Search

Das sich stetig vergrosernde Spektrum von Behandlungsoptionen der Multiplen Sklerose (MS) erfordert ein spezifisches Therapie- und Risikomanagement, um das individuelle Ansprechen, aber auch potenzielle Nebenwirkungen zu erfassen. Der vorliegende Artikel stellt das neuartige computergestutzte Patientenmanagementsystem Multiple-Sklerose-Dokumentationssystem 3D (MSDS 3D) vor. MSDS 3D integriert Daten von Patienten, betreuenden Arzten und MS-Schwestern (3 Dimensionen). Es erlaubt die Dokumentation von Vorstellungsterminen (Visiten) sowie Untersuchungsbefunden uber interaktive Bildschirmoberflachen (Touchscreens). Ein spezifisches, in die aktuelle Version von MSDS 3D integriertes Modul dient der monatlichen Evaluation von Patienten unter der Therapie mit Natalizumab. Die Entwicklung einer Checkliste fur Zeichen einer progressiven multifokalen Leukenzephalopathie (PML) sowie eines Natalizumab-Fragebogens konnten dazu beitragen, diese in Fruhstadien gut therapierbare Erkrankung zeitnah zu erkennen.

In the summer of 2001, a nationwide epidemiological multiple sclerosis (MS) register was initiated under the auspices of the German MS Society (DMSG). This project aimed at collecting epidemiological data on the number of patients with MS, course of the disease, and their social situation in Germany. During the 2-year pilot phase, five MS centers with various regional differences and treatment methods participated, leading to a representative selection of patients. In December 2003, standardised data sets of 3,458 MS patients were available for evaluation. After examining the quality of the data, 3,223 sets remained for further analysis. The demographics were similar to those obtained from other epidemiological studies: 72% of the patients were female, mean age was 42.9+/-11.2 years, mean disease duration 12.6+/-8.7 years, and 64% suffered from the relapsing-remitting form of the disease. The median EDSS was 3.0, and 69% of patients had an EDSS

Das Multiple-Sklerose-Dokumentationssystem (MSDS) wurde wahrend der vergangenen 4 Jahre an der Neurologischen Universitatsklinik Dresden entwickelt. Die erste Version der Datenbankapplikation befindet sich seit 10/2000 im praktischen Einsatz. MSDS verwaltet Patientenstammdaten, Arztestammdaten, anamnestische Angaben, korperliche Untersuchungsbefunde, Ergebnisse relevanter Zusatzdiagnostik, MS-relevante Scores sowie Bioproben. Grundsatzlich erlaubt MSDS die “Online”-Dateneingabe und generiert halbautomatisch Arztberichte an alle betreuenden Haus- bzw. Facharzte. Patientenaufklarungsblatter wie auch Informationen fur Arzte sind Teil des Systems. Im Rahmen einer 3-monatigen Evaluierung wurde die erste Version von MSDS an 9 Kliniken (8 Universitatskliniken, ein Landeskrankenhaus) getestet und positiv bewertet. Anderungswunsche und Verbesserungsvorschlage nebst den eigenen praktischen Erfahrungen fanden bei der Entwicklung von MSDS 2.0 Berucksichtigung. Diese Version wird bis Ende 2001 verfugbar sein.

Die Myasthenia gravis (MG) ist eine Autoimmunerkrankung, bei der polyklonale IgG-Autoantikorper mit den postsynaptischen Acetylcholin-Rezeptoren der neuromuskularen Endplatte reagieren. Die Bildung dieser Autoantikorper nimmt nach gangigen pathogenetischen Konzepten ihren Ausgang im Thymus, so das eine kausale, Therapie in der moglichst fruhzeitigen Thymektomie besteht. Im weiteren bildet die pharmakologische Immunsuppression durch Glukokortikoide und Azathioprin, in resistenten Fallen auch durch Cyclosporin A, Methotrexat oder Cyclophosphamid eine Hauptsaule der MG-Therapie. Fur die Akutintervention bei einer myasthenen Krise scheint die intravenose Gabe von Immunglobulin G (IgG) ahnlich wirksam zu sein wie die bisher applizierte Plasmapherese oder Immunabsorption. Die vorliegende Ubersicht fast Aktuelles zu Wirkmechanismen, unerwunschten Effekten und zur praktischen Handhabung der in der Behandlung der MG eingesetzten Immunpharmaka zusammen.

Background: Analyse of factors referring to ethnical origin that indicate unequal approach as well as different care conditions for foreign-born female patients compared to German female patients in hospital. Study design and methods: A retrospective, cross-sectional study was based on the examination of 258 German and 311 non-German female patients in the Emergency Department of Gynaecology of a Berlin hospital affording maximum care. Statistical evaluation of data was performed, the data having been selected according to defined criteria (p

In order to facilitate cytokine mRNA detection in blood cells, we have developed a highly reproducible and easily performed RNA isolation method for use with whole blood. Previously frozen human whole blood samples were lysed in guanidine thiocyanate solution to isolate total RNA. After reverse transcription a PCR method was applied to detect beta-actin and cytokine mRNA expression (interleukin-(IL)2, IL4, IL10, tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma)). The presence of cDNA was confirmed by agarose gel electrophoresis and quantitated on-line using sequence-specific fluorochrome labeled internal oligonucleotide probes. This quantitative method is based on the cleavage of fluorescent dye labeled probes by the 5' --> 3' endonuclease activity of the Taq DNA polymerase during PCR and measurement of fluorescence intensity by a Sequence Detector System. The signal generated was directly proportional to the starting copy number of target molecules in the sample over 6 log concentrations and quantitative analysis of cDNA concentrations was performed in comparison to beta-actin or cytokine cDNA standards. mRNAs coding for beta-actin and TNF alpha were readily detectable in cDNAs prepared from the whole blood of eight healthy donors, while the other cytokines were expressed in lower amounts (IFN gamma, IL10) or were undetectable (IL2, IL4). The assay described is highly reproducible, requires no post PCR manipulation of the amplicons and permits the analysis of several hundred PCR reactions per day. Using this method it is possible to detect and quantify cytokine mRNA expression reliably in small amounts of previously frozen blood even after storage of samples for at least several months.

The PNS is an immunocompetent organ. The participating cellular and humoral elements in the local immune circuitry have been identified. A number of acute and chronic neuropathies appear to result from disturbed immune homeostasis. The model disorder EAN has been useful in examining the induction, amplification and effector phase of autoimmune responses to peripheral nerve antigens. Potential autoantigens contained in the myelin sheath and on the axolemma have been characterized. Thus, the recent years have seen a rapid growth of information concerning the pathogenesis of the important group of immune-mediated neuropathies. It can be anticipated that the better understanding of the principal mechanisms of autoimmunity in the PNS will aid in the development of more specific and efficacious treatments for these crippling diseases.

Synthetic peptides corresponding to the extracellular and cytoplasmic domain of bovine (b) or rat (r) peripheral myelin P 0 protein were used to establish a total of 50 short-term T cell lines (TCL) from blood of eight healthy subjects. Despite expressing different HLA-DR and HLA-DQ specificities, one or more TCL (range 1–16) specific for peptide bovine P 0 19–38 could be isolated from the blood of each donor. Therefore, this peptide covers an immunodominant T cell recognition site in humans. However, when testing seven bP 0 -19-38-specific TCL derived from blood of two healthy subjects for recognition of the corresponding human P 0 sequence, no TCL showed any proliferative response. Bovine P 0 -19-38 differs in only two amino acid residues from the human peptide. This observation stresses the necessity for using homologous antigens when screening for T cell-mediated autoreactivity to myelin antigens in humans. Unexpectedly, we failed to establish a single P 0 peptide-specific TCL from blood of four patients with acute Guillain-Barre syndrome (GBS), in which P 0 is considered a putative target autoantigen. As already suggested by others, this could indicate that T cell responses to P 0 do not play a pathogenic role in all GBS cases. Alternatively, in these four patients neuritogenic P 0 -specific T lymphocytes may have been sequestrated to peripheral nerves.

The development of easy-to-use, clinically oriented multiple sclerosis (MS) database programs has been started, thus paving the way for MS centers to computerize their patient records and to improve quality management. To evaluate the prevalence of such programs at German neurological hospitals, a questionnaire was designed and sent to all clinic directors. With a return of more than 92%, it became evident that MS databases are still being used only by a minority of 22% on a regular basis. We did not recognize the predominance of a single program. A new MS database system that is being presently implemented in Germany is described.

The increasing therapeutic options for relapsing-remitting multiple sclerosis require a specific treatment and risk management to recognize the individual response as well as potential side effects. To switch from pure MS documentation to MS management by implementing a new multiple sclerosis management and documentation tool may be of importance.This article presents the novel computer-based patient management system "multiple sclerosis management system 3D" (MSDS 3D).MSDS 3D allows documentation and visualization of visit schedules and mandatory examinations via defined study modules by integration of data input from patients, attending physicians and MS nurses. It provides forms for the documentation of patient visits as well as clinical and diagnostic findings. Information is collected via interactive touch screens. A specific module which is part of MSDS 3D's current version allows the monthly monitoring of patients under treatment with natalizumab. A checklist covering clinical signs of progressive multifocal leukoencephalopathy (PML) and a detailed questionnaire about the handling of natalizumab in practice have additionally been added.The MS patient management system MSDS 3D has successfully been implemented and is currently being evaluated in a multi-centre setting. Advanced assessment of patient data may allow improvements in clinical practice and research work. The addition of a checklist and a questionnaire into the natalizumab module may support the recognition of PML during its early, treatable course.

An acute infectious illness frequently precedes the Guillain-Barre syndrome. Recently, Campylobacter jejuni was claimed to be a predominant precipitating agent that may also trigger a humoral immune response to glycoconjugates of peripheral myelin in Guillain-Barre syndrome. Because of conflicting reports, we determined the frequency of a recent infection with C. jejuni in 38 patients with Guillain-Barre syndrome using a highly sensitive and specific immunoblot technique, and of the presence of circulating antibodies to gangliosides. We detected IgM and/or IgG C. jejuni directed antibodies in 15 of 38 patients with Guillain-Barre syndrome. In contrast, only 7 of 39 healthy control subjects, 3 of 20 patients with multiple sclerosis, and 2 of 72 patients with neuroborreliosis showed IgA or IgM antibody responses to C. jejuni. In Guillain-Barre syndrome, C. jejuni-specific antibodies were predominantly directed to outer membrane proteins of one specific serotype, Lior 11, whereas the most common serotype associated with enteritis in Germany is Lior 4. Two of 27 patients with Guillain-Barre syndrome had ganglioside-specific IgA antibodies; 1 of 32 patients, antibodies of IgM; and 4 of 31 patients, antibodies of IgG class. There was no correlation between severity, type (axonal versus demyelinating), and outcome of the disease and the presence or absence of a humoral immune response to C. jejuni or to glycoconjugates. Our findings do not support previous suggestions that a preceding C. jejuni infection heralds a poorer outcome or that antibodies to gangliosides carry prognostic significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Unter Federfuhrung der DMSG, Bundesverband e.V. wurde 2001 die Einrichtung eines flachendeckenden MS-Registers initiiert, um epidemiologische Daten zur Anzahl der an multipler Sklerose (MS) Erkrankten, deren Verlaufsformen und die Versorgungssituation in Deutschland zu gewinnen. Wahrend der zweijahrigen Pilotphase wurden in 5 Zentren 3.223 Patienten standardisiert dokumentiert (Flachenecker et al, Nervenarzt 2005;76:967-975). Im Anschluss wurde der Basisdatensatz modifiziert und neue Zentren rekrutiert.

In the summer of 2001, a nationwide epidemiological multiple sclerosis (MS) register was initiated under the auspices of the German MS Society (DMSG). This project aimed at collecting epidemiological data on the number of patients with MS, course of the disease, and their social situation in Germany. During the 2-year pilot phase, five MS centers with various regional differences and treatment methods participated, leading to a representative selection of patients. In December 2003, standardised data sets of 3,458 MS patients were available for evaluation. After examining the quality of the data, 3,223 sets remained for further analysis. The demographics were similar to those obtained from other epidemiological studies: 72% of the patients were female, mean age was 42.9+/-11.2 years, mean disease duration 12.6+/-8.7 years, and 64% suffered from the relapsing-remitting form of the disease. The median EDSS was 3.0, and 69% of patients had an EDSS/=4.0. The great effect of this disorder was underscored by the fact that one third of the patients had prematurely retired due to MS. After successful completion of the pilot phase, the MS register will provide reliable data and thus serve as an important tool to improve the overall situation of MS patients in Germany.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

The MSDS (multiple sclerosis documentation system) has been developed at the Department of Neurology, Technical University of Dresden, Germany, during the last 4 years. The first version of this database application has been in use since October 2000. The MSDS manages information on MS patients, their treating physicians, patient history (symptoms, other diseases, biographical history, family history, habits, medication), clinical signs, results of laboratory examinations (blood chemistry, autoantibodies, borrelia serology, evoked potentials, cranial and spinal cord magnetic resonance imaging), clinical scores relevant for MS, and biosamples. In principle, MSDS allows online data input and semiautomatically generates reports to all general practitioners and neurologists treating the respective patient. Patient information sheets and internal treatment guidelines are part of the system. During a 3-month evaluation, the first version of MSDS was tested at eight university multiple sclerosis ambulatory care units and one general neurology hospital. The overall judgement was favorable. Suggestions for changes and improvements, as well as practical experiences, were considered when developing MSDS 2.0, which will be available by the end of 2001.

Ti((i)OPr)(4) was treated with 2.58 equiv of hydroquinone in THF to yield a red-orange powder formulated as [Ti(OC(6)H(4)O)(a)()(OC(6)H(4)OH)(3.34)(-)(1.83)(a)()(O(i)Pr)(0.66)(-)(0.17)(a)() (THF)(0.2)](n)() (1, (0.91/= a/= 1.82)) based upon D(2)O/DCl quenching studies. Treatment of 1 with an excess of hydroquinone in Et(2)O or DME afforded burgundy [Ti(2)(mgr;(1,4)-OC(6)H(4)O)(2)(mgr;(1,4)-OC(6)H(4)OH)(2)(mgr;-OC(6)H(4)OH)(2)](infinity) (2). Burgundy [Ti(2)(mgr;(1,4)-OC(6)H(4)O)(2)(mgr;(1,4):eta(2),eta(1)-OC(6)H(4)O)(2)(OH(2))(2).(H(2)O)(2).(H-OC(6)H(4)OH).(MeCN)](infinity) (4) was prepared from 1 and excess wet hydroquinone in CH(3)CN. The acetonitrile in 4 can be exchanged for THF or DME. Treatment of Ti(O(i)Pr)(4) with approximately 4 equiv of 2,7-dihydroxynaphthalene in Et(2)O at 100 degrees C (2 days) in a sealed tube yielded orange crystals of [Ti(2)(mgr;(1,7)-OC(10)H(6)O)(2)(mgr;(1,7):eta(2),eta(1)-OC(10)H(6)OH)(2)(O(i)Pr)(2)](infinity) (5). Diffraction studies were conducted at the Cornell High Energy Synchrotron Source (CHESS) because of the small crystal sizes. 2 (C(18)H(14)O(6)Ti, monoclinic, P2(1)/n, a = 9.624 (2), b = 11.283 (2), c = 14.916 (3), beta = 90.47(3) degrees, Z = 4), 4 (C(32)H(33)NO(14)Ti(2), monoclinic, P2(1)/n, a = 16.137 (3), b = 10.762 (2), c = 20.368 (4), beta = 111.65(3) degrees, Z = 4), and 5 (C(23)H(20)O(5)Ti, orthorhombic, Pbca, a = 11.095 (2), b = 17.970 (4), c = 19.484 (4), Z = 8) are 3-dimensional materials based on diaryloxide connectivity between geometrically similar edge shared (i.e., Ti(2)(mgr;-OAr)(2)) bioctahedral dititanium building blocks. While 2 and 5 possess a roughly body-centered arrangement of dititanium units, 4 has a hexagonal secondary structural motif. The nature of crystallization through alcoholysis is also discussed.

The major neuritogenic protein of peripheral nerve myelin is the P2 protein. Human P2 is a candidate autoantigen in inflammatory demyelinating diseases of the peripheral nervous system. Since human P2 is not readily available, we produced full-length recombinant human P2 protein (rhP2) in Escherichia coli. RhP2 was recognized by neuritogenic rat T cell lines and induced experimental autoimmune neuritis in Lewis rats. Production of rhP2 allowed the generation of human T cell lines reactive to the autologous protein. Studies of human T cell autoreactivity as well as efforts to use hP2 as a tolerogen will be facilitated by the large-scale expression of rhP2.

Cyclophosphamide, an alkylating agent belonging to the family of nitrogen mustards, is commonly used to treat progressive autoimmune diseases in humans. At the molecular level, its cytotoxicity results from DNA double strand crosslinks and, at higher concentrations, from DNA strand breaks. At the cellular level, cyclophosphamide may selectively affect mature lymphocytes with relative sparing of the respective precursor cells. In this study, we show that 4-hydroxycyclophosphamide (4-OH-CP), the active metabolite of cyclophosphamide, induces apoptosis in mature human lymphocytes at concentrations that are achieved in vivo. Since cyclophosphamide requires enzymatic conversion in the liver to yield its active metabolite, 4-OH-CP was generated in vitro by non-enzymatic hydrolysis of mafosfamide. Apoptotic cell death of lymphocytes was characterized by typical morphological changes, nucleosomal DNA fragmentation, and quantified by 3′-OH end labeling of fragmented DNA. The percentage of apoptotic cells both depended on drug concentration and time of exposure. Cycloheximide or ZnSO4 did not suppress 4-OH-CP induced apoptosis. Etoposide, a topoisomerase II inhibitor known to induce apoptosis in human tumor cell lines like 4-OH-CP, did induce detectable DNA fragmentation in only a minor proportion of T-lymphocytes but suppressed T-cell proliferation.

In patients with inflammatory demyelinating neuropathy, which is possibly mediated by autoreactive, myelin-specific T lymphocytes, most studies focusing on immune responses to the major neuritogenic myelin protein P2 have been performed with bovine P2. However, the primary structure of bovine P2 differs from the human protein by nine amino acid residues that may profoundly influence the antigen recognition by T lymphocytes. We purified bovine and human P2 from peripheral nervous tissue and established a total of 19 T cell lines (TCL) reactive with bovine P2 from blood of two patients with acute Guillain-Barre syndrome (n = 5 TCL) and from six healthy individuals. Only four of these TCL, all raised from the blood of the GBS patients, transiently cross-recognized human P2 protein. Our results suggest that the use of human autoantigen may be crucial for the characterization of T cellular immune responses against P2 protein both in patients with inflammatory demyelinating neuropathy and in healthy controls.

Reversed-phase high-performance liquid chromatography was applied to isolate myelin basic protein from human brain, followed by separation of proteolytic peptides thereof on the same chromatographic system. Brain tissue was delipidated under conditions that keep copurifying proteases inactive. The crude brain protein fraction was applied directly to a C4 column. The homogeneous protein obtained in this way was digested with thrombin and endoproteinase Lys-C in order to produce short defined myelin basic protein peptides. The purified peptides were used to determine the antigen fine specificity of myelin basic protein recognizing T lymphocyte lines isolated from multiple sclerosis patients.

To analyze the antigen specificities of measles virus (MV)-reactive CD4+ T cells in multiple sclerosis (MS) patients as compared with those of healthy donors, we established 492 MV-reactive short-term T-cell lines (TCL) from blood of 12 MS patients (n = 243 TCL) and 12 healthy subjects (n = 249 TCL). We determined antigen specificities of these TCL by proliferative responses to optimal concentrations of recombinant MV structural proteins (MV-SP) and human myelin basic protein (MBP). In both donor groups, there was a dominant reactivity against the MV fusion protein and the MV nucleocapsid protein. However, there was a substantial heterogeneity of T-cellular polypeptide specificities among MS patients as well as among healthy individuals, which was true even in subjects sharing identical HLA-DR and HLA-DQ haplotypes. By comparing the T-cell antigen specificity patterns obtained in both donor populations, we found decreased percentages of TCL reactive with the MV fusion protein, the hemagglutinin, and the phosphoprotein in MS patients, but these differences failed to reach statistical significance. None of the 492 MV-specific TCL, nor an additional 276 TCL, showed any reactivity to MBP. Therefore, we did not detect any MS-specific pattern of T-cell responses to MV-SP. Furthermore, our study suggests that mechanisms other than molecular mimicry between MV-SP and MBP may cause myelin-directed autoimmunity.

There are many ways to analyse immunological self tolerance. For example, studies on the generation of T cell clonal diversity and of the regulation or elimination of self reactive T cell clones in the thymus have been invaluable for better understanding self-nonself discrimination. We have chosen an alternative approach studying autoimmunity and self tolerance by means of experimentally induced, autoimmune diseases with the aim to define the factors that have led to this aberrant situation. Identification of the defective factors may not only help us to understand the pathogenic mechanisms of clinical autoimmunity, but, by extrapolation, the same information can be expected to help us understand, why, under normal conditions, the immune system tolerates the own organism.