[Community mental health approaches for avoidance of patient placement in closed psychiatric facilities-a positioning]. / Gemeindepsychiatrische Ansätze zur Vermeidung der Unterbringung in geschlossenen Heimen ­ eine Positionsbestimmung.

BACKGROUND: In many cases the placement of people with mental disorders in closed residential homes is an expression of the lack of alternative care options. In the area of tension between the need for security in the case of chronically self-endangering behavior, recurrent acute psychiatric crisis interventions and a lack of perspective to establish a permanent therapy, in many places a placement in a closed facility approved under care law is carried out. OBJECTIVE: What alternatives are there to closed institutional care in the psychiatric care system in Germany? METHODS: A trialogical discussion process was carried out in an expert panel taking the relevant literature into consideration and with the participation of organizations of those affected and their relatives. RESULTS: The community psychiatric care system in Germany is extremely heterogeneous. The fragmented sociolegal and financing systems makes cross-sectoral and continuous care planning and service provision difficult. Precisely tailored and individualized services that could prevent the persons concerned from being placed in a closed home exist in Germany only at a few locations and in the form of individual model projects. CONCLUSION: The structural and sociolegal deficits addressed require a reform of the institutional framework and a redirection of all actors involved, including the clinics. Alternative approaches to the care of people with severe mental disorders are outlined. These include the Wedding model, binding community psychiatric structures, the basic functional model and assistance services under the German Social Code IX following the revision of the Federal Participation Act.

Genetic background and 227Thorium as risk factors in biologically based models for induction of bone cancer in mice.

We explore the potential for the biologically based two-stage clonal expansion model to make statements about the influence of genetic factors on the steps in the model. We find evidence that the different susceptibility of BALB/C and CBA/Ca mice to bone cancer after (227)Thorium injection may be mostly due to different promotional responses to radiation. In BALB/C × CBA/Ca back-crossed mice, we analyzed the specific contribution of two individual loci in the carcinogenic process. This analysis suggests that the two high- or low-risk alleles are acting on promotion or on the background parameters, but not on radiation-induced initiation. Taken together with the comparison of CBA/Ca and BALB/C mice, this hints at the possibility that the two loci are candidates for modifying radiation-induced promotion.

[Characterization of ENU-mutant mice. Animal models for human diseases using morphological and molecular methods]. / Charakterisierung von ENU-Mausmutanten. Tiermodelle für menschliche Erkrankungen mittels morphologischer und molekularer Methoden.

Following sequencing of the human genome there are new challenges to decipher the knowledge concerning gene function and the role of gene interactions and pathways leading to disease. Mouse models have proven to be an ideal tool for this purpose. Point mutations induced by chemical mutagenesis by N-ethyl-N-nitrosourea (ENU) offer possibilities for the analysis of the phenotypic outcome of a single base pair exchange on the entire organism. The Munich ENU mouse mutagenesis project is part of the worldwide efforts to obtain mutations for each gene. The generation of new alleles or allelic series offers relevant insights into the relevance of single gene sections. Various mouse models for human diseases have been generated by a systematic large-scale genome-wide phenotyping screen in the last decade. This work illustrates how the implementation of the ENU mouse mutagenesis project with gene identification and parallel high-throughput screening is taking advantage of local cooperation with experienced phenotyping groups at the Helmholtz Zentrum München, leading to major advances in the functional analysis of the mammalian genome.

Bone cancer risk in mice exposed to 224Ra: protraction effects from promotion.

This paper analyzes data for the osteosarcoma incidence in life-time experiments of (224)Ra injected mice with respect to the importance of initiating and promoting action of ionizing high LET-radiation. This was done with the biologically motivated two step clonal expansion (TSCE) model of tumor induction. Experimentally derived osteosarcoma incidence in 1,194 mice following exposure to (224)Ra with different total radiation doses and different fractionation patterns were analyzed together with incidence data from 1,710 unirradiated control animals. Effects of radiation on the initiating event and on the clonal expansion rate, i.e. on promotion were found to be necessary to explain the observed patterns with this model. The data show a distinct inverse protraction effect at high doses, whereas at lower doses this effect becomes insignificant. Such a behavior is well reproduced in the proposed model: At dose rates above 6 mGy/day a longer exposure produces higher ERR per dose, while for lower rates the reverse is the case. The TSCE model permits the deduction of several kinetic parameters of a postulated two-step bone tumorigenesis process. Mean exposure rates of 0.13 mGy/day are found to double the baseline initiation rate. At rates above 100 mGy/day, the initiation rate decreases. The clonal expansion rate is doubled at 8 mGy/day, and it levels out at rates beyond 100 mGy/day.

Allelic imbalance at intragenic markers of Tbx18 is a hallmark of murine osteosarcoma.

We have recently identified a locus exhibiting a high frequency of allelic imbalance (AI) in both spontaneous human (HSA 6q14.1-15) and radiogenic murine (MMU9, 42 cM) osteosarcoma. Here we describe the fine mapping of the locus in osteosarcoma arising in (BALB/cxCBA) F(1) hybrid mice. These studies have allowed us to identify Tbx18, a member of the T-box transcriptional regulator gene family, as a candidate gene. Three intragenic Tbx18 polymorphisms were used to map the region of maximum AI to within the gene itself; 16 of 17 tumours exhibited imbalances of at least one of these markers. The highest frequency was found in exon 1, where 14 of 17 tumours were affected at a single nucleotide polymorphism at 541 nt. Two polymorphic CA repeat markers in intron 2 and intron 5 demonstrated overlapping regions of imbalance in several tumours. Both markers flanking the Tbx18 gene (D9Osm48 and D9Mit269) revealed significantly lower frequencies of imbalance and confirmed the limitation of the common interval to Tbx18. Examination of both the mouse and human annotated genomic sequences indicated Tbx18 to be the only gene within the interval. Sequence analysis of the Tbx18 coding region did not reveal any evidence of mutation. Given the haploinsufficiency phenotypes reported for other T-box genes, we speculate that AI may influence the function of Tbx18 during osteosarcomagenesis.

The genetics of radiation-induced osteosarcoma.

Individual genetic variation can influence susceptibility to the carcinogenic effects of many environmental carcinogens. In radiation-exposed populations those individuals with a greater genetically determined susceptibility would be at greater risk of developing cancer. To include this modification of risk into radiation protection schemes it is necessary to identify the genes responsible for determining individual sensitivity. Alpha-particle-induced osteosarcoma in the mouse has been adopted as a model of human radiation carcinogenesis, and genome-wide screens have been conducted for allelic imbalance and genetic linkage. These studies have revealed a series of genes involved in determining the sensitivity to radiogenic osteosarcoma formation.

Molecular mechanisms of radiation carcinogenesis and the linear, non-threshold dose response model of radiation risk estimation.

Recent research in molecular radiation carcinogenesis is reviewed with the specific aim of exploring the implications this research may have on the dose response relationship of radiation-induced cancer at low doses and low dose rates. It is concluded that the linear non-threshold dose response hypothesis may be used in radiation protection planning as a simple, convenient method to optimize procedures and regulations, but should not be mistaken as a stringent scientific conclusion directly derived from the present state of knowledge of the processes involved in radiation carcinogenesis.

Chromosomal instability in haemopoietic cells of the foetus, mother and offspring after in utero irradiation of the CBA/Ca mouse.

PURPOSE: The present study was conducted to test the susceptibility of the mouse foetus to transmit chromosomal instability to the haemopoietic stem cells of offspring after in utero X-or plutonium-239-irradiation. MATERIALS AND METHODS: Pregnant CBA/Ca-mice were injected with 80 kBq/kg 239Pu or X-irradiated with 1 Gy X-rays on days 13 or 14 of gestation. CFU-A cultures were grown from haemopoietic stem cells sampled from foetal liver and the bone marrow from the offspring and from the mother. Non-clonal, unstable chromosomal aberrations were scored in metaphases from individual stem cell colonies. RESULTS: The relative excess (RE) of unstable chromosomal aberrations in foetal liver cells irradiated with 1 Gy X-rays increased from 1.6 at day 2 up to 2.7 at day 4 after irradiation. In the bone marrow cells from the mother, this value was 1.8 (average from cells sampled at days 3 and 14 after irradiation). After injection of the pregnant mice with 235Pu, the yield of unstable chromosomal aberrations per cell was 0.14+/-0.03 (RE approximately 10) in descendants of bone marrow cells from the mother, 0.11+/-0.02 (RE = 10) in descendants of foetal liver cells and 0.16+/-0.05 (RE = 10) in descendants of bone marrow cells from the offspring. CONCLUSIONS: From the numerical analysis of non-clonal, unstable aberrations in haemopoietic cells from the foetus, the mother and the offspring after in utero irradiation, it was concluded that in utero irradiation of the CBA/Ca mouse was not more efficient in inducing chromosomal instability in the offspring than in the foetus or the mother. All three cell populations exhibited a similar degree of unstable aberrations, both in terms of the absolute numbers of non-clonal aberrations and in terms of relative excess compared with unexposed controls.

An action approach to redesigning a patient-centred unit.

Receptiveness to innovation is critical in orchestrating change and learning to use new technology in a redesigned work environment. The patient-centred unit redesign approach (PCURA) provides a guide for unit assessment in many healthcare settings. The backbone of the PCURA approach: work excitement and unit culture assessment.

Chromatin structure and cellular radiosensitivity: a comparison of two human tumour cell lines.

The role of variation in susceptibility to DNA damage induction was studied as a determinant for cellular radiosensitivity. Comparison of the radiosensitive HX142 and radioresistant RT112 cell lines previously revealed higher susceptibility to X-ray-induced DNA damage in the sensitive cell line using non-denaturing elution, but not when using alkaline unwinding. The present data also show that no difference in the amount of initial damage is seen when pulsed-field gel electrophoresis (PFGE) or comet analysis are used for DNA damage assessment. However, using the halo assay or a modified version of PFGE in which the higher DNA architecture remained partially intact, the radiosensitive cells showed steeper dose-response curves for initial DNA damage than the radioresistant cells. Analysis of the protein composition, of DNA-nucleoid structures revealed substantial differences when isolated from HX142 or RT112 cells. From our data, it is concluded that HX142 and RT112 differ in their structural organization of chromatin. As no differences in the kinetics of DNA damage rejoining were found, it is hypothesized that the same amount of lesions have a different impact in the two cell lines in that the 'presentation' of DNA damage alters the ratio of repairable to non-repairable DNA damage.

An image analysis technique for detection of radiation-induced DNA fragmentation after CHEF electrophoresis.

CHEF-electrophoresis was used as a technique to detect radiation-induced DNA breakage with special emphasis to biological relevant X-ray doses (0-10 Gy). Fluorescence detection of DNA-fragments using a sensitive image analysis system was directly compared with conventional scintillation counting of 3H-thymidine prelabelled DNA in HeLa S3 cells. It is shown that the image analysis-based fluorescence detection of fragmented DNA after ionizing radiation is as sensitive and reproducible as detection using radioactively prelabelled cells without the putative shortcomings of fluorescence detection methods described earlier (Blöcher and Kuhni 1990). Therefore, the image analysis-based detection of radiation-induced DNA fragmentation after CHEF electrophoresis seems to be the most reliable method for applications to non-cycling cells and biopsy material.

DNA structures and radiation injury.

In the present paper experimental results from radiobiological investigations of the sedimentation behaviour of damaged and restored DNA-subunits attached to the nuclear membrane have been summarized. The studies were carried out preferably with Chinese Hamster cells V79-4 irradiated with different kinds of radiation (gamma-rays, neutrons and carbon ions) using the nucleoid sedimentation technique. Single-strand breaks relax the supercoiled DNA in the subunits resulting in a decreased sedimentation velocity. Rejoining leads to a correct restoration of the structure as can be studied by means of postincubation irradiation. Double-strand breaks release DNA fragments, again leading to an increased sedimentation velocity. If the average number of the induced double-strand breaks per subunit increases to a number higher than one, the measured results suggest that the structures should not be restored completely. The results are compatible with a new repair model developed in our laboratory on the assumption that, firstly, the single DNA subunits are the sensitive target rather than the whole DNA and, secondly, the repair of DNA damage takes place independently in each subunit.