Distribution and Severity of Neuropathology in ß-Mannosidase-Deficient Mice is Strain Dependent.

Neurological dysfunction is common in humans and animals with lysosomal storage diseases. ß-Mannosidosis, an autosomal recessive inherited disorder of glycoprotein catabolism caused by deficiency of the lysosomal enzyme ß-mannosidase, is characterized by intracellular accumulation of small oligosaccharides in selected cell types. In ruminants, clinical manifestation is severe, and neuropathology includes extensive intracellular vacuolation and dysmyelination. In human cases of ß-mannosidosis, the clinical symptoms, including intellectual disability, are variable and can be relatively mild. A ß-mannosidosis knockout mouse was previously characterized and showed normal growth, appearance, and lifespan. Neuropathology between 1 and 9 months of age included selective, variable neuronal vacuolation with no hypomyelination. This study characterized distribution of brain pathology in older mutant mice, investigating the effects of two strain backgrounds. Morphological analysis indicated a severe consistent pattern of neuronal vacuolation and disintegrative degeneration in all five 129X1/SvJ mice. However, the mice with a mixed genetic background showed substantial variability in the severity of pathology. In the severely affected animals, neuronal vacuolation was prominent in specific layers of piriform area, retrosplenial area, anterior cingulate area, selected regions of isocortex, and in hippocampus CA3. Silver degeneration reaction product was prominent in regions including specific cortical layers and cerebellar molecular layer. The very consistent pattern of neuropathology suggests metabolic differences among neuronal populations that are not yet understood and will serve as a basis for future comparison with human neuropathological analysis. The variation in severity of pathology in different mouse strains implicates genetic modifiers in the variable phenotypic expression in humans.

Beta-mannosidosis mice: a model for the human lysosomal storage disease.

Beta-mannosidase, a lysosomal enzyme which acts exclusively at the last step of oligosaccharide catabolism in glycoprotein degradation, functions to cleave the unique beta-linked mannose sugar found in all N-linked oligosaccharides of glycoproteins. Deficiency of this enzyme results in beta-mannosidosis, a lysosomal storage disease characterized by the cellular accumulation of small oligosaccharides. In human beta-mannosidosis, the clinical presentation is variable and can be mild, even when caused by functionally null mutations. In contrast, two existing ruminant animal models have disease that is consistent and severe. To further explore the molecular pathology of this disease and to investigate potential treatment strategies, we produced a beta-mannosidase knockout mouse. Homozygous mutant mice have undetectable beta-mannosidase activity. General appearance and growth of the knockout mice are similar to the wild-type littermates. At >1 year of age, these mice exhibit no dysmorphology or overt neurological problems. The mutant animals have consistent cytoplasmic vacuolation in the central nervous system and minimal vacuolation in most visceral organs. Thin-layer chromatography demonstrated an accumulation of disaccharide in epididymis and brain. This mouse model closely resembles human beta-mannosidosis and provides a useful tool for studying the phenotypic variation in different species and will facilitate the study of potential therapies for lysosomal storage diseases.

Medical students as standardized patients to assess interviewing skills for pain evaluation.

PURPOSE: The use of medical students as standardized patients in a performance assessment of pain evaluation was studied. METHODS: Fifty-two pairs of second-year medical students participated. One student portrayed a patient presenting with cancer pain and was interviewed by the other medical student. The student-patient then rated the interview using a checklist of pain assessment and general interviewing skills. The interviews were audiotaped and also rated independently. RESULTS: Based on student-patient ratings, 36 (69%) students demonstrated 9 or more of the 11 pain-specific checklist items, compared to 34 (65%) students according to the trained rater. Highly specific pain-related items had higher agreement than broader interviewing skill items. There would be differences in the summary assessments of students depending on which rating data were used. DISCUSSION: Medical students represent a readily accessible resource as patients for clinical simulations. Students tended to overestimate the performance of fellow students, but acting as a standardized patient had educational value, and can be used to extend simulated patient encounters within the curriculum. Further investigation is needed to improve the reliability of the feedback provided by student-patients.

Why Johnnie Can't Apply Neuroscience: Testing Alternative Hypotheses Using Performance-Based Assessment.

When second year medical students were less successful than expected in solving an OSCE neurologic case, a subsequent performance-based assessment was modified to permit testing of four hypotheses related to knowledge application, ability decay over time, skill performance, and case complexity. Two cohorts of second year medical students were presented with neurologic cases in the context of performance-based assessment. Although many students demonstrated that they had the requisite knowledge, few were able to access the knowledge in less structured testing formats. Students had the skills necessary to conduct a physical examination but were unable to appropriately focus the examination. Case complexity also was related to some performance domains. There was evidence of knowledge and skill decay over time. In summary, it is apparent that multiple factors influence students' performance and are important considerations in designing performance assessments to evaluate competence.