Intravenous cidofovir treatment for recalcitrant warts in the setting of a patient with myelodysplastic syndrome

Cidofovir is an acyclic nucleoside phosphonate with broad-spectrum activity against DNA viruses, including human papilloma virus (HPV). However, data on the efficacy of cidofovir in an immunosuppressive setting remain contradictory. We report for the first time on the promotion of the healing of recalcitrant warts in a patient with myelodysplastic syndrome with intravenous cidofovir treatment.     

The social behavior of autistic children with younger and same-age nonhandicapped peers

Results of a study observing autistic children's interactions with nonhandicapped and autistic peers are reported. Six 8- to 12-year-old autistic children played in dyads with younger, normally developing kindergarten children and with nonhandicapped peers matched on chronological age for 10 15-minute sessions spaced over 3 weeks and then with a playmate of the alternate age for another 10 sessions. After intervention, all subjects showed gains in proximity, orientation, and responsiveness when playing with nonhandicapped peers and with autistic classmates. Same-age nonhandicapped playmates initiated more frequently than did younger nonhandicapped playmates and were better able to modify their initiations in ways that increased the likelihood of response from the autistic children.     

Point mutation analysis of ras genes in spontaneous and chemically induced C57Bl/10J mouse liver tumours.

The high incidence and profile of ras gene mutations reported in spontaneous and chemically induced liver tumours of the B6C3F1 mouse provides a potential means of determining in vivo genotoxicity and its relevance to carcinogenicity. We analysed spontaneous and chemically induced [with 4-amino-biphenyl (ABP), 2-acetylaminofluorene (AAF) and diethylnitrosamine (DEN)] hepatocellular tumours of the C57Bl/10J mouse for H-ras, K-ras and N-ras gene mutations to see if mutational analysis of the ras genes could be useful for such a determination in this strain. Regions of DNA spanning codons 12, 13 and 61 of the ras genes were amplified from formalin fixed liver tumour sections using the polymerase chain reaction. Mutations were detected using allele specific oligonucleotide probing and confirmed by sequencing. We have found that there are few ras mutations in either spontaneous or chemically induced liver tumours in the C57Bl/10J mouse. Out of 25 spontaneous tumours two contained an A to T transversion and one contained an A to G transition in base 2 of H-ras codon 61 and two contained a G to A transition in base 2 of K-ras codon 13 (the K-ras mutations were only faintly detectable and may be present in a subpopulation of the tumour cells). In the case of the 18 ABP induced tumours one contained a C to A transversion in base 1 of H-ras codon 61, and one contained an A to T transversion in base 2 of H-ras codon 61 and one contained a G to C transversion in base 1 of K-ras codon 13. One C to A transversion in base 1 of H-ras codon 61 was detected out of eight AAF induced tumours. Of the 25 DEN induced tumours, one contained an A to G transition and one contained an A to C transversion in base 2 of H-ras codon 61. The data indicate that at least in hepatocellular tumours of the C57Bl/10J strain and using chronic dosing regimes the ras genes do not represent markers for in vivo genotoxic activity.     

Changes in the phosphorylation status of a 19 kD cytosolic protein are linked to the growth arrest of HL-60 cells.

A major 19 kD cytosolic protein (p19) has been described in a number of cell systems with respect to its rapid phosphorylation when protein kinase C is activated and has been proposed as a key substrate of this enzyme. Phosphorylation of p19 occurs when the growth of cells is affected by 12-O-tetradecanoylphorbol-13-acetate (TPA) and it has been proposed that increased phosphorylation of p19 relates to the cessation of cell growth. This study delineates precisely the relationship between p19 phosphorylation changes in the growth and differentiation status of cells. Changes in the levels of two phosphorylated forms of p19 were assessed in HL-60 promyelocytic cells and a variant HL-60 cell line which stopped growing and differentiated in response to TPA and were compared to changes seen in HL-60 variant lines which merely growth arrested when treated with TPA. In lines which either did or did not differentiate, in response to TPA, the p19 protein was rapidly and transiently phosphorylated. Thus, this alteration in the phosphorylation status of p19 is associated with the process of growth arrest and not related to the onset of cell differentiation. The p19 protein and the enzymes which effect its phosphorylation status modulate the growth of cells and possible disregulation of p19 and/or its kinases and phosphatases is of interest as regards the leukaemic transformation of cells.     

Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation

The receptor tyrosine kinase (RTK) Ret is activated by the formation of a complex consisting of ligands such as glial cell line-derived neurotrophic factor (GDNF) and glycerophosphatidylinositol-anchored coreceptors termed GFRalphas. During activation, Ret translocates into lipid rafts, which is critical for functional responses to GDNF. We found that Ret was rapidly ubiquitinated and degraded in sympathetic neurons when activated with GDNF, but, unlike other RTKs that are trafficked to lysosomes for degradation, Ret was degraded predominantly by the proteasome. After GDNF stimulation, the majority of ubiquitinated Ret was located outside of lipid rafts and Ret was lost predominantly from nonraft membrane domains. Consistent with the predominance of Ret degradation outside of rafts, disruption of lipid rafts in neurons did not alter either the GDNF-dependent ubiquitination or degradation of Ret. GDNF-mediated survival of sympathetic neurons was inhibited by lipid raft depletion, and this inhibitory effect of raft disruption on GDNF-mediated survival was reversed if Ret degradation was blocked via proteasome inhibition. Therefore, lipid rafts sequester Ret away from the degradation machinery located in nonraft membrane domains, such as Cbl family E3 ligases, thereby sustaining Ret signaling.