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Chitin ist eines der am haufigsten vorkommenden Biopolymere der Erde. Grose Mengen dieses Rohstoffes konnen aus Schalenresten der Fischerei-Industrie gewonnen werden. Allerdings sind die etablierten chemischen Technologien mit hohen Umweltbelastungen verbunden. Die mikrobiologische Fermentation und der Einsatz von Enzymen zur Gewinnung des Polymers haben sich als wertvolle Alternative erwiesen, bei der gleichzeitig auch andere Wertstoffe gewonnen werden konnen. Allerdings ist durch die Vielfalt der benutzten Organismen und Bedingungen und die daraus folgenden unterschiedlichen Ausbeuten schwer zu beurteilen, welche Methode sich am besten zur industriellen Produktion eignet. Chitin und seine Derivate zeigen jedoch groses Potenzial als Antioxidantien, Antimikrobiotika und Bindemittel und finden bereits in der Lebensmitteltechnik, der Medizin, in der Landwirtschaft und in Konsumgutern Verwendung. Um die Innovation auf diesem Gebiet voranzutreiben, ist ein interdisziplinarer Ansatz aus Biologie und Chemie erforderlich. From crustacean to cream Chitin is one of the most abundant biopolymers on earth and can be obtained in large quantities from shell waste from the fishing industry. However, established chemical technologies are hazardous to human health and the environment due to the use of highly acidic and alkali conditions. Microbiological fermentation and the use of enzymes for the extraction of the polymer have been proven valuable alternatives which also yield other added-value compounds from this raw material. However, the variety of organisms and conditions used and the varying yields that are obtained make it difficult to evaluate and compare these methods for upscaling to industrial use. Nonetheless, chitin and its derivatives have shown great potential in their antimicrobial antioxidative and binding properties that find use in food technology and medicine as well as in agriculture and consumer goods. To drive the innovation forward in this field, an interdisciplinary approach joining biology and chemistry is required.

The use of insects as a source of protein is becoming an important factor for feeding an increasing population. After protein extraction for food use, the insect exoskeleton may offer the possibility for the production of added value products. Here, the aim was to isolate bacteria from the surface of farmed mealworms (Tenebrio molitor Linnaeus, 1758) for the production of chitinous material from insect exoskeletons using microbial fermentation. Isolates were screened for proteases and acid production that may aid deproteination and demineralisation of insects through fermentation to produce chitin. Selected isolates were used single-step (isolated bacteria only) or two-step fermentations with Lactobacillus plantarum (DSM 20174). Two-step fermentations with isolates from mealworm exoskeletons resulted in a demineralisation of 97.9 and 98.5% from deproteinated mealworm fractions. Attenuated total reflectance-Fourier- transform infrared spectroscopy analysis showed that crude chitin was produced. However, further optimisation is needed before the process can be upscaled. This is, to our knowledge, the first report using microbial fermentation for the extraction of chitin from insects.

With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated.

Erythropoietin (EPO) is used to treat anemia in neoplastic disease. EPO also exerts neuroprotective effects on neuronal cells, making a prophylactic use against the neurocognitive effects of radiochemotherapy probable. However, EPO/EPO-receptor (EPOR) signalling has been also detected in glioblastoma cells. Data collected in vitro and in vivo show conflicting results on the effect of EPO on malignant gliomas. The association between EPO and EPOR expression and the prognosis of human glioblastomas was analyzed. Probes of human glioblastomas with complete documentation of clinical course and treatment were assessed by immunohistochemistry for the expression of EPO and EPOR (n=80). Using univariate and multivariate survival analysis, the association with age, gender, radiation, chemotherapy and extent of resection was determined. High levels of EPOR were correlated with a median survival advantage of 7 months (p

The p53 family member p73 is essential for brain development, but its precise role and scope remain unclear. Global p73 deficiency determines an overt and highly penetrant brain phenotype marked by cortical hypoplasia with ensuing hydrocephalus and hippocampal dysgenesis. The ΔNp73 isoform is known to function as a prosurvival factor of mature postmitotic neurons. In this study, we define a novel essential role of p73 in the regulation of the neural stem cell compartment. In both embryonic and adult neurogenesis, p73 has a critical role in maintaining an adequate neurogenic pool by promoting self-renewal and proliferation and inhibiting premature senescence of neural stem and early progenitor cells. Thus, products of the p73 gene locus are essential maintenance factors in the central nervous system, whose broad action stretches across the entire differentiation arch from stem cells to mature postmitotic neurons.

Impaired function/differentiation of progenitor cells might provide an explanation for the limited remyelination observed in the majority of chronic multiple sclerosis lesions. Here, we establish that in the normal adult human CNS, the transcription factors Nkx2.2 and Olig2 are strongly expressed in progenitor cells while mature oligodendrocytes are characterized by low levels of Olig2 or Nkx2.2. In vitro studies confirmed the expression of Olig2 in oligodendroglial progenitor cells and mature oligodendrocytes while astrocytes, microglial cells and neurons were negative for Olig2. In early multiple sclerosis lesions, we found Olig2-positive progenitor cells throughout all lesion stages and in periplaque white matter (PPWM). The number of progenitors in PPWM was significantly increased compared with the white matter from controls. In chronic multiple sclerosis lesions progenitor cells were still present, however, in significantly lower numbers than in early multiple sclerosis lesions. A subpopulation of progenitor cells in early multiple sclerosis lesions and PPWM but not in control cases co-expressed NogoA, a marker of mature oligodendrocytes. The co-expression of these two markers suggested that these cells were maturing oligodendrocytes recently recruited from the progenitor pool. In contrast, in chronic multiple sclerosis lesions maturing progenitors were only rarely present. In summary, we provide evidence that a differentiation block of oligodendroglial progenitors is a major determinant of remyelination failure in chronic multiple sclerosis lesions.

The pathogenesis of multiple sclerosis is heterogenous and complex. Pathological changes in the brains of multiple sclerosis patients occur not only in focal lesions of the white matter. Rather, the normal-appearing white matter as well as the grey matter are included in the global inflammatory process and contribute also to the clinical findings and imaging characteristics.

ZusammenfassungIn dieser Übersichtsarbeit stellen wir die in den letzten Jahren erzielten Fortschritte im Verständnis der Multiplen Sklerose (MS) dar. Aus molekularen, pathologischen, immunologischen und tierexperimentellen Studien resultierten neue Erkenntnisse zur Pathogenese, die durch bildgebende Verfahren und klinische Studien ergänzt wurden. Schwerpunkte liegen insbesondere auf neurodegenerativen Aspekten der Erkrankung sowie auf therapierelevanten Befunden, die bereits zu einer deutlichen Verbesserung der Immuntherapie im letzten Jahrzehnt führten. Vor allem bei der schubförmig verlaufenden MS kann seit der Einführung moderner Immuntherapien in vielen Fällen die Krankheit früh stabilisiert werden. Bei der primär progredienten Verlaufsform sind unsere pathogenetischen Fortschritte leider deutlich begrenzt, vor allem auch durch den limitierten Zugang zu Gewebeproben und Fehlen adäquater Modelle. Die weitere Entwicklung neurobiologisch-protektiver Strategien soll gezielt das Überleben von Gliaund Nervenzellen fördern.

In recent years the approval of new substances has led to a substantial increase in the number of course-modifying immunotherapies available for multiple sclerosis. Therapy conversion therefore represents an increasing challenge. The treatment options sometimes show complex adverse effect profiles and necessitate a long-term and comprehensive monitoring. This article presents an overview of therapy conversion of immunotherapies for multiple sclerosis in accordance with the recommendations of the Disease-Related Competence Network for Multiple Sclerosis and the German Multiple Sclerosis Society as well as the guidelines on diagnostics and therapy for multiple sclerosis of the German Society of Neurology and the latest research results. At the present point in time it should be noted that no studies have been carried out for most of the approaches for therapy conversion given here; however, the recommendations are based on theoretical considerations and therefore correspond to recommendations at the level of expert consensus, which is currently essential for the clinical daily routine.

HIV infection affects the central nervous system (CNS), frequently causing cognitive impairment. Hippocampal injury impedes the ability to transfer information into memory. Therefore, we aimed to examine neuronal injury and repair in the hippocampal formation in HIV encephalopathy.We compared neuropathological findings in 14 autopsy cases after death from systemic complications of HIV infection and in 15 age-matched HIV-negative control cases after sudden death from nonneurological causes using immunohistochemistry.The density of apoptotic granule cells in the dentate gyrus was higher in HIV-infected than in control cases (P = 0.048). Proliferation of neural progenitor cells in the dentate gyrus was increased in HIV infection (P = 0.028), whereas the density of recently generated TUC-4 [TOAD (turned on after division)/Ulip/CRMP family 4]-expressing neurons in this region was not significantly elevated in HIV-infected cases (P = 0.13). HIV infection caused microglial activation and astrocytosis in the neocortex and hippocampal formation. Conversely, we were unable to detect more pronounced axonal injury in HIV-infected than in control cases.As in other infections involving the CNS, apoptosis of hippocampal neurons accompanied by microglial activation and astrocytosis is a prominent feature of HIV encephalopathy. The regenerative potential, assessed using the density of young neurons in the hippocampal dentate gyrus, in HIV infection appears to be lower than in acute bacterial meningitis and septic encephalitis.

The present review will focus on the current knowledge of the pathology of primary progressive multiple sclerosis lesions. Multiple sclerosis (MS) is an inflammatory demyelinating disease with a broad clinical variability. The main disease courses are relapsing-remitting, secondary progressive and primary progressive MS. Pathological studies examining the specific underlying pathology of a defined clinical subtype are rare. Here, we focus on the phatological characteristics of the MS lesions and summarize the current findings of the phatology of primary progressive MS with respect to inflammation, oligodendrocyte/myelin pathology, axon destruction and immunopathology of the lesions.

Chronic muscular limb pain requires the adoption of motor patterns distinct from the classic ipsilateral flexion, crossed extension and corresponding reciprocal inhibitions to acute exteroceptive stimulation. Using selective chemical activation of group III/IV afferents in gastrocnemius-soleus (GS) muscles we investigated bilaterally their reflex responses conditioned by (a) acute ‘myositis’ induced by intramuscular carrageenan; and (b) sub-acute ‘myositis’ induced by infusion of complete Freund's adjuvant (CFA). Reflex transmission was detected by monosynaptic testing and c-fos staining used to identify increased neuronal activity. In all control experiments with chemical stimulation of group III/IV afferents, ipsilateral responses conformed to the flexor reflex pattern. However, the expected contralateral facilitation of GS motoneurones occurred in fewer than 50% trials while only 9% of trials induced contralateral inhibition of flexor posterior-biceps-semitendinosus (PBSt) motoneurones. During carrageenan acute myositis contralateral PBSt was transiently facilitated by selective activation of group III/IV afferents. During CFA-induced myositis, contralateral only inhibition of GS motoneurones occurred instead of any facilitation, while bidirectionally a crossed facilitation of PBST dominated. These reflex changes were mirrored in an enhanced number of neurones with enhanced c-fos expression. Muscle pain, particularly if chronically persistent, requires another behavioural response pattern than acute exteroceptive pain.

Im April 1997 wurde durch die Stadtwerke Saarbrucken AG in der Saarbrucker Wohnsiedlung Nachtweide ein zukunftsweisendes Heizkraftwerk auf der Basis einer Brennstoffzelle fur die Versorgung eines Nahwarmegebiets in Betrieb genommen. Die bisherigen Betriebsergebnisse nach rund 18000 Betriebsstunden haben gezeigt, dass die Brennstofftechnologie auch bei dezentralen Nahwarmeversorgungslosungen eine Alternative zu den etablierten Erzeugungstechnologien sein kann. Insbesondere das ausgezeichnete Teillastverhalten der Brennstoffzelle im warmegefuhrten Betrieb mit elektrischen Wirkungsgraden von 38%–40% stellt einen deutlichen Vorteil gegenuber erdgasmotorischen Blockheizkraftwerken vergleichbarer Leistung dar. Von zentraler technischer und wirtschaftlicher Bedeutung ist die Frage der Zellstapellebensdauer. Die bisher gemessene gleichmasige Abnahme der Zellspannung in allen Substacks in Hohe von rund 7% korreliert mit den Ergebnissen anderer europaischer Brennstoffzellenbetreiber.

In the following case report we present a female multiple sclerosis (MS) patient in whom brain biopsy was performed due to differential diagnosis of lymphoma. An inflammatory-demyelinating CNS process was diagnosed histologically. We discuss the pathology of MS as well as the response to therapy depending on histological subtypes.

SUMMARY Dexamethasone appears to show some adverse side-effects as adjunctive anti-inflammatory agent in bacterial meningitis. For this reason, we tested the anti-inflammatory and neuroprotective effect of pentoxifylline administered 15 min before starting antibiotic treatment with ceftriaxone (n = 10) versus antibiotic therapy alone (n = 9) in the rabbit model of pneumococcal meningitis. Pentoxifylline lowered the medians of leucocyte density, tumour necrosis factor-alpha (TNF-α) and lactate in the cerebrospinal fluid (CSF), but only leucocyte migration into the subarachnoid space was significantly inhibited 8 h after initiation of therapy (P = 0.01). CSF protein, brain water content, and the entry of ceftriaxone into CSF were not influenced by pentoxifylline. The density of neuronal apoptoses in the dentate gyrus was slightly lower in animals receiving pentoxifylline than in those treated with ceftriaxone only. The median concentration of neuron-specific enolase in CSF was lower in the pentoxifylline-treated group, but the difference was not significant. In conclusion, pentoxifylline showed some anti-inflammatory activity in pneumococcal meningitis, but the substance failed significantly to reduce neuronal damage.

To determine the clinical, histopathological, and immunohistochemical ocular changes associated with a null mutation in the Norrie disease protein (NDP) gene.Tissue from a six-month-old boy with bilateral retrolental membranes and retinal detachment was obtained during vitreoretinal surgery. Histological sections were stained immunohistochemically with specific antibodies. No eye diseases with severe visual impairment or blindness were reported in the parents and their families. The NDP gene was analyzed by standard molecular genetic methods.A severe reduction in the number of retinal ganglion cells and a largely disarranged and hypoplastic inner nuclear layer were visible in the tissue specimen. Areas of the tissue with advanced pathology displayed massive fibrovascular proliferation in the vitreous cavity. Shrinkage and traction resulted in folding and detachment of the outer retina. Immunohistochemical reactivity for MIB(1) antigen demonstrated many proliferating cells in the vitreous, but no proliferative activity in the neuroretina. Retinal neurons showed a high grade of differentiation and expressed uniformly neuron-specific enolase and synaptophysin. A 1-base pair insertion (544/545insA) in the NDP gene was found in the affected boy. This mutation predicts a 'functional null-allele' due to a shift in the reading frame and, thus, a premature termination of mRNA translation after 55 instead of 133 amino acids.Loss of function of the NDP gene causes marked hypoplasia of the inner retinal cell layers and fibrovascular proliferation in the vitreous cavity, leading to retinal folding and detachment. The NDP therefore seems to play a critical role in terminal differentiation of the inner retinal cell layers and establishment and maintaining of anti-proliferative cellular interactions in the vitreous.

The differential diagnosis of lymphoid lesions in the central nervous system covers a broad spectrum of neoplastic and inflammatory disorders. Complex cases benefit from the combined expertise in the fields of hematopoietic and neuroepithelial tumors as well as neuroimmunology. The Network Lymphomas and Lymphomatoid Lesions in the Nervous System (NLLLN) recommends performing a biopsy prior to any therapeutic intervention as a precise diagnosis was impossible in approximately 50 % of patients pretreated with corticosteroids. This is based on the analysis of approximately 1,000 cases in the past 4 years. In addition to total NLLLN experiences the characteristics, pathogenesis and differential diagnosis of primary lymphoma of the central nervous system are discussed.

Background: Primary angiitis of the central nervous system (PACNS) is a rare but serious condition. A fraction of patients suffering from PACNS concurrently exhibit pronounced cerebral amyloid angiopathy (CAA) which is characterized by deposits of amyloid-β (Aβ) in and around the walls of small and medium-sized arteries of the brain. PACNS with CAA has been identified as a distinct disease entity, termed Aβ-related angiitis (ABRA). Evidence points to an immune reaction to vessel wall Aβ as the trigger of vasculitis. Objective: To investigate whether the inflammatory response to Aβ has (1) any effect on the status of immune activation in the brain parenchyma and (2) leads to clearance of Aβ from brain parenchyma. Methods: We studied immune activation and Aβ load by quantitative immunohistochemical analysis in brain parenchyma adjacent to affected vessels in 11 ABRA patients and 10 matched CAA controls. Results: ABRA patients showed significantly increased immune activation and decreased Aβ loads in the brain parenchyma adjacent to affected vessels. Conclusion: Our results are in line with the hypothesis of ABRA being the result of an excessive immune response to Aβ and show that this can lead to enhanced clearance of Aβ from the brain parenchyma by immune-mediated mechanisms.

Septic metastatic encephalitis (SME) arises from systemic bacterial infections and is a severe complication of sepsis with a high mortality. In this study, we examined the neuropathological findings in humans suffering from SME including white matter pathology and proliferation of neural precursor cells in the hippocampal dentate gyrus.The brains of 10 autopsy cases with SME and 10 control cases after sudden death from non-neurological causes were studied by means of immunohistochemistry.We found diffuse axonal injury and demyelination in the frontal cortex (P = 0.01) as well as increased numbers of recently generated TUC-4 expressing neurones in the hippocampal dentate gyrus in SME cases (P = 0.01). The median density of apoptotic granule cells in the dentate gyrus also was higher in SME cases, the difference, however, failed to reach statistical significance (P = 0.25).The coexistence of degenerative processes predominantly in the neocortex and regenerative activity in the hippocampal formation known from bacterial meningitis also characterizes the pathology of SME.

Mitoxantrone (MH(2)X), an anthraquinone-type anti-cancer agent used clinically in the treatment of human malignancies, is oxidatively activated by the peroxidase/H(2)O(2) enzyme system. In contrast to the enzymatic mechanisms of drug oxidation, the chemical transformations of MH(2)X are not well described. In this study, MH(2)X metabolites, produced by the horseradish, lacto- or lignin peroxidase (respectively HRP, LPO and LIP)/H(2)O(2) system, were investigated by steady-state spectrokinetic and HPLC-MS methods. At an equimolar mitoxantrone/H(2)O(2) ratio, the efficacy of the enzyme-catalyzed oxidation of mitoxantrone decreased in the following order: LPO HRP LIP, which accorded with the decreasing size of the substrate access channel in the enzyme panel examined. In all cases, the central drug oxidation product was the redox-active cyclic metabolite, hexahydronaphtho-[2,3-f]-quinoxaline-7,12-dione (MH(2)), previously identified in the urine of mitoxantrone-treated patients. As the reaction progressed, data gathered in this study suggests that further oxidation of the MH(2) side-chains occurred, yielding the mono- and dicarboxylic acid derivatives respectively. Based on the available data a further MH(2) derivative is proposed, in which the amino-alkyl side-chain(s) are cyclised. With increasing H(2)O(2) concentrations, these novel MH(2) derivatives were oxidised to additional metabolites, whose spectral properties and MS data indicated a stepwise destruction of the MH(2) chromophore due to an oxidative cleavage of the 9,10-anthracenedione moiety. The novel metabolites extend the known sequence of peroxidase-induced mitoxantrone metabolism, and may contribute to the cytotoxic effects of the drug in vivo. Based on the structural features of the proposed MH(2) oxidation products we elaborate on various biochemical mechanisms, which extend the understanding of mitoxantrone's pharmaceutical action and its clinical effectiveness with a particular focus on peroxidase-expressing solid tumors, such as breast carcinoma.

Bei der Multiplen Sklerose kommt es neben der gut untersuchten Demyelinisierung der weissen Substanz haufig zu einer Beteiligung der grauen Hirnsubstanz. Die Bedeutung der kortikalen Entmarkung fur den Krankheitsverlauf ist jedoch ungeklart, da ihr Nachweis der Autopsie vorbehalten ist. Gliazellen bzw. Oligodendrozyten wird eine zentrale Rolle bei der Entstehung der Cortical Spreading Depression (CSD) zugeschrieben. Wir untersuchten, ob pathologische kortikale Myelinisierung die Ausbreitungsgeschwindigkeit der CSD (vCSD) beeinflusst und vCSD somit als mogliches elektrophysiologisches Korrelat zur Messung von entmarkenden kortikalen Lasionen dienen kann. Im Rattenmodel der fokalen experimentellen autoimmunen Enzephalitis (fEAE) wurde zu unterschiedlichen Zeitpunkten (3, 8, 15 Tage) nach Induktion der kortikalen demyelinisierenden Lasion die vCSD ermittelt, indem die Laufzeit der KCl-induzierten CSD uber die Ableitung eines Elektrokortikogramms an zwei epiduralen Elektroden mit definiertem Abstand gemessen wurde. Die nicht lasionierte Hemisphare diente als interne Kontrolle. Eine zusatzliche Kontrollgruppe erhielt lediglich eine Cytokininjektion ohne vorherige Immunisierung. Fur die Zeitpunkte 3 Tage und 8 Tage nach Induktion der Entmarkung zeigte sich eine signifikante Verkurzung der Laufzeit der CSD auf der lasionierten Seite mit einer Differenz zur Kontrollseite von 9,1s±3,8 (p

In this article, recent advances in the research on pathogenesis and therapy of multiple sclerosis (MS) will be summarized. New evidence from clinical studies, imaging, histopathology and experimental models are discussed with a focus on neurodegenerative aspects and evidence from recent therapeutic studies. During the last decade, important advances in immunotherapy have been achieved, which proved especially useful for patients with relapsing remitting MS. The introduction of interferons and glatiramer acetate into MS therapy often leads to a stabilization of the disease course if administered adequately and early. The pathogenetic insights presented here may open new avenues for innovative immunomodulatory approaches and lead to an individualized MS therapy in the future. Neuroprotective treatment strategies aim at the protection of glial and neuronal cells.

Patients with severe multiple sclerosis (MS) relapses which do not respond sufficiently to corticosteroids can undergo escalating immunotherapy with plasma exchange. We review the course of 14 apheresis cycles in 13 adult patients and three pediatric cases from our center between 2004 and 2005. Nine cases were due to optic neuritis, five had experienced clinically isolated syndromes, and two suffered from Devic's disease. Of the adult patients, 71% had good or very good outcome. The mean time point of improvement was after the third plasmapheresis session, and early initiation of plasma exchange therapy (within 1 month after begin of relapse) was associated with better outcome. In pediatric MS, two of three patients showed clear improvement. These data argue for a very good therapeutic effect of plasma exchange if performed early and with adequate indication.

Multiple sclerosis (MS) is regarded a chronic inflammatory disease of the central nervous system (CNS) leading to multifocal demyelinated plaques. The pathological hallmarks of the lesions are (1) inflammation with a cellular infiltrate consisting of T cells, a few B cells and macrophages/microglia; (2) demyelination with loss of oligodendrocytes in the chronic disease stage and a variable degree of remyelination especially in the early disease course; (3) axonal damage with significant axonal loss in chronic MS plaques; and (4) gliosis with astrocyte proliferation and intensive glial fibre production [1, 2]. The majority of MS patients start with a relapsing-remitting course, in which the inflammatory-demyelinating component of the disease predominates. In the progressive disease stage, which may be either primary or secondary, an additional neurodegenerative component appears to be involved [3], leading to extensive neuroaxonal damage in the chronic MS brain [4]. Loss of axons seems to be the major determinant of the persistent neurological deficit in the progressive disease stage of MS patients [5].

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.

We report on a case of dementia and extensive cerebral white matter abnormalities seen on magnetic resonance-images which meet the criteria for leukoencephalopathy with vanishing white matter. This is an inherited condition that was first thought to occur only in children. Our patient shows that vanishing white matter should be considered in adult patients with early-onset dementia and extensive white matter changes seen on magnetic resonance images.

We describe histopathological changes in a 2-year-old boy who died from myelinopathia centralis diffusa. Despite extensive white matter destruction, surprisingly high numbers of oligodendrocytes expressing proteolipid protein mRNA were detected. In an active demyelinating lesion in the brainstem, oligodendrocytes showed typical signs of apoptosis. We suggest that death of mature oligodendrocytes is the critical event in the disease.

Traumatic brain injury is followed by increased extracellular glutamate concentration. Uptake of glutamate is mainly mediated by the glial glutamate transporters GLAST and GLT-1. Extent and distribution of GLAST and GLT-1 were studied in a rat model of controlled cortical impact injury (CCII). Western Blot analysis revealed lowest levels of GLAST and GLT-1 with a decrease by 40%-54% and 42%-49% between 24 and 72 h posttrauma. By 8 h after CCII, CSF glutamate levels were increased (10.5 microM vs. 2.56 microM in controls; P0.001), reaching maximum values by 48 h. A significant increase in de novo GLAST and GLT-1 expressing ramified microglia was observed within 4 h, reached a stable level by 48 h, and remained high up to 72 h after CCII. Furthermore, ramified microglia de novo expressed the neuronal glutamate transporter EAAC1 after CCII. Following CCII, GLAST/GLT-1 and GFAP coexpressing astrocytes were immediately reduced, reaching minimum levels within 8 h. This reduction of expression could be either due to protein downregulation or loss of astrocytes. At 72 h, a marked population of GLAST- and GLT-1-positive reactive astrocytes appeared. These results support the hypothesis that reduced astrocytic GLAST and GLT-1 protein levels following CCII contribute to evolving secondary injury. Microglia are capable of de novo expressing glutamate transporter proteins, indicating that the expression of glial and neuronal glutamate transporters is not restricted to a specific glial or neuronal lineage. Ramified microglia may play an important compensatory role in the early regulation of extracellular glutamate after CCII.

Severe tissue destruction is the presumed histopathological correlate of hypointense multiple sclerosis (MS) lesions. In this study we correlated changes of lesion hypointensity over time with initial histopathological features in 14 biopsied MS lesions. The extent of hypointensity increased in initially demyelinated plaques and decreased in remyelinating lesions. The initial axonal loss determined the increase of hypointensity over time. In conclusion, both axonal loss and demyelinating activity determine the evolution of hypointensity over time.

We report on a 10-year old previously healthy boy who exhibited a fulminant and nearly monophasic clinical course of demyelinating encephalitis with relapsing intracranial hypertension syndrome. Histologic examination of a diagnostic brain biopsy revealed an inflammatory demyelinating process with perivascular T lymphocytic infiltration and axonal damage reminiscent of multiple sclerosis-like lesions. In the brain, the DNA of human Herpes virus 6 (HHV6) was detectable. Eleven months after the initial symptoms and on maintainance with oral steroids, MRI showed demyelination of both hemispheres as well as demyelination of the brain stem and Wallerian degeneration. The boy exhibited a severe neurologic defect syndrome. The clinical and radiological course is unusual because of the asymmetric progression of the encephalitis and the extensive confluent lesions without demarcated border or enhancement of the rim after injection of gadolinium. The clinical course showed no definite steroid response. The pathogenetic relevance of HHV6 remains elusive. Although single patients with HHV6-associated encephalomyelitis have been reported, HHV6 DNA is occasionally detected in brains of healthy individuals.

Die Multiple Sklerose (MS) ist die haufigste entzundliche demyelinisierende Erkrankung des zentralen Nervensystems (ZNS). Der entmarkte Plaque ist das Hauptcharakteristikum dieser Erkrankung. Die demyelinisierten Herde sind bevorzugt im Bereich der Kleinhirnstiele, der Nervi optici, der periventrikularen weisen Substanz und im Ruckenmark lokalisiert, seltener finden sie sich in den Kerngebieten des Hirnstamms oder in der Groshirnrinde.Innerhalb der Plaques kommt es zu einer Zerstorung des Myelins und/oder der Oligodendrozyten, begleitet von einer Entzundungsreaktion (Lassmann 1998; Prineas 1985). Das entzundliche Infiltrat setzt sich hauptsachlich aus Lymphozyten und Makrophagen zusammen. Trotz dieser grundsatzlichen Gemeinsamkeiten gibt es jedoch Kriterien, anhand derer unterschiedlichehistologische Subtypen definiert werden konnen (Lucchinetti et al. 1996). In MS-Lasionen finden sich ganz unterschiedliche Veranderungen hinsichtlich der Myelin- und Oligodendrozytenschadigung. Einige Patienten weisen einen fast vollstandigen Verlust an Oligodendrozyten in den Plaques auf, bei anderen ist lediglich das Myelin zerstort. Gelegentlich kommt es auch zu einer Rekrutierung von Oligodendrozytenvorlauferzellen (Lucchinetti et al. 1999). Mit einem einheitlichen Schadigungsmechanismus lassen sich diese unterschiedlichen histopathologischen Befunde nur schwer erklaren. Vielmehr ist anzunehmen, dass verschiedene immunologische und toxische Mechanismen fur diese unterschiedlichen histologischen Muster verantwortlich sind.

Als Grundlagen der Klassifikation einer entzundlichen ZNS-Erkrankung als Multiple Sklerose (MS) dienen zum einen klinische und verlaufskinetische Parameter, zum anderen zusatzdiagnostische Befunde (Noseworthy et al. 2000). Zu letzteren gehoren charakteristische Liquorveranderungen mit intrathekaler IgG-Synthese, Latenzverzogerungen in den zentralen Leitungsstudien als neurophysiologisches Korrelat der Entmarkung und periventrikulare Marklagerherde in der Magnetresonanztomografie. Die Zusammenschau dieser Befunde lasst die Diagnose MS mehr oder weniger wahrscheinlich bzw. als sicher erscheinen, entsprechend den international anerkannten Poser-Kriterien (Poser et al. 1983). Es gibt eine ganze Reihe entzundlicher ZNS-Erkrankungen, die die oben genannten Kriterien teilweise erfullen, daruber hinaus aber charakteristische Unterschiede aufweisen. Dazu gehort die Marburg-Variante der MS und die davon abzugrenzende akute disseminierte Enzephalomyelitis (ADEM), die Neuromyelitis optica (Devic-Syndrom) und der Symptomenkomplex, der sich hinter dem Epinym der Schilder-Erkrankung verbirgt. Entsprechend der relativen Seltenheit dieser Krankheitsbilder im Vergleich zur MS ist nicht nur deren Klassifikation haufig schwierig und erfordert teils eine bioptische Abklarung, es fehlen auch grosere kontrollierte Therapiestudien. Die Behandlungsoptionen basieren deshalb haufig auf Einzelfallbeschreibungen.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Inflammation, demyelination and a variable degree of oligodendrocyte loss belong to the key features of this disorder.In MS plaques, different stages of demyelinating activity can be distinguished based on the presence of myelin proteins within the cytoplasm of macrophages, the degree of remyelination and the expression of macrophage activation antigens. Additionally, different patterns of oligodendrocyte loss and preservation can be found indicating a heterogenous pathogenesis of demyelination in MS. In the present report, we present criteria for classification of demyelinating activity as well as patterns of oligodendrocyte pathology.

The role of TNF-alpha in the course of Wallerian degeneration of the sciatic nerve was studied in control and TNF-alpha deficient mice. In control animals, the characteristic phenomena of Wallerian degeneration such as axon and myelin degeneration as well as macrophage recruitment with subsequent myelin removal were observed. In TNF-alpha deficient mice, in contrast, macrophage recruitment into the degenerating nerves was impaired resulting in a delayed myelin removal. However, the myelin phagocytic capacity of macrophages was not affected as it could be demonstrated by a similar myelin load of control and TNF-alpha deficient macrophages. These data indicate that the main function of TNF-alpha during Wallerian degeneration is the induction of macrophage recruitment from the periphery without affecting myelin damage or phagocytosis.

Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course, neuroradiological appearance of the lesions, involvement of susceptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different processes, such as autoimmunity or virus infection, may induce MS-like inflammatory demyelinating plaques and suggest that MS may be a disease with heterogeneous pathogenetic mechanisms. From a large pathology sample of MS, collected in three international centers, we selected 51 biopsies and 32 autopsies that contained actively demyelinating lesions defined by stringent criteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different patterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. At a given time point of the disease--as reflected in autopsy cases--the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this disease.

We studied quantitatively the fate of oligodendrocytes (OGs) during lesion formation in 395 lesion areas from biopsy and autopsy tissue of 113 multiple sclerosis cases. The density of OGs in multiple sclerosis lesions was variable at all stages of demyelinating activity, ranging from nearly complete loss to values exceeding those in the periplaque white matter (range 0-970 OGs/mm2) determine whether there were distinct patterns of OG pathology in different patients, we restricted our analysis to the 56 cases in which the longitudinal extent of the lesion extended from periplaque white matter into the active demyelinating edge and inactive plaque centre. Two major groups of OG pathology were defined by the presence or absence of increased OGs within the lesion. In 70% (39 out of 56) of the cases, OGs were variably reduced during active stages of myelin destruction, but reappeared within inactive or remyelinating areas. In inactive areas, an increased number of OGs expressing proteolipid protein (PLP) mRNA compared with those expressing myelin oligodendrocyte glycoprotein (MOG) suggested these cells may have been derived from the progenitor pool. In the remaining 30% (17 out of 56) of the cases, extensive destruction of myelinating cells at active sites of demyelination was observed, but OGs were absent in inactive plaque areas without remyelination. In all lesions from a given patient the pattern of OG pathology remained consistent. A highly significant negative correlation was observed between number of macrophages in lesions and number of MOG- and PLP mRNA-labelled OGs (MOG: r = -0.32, P0.0000118; PLP mRNA: r = -0.23, P0.00238). OG density did not correlate with T-cell and plasma cell inflammation, or axonal loss. The profound heterogeneity in extent and topography of OG destruction in active demyelinating lesions suggests that in subsets of multiple sclerosis patients, myelin, mature OGs and possibly OG progenitors are differentially affected.

Neuronal loss is prominent in Alzheimer’s disease (AD), and its mechanisms remain unresolved. Apoptotic cell death has been implicated on the basis of studies demonstrating DNA fragmentation and an up-regulation of proapoptotic proteins in the AD brain. However, DNA fragmentation in neurons is too frequent to account for the continuous neuronal loss in a degenerative disease extending over many years. Furthermore, the typical apoptotic morphology has not been convincingly documented in AD neurons with fragmented DNA. We report the detection of the activated form of caspase-3, the central effector enzyme of the apoptotic cascade, in AD and Down’s syndrome (DS) brain using an affinity-purified antiserum. In AD and DS, single neurons with apoptotic morphology showed cytoplasmic immunoreactivity for activated caspase-3, whereas no neurons were labeled in age-matched controls. Apoptotic neurons were identified at an approximate frequency of 1 in 1100 to 5000 neurons in the cases examined. Furthermore, caspase-3 immunoreactivity was detected in granules of granulovacuolar degeneration. Our results provide direct evidence for apoptotic neuronal death in AD with a frequency compatible with the progression of neuronal degeneration in this chronic disease and identify autophagic vacuoles of granulovacuolar degeneration as possible means for the protective segregation of early apoptotic alterations in the neuronal cytoplasm.