Longitudinal follow-up of adductor spasmodic dysphonia patients after botulinum toxin injection: quality of life results.

OBJECTIVE: Botulinum toxin injections are used routinely to treat patients with adductor spasmodic dysphonia. After an initial "breathy phase," most patients experience improvement for a few weeks to months and then a gradual decline until their next injection. In this study, voice-related quality of life (VRQOL) data were collected at 4 week intervals through one to three injection cycles in an attempt to quantify the proportion of each cycle during which patients experience meaningful benefit. STUDY DESIGN: Prospective, nonrandomized case series. METHODS: Patients receiving stable-dose botulinum injections for adductor spasmodic dysphonia were invited to participate. Voice recordings and clinical outcomes data were collected by telephone every 4 weeks throughout each injection cycle. Quality of life data were normalized for cycle length and interpolated to generate composite curves. RESULTS: Twenty-two patients completed data collection for at least one full injection cycle. The average cycle was 25.9 weeks; the mean age was 59.8 years. On a 100-point scale, the total VRQOL scores peaked at 77.4, at 30% of the cycle, then gradually declined. The social-emotional (SE) subscale scores were significantly better than the physical subscale scores (P < .05). The total VRQOL score exceeded 75 during only 14% of the cycle (52.6% for SE subscores, 0% for physical subscores). If the threshold is lowered to 70, the total VRQOL exceeded this level during 54.6% of the cycle (69.6% for SE subscores, 44.1% for physical subscores). For the 11 patients completing three full injection cycles, there were no significant differences between the three cycles, and the mean VRQOL scores were similar to the values given above. At the beginning and end of each cycle, the total VRQOL scores averaged 52.8 (56.0 for SE subscale, 50.7 for physical subscale). CONCLUSION: Although botulinum toxin injections provide significant improvement for these patients, the initial breathy phase and the late declining phase add up to a significant proportion of each cycle spent with a reduced quality of life. At best, the total VRQOL averaged below 80%. This longitudinal study provides a unique look at the effect of this condition and its treatment on these patients' lives. A suitable long-term treatment for this condition is needed to eliminate the cyclical voice results experienced with the botulinum toxin injection approach.

Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in astrocytes.

Acute mu and kappa opioids activate the ERK/MAPK phosphorylation cascade that represents an integral part of the signaling pathway of growth factors in astrocytes. By this cross-talk, opioids may impact neural development and plasticity among other basic neurobiological processes in vivo. The mu agonist, [D-ala2,mephe4,glyol5]enkephalin (DAMGO), induces a transient stimulation of ERK phosphorylation, whereas kappa agonist, U69,593, engenders sustained ERK activation. Here we demonstrate that acute U69,593 and DAMGO stimulate ERK phosphorylation by utilization of different secondary messengers and protein kinase C (PKC) isoforms upstream of the growth factor pathway. Immortalized astrocytes transfected with either antisense calmodulin (CaM), a mutant mu opioid receptor that binds CaM poorly or a dominant negative mutant of PKCepsilon were used as a model system to study mu signaling. Evidence was gained to implicate CaM and PKCepsilon in DAMGO stimulation of ERK. DAMGO activation of PKCepsilon and/or ERK was insensitive to selective inhibitors of Ca2+ mobilization, but it was blocked upon phospholipase C inhibition. These results suggest a novel mechanism wherein, upon DAMGO binding, CaM is released from the mu receptor and activates phospholipase C. Subsequently, phospholipase C generates diacylglycerides that activate PKCepsilon. In contrast, U69,593 appears to act via phosphoinositide 3-kinase, PKCzeta, and Ca2+ mobilization. These signaling components were implicated based on studies with specific inhibitors and a dominant negative mutant of PKCzeta. Collectively, our findings on acute opioid effects suggest that differences in their mechanism of signaling may contribute to the distinct outcomes on ERK modulation induced by chronic mu and kappa opioids.

The Arabidopsis Rab GTPase RabA4b localizes to the tips of growing root hair cells.

Spatial and temporal control of cell wall deposition plays a unique and critical role during growth and development in plants. To characterize membrane trafficking pathways involved in these processes, we have examined the function of a plant Rab GTPase, RabA4b, during polarized expansion in developing root hair cells. Whereas a small fraction of RabA4b cofractionated with Golgi membrane marker proteins, the majority of this protein labeled a unique membrane compartment that did not cofractionate with the previously characterized trans-Golgi network syntaxin proteins SYP41 and SYP51. An enhanced yellow fluorescent protein (EYFP)-RabA4b fusion protein specifically localizes to the tips of growing root hair cells in Arabidopsis thaliana. Tip-localized EYFP-RabA4b disappears in mature root hair cells that have stopped expanding, and polar localization of the EYFP-RabA4b is disrupted by latrunculin B treatment. Loss of tip localization of EYFP-RabA4b was correlated with inhibition of expansion; upon washout of the inhibitor, root hair expansion recovered only after tip localization of the EYFP-RabA4b compartments was reestablished. Furthermore, in mutants with defective root hair morphology, EYFP-RabA4b was improperly localized or was absent from the tips of root hair cells. We propose that RabA4b regulates membrane trafficking through a compartment involved in the polarized secretion of cell wall components in plant cells.