Current evidence for treatment with nusinersen for spinal muscular atrophy : a systematic review

Recent discovery of nusinersen, an antisense oligonucleotide drug, has provided encouragement for improving treatment of spinal muscular atrophy. No therapeutic options currently exist for this autosomal recessive motor neuron disorder. Nusinersen is developed for intrathecal use and binds to a specific sequence within the survival motor neuron 2 pre-messenger RNA, modifying the splicing process to promote expression of full-length survival motor neuron protein. We performed a MEDLINE and CENTRAL search to investigate the current evidence for treatment with nusinersen in patients with spinal muscular atrophy. Four papers were withheld, including two phase-3 randomized controlled trials, one phase-2 open-label clinical trial and one phase-1 open-label clinical trial. Outcome measures concerned improvement in motor function and milestones, as well as event-free survival and survival. Results of these trials are hopeful with significant and clinically meaningful improvement due to treatment with intrathecal nusinersen in patients with early- and later-onset spinal muscular atrophy, although this does not restore age-appropriate function. Intrathecal nusinersen has acceptable safety and tolerability. Further trials regarding long-term effects and safety aspects as well as trials including broader spinal muscular atrophy and age categories are required and ongoing

Spectral Invariants of Operators of Dirac Type on Partitioned Manifolds

We review the concepts of the index of a Fredholm operator, the spectral flow of a curve of self-adjoint Fredholm operators, the Maslov index of a curve of Lagrangian subspaces in symplectic Hilbert space, and the eta invariant of operators of Dirac type on closed manifolds and manifolds with boundary. We emphasize various (occasionally overlooked) aspects of rigorous definitions and explain the quite different stability properties. Moreover, we utilize the heat equation approach in various settings and show how these topological and spectral invariants are mutually related in the study of additivity and nonadditivity properties on partitioned manifolds.Comment: 131 pages, 9 figure

Cytokines and chemokines as regulators of skeletal muscle inflammation: presenting the case of Duchenne muscular dystrophy

Duchenne muscular dystrophy is a severe inherited muscle disease that affects 1 in 3500 boys worldwide. Infiltration of skeletal muscle by inflammatory cells is an important facet of disease pathophysiology and is strongly associated with disease severity in the individual patient. In the chronic inflammation that characterizes Duchenne muscle, cytokines and chemokines are considered essential activators and recruiters of inflammatory cells. In addition, they provide potential beneficiary effects on muscle fiber damage control and tissue regeneration. In this review, current knowledge of cytokine and chemokine expression in Duchenne muscular dystrophy and its relevant animal disease models is listed, and implications for future therapeutic avenues are discussed

Dequantisation of the Dirac Monopole

Using a sheaf-theoretic extension of conventional principal bundle theory, the Dirac monopole is formulated as a spherically symmetric model free of singularities outside the origin such that the charge may assume arbitrary real values. For integral charges, the construction effectively coincides with the usual model. Spin structures and Dirac operators are also generalised by the same technique.Comment: 22 pages. Version to appear in Proc. R. Soc. London

The myokine GDF-15 is a potential biomarker for myositis and associates with the protein aggregates of sporadic inclusion body myositis.

Background: The cytokine growth differentiation factor-15 (GDF-15) has been associated with inflammatory and mitochondrial disease, warranting exploration of its expression in myositis patients. Methods: GDF-15 protein levels are evaluated in 35 idiopathic inflammatory myopathy (IIM) serum samples using enzyme-linked immunosorbent assays, comparing with levels in samples from healthy individuals and from patients with genetically confirmed hereditary muscular dystrophies and mitochondrial disorders. Muscle tissue expression of GDF-15 protein is evaluated using immunofluorescent staining and Western blotting. Results: GDF-15 protein levels are significantly higher in IIM sera (625 +/- 358 pg/ml) than in that of healthy controls (326 +/- 204 pg/ml, p = 0.01). Western blotting confirms increased GDF-15 protein levels in IIM muscle. In skeletal muscle tissue of IIM patients, GDF-15 localizes mostly to small regenerating or denervated muscle fibres. In patients diagnosed with sporadic inclusion body myositis, GDF-15 co-localizes with the characteristic protein aggregates within affected muscle fibres. Conclusions: We describe for the first time that GDF-15 is a myokine upregulated in myositis and present the cytokine as a potential diagnostic serum biomarker

Some extensions of the Einstein-Dirac equation

We considered an extension of the standard functional for the Einstein-Dirac equation where the Dirac operator is replaced by the square of the Dirac operator and a real parameter controlling the length of spinors is introduced. For one distinguished value of the parameter, the resulting Euler-Lagrange equations provide a new type of Einstein-Dirac coupling. We establish a special method for constructing global smooth solutions of a newly derived Einstein-Dirac system called the {\it CL-Einstein-Dirac equation of type II} (see Definition 3.1).Comment: 21page

Singularities of Blaschke normal maps of convex surfaces

We prove that the difference between the numbers of positive swallowtails and negative swallowtails of the Blaschke normal map for a given convex surface in affine space is equal to the Euler number of the subset where the affine shape operator has negative determinant.Comment: 5 pages Version 3; to appear in Comptes Rendus Mathematiqu