[Formative Evaluation of the "MBO® Kompakt-Neurowoche" - An Intensified Work-Related Rehabilitation Program for Neurological Patients]. / Formative Evaluation der "MBO® Kompakt-Neurowoche" ­ Eine intensivierte berufsbezogene Behandlungsmaßnahme für neurologische Patienten.

Objectives: The MBO® Kompakt-Neurowoche is offered as a work-related medical rehabilitation measure (based on allocation by a physician) following a regular neurological rehabilitation program with a duration of 7 days. Program access, process, and outcomes were examined in terms of a formative evaluation. Method: Pre-post-questionnaire data from 5 data points were used: start of regular rehabilitation (T0); start of work-related rehabilitation (T1); end of work-related rehabilitation (T2); 6-months follow-up (T3); 12-months follow-up (T4). Results: N=252 patients (75% male, 48±10 years) were included. Participants report a higher work-related treatment motivation and a more positive subjective return-to-work prognosis as compared to nonparticipants (N=215). At T4, 76% are (very) satisfied with the program. Patients rate therapy elements focusing on the assessment and improvement of work-related capacity and memory as especially useful. Assistance in developing job-related alternatives should be optimized. Conclusions: Patients participating in the work-related program report both vocational problems and a high motivation to deal with these problems during rehabilitation. The program is rated as useful with regard to return to work and the management of workplace issues.

Mitoxantrone induces cell death in peripheral blood leucocytes of multiple sclerosis patients.

Mitoxantrone (MX) is a cytotoxic drug with proven clinical efficacy in active multiple sclerosis (MS). In this ex vivo study we investigated the immunological effects of MX on peripheral blood leucocytes (PBL) from MS patients. PBL were isolated from 46 patients with active MS (mean age 42 years, female : male 1.4 : 1) before and immediately after 1 h MX infusion. Isolated PBL were cultured and stimulated with phytohaemagglutinin (PHA), T cell receptor stimulating monoclonal antibody (MoAb) X35 or kept in culture medium alone. Proliferation was measured by [3H]-thymidine incorporation. MX-uptake and cell death in PBL subpopulations was analysed by flow cytometry using antibodies against cluster of differentiation (CD)-surface antigens, annexin V (AnnV) and propidium iodide (PI). MX was incorporated rapidly into PBL. After only a 1-h in vivo exposure, MX reduced proliferative responses in unstimulated and stimulated PBL (PHA: - 17%, MoAb X35: -13%). MX-exposed PBL showed an increase of AnnV+/PI+ cells (unstimulated: 12%, PHA: 15%), which was even more pronounced 2 weeks after infusion. No difference was observed between de novo MX-treated patients and those on long-term MX treatment. In T cell receptor stimulated PBL, cell death was induced preferentially in CD19-positive B cells and to a lesser extent in CD8-positive T cells. MX is incorporated rapidly in circulating PBL of MS patients and induces a pronounced suppression of proliferative responses. This suppression appears to be mediated at least partly by the induction of late apoptotic/necrotic cell death with a preferential susceptibility of B cells.

The cardioprotector dexrazoxane augments therapeutic efficacy of mitoxantrone in experimental autoimmune encephalomyelitis.

The present study investigates the immunological effects of a combination treatment of mitoxantrone and the cardioprotector dexrazoxane in experimental autoimmune encephalomyelitis (EAE). Mitoxantrone, an anthracycline-derived immunosuppressive drug has been approved recently for treatment of very active multiple sclerosis (MS). Its prolonged use is limited due to its cardiotoxic properties. Dexrazoxane (DZR (S)-(+)-1,2-bis (3,5.dioxopiperazinyl)propane, ICRF-187) is an iron III chelator which in animal models and in cancer patients reduces anthracycline and mitoxantrone induced cardiotoxicity when given immediately before these agents. We examined the immunological effects of dexrazoxane in combination with mitoxantrone in experimental autoimmune encephalomyelitis (EAE) in Lewis rats. EAE was induced by active immunization with myelin basic protein (MBP) or by adoptive transfer of MBP specific T cells (AT-EAE). The clinical course, spinal cord pathology, activity of metalloproteinases (MMP-2 and MMP-9) and T cell apoptosis were assessed. Monotherapy with DZR ameliorated slightly the course of actively induced EAE and AT-EAE. The combination of DZR and mitoxantrone was superior to mitoxantrone given alone. Clinical amelioration ran in parallel with the marked reduction of inflammatory infiltration which was nearly abolished by the combination treatment. DZR did not affect the activity of metalloproteinase 9 and did not increase the proportion of apoptotic lymph node cells ex vivo or T cells in situ. We conclude that in addition to its cardioprotective role, DZR augments mitoxantrone-mediated immunosuppressive effects in animal models of human central nervous system (CNS) autoimmune disease. Clinical trials in MS patients are warranted to evaluate the unexpected immunosuppressive efficacy of DZR as add-on treatment.

[DRGs as future reimbursement system for hospital services exemplified by multiple sclerosis]. / Die DRGs als zukünftiges Abrechnungssystem der Krankenhausleistungen am Beispiel der Multiplen Sklerose.

Introducing the Diagnosis Related Groups (DRG) system into the German public health sector will prompt important changes for in- and outpatient care. Especially admission to hospital, extent of diagnostic and therapeutic procedures, and duration of hospitalisation might be affected. Taking multiple sclerosis, the most frequent inflammatory disease of the nervous system for Europe, with yearly treatment costs of about 2.3 billion Euro in Germany as example, the effect on reimbursement of complete documentation of the medical output is illustrated. Extensive information on clinically relevant items is given. The possible role of the DRG system as a cost- and quality-controlling tool in the German public health system as well as its potential risks in the absence of broadly accepted treatment guidelines is discussed.

Cardiac metabolism and function in patients with multiple sclerosis: a combined 31P-MR-spectroscopy and MRI study.

OBJECTIVE: Involvement of the autonomic system in multiple sclerosis (MS) may concur with dysfunction of the cardiovascular system. The introduction of potentially cardiotoxic immunosuppressive drugs like Mitoxantrone into the treatment of MS warrants proper assessment of preexisting heart disease. However, systematic analyses of functional and metabolic derangements in MS are missing. Using quantitative 31P-MR-spectroscopy (MRS) and MR-imaging (MRI) metabolic and functional parameters were analyzed in patients with MS in comparison to healthy volunteers. SUBJECTS/METHODS: 14/15 patients with MS could be included in the study, as the MRS examination of one patient had to be excluded from analysis due to movement during the examination. Using chemical shift imaging (CSI) and AMARES, phosphocreatine (PCr) to adenosine triphosphate (ATP) ratios, characterizing myocardial high-energy phosphate metabolism, were determined. Additionally, absolute concentrations of PCr and ATP were calculated by SLOOP (Spatial Localization with Optimal Pointspread Function). Analysis of functional changes was performed by Cine-MRI. 14 healthy volunteers matched for age and gender served as control. RESULTS: A significant decrease of absolute PCr concentration was observed in patients with MS compared to matched volunteers (p < 0.05), whereas ATP concentrations showed no significant changes (p = 0.27). Metabolite ratios calculated by SLOOP or AMARES showed a tendency to be reduced in patients, however, did not reach significance (p = 0.08, SLOOP; p = 0.47, AMARES). Using volunteers' mean values +/- 2 x SD as cut off value revealed PCr changes in 5 of 14 patients, whereas only 2 also had pathologic PCr/ATP ratios. Functional analysis by MRI depicted depressed left ventricular ejection fraction in 4 patients. CONCLUSIONS: The reduction in cardiac high-energy phosphates in some patients with MS points to a subclinical involvement of the heart. This may be important for treatment with potentially cardiotoxic drugs. Longitudinal studies are need to understand the clinical relevance of our findings.

Heterogeneity of T-cell receptor usage in experimental autoimmune neuritis in the Lewis rat.

In experimental autoimmune neuritis (EAN), T-cell receptor (TCR) variable (V)-region gene usage by neuritogenic T cells has been reported to be clonally restricted at the RNA level. This study was designed to verify TCR usage by neuritogenic T cells at the protein level. We generated two monoclonal antibodies (mAbs) 7H4 and 8G8 specific for a Vbeta4/Valpha11 associated idiotype expressed by the majority of neuritogenic cells of P2-specific T-cell lines. The remaining neuritogenic P2-specific T cells either exhibited a dominant usage of the TCR Vbeta13 chain recognized by the recently generated mAbs 17D5 and 18B1 or showed diverse Vbeta usage. Treatment of adoptive-transfer (AT)-EAN or of EAN actively induced with the neuritogenic P2 peptide by mAbs 7H4 and 8G8 led to a partial, but significant, reduction of clinical disease. Treatment with Vbeta13-specific mAb 17D5 had no clear effect on active EAN. Our data show that at least three different TCR are used by P2-specific pathogenic T cells in EAN, an animal model for human inflammatory neuropathies.

[Current diagnosis in muscular dystrophies. New developments, methods of examination and case examples]. / Aktuelle Diagnostik bei Muskeldystrophien. Neue Entwicklungen, Untersuchungsmethoden und Fallbeispiele.

Recent progress in the field of molecular genetics revealed a broader spectrum of dystrophin-related disorders than previously assumed. In addition, the pathogenetic basis of other types of muscular dystrophies could be identified: some autosomal-recessive limb girdle dystrophies are caused by mutations of sarcoglycan genes, others are caused by deficiency of the sarcoplasmatic enzyme calpain-3. Emery-Dreifuss muscular dystrophy is due to the deficiency of the nuclear membrane protein emerin. About 50% of congenital muscular dystrophies are related to mutations of a extracellular matrix protein merosin (alpha-laminin). A series of monoclonal antibodies for immunohistochemistry is now available recognizing many cytoskeletal muscle proteins. In combination with molecular genetics a diagnostic flow chart can be developed which allows a definite diagnosis in most cases. In this review disease entities are illustrated by case reports. We discuss the significance of immunohistochemical and molecular methods for diagnosis.

T-cell receptor V beta-element expression in peripheral nerves of Lewis rats suffering from experimental autoimmune neuritis.

In experimental autoimmune neuritis (EAN), peripheral nerves are infiltrated by T-lymphocytes and macrophages. By RT-PCR and sequence analysis we characterized TCR V beta-element usage in sciatic nerve tissue of Lewis rats suffering from EAN induced by immunization with peripheral myelin antigens. Several TCR V beta-chain sequences were detected, which did not show homology to sequences of P2-reactive T cells published so far. In EAN induced with peripheral nerve myelin, but not with P2-protein or P2 peptide aa 53-78, TCR V beta 8.2 sequences identical to sequences of encephalitogenic myelin basic protein (MBP) reactive T-cells were identified. These results provide further evidence for a contribution of MBP-directed T-cell reactivity to the pathogenesis of myelin induced EAN and may have implications for the pathogenesis of human demyelinating neuropathies.

[Physical trauma and multiple sclerosis]. / Physikalisches Trauma und multiple Sklerose.

Without a more detailed knowledge of etiology and pathogenesis of multiple sclerosis final conclusions regarding an association between physical trauma and the onset or course of multiple sclerosis cannot be drawn. Only a few prospective studies which are appropriately designed to prove a putative correlation have been published. A critical review of these studies and some case reports, in the light of the current pathophysiological concepts of multiple sclerosis, does not indicate a causal relationship between physical trauma and onset of multiple sclerosis or exacerbations.

Sclerosis of the skin in the GEMSS syndrome. An overproduction of normal collagen.

BACKGROUND: We describe a recently observed set of autosomal dominant GEMSS (glaucoma, lens ectopia, microspherophakia, stiffness of the joints, and shortness) syndrome in a 47-year-old woman and her 23-year-old son. In addition, sclerosis of the skin, from which both patients suffered, is investigated in detail. OBSERVATIONS: The histologic examination of skin biopsy specimens obtained from the upper aspects of the backs of both patients revealed a markedly thickened dermis. Immunohistochemical examination of the dermal collagen bundles showed a collagen pattern similar to systemic sclerosis and normal control skin. In situ hybridization showed a markedly enhanced gene expression of transforming growth factor beta 1. CONCLUSION: The sclerotic skin changes in GEMSS syndrome are the result of an abnormally increased production of normal collagen that might be attributable to the enhanced in situ production of transforming growth factor beta 1.

Melanoma-inhibiting activity inhibits cell proliferation by prolongation of the S-phase and arrest of cells in the G2 compartment.

Autocrine-secreted melanoma tumor growth-inhibiting activity (MIA, approximately Mr 8000) was isolated from supernatants of a malignant melanoma cell line HTZ-19 dM, established from a central nervous system-melanoma metastasis. Cell cycle kinetic analysis performed with bromodeoxyuridine/Hoechst flow cytometry revealed a MIA-sensitive period at the G0/G1 to S traverse; MIA mediated prolongation of the S-phase and increased arrest of cells in the G2 compartment. Growth inhibition by MIA is cell-density dependent; maximal effect is seen at low densities, and the effect may be partially antagonized by whole serum. MIA may cause growth stimulation at high cell densities and low MIA concentrations. The effect of MIA on different histological neuroectodermal cell types was compared by the same methodology: proliferation of a second malignant melanoma was inhibited, and no effect was observed with an ependymoma; 2 glioblastomas were slightly stimulated. Effects on human fibroblast-like cell strains were inconsistent. The mechanism of MIA is discussed in relation to other endogenous autocrine growth inhibitors.