PubMed · 7802363
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P J Whiteman. 1995. Verapamil toxicity.. https://doi.org/10.1016/s0196-0644(95)70368-3
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Spinocerebellar ataxia 27B (SCA27B), caused by an FGF14 GAA repeat expansion, is an emerging cause of late-onset ataxia. We report the first genetically confirmed Argentinean case, initially misdiagnosed as alcoholic cerebellar degeneration. This case highlights diagnostic challenges, phenotypic heterogeneity, and the importance of genetic testing for this treatable disorder.
Building on prototype 1, which achieves 120 degrees of phosgene-powered unidirectional rotation to rotamer 6 (see Figure 5 in the full article), 7 was designed to accomplish repeated unidirectional rotation (see Scheme 7). Compound 7 contains an amino group on each blade of the triptycene and a 4-(dimethylamino)pyridine (DMAP) unit to selectively deliver phosgene (or its equivalent) to the amine in the "firing position". The synthesis of 7 is described: the key constructive steps are a benzyne addition to an anthracene to generate the triptycene, a stilbene photocyclization to construct the helicene, and a Stille coupling to incorporate the DMAP unit. The DMAP unit was shown to regioselectively relay 1,1'-carbonyldiimidazole (but not phosgene) to the proximal amino group, as designed, but rotation of the triptycene does not occur. Extensive attempts to troubleshoot the problem led to the conclusion that the requisite intramolecular urethane formation, as demonstrated in the prototype (1 --> 4), does not occur with 7 (to give 85) or 97 (to give 100). We speculate that either (i) hydrogen bonding between the hydroxypropyl group and functionality present in 7 but absent from 1 or (ii) a Bürgi-Dunitz (or similar) interaction involving the DMAP (see 106) prevents achievement of a conformation conducive to intramolecular urethane formation.
It was recently shown that the persistent Na(+) current (I(NaP)) is generated in the proximal axon in response to somatic depolarization in neocortical pyramidal neurons, although the involvement of I(NaP) in spike initiation is still unclear. Here we show a potential role of I(NaP) in spike initiation of primary sensory neurons in the mesencephalic trigeminal nucleus (MTN) that display a backpropagation of the spike initiated in the stem axon toward the soma in response to soma depolarization. Riluzole (10 muM) and tetrodotoxin (TTX, 10 nM) caused an activation delay or a stepwise increase in the threshold for evoking soma spikes (S-spikes) without affecting the spike itself. Simultaneous patch-clamp recordings from the soma and axon hillock (AH) revealed that bath application of 50 nM TTX increased the delay in spike activation in response to soma depolarization, leaving the spike-backpropagation time from the AH to soma unchanged. This indicates that the increase in activation delay occurred in the stem axon. Furthermore, under a decreasing intracellular concentration gradient of QX-314 from the soma to AH created by QX-314-containing and QX-314-free patch pipettes, the amplitude and maximum rate of rise (MRR) of AH-spikes decreased with an increase in the activation delay following repetition of current-pulse injections, whereas S-spikes displayed decreases of considerably lesser degree in amplitude and MRR. This suggests that compared to S-spikes, AH-spikes more accurately reflect the attenuation of axonal spike by QX-314, consistent with the nature of spike backpropagation. These observations strongly suggest that low-voltage-activated I(NaP) is involved in spike initiation in the stem axon of MTN neurons.