrete vessels, were used. A 7-catheter hexagonal implant geometry with a nearest neighbour distance of 15 mm was used. In each interstitial catheter with a diameter of 2.1 mm a number of 1 up to 4 electrodes were placed along an 'active section' with a length of 50 mm. The electrode segments had lengths of 50, 20, 12 and 9 mm respectively. Both single vessel and vessel network situations were analysed. This study shows that even in situations with discrete vasculature and perfusion heterogeneity it remains possible to obtain satisfactory temperature distributions with the MECS IHT system. Due to its 3D spatial control the temperature homogeneity in the implant can be made quite satisfactory.

Hair loss is a feared side effect of chemotherapy treatment. It may be prevented by cooling the scalp during administration of cytostatics. The supposed mechanism is that by cooling the scalp, both temperature and perfusion are diminished, affecting drug supply and drug uptake in the hair follicle. However, the effect of scalp cooling varies strongly. To gain more insight into the effect of cooling, a computer model has been developed that describes heat transfer in the human head during scalp cooling. Of main interest in this study are the mutual influences of scalp temperature and perfusion during cooling. Results of the standard head model show that the temperature of the scalp skin is reduced from 34.4 degrees C to 18.3 degrees C, reducing tissue blood flow to 25%. Based upon variations in both thermal properties and head anatomies found in the literature, a parameter study was performed. The results of this parameter study show that the most important parameters affecting both temperature and perfusion are the perfusion coefficient Q10 and the thermal resistances of both the fat and the hair layer. The variations in the parameter study led to skin temperature ranging from 10.1 degrees C to 21.8 degrees C, which in turn reduced relative perfusion to 13% and 33%, respectively.

The practical use of a discrete vessel thermal model for hyperthermia treatment planning requires a number of choices with respect to the unknown part of the patient's vasculature. This work presents a study of the thermal effects of blood flow in a simple tissue geometry with a detailed artificial vessel network. The simulations presented here demonstrate that an incomplete discrete description of the detailed network results in a better prediction of the temperature distribution than is obtained using the conventional bio-heatsink equation. Therefore, efforts to obtain information on the positions of the large vessels in an individual hyperthermia patient will be rewarded with a more accurate prediction of the temperature distribution.

In this study we evaluated for a realistic head model the 3D temperature rise induced by a mobile phone. This was done numerically with the consecutive use of an FDTD model to predict the absorbed electromagnetic power distribution, and a thermal model describing bioheat transfer both by conduction and by blood flow. We calculated a maximum rise in brain temperature of 0.11 degrees C for an antenna with an average emitted power of 0.25 W, the maximum value in common mobile phones, and indefinite exposure. Maximum temperature rise is at the skin. The power distributions were characterized by a maximum averaged SAR over an arbitrarily shaped 10 g volume of approximately 1.6 W kg(-1). Although these power distributions are not in compliance with all proposed safety standards, temperature rises are far too small to have lasting effects. We verified our simulations by measuring the skin temperature rise experimentally. Our simulation method can be instrumental in further development of safety standards.

The results from simulations with a new three-dimensional treatment planning system for interstitial hyperthermia with ferromagnetic seeds are presented in this study. The thermal model incorporates discrete vessel structures as well as a heat sink and enhanced thermal conductivity. Both the discrete vessels and the ferroseeds are described parametrically in separate calculation spaces. This parametric description has the advantage of an arbitrary orientation of the structures within the tissue grid, easy manipulation of the structures and independence from the resolution of the tissue voxels (tissue calculation space). The power absorption of the self-regulating seeds is according to empirical data. The thermal effects of an unlimited number of thin layers surrounding the seed (coatings, catheters) can be modelled. The initial calculations have been performed for an array of 12 identical ferromagnetic seeds in a tissue volume with a computer generated artificial vessel network spanning four vessel generations in both the arterial and venous tree. The heterogeneously distributed large isolated vessels impair the temperature distribution significantly, indicating the limited accuracy of continuum models. Simulations with different types of ferromagnetic seeds have confirmed that the efforts of previous studies to optimize the self-regulating temperature control and the implantation techniques of the ferroseeds will improve the homogeneity of the temperature distribution in the target volume. Multifilament seeds implanted in brachytherapy needles and tubular seeds appear to be the most favourable configurations. The division of long seeds into shorter segments with the appropriate Curie temperature will further improve the homogeneity of the temperature distribution without increasing the average temperature in the volume of interest. Given the proper thermal tissue data, the model presented in this study will prove to be a useful tool in making choices for the implant geometry, seed spacing and Curie temperature.

The quality of temperature distributions that can be generated with the multi-electrode current source (MECS) interstitial hyperthermia system, which allows 3D control of the spatial SAR distribution, has been investigated. For the investigations, computer models of idealized anatomies were used. These anatomical models did not contain discrete vessels. Binary-media anatomies, containing media interfaces oriented parallel, perpendicular or oblique with respect to the long axis of the implant, represent simple anatomies which can be encountered in the clinic. The implant volume was about 40 cm3. A seven-catheter hexagonal implant geometry with a nearest-neighbor distance of 15 mm was used. In each interstitial probe between one and four electrodes with a diameter of 2.1 mm were placed along an "active section' with a length of 50 mm. The electrode segments had lengths of 50, 20, 12 and 9 mm. This study shows that even with high contrasts in electrical and thermal conductivity in the implant it remains possible to obtain satisfactory temperature distributions with the MECS system. Due to its 3D spatial control the temperature homogeneity in the implant can be made quite satisfactory, with T10-T90 of the order of 2-3 K. Treatment planning must ensure that the placement of the current source electrodes is compatible with the media configuration.

A solution to the inverse problem of retrieving temperature from a set of microwave brightness temperatures together with a priori information regarding weighting functions and heat transfer within the infant head is introduced. The method offers the basis for non-invasive temperature monitoring appropriate for hypothermal neural rescue therapy.