3 research outputs found
In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy
Until the recent development of disease-modifying therapeutics, spinal muscular atrophy (SMA) was considered a devastating neuromuscular disease with a poor prognosis for most affected individuals. Symptoms generally present during early childhood and manifest as muscle weakness and progressive paralysis, severely compromising the affected individual’s quality of life, independence, and lifespan. SMA is most commonly caused by the inheritance of homozygously deleted SMN1 alleles with retention of one or more copies of a paralog gene, SMN2, which inversely correlates with disease severity. The recent advent and use of genetically targeted therapies have transformed SMA into a prototype for monogenic disease treatment in the era of genetic medicine. Many SMA-affected individuals receiving these therapies achieve traditionally unobtainable motor milestones and survival rates as medicines drastically alter the natural progression of this disease. This review discusses historical SMA progression and underlying disease mechanisms, highlights advances made in therapeutic research, clinical trials, and FDA-approved medicines, and discusses possible second-generation and complementary medicines as well as optimal temporal intervention windows in order to optimize motor function and improve quality of life for all SMA-affected individuals
A high affinity, partial antagonist effect of 3,4-diaminopyridine mediates action potential broadening and enhancement of transmitter release at NMJs
3,4-Diaminopyridine (3,4-DAP) increases transmitter release from neuromuscular junctions (NMJs), and low doses of 3,4-DAP (estimated to reach ∼1 μM in serum) are the Food and Drug Administration (FDA)-Approved treatment for neuro muscular weakness caused by Lambert-Eaton myasthenic syn drome. Canonically, 3,4-DAP is thought to block voltage-gated potassium (Kv) channels, resulting in prolongation of the pre synaptic action potential (AP). However, recent reports have shown that low millimolar concentrations of 3,4-DAP have an off-Target agonist effect on the Cav1 subtype ( L-Type ) of voltage-gated calcium (Cav) channels and have speculated that this agonist effect might contribute to 3,4-DAP effects on transmitter release at the NMJ. To address 3,4-DAPs mecha nism(s) of action, we first used the patch-clamp electrophysi ology to characterize the concentration-dependent block of 3,4-DAP on the predominant presynaptic Kv channel subtypes found at the mammalian NMJ (Kv3.3 and Kv3.4). We identified a previously unreported high-Affinity (1-10 μM) partial antag onist effect of 3,4-DAP in addition to the well-known low-Af finity (0.1-1 mM) antagonist activity. We also showed that 1.5-μM DAP had no effects on Cav1.2 or Cav2.1 current. Next, we used voltage imaging to show that 1.5-or 100-μM 3,4-DAP broadened the AP waveform in a dose-dependent manner, in dependent of Cav1 calcium channels. Finally, we demonstrated that 1.5-or 100-μM 3,4-DAP augmented transmitter release in a dose-dependent manner and this effect was also independent of Cav1 channels. From these results, we conclude that low micromolar concentrations of 3,4-DAP act solely on Kv chan nels to mediate AP broadening and enhance transmitter release at the NMJ
Non-standard work in the Nordics : Troubled waters under the still surface
Most Nordic labour market and welfare state models are shaped around the notion of the standard full-time open-ended contract. However, the recent development in non-standard work (NSW) may challenge these institutions. In this TemaNord report, we analyse the recent development of NSW within the context of the Nordic models. We draw on Nordic Labour Force Survey data to map the recent development in the well-known forms of NSW, and through in-depth case studies, we explore emerging NSW practices and policy responses. There has been a fairly stable development in NSW across the Nordics, but the sector specific statistics and case studies display significant changes beneath this still surface. We find examples of novel policy responses to these developments, but the corona crisis also revealed gaps in the Nordic social- and employment protection regarding emerging forms of NSW.