Complex interactions in Parkinson's disease: a two-phased approach.

The identification of pathogenic mutations in the three genes alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) has elucidated the ubiquitin proteasome system (UPS) and its potential role as a causal pathway in Parkinson's disease (PD). In addition, polymorphisms of these three genes have been shown to be independently associated with PD. In a sample of 298 unrelated PD cases and 185 controls, we applied a two-phased approach of recursive partitioning and logistic regression analyses to explore complex interactions. For women only, we observed an epistatic interaction of UCHL1 and alpha-synuclein genotypes with significant effects on PD risk (odds ratio = 2.42; P = 0.003). Our findings are consistent with the hypothesis that PD is a multigenic disorder of the UPS.     

Long-term result of guided nerve regeneration with an inert microporous polytetrafluoroethylene conduit

Thedevelopmentinmicrosurgicaltechniqueshasgreatlyimprovednervefunctionalrecovery .However ,owingtotheinabilitytocoaptateandsuturethousandsofnervefiberstotheirfunctionallysimilarnervefibersandinaccuratesutureofthenervestumps ,regeneratednervefiberspartiallylosethechancetoselectivelyregrowintotheirtargetendoneurialtubes,1 4whichresultsinaninevitablemismatchofmotorandsensorynervefibers .Thus,thecontact guidance basedmicrosurgicalnerverepairhasfailedtoachieveconsistentsatisfactoryfunctionalrecover…     

Reduced Serum Theophylline Concentrations after Discontinuation of Azithromycin: Evidence for an Unusual Interaction

A 68-year-old man receiving long-term therapy with oral sustained-release theophylline 450 mg twice/day was admitted to the hospital after failing treatment with azithromycin for an acute exacerbation of obstructive lung disease. Peak serum theophylline concentration was 20 μg/ml (normal 10–20 μg/ml). Azithromycin was discontinued and the theophylline dosage reduced by 33%. The subsequent 80% decrease in serum theophylline to 4.6 μg/ml was unexpectedly large. Two rechallenges produced similar transient depressions of serum theophylline concentrations after withdrawal of azithromycin, suggesting an interaction. Withdrawal of azithromycin may leave an increased number of active enzyme sites available as the drug is cleared from the system. In some circumstances, it may be useful for pharmacokinetic interaction studies to continue measuring concentrations after the suspected interacting agent is stopped.     

Folding of the conserved domain but not of flanking regions in the integrin β2 subunit requires association with the α subunit

We have used immunoprecipitation with mAbs to probe folding during biosynthesis of the β₂ integrin subunit of lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) before and after association with the α_L subunit. An evolutionarily conserved region is present in the β₂ subunit between amino acid residues 102 and 344. mAbs to one subregion before the conserved region, and two subregions after the conserved domain, immunoprecipitated both the unassociated β′₂ precursor and mature α_L/β₂ complex, suggesting portions of these subregions are folded before association with α_L. An activating mAb to the C-terminal cysteine-rich region, KIM127, preferentially bound to the unassociated β subunit, suggesting that it may bind to an epitope that is in an αβ interface in unactivated LFA-1. By contrast, mAbs to five different epitopes in the conserved region did not react with unassociated β′₂ precursor, suggesting that this region folds after α_L association and is intimately associated with the α_L subunit in the α_L/β₂ complex. mAbs to two different epitopes that involve the border between the conserved region and the C-terminal segment, were fully or partially reactive with the β′₂ precursor, suggesting that this region is partially folded before association with α_L. The findings suggest that the conserved region is a distinct folding and hence structural unit, and is intimately associated with the α subunit.     

Event-related Potentials as Markers for Alcoholism Risk in High Density Families

One hundred sixty-eight adult siblings and parents from affected and control families were tested for ERP characteristics using two tasks involving an auditory oddball paradigm. Significant within family differences among affected families suggest that risk for developing alcoholism may be seen even in adult subjects who have had experience consuming alcohol. Further, analysis of quantity and recency of drinking in the past seven days were not correlated with either amplitude or latency of P300, suggesting that the within-family differences observed reflect relative risk for developing alcoholism rather than experience with alcohol.     

Erythromycin-Induced Immune Hemolytic Anemia

A 3-year-old female receiving Pediazole (erythromycin ethylsuccinate and sulfisoxazole) for tonsillitis and otitis media developed severe hemolytic anemia. No serum drug-dependent antibodies could be demonstrated with an in vitro 'immune-complex' method using Pediazole, pure erythromycin ethylsuccinate or pure sulfisoxazole. However, a method using red cells coated with erythromycin base showed in vitro lysis of the erythromycin-coated red cells. This is only the second case of immune hemolytic anemia associated with erythromycin and the first where in vitro drug-dependent hemolysis was demonstrable.