Vanishing of Massey products and Brauer groups

Let p be a prime number and F a field containing a root of unity of order p. We relate recent results on vanishing of triple Massey products in the mod-p Galois cohomology of F, due to Hopkins, Wickelgren, Minac, and Tan, to classical results in the theory of central simple algebras. For global fields, we prove a stronger form of the vanishing property.Comment: Added more references. Section 5 revised. To appear in the Canadian Mathematical Bulleti

Anti-TNF-Alpha Therapy Enhances the Effects of Enzyme Replacement Therapy in Rats with Mucopolysaccharidosis Type VI

Although enzyme replacement therapy (ERT) is available for several lysosomal storage disorders, the benefit of this treatment to the skeletal system is very limited. Our previous work has shown the importance of the Toll-like receptor 4/TNF-alpha inflammatory pathway in the skeletal pathology of the mucopolysaccharidoses (MPS), and we therefore undertook a study to examine the additive benefit of combining anti-TNF-alpha therapy with ERT in a rat model of MPS type VI.MPS VI rats were treated for 8 months with Naglazyme® (recombinant human N-acetyl-galactosamine-4-sulfatase), or by a combined protocol using Naglazyme® and the rat-specific anti-TNF-alpha drug, CNTO1081. Both protocols led to markedly reduced serum levels of TNF-alpha and RANKL, although only the combined treatment reduced TNF-alpha in the articular cartilage. Analysis of cultured articular chondrocytes showed that the combination therapy also restored collagen IIA1 expression, and reduced expression of the apoptotic marker, PARP. Motor activity and mobility were improved by ERT, and these were significantly enhanced by combination treatment. Tracheal deformities in the MPS VI animals were only improved by combination therapy, and there was a modest improvement in bone length. Ceramide levels in the trachea also were markedly reduced. MicroCT analysis did not demonstrate any significant positive effects on bone microarchitecture from either treatment, nor was there histological improvement in the bone growth plates.The results demonstrate that combining ERT with anti-TNF-alpha therapy improved the treatment outcome and led to significant clinical benefit. They also further validate the usefulness of TNF-alpha, RANKL and other inflammatory molecules as biomarkers for the MPS disorders. Further evaluation of this combination approach in other MPS animal models and patients is warranted

Imprinting at the SMPD1 Locus: Implications for Acid Sphingomyelinase–Deficient Niemann-Pick Disease

Acid sphingomyelinase (ASM) is the lipid hydrolase that is deficient in types A and B Niemann-Pick disease (NPD). Here, we demonstrate that the gene encoding ASM (SMPD1) is paternally imprinted and that differential expression of the mutant alleles in patients with ASM-deficient NPD and in carriers influences the disease phenotype. Comparison of the results of genomic sequencing versus reverse-transcriptase polymerase chain reaction sequencing for several patients with NPD revealed preferential expression of one mutant allele. Further analysis of one family showed that the expressed allele was maternally inherited and that the distinct clinical presentations of the individual patients were correlated with the amount of residual ASM activity expressed from the maternal mutation. Treatment of NPD cell lines with 5-aza-2′-deoxycytidine enhanced the expression of the paternal SMPD1 allele, and bisulfite genomic sequencing identified which CpG dinucleotides within the SMPD1 promoter were methylated. In a related set of studies, we identified a carrier individual who had ∼15% of normal ASM activity and clinical features of ASM-deficient NPD. DNA sequencing confirmed that this individual carried a single SMPD1 mutation and that this mutant allele was preferentially expressed. These data thus demonstrate, for the first time, imprinting at the SMPD1 gene and reveal the influence of this epigenetic modification on the presentation of ASM-deficient NPD

Mechanism of Glycosaminoglycan-Mediated Bone and Joint Disease : Implications for the Mucopolysaccharidoses and Other Connective Tissue Diseases

We have previously shown that glycosaminoglycan (GAG) storage in animal models of the mucopolysaccharidoses (MPS) leads to inflammation and apoptosis within cartilage. We have now extended these findings to synovial tissue and further explored the mechanism underlying GAG-mediated disease. Analysis of MPS rats, cats, and/or dogs revealed that MPS synovial fibroblasts and fluid displayed elevated expression of numerous inflammatory molecules, including several proteins important for lipopolysaccharide signaling (eg, Toll-like receptor 4 and lipoprotein-binding protein). The expression of tumor necrosis factor, in particular, was elevated up to 50-fold, leading to up-regulation of the osteoclast survival factor, receptor activator of nuclear factor-κB ligand, and the appearance of multinucleated osteoclast-like cells in the MPS bone marrow. Treatment of normal synovial fibroblasts with GAGs also led to production of the prosurvival lipid sphingosine-1-phosphate, resulting in enhanced cell proliferation, consistent with the hyperplastic synovial tissue observed in MPS patients. In contrast, GAG treatment of normal chondrocytes led to production of the proapoptotic lipid ceramide, confirming the enhanced cell death we had previously observed in MPS cartilage. These findings have important implications for the pathogenesis and treatment of MPS and have further defined the mechanism of GAG-stimulated disease

Bone length and microarchitecture in untreated and treated MPS VI rats.

<p>(<b>A</b>) MPS VI rats were subjected to the ERT (black) or combined ERT/anti-TNF-alpha (gray) treatment for 8 months, as described in the text (n = 8/group). The animals were euthanized 2 days after the last injection, and the femora and tibia were collected for microCT analysis. The results were compared to untreated age and gender-matched MPS VI rats (white), and the values expressed as a percentage of normal controls. ERT did not increase the length of the femora or tibia, while the combined protocol led to increases of ∼6 and 14%, respectively. Of note, the tibia and femora in the combined treatment group were on average ∼88 and 84% of normal, compared to 74 and 77% in the untreated MPS VI group. (<b>B</b>) microCT analysis of the coronal views. In untreated and treated MPS VI rats the trabecular density within the metaphyseal bone was reduced, the physeal growth plate was dysmorphic and disrupted, and the epiphyseal trabeculae were disorganized relative to the normal femora. Mild improvement from the combined treatment was detected. (<b>C</b>) microCT analysis of the mid-diaphyseal region of the femora showing axial views with subcortical trabecular infiltration into the marrow space. Although some reductions in trabecular infiltration were noted following treatment, these could not be confirmed by quantitative measures.</p

Tracheal defects in untreated and treated MPS VI rats.

<p>(<b>A</b>) Tracheas were collected from treated and untreated MPS VI and normal animals at the end of the study (37 weeks of age). As illustrated by this representative figure, untreated MPS VI rats had markedly thickened and abnormal, collapsed tracheas with narrow, flattened interior openings. These abnormalities were not altered by ERT, but were clearly improved by the combined treatment which resulted in rounded tracheas with almost statistically normalized cross sectional areas. (<b>B</b>) Immunohistochemical analysis of the tracheas showed increased expression of the pro-inflammatory and pro-apoptotic sphingolipid, ceramide, in the epithelial cells of untreated and ERT-treated animals (red), consistent with the occurrence of inflammatory disease. Tracheas from the combined treatment group showed almost normal ceramide expression.</p