[Stem cell transplantation for multiple sclerosis. Hamburg experiences and state of international research]. / Stammzelltransplantation bei Multipler Sklerose. Hamburger Erfahrungen und internationaler Forschungsstand.

BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) is still not the standard treatment for highly inflammatory multiple sclerosis (MS). Even though randomized controlled trials are lacking, predictors for treatment response have been established. Since 2007, ten patients have received aHSCT in Hamburg. OBJECTIVE: To present observational data from patients treated in Hamburg and a review of the literature. METHODS: Descriptive statistics were used for evaluating the course of the expanded disability status scale (EDSS) as a measure for clinical outcome, magnetic resonance imaging (MRI) and neuropsychology. New gadolinium and T2-MRI uptake lesions per scan were compared. In addition, a systematic review of the currently available literature was performed. RESULTS: The Hamburg series can be divided in two groups, one group including four patients with chronic progressive MS with low inflammatory activity (median EDSS = 6.25, 0.5 relapses per year, no gadolinium-enhancing lesions) and the other group including six patients with mild to moderate disability, relapses and inflammatory activity (median EDSS = 4.25, 1 relapse per year, 2 gadolinium-enhancing lesions). The median follow-up was 2.4 years. While the first group did not seem to benefit from aHSCT, an improvement in five out of six patients was observed in the second group. New T2 lesions occurred within the first 6 months but gadolinium-enhancing lesions were not observed (p < 0.05). A systematic literature search identified a higher efficacy of aHSCT in younger, less disabled MS patients with inflammatory activity, similar to the findings from Hamburg. CONCLUSION: Cohort reports describe aHSCT as a safe and efficient treatment option in highly inflammatory MS. Based on these data aHSCT seems to be a reasonable option in selected patients with highly inflammatory MS but a randomized controlled trial is warranted.

[Autoimmune synaptic encephalopathies]. / Autoimmune synaptische Enzephalopathien.

Antibody-associated limbic encephalitis was usually seen as a paraneoplastic syndrome where the antibodies would target intracellular proteins. However, recent reports challenged this idea and described antibodies that target synaptic proteins expressed on the cell surface. These antibodies are not necessarily linked to tumors and should be regarded as a distinct entity of different autoimmune diseases. They are of direct clinical relevance since their binding to their target antigen is likely the cause of the clinical symptoms and, therefore, immune treatment often results in a beneficial outcome. Tests which differentiate these antibodies are now available in specialized laboratories.

Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction.

Clonal composition and T cell receptor (TCR) repertoire of CD4(+) and CD8(+) T cells infiltrating actively demyelinating multiple sclerosis (MS) lesions were determined with unprecedented resolution at the level of single cells. Individual CD4(+) or CD8(+) T cells were isolated from frozen sections of lesional tissue by micromanipulation and subjected to single target amplification of TCR-beta gene rearrangements. This strategy allows the assignment of a TCR variable region (V region) sequence to the particular T cell from which it was amplified. Sequence analysis revealed that in both cases investigated, the majority of CD8(+) T cells belonged to few clones. One of these clones accounted for 35% of CD8(+) T cells in case 1. V region sequence comparison revealed signs of selection for common peptide specificities for some of the CD8(+) T cells in case 1. In both cases, the CD4(+) T cell population was more heterogeneous. Most CD4(+) and CD8(+) clones were represented in perivascular infiltrates as well as among parenchymal T cells. In case 2, two of the CD8(+) clones identified in brain tissue were also detected in peripheral blood. Investigation of the antigenic specificities of expanded clones may help to elucidate their functional properties.

Factor H and disease: a complement regulator affects vital body functions.

Factor H is a multidomain and multifunctional protein. As a complement regulator factor H determines the fate of newly formed C3b and controls formation and stability of C3 convertases both in the fluid phase and on cell surfaces. In addition, this plasma protein displays functions outside complement control as it has been suggested to act as an adhesion protein, to be a ligand for the cellular integrin receptor CR3 (CD11b/CD18) and to display chemotactic activity. Genetic and pathophysiological analyses describe a role for factor H in vital body functions. Depletion or the absence of factor H due to genetic reasons leads to unrestricted C3 consumption. A reduced amount of factor H in plasma or mutations within the factor H gene may lead to glomerulonephritis (type II MPGN) or hemolytic uremic syndrome (HUS). Certain pathogenic organisms have been shown to evade complement attack by binding factor H from the host. Such specific factor H binding components have been demonstrated on the surface of microbes, e.g., Streptococcus pyogenes and Neisseria gonorrhoeae. Here, we summarize the current knowledge how abnormalities in function of the central complement regulator factor H are associated with human diseases.

FHL-1/reconectin and factor H: two human complement regulators which are encoded by the same gene are differently expressed and regulated.

FHL-1/reconectin and factor H are two human complement regulators which are encoded by a single gene. FHL-1/reconectin contains the first 7 of 20 SCR protein domains of factor H and has four unique residues attached to its C-terminal end. The overlapping region of 445 amino acids explains the related complement regulatory functions of the two proteins. However, unique biological functions have also been reported for FHL-1/reconectin, such as cell adhesion and binding to microbial surfaces. Both proteins are synthesised and secreted by the liver. Extrahepatic synthesis occurs in a wide variety of cells, e.g. in monocytes, fibroblasts or neuronal cells. Unexpectedly, FHL-1/reconectin and factor H exhibit distinct expression patterns. This is also observed in disease situations such as in rheumatoid arthritis or malignancies. In rheumatoid arthritis a potentially protective role is suggested by the local synthesis of both FHL-1/reconectin and factor H in synovial fibroblasts and their induction by the anti-inflammatory agent dexamethasone and the cytokine IFN-gamma, but not by TNF-alpha. FHL-1/reconectin is overexpressed in certain tumor cells such as glioblastoma, conferring an exceptional resistance to such cells against complement mediated lysis. Although FHL-1/reconectin and factor H are encoded by a single gene, regulated by the same gene promoter and initiate transcription at the same start site, their transcripts are differently regulated. The putative control levels, which are responsible for this complex regulation, include transcript elongation, RNA processing, alternative splicing and differential poly(A) site selection.

A Drosophila derailed homolog, doughnut, expressed in invaginating cells during embryogenesis.

Members of the RYK family of receptors are homologous to tyrosine kinases but do not exhibit kinase activity in vitro. We describe a new member of this family in Drosophila, which we call Doughnut (DNT). The protein product was found to be 70% identical to the Drosophila Derailed (DRL) protein and 35-40% identical to the mammalian RYK proteins. During Drosophila embryogenesis, DNT was found to be expressed in a highly dynamic pattern, including many invaginating cells. Many aspects of the expression pattern resembled that of unpaired, a gene that encodes a secreted protein that stimulates the Drosophila JAK/STAT signaling pathway. RYK proteins contain amino acid substitutions at residues that are highly conserved amongst proteins that exhibit kinase activity. Therefore, it has been unclear whether RYK family members are catalytically active or, if they are not, how they might transduce a signal. When expressed in cell culture DNT became phosphorylated on tyrosine, as did a mutant form of the receptor, containing an arginine residue in place of lysine within the predicted nucleotide binding site. These results suggest that DNT associates with a catalytically active kinase, but may not be capable of autophosphorylation.

Significant reduction of cytomegalovirus (CMV) disease by prophylaxis with CMV hyperimmune globulin plus oral acyclovir.

The effect of prophylactic intravenous administration of a cytomegalovirus (CMV) hyperimmune globulin with a high titer of neutralizing antibodies plus oral acyclovir was studied in 93 consecutive bone marrow transplant recipients. In spite of receiving blood products unscreened for CMV only six patients developed CMV infections during the time they received passive immunization. Five patients reactivated virus after hyperimmune globulin infusions were stopped; four of them suffered from chronic graft-versus-host disease (GVHD) Among the patients suffering from acute GVHD grade III/IV and/or chronic GVHD the incidence of CMV infection (10/38) was significantly higher than among those with no or milder forms of GVHD (1/55) (p less than 0.01). Only three patients suffered from symptomatic CMV infections; two with gastrointestinal manifestations and one with fatal CMV pneumonia. Thus CMV prophylaxis as used here proved highly effective in combating one of the major difficulties encountered in BMT.

Dimensions of hostility and cardiovascular response to interpersonal stress.

Emerging research suggests that hostility is a multidimensional construct with different dimensions conferring different cardiovascular disease risk. This study examined two dimensions of hostility, expressive and neurotic, and their hemodynamic response patterns upon exposure to interpersonal stress. Fifty-seven male undergraduates were categorized into high and low expressive hostility (HiEH, LoEH) and high and low neurotic hostility (HiNH, LoNH) groups based on their Buss-Durkee Hostility Inventory scores. Subjects engaged in a mathematical subtraction task, with half of the subjects harassed through anger-provoking statements. Separate analyses were conducted for the expressive and neurotic hostility groupings. For expressive hostility, results indicated that HiEH/harassed subjects exhibited greater systolic blood pressure, heart rate, and cardiac output responses than did HiEH/nonharassed subjects or LoEH subjects irrespective of harassment. Neurotic hostility analyses revealed elevated forearm blood flow in HiNH/harassed subjects as compared to HiNH/nonharassed subjects or LoNH subjects in either harassment condition. The hemodynamic response pattern of expressive hostiles is consistent with their risk for heart disease. The response pattern of neurotic hostiles may indicate risk for hypertension, though this remains to be established.

Parental history of hypertension and hostility moderate cardiovascular responses to interpersonal conflict.

A parental history of hypertension has been implicated in the development of hypertension, perhaps by virtue of an elevated cardiovascular response to stress. Similarly, hostility has been hypothesized to be linked to cardiovascular disease through cardiovascular hyperreactivity. The interaction of parental history and hostility in moderating cardiovascular response has been infrequently examined, though research suggests the two may be linked through familial factors. The present study examined the cardiovascular response of 98 healthy young adult males categorized as offspring of hypertensive subjects (PH+) or offspring of normotensive subjects (PH-) and as high or low hostile, based on Cook-Medley Hostility scores (HiHo vs. LoHo). Subjects were exposed to either an harassment or non-harassment stressor. Results indicated elevated cardiac output and forearm blood flow responses in PH+/HiHo subjects who were harassed as compared to any other harassed subject and all non-harassed individuals. This hemodynamic response pattern of elevated blood flow suggests a mechanism of hypertensive disease development.

Subacute encephalopathy with seizures in chronic alcoholism (SESA syndrome).

Report of a case of SESA syndrome: a rare CNS complication of chronic alcoholism, known since 1981 and characterized by epileptic seizures, multiple and reversible neurological deficits, as well as PLEDs in the EEG. The MRI showed enhanced occipital signals in the T2-weighted sequence, which resolved together with the clinical findings.

Linewidth reduction in a large-smile laser diode array.

We present theory and simulations for a spectral narrowing scheme for laser diode arrays (LDAs) that employs optical feedback from a diffraction grating. We calculate the effect of the so-called smile of the LDA and show that it is possible to reduce the effect by using a cylindrical lens set at an angle to the beam. The scheme is implemented on a 19-element LDA with smile of 7.6 microm and yields frequency narrowing from a free-running width of 2 to 0.15 nm. The experimental results are in good agreement with the theory.

[Changes in the form of perigraft reaction]. / Formenwandel der Perigraft-Reaktion.

Perigraft-reaction is characterized by a late fluid accumulation around a graft. As a rule bacterial contamination is missed. The fluid has the same characteristics as blood serum. An aggressive surgical approach is necessary. The cyst wall must be excized and the prosthesis has to be replaced by a different synthetic material. In these cases a healing can be expected in more than 90%. By using the same material after resection of the cyst wall is followed by a recurrence rate of 79%.

Parental history of hypertension, sodium loading, and cardiovascular response to stress.

Parental history of hypertension, dietary sodium, and psychological stress have all been implicated in the development of essential hypertension and may interact in elevating disease risk. The mechanism by which this might occur is unclear, but it may be related to changes in the peripheral vasculature. The present study examined the effects of parental history and sodium on cardiovascular responses to an extended stressor. Eighteen normotensive offspring of hypertensives and 18 offspring of normotensives were exposed to a 1-hour shock-avoidance video-game procedure after 14 days of sodium loading (10 1-g tablets/day) and again after 14 days of placebo tablets. Order of sessions was counterbalanced between subjects in a double-blind design. In offspring of hypertensives, sodium loading elevated total peripheral resistance and norepinephrine responses to stress relative to placebo conditions and compared with offspring of normotensives. These increases were accompanied by decreases in stroke volume and cardiac output, which may explain the absence of familial differences in blood pressure responses to stress and sodium. Sodium loading had no effect on offspring of normotensives. The elevated resistance in offspring of hypertensives may suggest the initiation of pathological processes. The absence of sodium effects on resting values indicates the importance of research under conditions of stress.

The innate immune response in the central nervous system and its role in glioma immune surveillance.

The innate immune system encompasses natural killer (NK) cells, macrophages and granulocytes, the complement system and antimicrobial peptides. Recognition pathways of the innate immune system include microbial non-self recognition, missing-self recognition and induced- self recognition. The central nervous system (CNS) participates in responses of the innate immune system. However, immune inhibitory and anti-inflammatory mechanisms physiologically outbalance and counteract immune activity and thereby limit immune-mediated tissue damage in the brain. Human gliomas appear to take advantage of this immunosuppressive milieu. Moreover, glioma cells themselves interfere with anti-tumor immune responses by expressing immune inhibitory cell surface molecules, such as HLA-G, or by releasing soluble immunosuppressants such as transforming growth factor (TGF)-beta. Yet, although glioma cells exhibit all cellular features of malignancy, these tumors very rarely metastasize outside the brain, raising the possibility of immune-mediated control of these cells outside, but not inside, the brain. Accordingly, activating the innate immune system by forcing glioma cells to express danger signals such as NKG2D ligands is a promising strategy of immunotherapy for these tumors.