Successful treatment of gynaecological involvement of granulomatosis with polyangiitis (Wegener's granulomatosis) by rituximab.

Granulomatosis with polyangiitis, formerly called Wegener's granulomatosis, is a disease for which the treatment options are increasing, with the recent publication of several studies concerning the use of rituximab. The disease typically involves the upper airways, lungs and kidneys, but other far less frequent localisations are possible. Here, we describe a case of isolated relapse of granulomatosis with polyangiitis affecting the uterine cervix and upper vagina which dramatically responded to rituximab therapy, after failure of methotrexate treatment. This is the first documented response to rituximab of gynaecological involvement in granulomatosis with polyangiitis.

Role of the netrin system of repellent factors on synovial fibroblasts in rheumatoid arthritis and osteoarthritis.

Changes in the expression of repellent factors, i.e., Netrins and their receptors, may be responsible for the invasive behavior of the synovial tissue cells in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). This study was carried out to analyze the expression of Netrins and their receptors in synovial cells of patients with RA, OA, and control subjects without synovial inflammation. Quantitative RT-PCR was performed to measure the expression of Netrin-1, -3, -4, Neogenin, DCC, UNC5A-D. The influence of Netrin-1 on synovial fibroblasts (SF) was analyzed by determining proliferation, migration, and their ability to organize collagen. SF expressed all repellent factors of the Netrin family. When comparing SF of healthy donors to patients with RA and OA, a stronger expression of UNC5B (4 fold) and UNC5C (769 fold) in RA and OA was found, whereas expression of the other molecules revealed no significant differences. Treating the SF-cells with recombinant Netrin-1 resulted in inhibition of migration of RA- and OA-SFs whereas control cells were not affected. The stronger expression of UNC5B and UNC5C receptors might contribute to the disordered phenotype of RA- and OA-SFs. Addition of Netrin-1 reduces the migratory ability of SFs, potentially by repulsion, as seen in neuronal cells in embryonic development. Due to its function, Netrin-1 may constitute a novel target in the treatment of OA and RA.

Construction and characterization of efficient, stable and safe replication-deficient foamy virus vectors.

As serious side effects affected recent virus-mediated gene transfer studies, novel vectors with improved safety profiles are urgently needed. In the present study, replication-deficient retroviral vectors based on feline foamy virus (FFV) were constructed and analyzed. The novel FFV vectors are devoid of almost the complete env gene plus the internal promoter - accessory bel gene cassette including the gene for the viral transcriptional transactivator Bel1/Tas. In these Bel1/Tas-independent vectors, expression of the lacZ (beta-galactosidase) marker gene is directed by the heterologous, constitutively active human ubiquitin C promoter (ubi). Env-transcomplemented vectors have un-concentrated titers of more than 10(5) transducing units/ml. The vectors allow efficient transduction of a broad array of diverse target cells, which can be increased by repeated vector exposure. However, the number of lacZ marker gene expressing cells decreased slightly upon serial passages of the transduced cells. Vectors carrying a self-inactivating (SIN) deletion of the TATA box and most parts of the viral promoter were not rescued by wt FFV whereas those with the intact or a partially deleted promoter were readily reactivated. This finding indicates that the viral promoters are in fact non-functional, pointing to a highly advantageous safety profile of these new FFV-ubi-lacZ-SIN vectors.

Kinetics and characteristics of replication-competent revertants derived from self-inactivating foamy virus vectors.

In this study, self-inactivating (SIN) retroviral vectors based on feline foamy virus (FFV) were constructed and analysed. The FFV SIN vectors were devoid of the core FFV long terminal repeat promoter plus upstream sequences but contained all structural and regulatory genes. This design allowed sensitive detection of replication-competent revertants (RCRs). The FFV SIN vectors efficiently transduced the green fluorescence protein into recipient cells. However, RCRs appeared after serial passages of transduced cells. In all RCR clones analysed, parts of the heterologous cytomegalovirus immediate early promoter, originally driving expression of the FFV vector genome, were taken up to restore the deleted SIN promoter function required for replication competence. The RCRs were strongly reduced in replication capacity compared with the parental replication-competent vectors containing the FFV promoter. In all RCR genomes analysed, the uptake of the heterologous promoter was accompanied by deletion of almost the complete marker gene. Although the RCRs described in this study may not have the capacity to spread in humans and animals, they may pose a theoretical risk, for instance during transduction of haematopoietic stem cells. Thus, FV-based SIN vectors require additional genetic modifications in order to avoid RCRs.

Potential of zoonotic transmission of non-primate foamy viruses to humans.

The zoonotic introduction of an animal pathogen into the human population and the subsequent extension or alteration of its host range leading to the successful maintenance of the corresponding pathogen by human-to-human transmission pose a serious risk for world-wide health care. Such a scenario occurred for instance by the introduction of simian immunodeficiency viruses into the human population resulting in the human immunodeficiency viruses (HIV) and the subsequent AIDS pandemic or the proposed recent host range switch of the SARS coronavirus from a presently unknown animal species to humans. The occurrence of zoonotic transmissions of animal viruses to humans is a permanent threat to human health and is even increased by changes in the human lifestyle. In this review, the potential of the zoonotic transmission of bovine, feline and equine foamy retroviruses will be discussed in the light of well-documented cases of zoonotic transmissions of different simian foamy viruses to humans.

Education issues in disaster medicine: summary and action plan.

INTRODUCTION: Change must begin with education. Theme 8 explored issues that need attention in Disaster Medicine education. METHODS: Details of the methods used are provided in the introductory paper. The chairs moderated all presentations and produced a summary that was presented to an assembly of all of the delegates. The chairs then presided over a workshop that resulted in the generation of a set of action plans that then were reported to the collective group of all delegates. RESULTS: Main points developed during the presentations and discussion included: (1) formal education, (2) standardized definitions, (3) integration, (4) evaluation of programs and interventions, (5) international cooperation, (6) identifying the psychosocial consequences of disaster, (7) meaningful research, and (8) hazard, impact, risk and vulnerability analysis. DISCUSSION: Three main components of the action plans were identified as evaluation, research, and education. The action plans recommended that: (1) education on disasters should be formalized, (2) evaluation of education and interventions must be improved, and (3) meaningful research should be promulgated and published for use at multiple levels and that applied research techniques be the subject of future conferences. CONCLUSIONS: The one unanimous conclusion was that we need more and better education on the disaster phenomenon, both in its impacts and in our response to them. Such education must be increasingly evidence-based.