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Multiple Sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal damage. Early recognition and treatment are important for preventing or minimizing the long-term effects of the disease. Current gold standard modalities of diagnosis (e.g., CSF and MRI) are invasive and expensive in nature, warranting alternative methods of detection and screening. Oculomics, the interdisciplinary combination of ophthalmology, genetics, and bioinformatics to study the molecular basis of eye diseases, has seen rapid development through various technologies that detect structural, functional, and visual changes in the eye. Ophthalmic biomarkers (e.g., tear composition, retinal nerve fibre layer thickness, saccadic eye movements) are emerging as promising tools for evaluating MS progression. The eye's structural and embryological similarity to the brain makes it a potentially suitable assessment of neurological and microvascular changes in CNS. In the advent of more powerful machine learning algorithms, oculomics screening modalities such as optical coherence tomography (OCT), eye tracking, and protein analysis become more effective tools aiding in MS diagnosis. Artificial intelligence can analyse larger and more diverse data sets to potentially discover new parameters of pathology for efficiently diagnosing MS before symptom onset. While there is no known cure for MS, the integration of oculomics with current modalities of diagnosis creates a promising future for developing more sensitive, non-invasive, and cost-effective approaches to MS detection and diagnosis., (© 2024. The Author(s).)

Objective: Polycystic ovary syndrome (PCOS) is a chronic endocrine syndrome in reproductive-aged women which is very common among Aboriginal and Torres Strait Islander women. The objective of this study was to conduct a process evaluation of a pilot clinic on Thursday Island which aimed to provide a comprehensive evidence-based service for women with PCOS throughout the Torres Strait., Design: Mixed-method evaluation at 12 months comprising a medical record audit, semi-structured interviews and focus group discussions., Setting: Primary care., Participants: Audit of n = 11 clinics (n = 36 women), qualitative semi-structured interviews with n = 8 clinicians and focus group discussions with n = 8 women., Main Outcome Measures: (i) Fidelity to evidence-based guidelines, (ii) barriers and enablers to women using the service, (iii) the ability to meet the needs of women and the community., Results: The clinic was largely successful in providing evidence-based care with up to 78% of women receiving recommended cardiometabolic screening, 100% emotional screening and 89% lifestyle management despite the remoteness of the clinic and limited financial and human resources. Health care providers report sustainability of the clinic will be dependent on factors including staffing, administrative support and inclusion of Aboriginal and Torres Strait Islander health workers., Conclusion: While the clinic has been largely successful there are areas identified for potential improvement and to facilitate sustainability which should be considered before up-scaling this model to a national level. These include systems, administrative and staffing support, engaging with other community services to facilitate lifestyle changes and ongoing engagement and upskilling of Aboriginal and Torres Strait Islander health care providers., (© 2016 National Rural Health Alliance Inc.)

In this work we report some preliminary results regarding the analysis of electron paramagnetic resonance (EPR) response of alanine pellets and alanine pellets added with gadolinium used for dosimetry at the TRIGA research reactor in Mainz, Germany. Two set-ups were evaluated: irradiation inside PMMA phantom and irradiation inside boric acid phantom. We observed that the presence of Gd2O3 inside alanine pellets increases the EPR signal by a factor of 3.45 and 1.24 in case of PMMA and boric acid phantoms, respectively. We can conclude that in the case of neutron beam with a predominant thermal neutron component the addition of gadolinium oxide can significantly improve neutron sensitivity of alanine pellets. Monte Carlo (MC) simulations of both response of alanine and Gd-added alanine pellets with FLUKA code were performed and a good agreement was achieved for pure alanine dosimeters. For Gd2O3-alanine deviations between MC simulations and experimental data were observed and discussed., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

An analytical method using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was developed and applied to assess enrichment of 10B-containing p-boronophenylalanine-fructose (BPA-f) and its pharmacokinetic distribution in human tissues after application for boron neutron capture therapy (BNCT). High spatial resolution (50 μm) and limits of detection in the low parts-per-billion range were achieved using a Nd:YAG laser of 213 nm wavelength. External calibration by means of 10B-enriched standards based on whole blood proved to yield precise quantification results. Using this calibration method, quantification of 10B in cancerous and healthy tissue was carried out. Additionally, the distribution of 11B was investigated, providing 10B enrichment in the investigated tissues. Quantitative imaging of 10B by means of LA-ICP-MS was demonstrated as a new option to characterise the efficacy of boron compounds for BNCT.

Background: Neutron capture therapy for glioblastoma has focused mainly on the use of (10)B as neutron capture isotope. However, (157)Gd offers several advantages over boron, such as higher cross section for thermal neutrons and the possibility to perform magnetic resonance imaging during neutron irradiation, thereby combining therapy and diagnostics. We have developed different liposomal formulations of gadolinium-DTPA (Magnevist®) for application in neutron capture therapy of glioblastoma. The formulations were characterized physicochemically and tested in vitro in a glioma cell model for their effectiveness., Methods: Liposomes entrapping gadolinium-DTPA as neutron capture agent were manufactured via lipid/film-extrusion method and characterized with regard to size, entrapment efficiency and in vitro release. For neutron irradiation, F98 and LN229 glioma cells were incubated with the newly developed liposomes and subsequently irradiated at the thermal column of the TRIGA reactor in Mainz. The dose rate derived from neutron irradiation with (157)Gd as neutron capturing agent was calculated via Monte Carlo simulations and set in relation to the respective cell survival., Results: The liposomal Gd-DTPA reduced cell survival of F98 and LN229 cells significantly. Differences in liposomal composition of the formulations led to distinctly different outcome in cell survival. The amount of cellular Gd was not at all times proportional to cell survival, indicating that intracellular deposition of formulated Gd has a major influence on cell survival. The majority of the dose contribution arises from photon cross irradiation compared to a very small Gd-related dose., Conclusions: Liposomal gadolinium formulations represent a promising approach for neutron capture therapy of glioblastoma cells. The liposome composition determines the uptake and the survival of cells following radiation, presumably due to different uptake pathways of liposomes and intracellular deposition of gadolinium-DTPA. Due to the small range of the Auger and conversion electrons produced in (157)Gd capture, the proximity of Gd-atoms to cellular DNA is a crucial factor for infliction of lethal damage. Furthermore, Gd-containing liposomes may be used as MRI contrast agents for diagnostic purposes and surveillance of tumor targeting, thus enabling a theranostic approach for tumor therapy.

Peptidic ligands selectively targeting distinct G protein-coupled receptors that are highly expressed in tumor tissue represent a promising approach in drug delivery. Receptor-preferring analogues of neuropeptide Y (NPY) bind and activate the human Y1 receptor subtype (hY1 receptor), which is found in 90% of breast cancer tissue and in all breast-cancer-derived metastases. Herein, novel highly boron-loaded Y1 -receptor-preferring peptide analogues are described as smart shuttle systems for carbaboranes as (10) B-containing moieties. Various positions in the peptide were screened for their susceptibility to carbaborane modification, and the most promising positions were chosen to create a multi-carbaborane peptide containing 30 boron atoms per peptide with excellent activation and internalization patterns at the hY1 receptor. Boron uptake studies by inductively coupled plasma mass spectrometry revealed successful uptake of the multi-carbaborane peptide into hY1 -receptor-expressing cells, exceeding the required amount of 10(9) boron atoms per cell. This result demonstrates that the NPY/hY receptor system can act as an effective transport system for boron-containing moieties., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed., Methods: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a (60)Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes fluka and mcnp. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen & Olsen alanine response model., Results: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields., Conclusions: The alanine detector can be used without difficulty in neutron fields. The response has been understood with the model used which includes the relative effectiveness. Results and the corresponding discussion lead to the conclusion that application in neutron fields for medical purpose is limited by its sensitivity but that it is a useful tool as supplement to other detectors and verification of neutron source descriptions.

Purpose: In order to build up a reliable dose monitoring system for boron neutron capture therapy (BNCT) applications at the TRIGA reactor in Mainz, a computer model for the entire reactor was established, simulating the radiation field by means of the Monte Carlo method. The impact of different source definition techniques was compared and the model was validated by experimental fluence and dose determinations., Methods: The depletion calculation code origen2 was used to compute the burn-up and relevant material composition of each burned fuel element from the day of first reactor operation to its current core. The material composition of the current core was used in a mcnp5 model of the initial core developed earlier. To perform calculations for the region outside the reactor core, the model was expanded to include the thermal column and compared with the previously established attila model. Subsequently, the computational model is simplified in order to reduce the calculation time. Both simulation models are validated by experiments with different setups using alanine dosimetry and gold activation measurements with two different types of phantoms., Results: The mcnp5 simulated neutron spectrum and source strength are found to be in good agreement with the previous attila model whereas the photon production is much lower. Both mcnp5 simulation models predict all experimental dose values with an accuracy of about 5%. The simulations reveal that a Teflon environment favorably reduces the gamma dose component as compared to a polymethyl methacrylate phantom., Conclusions: A computer model for BNCT dosimetry was established, allowing the prediction of dosimetric quantities without further calibration and within a reasonable computation time for clinical applications. The good agreement between the mcnp5 simulations and experiments demonstrates that the attila model overestimates the gamma dose contribution. The detailed model can be used for the planning of structural modifications in the thermal column irradiation channel or the use of different irradiation sites than the thermal column, e.g., the beam tubes.

Boron determination in blood and tissue samples is a crucial task especially for treatment planning, preclinical research, and clinical application of boron neutron capture therapy (BNCT). Comparison of clinical findings remains difficult due to a variety of analytical methods, protocols, and standard reference materials in use. This paper addresses the comparability of inductively coupled plasma mass spectrometry, quantitative neutron capture radiography, and prompt gamma activation analysis for the determination of boron in biological samples. It was possible to demonstrate that three different methods relying on three different principles of sample preparation and boron detection can be validated against each other and yield consistent results for both blood and tissue samples. The samples were obtained during a clinical study for the application of BNCT for liver malignancies and therefore represent a realistic situation for boron analysis.

This study investigates the dosimetric feasibility of Boron Neutron Capture Therapy (BNCT) of explanted livers in the thermal column of the research reactor in Mainz. The Monte Carlo code MCNP5 is used to calculate the biologically weighted dose for different ratios of the (10)B-concentration in tumour to normal liver tissue. The simulation results show that dosimetric goals are only partially met. To guarantee effective BNCT treatment the organ has to be better shielded from all gamma radiation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Standard wafer solar cells are made of near-semiconductor quality silicon. This high quality material makes up a significant part of the total costs of a solar module. Therefore, new concepts with less expensive so called solar grade silicon directly based on physiochemically upgraded metallurgical grade silicon are investigated. Metallurgical grade silicon contains large amounts of impurities, mainly transition metals like Fe, Cr, Mn, and Co, which degrade the minority carrier lifetime and thus the solar cell efficiency. A major reduction of the transition metal content occurs during the unidirectional crystallization due to the low segregation coefficient between the solid and liquid phase. A further reduction of the impurity level has to be done by gettering procedures applied to the silicon wafers. The efficiency of such cleaning procedures of metallurgical grade silicon is studied by instrumental neutron activation analysis (INAA). Small sized silicon wafers of approximately 200mg with and without gettering step were analyzed. To accelerate the detection of transition metals in a crystallized silicon ingot, experiments of scanning whole vertical silicon columns with a diameter of approximately 1cm by gamma spectroscopy were carried out. It was demonstrated that impurity profiles can be obtained in a comparably short time. Relatively constant transition metal ratios were found throughout an entire silicon ingot. This led to the conclusion that the determination of several metal profiles might be possible by the detection of only one "leading element". As the determination of Mn in silicon can be done quite fast compared to elements like Fe, Cr, and Co, it could be used as a rough marker for the overall metal concentration level. Thus, a fast way to determine impurities in photovoltaic silicon material is demonstrated., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The typical primary malignancies of the liver are hepatocellular carcinoma and cholangiocarcinoma, whereas colorectal liver metastases are the most frequently occurring secondary tumors. In many cases, only palliative treatment is possible. Boron neutron capture therapy (BNCT) represents a technique that potentially destroys tumor tissue selectively by use of externally induced, locally confined secondary particle irradiation. In 2001 and 2003, BNCT was applied to two patients with colorectal liver metastases in Pavia, Italy. To scrutinize the rationale of BNCT, a clinical pilot study on patients with colorectal liver metastases was carried out at the University of Mainz. The distribution of the (10)B carrier (p-borono-phenylalanine) in the liver and its uptake in cancerous and tumor-free tissue were determined, focusing on a potential correlation between the uptake of p-borono-phenylalanine and the biological characteristics of cancerous tissue. Samples were analyzed using quantitative neutron capture radiography of cryosections combined with histological analysis. Methodological aspects of the combination of these techniques and results from four patients enrolled in the study are presented that indicate that the uptake of p-borono-phenylalanine strongly depends on the metabolic activity of cells.

Unlabelled: Boron Neutron Capture Therapy for liver malignancies is being investigated at the University of Mainz. One important aim is the set-up of a reliable dosimetry system. Alanine dosimeters have previously been applied for dosimetry of mixed radiation fields in antiproton therapy, and may be suitable for measurements in mixed neutron and gamma fields., Material and Methods: Two experiments have been carried out in the thermal column of the TRIGA Mark II reactor at the University of Mainz. Alanine dosimeters have been irradiated in a phantom and in liver tissue., Results: For the interpretation and prediction of the dose for each pellet, beside the results of the measurements, calculations with the Monte Carlo code FLUKA are presented here. For the phantom, as well as for the liver tissue, the measured and calculated dose and flux values are in good agreement., Discussion: Alanine dosimeters, in combination with flux measurements and Monte Carlo calculations with FLUKA, suggest that it is possible to establish a system for monitoring the dose in a mixed neutron and gamma field for BNCT and other applications in radiotherapy.

As part of the studies on Boron Neutron Capture Therapy at the University of Mainz, Germany, a clinical trial has been started in which, four patients suffering from liver metastases of colorectal carcinoma have been enrolled. Specimens of blood and healthy tissue samples taken from the patients were measured at the PGAA facilities at the HFR in Petten, The Netherlands, and at the FRM II in Munich, Germany. From the measured boron concentrations, pharmacokinetic curves and blood-to-tissue concentration ratios were produced., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Must and wine may be contaminated with elevated copper concentrations by the use of fungicides or in course of the vinification process. Hitherto only a few practicable and harmless procedures exist to reduce an excess of copper from must and wine. For this reason we investigated the biosorption of copper by eight wine-relevant Lactobacillus species. Both, living and heat-inactivated cells revealed a significant degree of Cu adsorption. It was shown that Cu binding correlated positively with an increasing pH value of the environment. The highest binding capacity of the tested lactic acid bacteria was found for L. buchneri DSM 20057 with a maximum of 46.17 μg Cu bound per mg cell in deionized water. In must, wine and grape juice Cu was removed less effective which is not solely attributed to low pH-values, but also to specific medium parameters such as intrinsic metal cations, organic acids or phenolic compounds. Nevertheless, about 0.5-1.0 μg Cu per ml could be removed from wine samples, which is sufficient enough to lower critical copper concentrations., (Copyright © 2010 Elsevier B.V. All rights reserved.)

To establish Boron Neutron Capture Therapy (BNCT) for non-resectable liver metastases and for in vitro experiments at the TRIGA Mark II reactor at the University of Mainz, Germany, it is necessary to have a reliable dose monitoring system. The in vitro experiments are used to determine the relative biological effectiveness (RBE) of liver and cancer cells in our mixed neutron and gamma field. We work with alanine detectors in combination with Monte Carlo simulations, where we can measure and characterize the dose. To verify our calculations we perform neutron flux measurements using gold foil activation and pin-diodes. Material and methods. When L-α-alanine is irradiated with ionizing radiation, it forms a stable radical which can be detected by electron spin resonance (ESR) spectroscopy. The value of the ESR signal correlates to the amount of absorbed dose. The dose for each pellet is calculated using FLUKA, a multipurpose Monte Carlo transport code. The pin-diode is augmented by a lithium fluoride foil. This foil converts the neutrons into alpha and tritium particles which are products of the (7)Li(n,α)(3)H-reaction. These particles are detected by the diode and their amount correlates to the neutron fluence directly. Results and discussion. Gold foil activation and the pin-diode are reliable fluence measurement systems for the TRIGA reactor, Mainz. Alanine dosimetry of the photon field and charged particle field from secondary reactions can in principle be carried out in combination with MC-calculations for mixed radiation fields and the Hansen & Olsen alanine detector response model. With the acquired data about the background dose and charged particle spectrum, and with the acquired information of the neutron flux, we are capable of calculating the dose to the tissue. Conclusion. Monte Carlo simulation of the mixed neutron and gamma field of the TRIGA Mainz is possible in order to characterize the neutron behavior in the thermal column. Currently we also speculate on sensitizing alanine to thermal neutrons by adding boron compounds.

Brick stones collected from different production facilities were studied for their elemental compositions under forensic aspects using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS), instrumental neutron activation analysis (INAA) and X-ray fluorescence analysis (XRF). The aim of these examinations was to assess the potential of these methods in forensic comparison analyses of brick stones. The accuracy of the analysis methods was evaluated using NIST standard reference materials (679, 98b and 97b). In order to compare the stones to each other, multivariate data analysis was used. The evaluation of the INAA results (based on the concentrations of V, Na, K, Sm, U, Sc, Fe, Co, Rb and Cs) using principal component analysis (PCA) and cluster analysis is presented as an example. The results derived from the different analytical methods are consistent. It was shown that elemental analysis using the described methods is a valuable tool for forensic examinations of brick stones.

Samples from 20 reverse paintings on glass from different regions have been analyzed by NAA with the aim to deduce the place and date of their origin. A separation of earlier and later paintings was due to different concentrations of K and Na, because a sodium-containing flux came into use after 1870. Since in southern Germany quartz sand, and in the eastern area quartz rock had been used for glass manufacture, specific impurities could be used to distinguish southern from eastern glasses.

For the application of the BNCT for the excorporal treatment of organs at the TRIGA Mainz, the basic characteristics of the radiation field in the thermal column as beam geometry, neutron and gamma ray energies, angular distributions, neutron flux, as well as absorbed gamma and neutron doses must be determined in a reproducible way. To determine the mixed irradiation field thermoluminescence detectors (TLD) made of CaF(2):Tm with a newly developed energy-compensation filter system and LiF:Mg,Ti materials with different (6)Li concentrations and different thicknesses as well as thin gold foils were used.

The TRIGA Mark II reactor at the University of Mainz provides ideal conditions for duplicating BNCT treatment as performed in Pavia, Italy, in 2001 and 2003 [Pinelli, T., Zonta, A., Altieri, S., Barni, S., Braghieri, A., Pedroni, P., Bruschi, P., Chiari, P., Ferrari, C., Fossati, F., Nano, R., Ngnitejeu Tata, S., Prati, U., Ricevuti, G., Roveda, L., Zonta, C., 2002. TAOrMINA: from the first idea to the application to the human liver. In: Sauerwein et al. (Eds.), Research and Development in Neutron Capture Therapy. Proceedings of the 10th International Congress on Neutron Capture Therapy, Monduzzi editore, Bologna, pp. 1065-1072]. In order to determine the optimal parameters for the planned therapy and therefore for the design of the thermal column, calculations were conducted using the MCNP-code and the transport code ATTILA. The results of the parameter study as well as a possible configuration for the irradiation of the liver are presented.

We have measured the acceleration of neutrons by the material optical potential of solid 2H2. Using a gravitational spectrometer, we find a minimal kinetic energy Ec = (99+/-7) neV of neutrons from a superthermal ultracold neutron (UCN) source with solid 2H2 as an UCN converter. The result is in excellent agreement with theoretical predictions, Ec = 106 neV.

Different approaches for the measurement of a relatively small gamma dose in strong fields of thermal and epithermal neutrons as used for Boron Neutron Capture Therapy (BNCT) have been studied with various thermoluminescence detectors (TLDs). CaF(2):Tm detectors are insensitive to thermal neutrons but not tissue-equivalent. A disadvantage of applying tissue-equivalent (7)LiF detectors is a strong neutron signal resulting from the unavoidable presence of (6)Li traces. To overcome this problem it is usual to apply pairs of LiF detectors with different (6)Li content. The experimental determination of the thermal neutron response ratio of such a pair at the Geesthacht Neutron Facility (GeNF) operated by PTB enables measurement of the photon dose. In the experimental mixed field of thermal neutrons and photons of the TRIGA reactor at Mainz the photon dose measured with different types of (7)LiF/(nat)LiF TLD pairs agree within a standard uncertainty of 6% whereas the CaF(2):Tm detectors exhibit a photon dose by more than a factor of 2 higher. It is proposed to determine suitable photon energy correction factors for CaF(2):Tm detectors with the help of the (7)LiF/(nat)LiF TLD pairs in the radiation field of interest.

Elevated activities of cysteine proteinases, the cathepsins B, H, L (CB, CH, CL) and diminished cysteine protease inhibitors (CPI) have been demonstrated in a variety of tumours and have been suggested to contribute to invasion and metastasis. The situation for prostate cancer is still unknown. In this study, using fluorimetric assays, the catalytic activities of CB, CH, CL were measured in prostatic tissue samples after radical prostatectomy, adenomectomy, transurethral resection of the prostate, in cell cultures grown from cancerous and non-cancerous parts of human prostate after prostatectomy and in the cell lines LNCaP, DU 145 and PC 3. CPIs were determined using heat activation before testing their inhibitory activity against purified CB. Comparing matched pairs of normal and cancerous tissue samples from the prostate, significantly decreased levels of CB, CL in malignant parts of the prostate were found. In contrast, primary cell cultures from cancerous samples showed elevated levels of CB, CH, CL and increased ratios of cathepsins to CPI compared with cell cultures from normal prostate. Established cell lines showed a similar distribution pattern of each cathepsin, DU 145 containing the highest levels, followed by LNCaP and PC 3. Our results suggest that elevated cathepsin levels and consequently increased ratios of cathepsins to CPI in primary cell cultures from cancerous versus non-cancerous parts of the prostate may be indicative of a cellular proteolytic imbalance in prostatic cancer cells. In this respect, primary cell culture experiments should be preferred to determinations in tissue samples.

Background: The classic methods for surveilling the efficacy of radiotherapy in prostate cancer are not accurate enough. The objective of this analysis was to determine whether prostate-specific antigen could perform this task., Materials and Methods: From 1/95 to 10/95, 16 patients were treated at our clinic. 7 of these underwent primary irradiation, 4 treatment for local recurrence, and 5 had adjuvant radiotherapy. Radiotherapy was carried out with a total dose of 60 Gy in 30 fractions, 10 fractions per week, to the prostate bed plus 2 cm safety margin., Results: PSA levels usually start to decline between the 3rd and the 4th week of radiotherapy with a half-life of 2.5 months. Five patients had equal or rising PSA levels, including all three patients with recurrent tumor., Discussion: In most cases, PSA declined continuously from the 3rd week of therapy. Our median half-life was similar to other reported results. Persisting or rising PSA levels are an indicator for local or distant recurrence; all our patients who developed a recurrence showed a corresponding PSA increase.

The antioxidant enzymes catalase, glutathione reductase (GR), glutathione S-transferase (GST), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were determined in the androgen-response LNCaP and androgen-nonresponsive PC-3 and DU 145 cells as well as in prostatic epithelial cell cultures of benign and malignant human prostatic tissue. There were no differences between the enzyme activities of the human primary cell cultures from cancerous tissue and their normal counterparts. The enzyme activities of the three permanent cell lines were either higher (SOD, catalase, GR) or lower (GST, GPx) than in the primary cell cultures. In LNCaP cells catalase and GR were significantly higher, GST, in contrast, was significantly lower than in PC-3 and DU 145 cells. GST in PC-3 and DU 145 cells, and SOD in all the three cell lines showed no significant differences. Catalase, GPx and GR values were significantly different in the three permanent cell lines. The different enzymatic equipment of the prostate cancer cell lines provides the basis for experimental testing of new concepts of cancer treatment with the help of systematic modulations of the antioxidant defence systems in prostate cancer.

Background: Keratoacanthoma is a fairly common, benign, usually self-resolving skin lesion that arises from the hair follicle. This nodular lesion shows a predilection for areas exposed to light, mainly for the face. We report on the intensive radiation therapy of 2 cases of a rare subset of keratoacanthoma which showed a locally aggressive, seriously destructive growth., Patients and Methods: Two female patients with previously treated, confluent-destructive growing keratoacanthoma were treated by multimodal, high-dose radiotherapy. Patient 1 showed a rapid progress of midfacial tumor with destructive infiltration of the left cheek, nasal cartilage, the cribriform plate of ethmoid and congestion of the conjunctiva close to the lacrimal caruncle. This could be shown in clinical and histopathological investigations and CT-scans. The coexistence of cutaneous and conjunctival lesions in locally rapidly enlarging keratoacanthoma of the face is unusual and unreported to our knowledge. One case of simultaneous conjunctival and multiple, eruptive keratoacanthoma of the body has been reported. Patient 2 had received soft X-ray pretreatment because of a large, relapsing keratoacanthoma of the left cheek., Results: Patient 1 underwent a parallel, intensive treatment of the conjunctiva with 90Sr-contact therapy, percutaneous high-dose 60Co-gamma- and megavoltage electron treatment (10 and 18 MeV) of the midfacial lesions. Conjunctiva and caruncle showed a complete remission of keratoacanthoma. In the other facial areas no long-term regression could be reached, despite giving a fully cancericidal, total dose of more than 100 Gy in some regions. Patient 2: Further high dose radiotherapy using megavoltage electron treatment with a total dose of 50 Gy showed a complete remission of the lesion for 5 months. Another relapse of this keratoacanthoma could be operated successfully. There was no more relapse established in follow-up checks., Conclusions: The 2 case reports show that in treatment of locally destructive growing subsets of keratoacanthoma a sufficient therapy should be initiated in time. Keratoacanthoma and subsets of this lesion that do not respond well to initial treatment, recur early or show seriously aggressive growth should be treated early by combined therapy that takes previous experiences into consideration.

Antioxidants play an important role in the regulation of phospholipid hydrolysis and arachidonate metabolism. Supplementation of cultured human mesangial cells with selenium resulted in suppression of phospholipase A2-activity and significantly increased production of three major prostaglandins. However, prostacyclin synthesis benefits most from selenium supplementation, suggesting that there is a specific action of selenium-dependent glutathione peroxidase on this pathway. Like in endothelial cells, production of platelet activating factor is significantly inhibited by selenium supplementation.

Selenium is an essential component of glutathione peroxidase, an enzyme which protects cells against peroxidation and controls concentrations of intracellular peroxides. Since selenium deficiency is clinically associated with an increased degree of atherosclerosis, the effects of selenium deficiency on prostacyclin (PGI2) and platelet activating factor (PAF) production by cultured human umbilical vein endothelial cells (HUVEC) were investigated. In selenium-deficient HUVEC, histamine-induced PGI2 synthesis was significantly decreased when compared to selenium-supplemented HUVEC; in contrast, histamine-induced PAF production was increased by selenium deficiency. Histamine-induced inositol trisphosphate and [Ca2+]i responses and the conversion of PGG2 and PGH2 to PGI2 were not altered by selenium deficiency. However, selenium deficiency decreased the conversion of exogenous arachidonate to PGI2 and markedly suppressed glutathione peroxidase activity. These results suggest that selenium deficiency, by decreasing glutathione peroxidase activity, makes HUVEC susceptible to peroxide-induced inhibition of the cyclooxygenase activity of PGH2 synthase, resulting in decreased PGI2 production. These changes may alter platelet function in vivo and thus play a role in the increased incidence of atherosclerosis reported in selenium-deficient individuals.

Se is an essential component of glutathione peroxidase and thereby protects cells against peroxidation of their membrane lipids. Dialysis patients have significantly lower plasma Se levels than healthy controls. The obvious role of Se in protection against development of certain forms of cardiomyopathy was investigated for the case of blood cells. There is evidence that decreased half-lives of erythrocytes and thrombocytes, found in dialysis patients, correlate with degree of Se deficiency.

1 Two cases of drug-induced rhabdomyolysis, one of them presenting with acute myoglobinuric renal failure are described. 2 The pathogenesis of rhabdomyolysis and renal failure in our cases is discussed with reference to work published by other authors. 3 Whereas there seems to be obvious evidence for direct toxic drug-muscle interaction, the mechanism for the development of myoglobinuric renal failure remains unclear.

Five different hemoperfusion devices have been used in the treatment of patients, intoxicated with barbiturates. The changes in drug clearance values which occurred during hemoperfusion varied according to the device used. Even after very long periods of hemoperfusion, however, drug clearance values never fell to zero. Using data collected from comparable cases, it has been shown that the rate of uptake of drug from the blood is independent of the amount of adsorbent in the columns, those containing 100 gm charcoal having the same efficiency as the conventional 300 gm. The prime factor which determines the rate of drug uptake has been shown to be the arterial plasma drug concentrations. Other factors, such as the deposition of cellular debris and proteins as hemoperfusion progresses, are also thought to influence the efficiency of drug removal.

A haemoperfusion column containing activated charcoal coated with cellulose acetate was used to treat 7 patients with barbiturate or ethchlorvynol poisoning. Six of the patients showed marked lightening of coma and all showed a significant fall in plasma drug concentration. Plasma drug clearance and platelet loss were similar to those reported for other coated charcoal columns. Cellulose acetate-coated charcoal haemoperfusion may reduce the period of coma in severe poisoning with barbiturates and other hypnotic drugs and thus the morbidity and mortality.

A combined intravenous and oral dosage regime for mexiletine has been evaluated in volunteer subjects. Therapeutically effective plasma concentrations of the drug were achieved rapidly and maintained over a four-hour period. Side-effects were minimal and the scheme would be suitable for the anti-arrhythmic protection of patients being transported to hospital and for the treatment of patients receiving hospital or, even, domicilliary care.

The effects of thrombin and histamine on protein phosphorylation in intact cultured human umbilical vein endothelial cells (HUVEC) prelabeled with 32PO4 were investigated. Incubation of HUVEC with either thrombin or histamine, agonists known to induce rapid transient increases in intracellular calcium levels in HUVEC, caused a rapid reversible increase in the phosphorylation of a protein with a Mr = 100,000 independent of the presence of extracellular calcium. Immunological and biochemical studies demonstrated that this Mr = 100,000 protein is elongation factor 2 (EF-2), a substrate previously shown to be phosphorylated by calcium/calmodulin-dependent protein kinase III (Nairn, A. C., and Palfrey, H. C. (1987) J. Biol. Chem. 262, 17299-17303). EF-2 is crucial for protein synthesis because it catalyzes the translocation of peptidyl-tRNA on the ribosome. Phosphoamino acid analysis of the EF-2 immunoprecipitated from HUVEC revealed that all of the thrombin-stimulated phosphorylation occurred on threonine. EF-2 was also phosphorylated when HUVEC were treated with the calcium ionophore, ionomycin. Phosphorylation of EF-2 was not increased by treatment with D-Phe-Pro-Arg-chloromethyl ketone thrombin, phorbol dibutyrate, forskolin, or 8-bromo-cGMP. The transient nature of the phosphorylation of EF-2 is consistent with it having a role in mediating some of the transient effects of thrombin and histamine on endothelial cell protein synthesis and functional capabilities.

Fifteen patients who were severely poisoned with either hypnotic drugs or salicylate were treated by charcoal haemoperfusion. The device contained 100g of activated charcoal immobilised by fixation to a polyester film. Two patients showed no response and eventually died. The remainder showed marked lightening of coma and recovered uneventfully. Complications of platelet loss and, in one patient, fibrinolysis were observed, but these had no serious consequences. No significant biochemical disturbances occurred with the exception of one patient who presented with hypocalcaemia and required intravenous calcium throughout the treatment. Drug clearance values were comparable with those obtained with columns containing 300 g of acrylic polymer coated charcoal.

Cultured human umbilical vein endothelial cells (HUVEC) stimulated with thrombin are known to synthesize prostacyclin at least in part from arachidonate released by phospholipase A2, an enzyme directly activated by calcium. In this study, thrombin stimulation of Quin 2-loaded HUVEC caused rapid and dose-dependent rises in inositol trisphosphate (IP3) and cytosolic free calcium (Ca2+i) levels which preceded a similarly dose-dependent rise in prostacyclin production measured as 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) by radioimmunoassay (ED50 = 0.6-0.7 units/ml for all three effects). Thrombin induced these effects in the absence of extracellular calcium (EGTA) or in the presence of either 8-bromo-cAMP or the calmodulin inhibitor W7. Thrombin inactivated with either diisopropyl fluorophosphate or D-Phe-Pro-Arg-chloromethyl ketone was inactive. In contrast, Quin 2-loaded cultured bovine aortic endothelial cells failed to respond to thrombin, although stimulation with trypsin elevated IP3 and Ca2+i levels and increased 6-keto-PGF1 alpha production. Restimulation of HUVEC with thrombin or histamine 5 min after an initial stimulation with thrombin (2 units/ml for 5 min) failed to induce a second rise in either IP3 or Ca2+i levels or further production of 6-keto-PGF1 alpha, whereas restimulation with ionomycin in the presence or absence of extracellular calcium elevated Ca2+i levels and induced further 6-keto-PGF1 alpha production. However, if the initial stimulation with thrombin was terminated by addition of D-Phe-Pro-Arg-chloromethyl ketone within 10-60 s, restimulation with a second dose of thrombin induced second rises in both IP3 and Ca2+i levels and additional 6-keto-PGF1 alpha production that were greatest when the initial thrombin stimulus was briefest. These results are consistent with the conclusion that IP3 acts as a second messenger by which thrombin elevates Ca2+i levels and initiates prostacyclin synthesis in HUVEC and that in vivo endothelial cells may be stimulated multiple times to synthesize prostacyclin if each period of stimulation is brief.

Out of 208 cases of coma of unknown aetiology referred to the poisons unit of this hospital during 1978 for emergency toxicological investigations, 108 were found to be due to self-poisoning medical conditions, mainly neurological, accounted for coma in 90 patients; the cause was not ascertained in the remaining 10 cases. More than one preparation had been ingested by 58 (54%) of the poisoned patients, although barbiturates were the drugs most commonly encountered in the severe cases. Toxicological investigations should be considered in the differential diagnosis of coma when history, physical examination, and emergency biochemical measurements yield little diagnostic information.