The role of the protein glycosylation state in the control of cellular transport of the amyloid beta precursor protein

The amyloid beta precursor protein can exist as both a membrane-bound and a secreted protein, with the former having the potential to generate the amyloid beta peptide present in the neuritic plaques which are characteristic of Alzheimer's disease. In this study, we have used a clone of the AtT20 mouse pituitary cell line which expresses high levels of the amyloid beta precursor protein to characterize the glycosylation state of the secreted and membrane-bound forms of the protein and to examine the role of post-translational modifications in protein processing. Lectin blot analysis of immunoprecipitated amyloid beta precursor protein demonstrated that the soluble form of the protein contains significant amounts of sialic acid, with the lectin staining being reduced in the particulate cellular fractions. Treatment of the cells with mannosidase inhibitors to interfere with the formation of complex-type N-linked glycans resulted in a decrease in secreted amyloid beta precursor protein and an increase in the level of the cellular form of the protein. The increase in amyloid beta precursor protein levels in the cellular fraction was accompanied by an increase in perinuclear staining. Furthermore, cells overexpressing the alpha2,6(N)-sialyltransferase enzyme also demonstrated an increase in amyloid beta precursor protein secretion. These results suggest that the presence of terminal sialic acid residues on complex-type N-glycans may be required for the optimal transport of the amyloid beta precursor protein from the Golgi to the cell membrane with the subsequent cleavage to generate the secreted form of the protein.     

Variable waveforms in downbeat nystagmus imply short-term gain changes

A patient with downbeat nystagmus subsequent to ankylosing spondylitis was studied. His nystagmus was found to exhibit both increasing- and decreasing-velocity exponential slow phases as well as the linear form more often reported. Alternation between waveforms sometimes occurred on a beat-to-beat or even intrabeat basis. Possible explanations for all three waveforms are presented in terms of short-term gain changes in cerebellar compensation for leaky brainstem neural integrators. A computer model was developed and its results are discussed.     

Acute poisoning caused by the herbicide dichlorprop (preparation SYS 67 PROP)

We report on the acute poisoning of a 5-year-old boy by the herbicide "dichlorprop". This preparation is described as an effective means of plant protection. The effects of the intoxication were established by changes observed in almost all of the child's organs. The predominant effect was haemolytic anemia. All the pathological parameters regressed as a result of symptomatic therapy. General conclusions are drawn about intoxication, especially by means of plant protection agents.     

Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors.

PURPOSE: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades. Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor. Therefore, we investigated a ligand-independent approach to hormonal therapy that depletes cellular levels of the receptor by inhibiting the function of Hsp90. EXPERIMENTAL DESIGN: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin (17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts. RESULTS: The ER was depleted by GA in several Tam-resistant cell lines, as were other Hsp90 client proteins such as Akt and Raf-1. Unexpectedly, Tam inhibited ER depletion by GA but had no effect on destabilization of Akt or Raf-1. When SCID mice supplemented with Tam were treated with 17AAG, their tumors also showed no decrease in ER levels as measured by immunofluorescent staining and laser scanning cytometry. In these same tumors, however, decreased Akt and Raf-1 levels were observed. Drug administration also led to inhibition of tumor xenograft growth. The mechanism by which Tam inhibits GA-mediated ER depletion is unclear, but immunoprecipitation experiments showed that Tam does not inhibit the ability of GA to alter the ER-chaperone complex. CONCLUSIONS: Based on its ability to deplete the ER as well as other critical signaling molecules in Tam-resistant breast cancer, 17AAG may provide a useful alternative treatment for patients with recurrent, hormone-refractory breast cancer that should be explored further in Phase II trials. In this context, combined treatment with 17AAG and Tam should be avoided because Tam may inhibit the ability of 17AAG to deplete the ER, potentially reducing its anticancer activity.     

Radioactive seed embolization to the lung following prostate brachytherapy

Over the past decade, prostate brachytherapy has been increasingly utilized as definitive management for early stage carcinoma of the prostate gland. One risk of the procedure is pulmonary seed embolization. In this article we report the incidence and timing of seed migration. Pulmonary embolization of radioactive seeds occurs in approximately 20% of patients undergoing prostate brachytherapy. To date, no acute or delayed detrimental effects have been reported which are attributable to the pulmonary embolization of the seeds; nevertheless, it is imperative that patients and health care providers be cognizant of this possible event.