IntroductionMultipotent human mesenchymal stromal cells (MSCs) are plasticadherent cells with triangular and fibroblastoid morphologic features, which have the capacity to differentiate into osteoblasts, adipocytes, and chondrocytes. Furthermore, they express the cell-surface markers CD73, CD90, and CD105, while being negative for CD34, CD45, and human leukocyte antigen (HLA-DR). 1 Various tissues including bone marrow, fat, umbilical cord blood, or fetal tissues have been used as sources for MSCs. 2 Not only are MSCs immunoprivileged because they are poorly lysed by T cells, but they also have strong immunosuppressive effects. [3][4][5][6] Therefore, MSCs are of clinical interest for both regenerative medicine and immune suppression. MSCs have been used successfully for treatment of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. 7 In addition, data from mouse models for rheumatoid arthritis or multiple sclerosis suggest that MSCs may be effective in the treatment of autoimmune diseases. 8 In vitro studies have analyzed the immunomodulatory effects of MSCs in detail and showed that MSCs inhibit the proliferation of T cells independent of the T-cell stimulus (ie, the suppression was observed when T cells were activated by alloantigens, mitogens, or through T-cell receptor engagement by anti-CD3 in combination with anti-CD28 antibodies). [4][5][6] Moreover, the inhibition is MHC independent. 9,10 MSCs do not only inhibit T-cell proliferation directly, but also impair dendritic cell function (ie, MSCs interfere with dentritic cell [DC] differentiation, maturation, and activation), which is shown by compromised antigen presentation and altered cytokine release. [11][12][13][14] MSCs also suppress the proliferation of NK cells and modulate the functions of B cells. 2 Most studies agree in that no cell-cell contact is required for the MSC-mediated immunosuppressive effects. 15 Instead, soluble molecules are thought to mediate this inhibition. Possible candidate molecules include transforming growth factor-␤ (TGF␤), hepatocyte growth factor, 5 indoleamine-2,3-dioxygenase (IDO), 16 prostaglandin E2 (PGE2), 11,17,18 insulin-like growth factorbinding proteins, 19 heme oxygenase-1 (HO), 20 and HLA-G5. 21 Moreover, the mechanism of the suppressive effects may be species dependent, as some molecules were described to be involved in suppressive effects of mouse MSCs such as nitric oxide (NO). 22 Another novel candidate molecule recently described to be involved in suppressive effects of mouse MSCs is the MSC-derived CC chemokine ligand CCL2; the proteolytically processed form of CCL2 modulates immunoglobulin production by plasma cells and is involved in the beneficial effects of MSCs in experimental autoimmune encephalomyelitis. 23,24 However, blocking any single one of these molecules did not completely abrogate the immuno suppressive functions of MSCs, indicating that several signaling pathways are involved and some important mediators may have not been identified yet. Several a...

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Objective:To compare disease progression between different onset forms of Metachromatic Leukodystrophy (MLD) and to investigate the influence of the type of first symptoms on the natural course and dynamic of disease progression.Methods:Clinical, genetic and biochemical parameters were analyzed within a nationwide study of patients with late-infantile (LI, onset ≤ 2.5 years), early-juvenile (EJ, onset 2.6 - < 6 years), late-juvenile (LJ, onset 6 – < 16 years), and adult (onset ≥ 16 years) forms of MLD. First symptoms were categorized as motor symptoms only, cognitive symptoms only, or both.. Standardized clinical endpoints included loss of motor and language functions, as well as dysphagia/tube feeding.Results:97 Patients with MLD were enrolled. Patients with LI (n=35) and EJ (n=18) MLD exhibited similarly rapid disease progression, all starting with motor symptoms (with or without additional cognitive symptoms). In LJ (n=38) and adult-onset (n=6) patients, the course of the disease was as rapid as in the early-onset forms, when motor symptoms were present at disease onset, while patients with only cognitive symptoms at disease onset exhibited significantly milder disease progression, independent of their age at onset. A certain genotype-phenotype correlation was observed.Conclusions:In addition to age at onset, the type of first symptoms predicts the rate of disease progression in MLD. These findings are important for counselling and therapy.Classification of Evidence:This study provides Class II evidence that in patients with MLD, age at onset and the type of first symptoms predict the rate of disease progression.

The structures of bacterial communities were studied in activated sludge samples obtained from the aerobic and anaerobic zones of a wastewater treatment plant showing enhanced phosphorous removal. Samples were analyzed by in situ hybridization with oligonucleotide probes complementary to selected regions of the 16S and 23S ribosomal RNA (rRNA) characteristic for defined phylogenetic entities (genera and larger groups). The microbial community structures revealed by molecular techniques were compared with the compositions of culturable bacterial communities, obtained from the characterization of 255 isolates from tryptone-soy (TS) agar and R2A agar. These isolates were characterized by 89 physiological tests and their cellular fatty acid patterns, and identified. Culture-dependent techniques indicated the following distribution: different Aeromonas spp. (2.7-8.3% on R2A agar; 45.0-63.7% on TS agar), Acinetobacter spp. (5.4-9.0% on R2A agar; 5.0-9.1% on TS agar), Pseudomonas spp. (up to 10% on R2A agar) and Shewanella putrefaciens (up to 3.0% on R2A agar), all members of the gamma subclass of Proteobacteria, were isolated most frequently. The relatively rare isolates of the beta subclass were identified as Acidovorax spp., Alcaligenes spp., and Comamonas spp.. The Gram-positive bacteria (high DNA G+C) were assigned mainly to Arthrobacter spp., Microbacterium spp., and Mycobacterium phlei. In order to assess the in situ abundance of the most frequently isolated genus, Aeromonas, two rRNA-targeted oligonucleotide probes were developed. The two

Objective: Metachromatic leukodystrophy (MLD) is a rare metabolic disorder leading to demyelination and rapid neurologic deterioration. As therapeutic options evolve, it seems essential to understand and quantify progression of the natural disease. The aim of this study was to assess cerebral volumetric changes in children with MLD in comparison to normal controls and in relation to disease course.Method: Eighteen patients with late-infantile MLD and 42 typically developing children in the same age range (20-59 months) were analyzed in a cross-sectional study. Patients underwent detailed genetic, biochemical, electrophysiologic, and clinical characterization. Cerebral gray matter (GM) and white matter (WM) volumes were assessed by multispectral segmentation of T1-and T2-weighted MRI. In addition, the demyelinated WM (demyelination load) was automatically quantified in T2-weighted images of the patients, and analyzed in relation to the clinical course.

Background Long-term outcomes of hematopoietic stem cell transplantation (HSCT) in children with juvenile metachromatic leukodystrophy (MLD) have been investigated systematically, while short-term effects of HSCT on the course of the disease remain to be elucidated. Results In this study, the clinical course was evaluated over the first 24 months following HSCT, conducted at our center in 12 children with juvenile MLD (mean follow-up 6.75 years, range 3–13.5) and compared with 35 non-transplanted children with juvenile MLD. Motor function (GMFM-88 and GMFC-MLD), cognitive function (FSIQ), peripheral neuropathy (tibial nerve conduction velocity), and cerebral changes (MLD-MR severity score) were tested prospectively. Seven children remained neurologically stable over a long period, five exhibited rapid disease progression over the first 12 to 18 months after transplantation. In the latter, time from first gross motor symptoms to loss of independent walking was significantly shorter compared with non-transplanted patients at the same stage of disease (p < 0.02). Positive prognostic factors were good motor function (GMFM = 100%, GMFC-MLD = 0) and a low MR severity score (≤ 17) at the time of HSCT. Conclusions Our results show that if disease progression occurs, this happens early on after HSCT and proceeds faster than in non-transplanted children with juvenile MLD, indicating that HSCT may trigger disease progression.

Background Metachromatic Leukodystrophy (MLD) is a rare autosomal-recessive lysosomal storage disorder caused by mutations in the ARSA gene. While interventional trials often use untreated siblings as controls, the genotype-phenotype correlation is only partly understood, and the variability of the clinical course between siblings is unclear with some evidence for a discrepant clinical course in juvenile patients. The aim of this study was to systematically investigate the phenotypic variation in MLD siblings in comparison to the variability in a larger MLD cohort and to case reports published in literature. Results Detailed clinical information was available from 12 sibling-pairs (3 late-infantile, 9 juvenile) and 61 single patients (29 late-infantile, 32 juvenile). Variability of age at onset was similar between the siblings and randomly chosen pairs of the remaining cohort (no statistically different Euclidean distances). However, in children with juvenile MLD both the type of first symptoms and the dynamic of the disease were less variable between siblings compared to the general cohort. In late-infantile patients, type of first symptoms and dynamic of disease were similarly homogeneous between siblings and the whole MLD cohort. Thirteen published case reports of families with affected siblings with MLD are presented with similar findings. Conclusions In a systematic analysis of phenotypic variation in families with MLD, siblings with the late-infantile form showed a similar variability as unrelated pairs of children with late-infantile MLD, whereas siblings with juvenile MLD showed a more homogeneous phenotype regarding type of first symptoms and disease evolution in comparison to unrelated children with juvenile MLD, but not regarding their age at onset. These results are highly relevant with respect to the evaluation of treatment effects and for counseling of families with affected siblings.

Our findings add to the increasing list of complex lipid cHSP genes. At the same time they redefine the phenotypic spectrum of SERAC1 deficiency. It is associated not only with the severe infantile-onset 'Methylglutaconic aciduria, Deafness, Encephalopathy, Leigh-like' syndrome (MEGDEL syndrome), but also with oligosystemic juvenile-onset cHSP as part of the now unfolding deficiency spectrum.