Identification of cis-acting determinants mediating the unconventional secretion of tau.

The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer's disease. While recent findings suggest the involvement of unconventional secretory pathways driving tau into the extracellular space and mediating the propagation of the disease-associated pathology, many of the mechanistic details governing this process remain elusive. In the current study, we provide an in-depth characterization of the unconventional secretory pathway of tau and identify novel molecular determinants that are required for this process. Here, using Drosophila models of tauopathy, we correlate the hyperphosphorylation and aggregation state of tau with the disease-related neurotoxicity. These newly established systems recapitulate all the previously identified hallmarks of tau secretion, including the contribution of tau hyperphosphorylation as well as the requirement for PI(4,5)P2 triggering the direct translocation of tau. Using a series of cellular assays, we demonstrate that both the sulfated proteoglycans on the cell surface and the correct orientation of the protein at the inner plasma membrane leaflet are critical determinants of this process. Finally, we identify two cysteine residues within the microtubule binding repeat domain as novel cis-elements that are important for both unconventional secretion and trans-cellular propagation of tau.

Aggressive treatment of acute anal fissure with 0.5% nifedipine ointment prevents its evolution to chronicity.

AIM: To investigate the efficacy of topical application of 0.5% nifedipine ointment in healing acute anal fissue and preventing its progress to chronicity. METHODS: Thirty-one patients (10 males, 21 females) with acute anal fissure from September 1999 to January 2005 were treated topically with 0.5% nifedipine ointment (t.i.d.) for 8 wk. The patients were encouraged to follow a high-fiber diet and assessed at 2, 4 and 8 wk post-treatment. The healing of fissure and any side effects were recorded. The patients were subsequently followed up in the outpatient clinic for one year and contacted by phone every three months thereafter, while they were encouraged to come back if symptoms recurred. RESULTS: Twenty-seven of the 31 patients completed the 8-wk treatment course, of them 23 (85.2%) achieved a complete remission indicated by resolution of symptoms and healing of fissure. Of the remaining four unhealed patients (14.8%), 2 opted to undergo lateral sphincterotomy and the other 2 to continue therapy for four additional weeks, resulting in healing of fissure. All the 25 patients with complete remission had a mean follow-up of 22.9 +/- 14 (range 6-52) mo. Recurrence of symptoms occurred in four of these 25 patients (16%) who were successfully treated with an additional 4-wk course of 0.5% nifedipine ointment. Two of the 27 (7.4%) patients who completed the 8-wk treatment presented with moderate headache as a side effect of nifedipine. CONCLUSION: Topical 0.5% nifedipine ointment, used as an agent in chemical sphincterotomy, appears to offer a significant healing rate for acute anal fissure and might prevent its evolution to chronicity.