Genetic aberrations in gliomatosis cerebri support monoclonal tumorigenesis

Gliomatosis cerebri is a rare condition in which the brain is infiltrated by an exceptionally diffusely growing glial cell population involving at least 2 lobes, though often more extensive, sometimes even affecting infratentorial regions. The neoplastic proliferation may have a monoclonal origin, or alternatively, reflect progressive neoplastic change of an entire tissue field ("field cancerization"). The presence of an identical set of genetic aberrations throughout the lesion would point to monoclonality of the proliferation. In contrast, the finding of non-identical genetic changes in widely separated regions within the neoplasm would support the concept of field cancerization. In the present study, a unique autopsy case of gliomatosis was available to verify either one of these hypotheses. Tissue samples were randomly taken from 24 locations throughout the brain and used for genetic investigation. In all samples the histology showed an identical picture of slightly elongated astrocytic cells, typical for gliomatosis. TP53 exon 5-8 mutation analysis was performed on all samples. Genome-wide screening for chromosomal aberrations was accomplished by comparative genomic hybridization (CGH). In addition, loss of heterozygosity analysis for polymorphic markers on chromosomal regions of the 2 most frequently observed DNA deletions was carried out. The most widespread genetic aberration was mutation of exon 7 of TP53, which was detected in 20 of 24 samples. Bidirectional sequencing revealed a mutation in codon 234 (TAC234TGC), resulting in an amino acid substitution Tyr-Cys. CGH analysis revealed losses on 2q11-q31 in 13 of 24 samples and losses on 19q13-qter in 10 of 24 samples from both left and right hemispheres. Allelic imbalances for markers on 2q (2q14.3 and 2q22.1) and 19q (both 19q13.2) were demonstrated in 10 of 24 and 18 of 24 samples, respectively. Other widespread chromosomal aberrations included losses on 3q13-qter and 16q22-qter and gains on 7q22-qter. The wide distribution of a particular set of genetic aberrations in this case supports the concept of monoclonal tumor proliferation. The results point to involvement of TP53 mutation in the tumorigenesis of gliomatosis cerebri.     

Interphase cytogenetics of prostatic adenocarcinoma and precursor lesions: Analysis of 25 radical prostatectomies and 17 adjacent prostatic intraepithelial neoplasias

Twenty-five radical prostatectomy specimens were screened for the presence of numerical chromosome changes within the adenocarcinoma as well as in 17 adjacent prostatic intraepithelial neoplasias (PIN) by means of interphase in situ hybridization (ISH) to routinely processed tissue sections. To this end a defined alfoid repetitive DNA probe set was used, specific for the centromeres of chromosomes 1, 7, 8, 10, 15, and Y. The cytogenetic information was correlated with histopathological and clinical features as well as with DNA ploidy. Numerical aberrations of at least one chromosome were shown in 13 of 25 cases (52%). Alterations of chromosome 8 and loss of the Y chromosome were the most frequent findings (both 20%), followed by loss of chromosomes 15 (16%) and 10 (12%). Gain of chromosome 7 was seen in 8% of cases. No aberrations of chromosomes 7, 8, 10, and 15 were found in the adjacent PIN lesions, whereas loss of the Y chromosome in both PIN and tumor occurred in two cases. Also, (low level) aneuploidy was observed in 76% of these PIN lesions. Ploidy of the carcinomas as assessed by ISH correlated well with ploidy measured by DNA flow cytometry (FCM; P < 0.02). Due to the more specific correspondence between ISH and tumor pathology, pathologic grade correlated with ISH aneuploidy (P < 0.05), whereas FCM ploidy did not. Furthermore, genetic heterogeneity within a tumor was seen, as judged by the focal appearance of chromosomal aberrations. Chromosomal alterations occurred in all grades and stages, although loss of chromosome 10, gain of chromosome 7, and aberrations of chromosome 8 tended to predominate in more advanced cancers.     

Implementation of an innovative health service a "real-world" diffusion study

BACKGROUND: Although reporting on the healthcare-setting level of continuance or discontinuance of an intervention once a trial is completed has been recommended, such "real-world" diffusion studies are rare. The present example was made possible by funding to explore opportunities for post-trial implementation of an innovative health counseling intervention for cardiovascular prevention in The Netherlands. METHODS: Between 2001 and 2004, in a longitudinal case study, we compared two healthcare settings: a cardiology outpatient clinic and general practices. Rogers' diffusion of innovations theory served as the theoretical background. Information was extracted from minutes of meetings and informal conversations with health counselors, and checked by the project manager. Additional data were collected from physicians with a short questionnaire. RESULTS: Implementation of the health counseling intervention was successful in the cardiology outpatient clinic, but was unsuccessful in the general practices. Success was related to a centralized diffusion system, stronger "change agent" efforts, avoidance of post-trial interruption of service delivery, easily achievable "reinventions," and positive physician perceptions of the service (i.e., not complex and compatible with current practice routines). Support came from changes in the organization of care that created opportunities for, instead of competition with, the innovative service. However, coincidental events may also have played a part. CONCLUSIONS: Our findings confirm the importance of most theoretically predicted individual and organizational diffusion variables. This implies that the implementation of innovative healthcare services requires attention at both levels.     

An economic appraisal of the Australian Medical Sheepskin for the prevention of sacral pressure ulcers from a nursing home perspective

Background  

Many devices are in use to prevent pressure ulcers, but from most little is known about their effects and costs. One such preventive device is the Australian Medical Sheepskin that has been proven effective in three randomized trials. In this study the costs and savings from the use of the Australian Medical Sheepskin were investigated from the perspective of a nursing home.     

Patient organisations and the reimbursement process for medicines: an exploratory study in eight European countries

Background  

Little is known about the role European patient organisations play in the process of deciding on reimbursement for medicines. Therefore we explore the current role of patient organisations in the process of reimbursement for medicines in Western Europe. We focus in particular on collaboration between patient organisations and the pharmaceutical industry in this respect.     

Localization of dopamine receptors in the tree shrew brain using [H]-SCH23390 and [I]-epidepride

The tree shrew is a mammalian species, which is phylogenetically related to insectivores and primates. The aim of the present study was to investigate the distribution of dopamine receptor D1- and D2-like binding sites in the brain of this non-rodent, non-primate mammal. Using in vitro autoradiography and employing the radioligands [³H]-SCH23390 and [¹²⁵I]-epidepride, dopamine receptors were mapped and quantified. Significant findings with regard to the D1-like binding pattern include the presence of a “patchy” binding in the striatum. In the cortex, D1-like binding sites were observed in both the superficial and the deep layers. In the hippocampal formation, D1-like binding sites were seen primarily in the CA1 region and not in the dentate gyrus. These characteristics of the D1 pattern in the tree shrew brain are shared by cat and monkey and human brain, but not by rodent brain. Significant findings with regard to the D2-like binding pattern include the presence of D2-like binding in the claustrum. In addition, the striatum demonstrated “patchy” D2-like binding. These characteristics of the D2 pattern in the tree shrew brain are shared by cat and monkey and human brain, but not by rodent brain. On the other hand, the significant densities of D2-like binding sites in the glomerular layer of the tree shrew olfactory bulb is a finding that discriminates tree shrews from higher evolutionary species who lack such binding. Overall, the evidence coincides with the view that tree shrews are phylogenetically related to primates.