A Toxicological Basis to Derive a Generic Interspecies Uncertainty Factor.

A new method is proposed to derive the size of the interspecies uncertainty factor (UF) that is toxicologically and statistically based. The method involves quantifying interspecies variation in susceptibility to numerous toxic substances via the use of binary interspecies comparisons that are converted to a 95% UF. This interspecies UF represents an estimate of the upper 95% of the population of 95% prediction intervals (PI) for binary interspecies comparisons within four categories of phylogenetic relatedness (species within genus, genera within family, families within order, orders within class). The 95% interspecies UFs range from a low of 10 for species within genus up to 65 for orders within class. Most mammalian toxicology studies involving mice, rats, cats, dogs, gerbils, and rabbits are orders-within- class categories for human risk assessment and would be provided a 65-fold UF. Larger or smaller interspecies UF values could be selected on the level of protection desired.     

The predictability of maxillary repositioning in LeFort I orthognathic surgery.

Our ability to predict the outcome of any orthognathic procedure relies on the surgeon's ability to accurately reproduce the desired skeletal movements and on our understanding of the soft tissue changes associated with those movements. The purpose of this retrospective study was to evaluate the surgical accuracy of maxillary repositioning by comparing the objectives obtained from cephalometric prediction tracings with the actual skeletal changes achieved during maxillary and maxillomandibular procedures. The sample consisted of 46 patients from the files of 1 orthodontist. Presurgical and immediately postsurgical cephalometric radiographs were digitized, and the original surgical prediction was reproduced with Dentofacial Planner (Dentofacial Software, Toronto, Ontario, Canada) software. Vertical and horizontal measurements to several skeletal landmarks were used to assess the differences between the predicted maxillary position and the actual maxillary postsurgical position. Statistical differences were found for some measurements, particularly those related to the vertical placement of the posterior maxilla. Three variables were evaluated for their effect on the surgical discrepancies. The 2 surgeons with the most patients were evaluated and found to have differences in the direction of discrepancies but not the amount (absolute values). Significant differences were also found when evaluating surgical complexity (single-jaw vs bimaxillary procedures) and the direction of movement (impaction vs advancement) in direction only. To assess the overall fit of individual predictions, we calculated an average discrepancy for each patient; 80% of the actual results fell within 2 mm of the prediction, and 43% fell within 1 mm of the prediction.     

Cobalamin (vitamin B12) deficiency detection by urinary methylmalonic acid quantitation

A study was made to assess the value of cobalamin deficiency detection through quantitation of urinary methylmalonic acid (MMA). Urinary MMA was measured in 1118 patients suffering from megaloblastic anemia, other anemias, elevated red cell mean corpuscular volume, or unexplained neurologic disorders. Patients without proven cobalamin deficiency had urinary MMA levels less than 20 micrograms/ml. All patients (n = 27) confirmed to have cobalamin deficiency showed MMA levels greater than 20 micrograms/ml. Data are presented showing the Schilling test results, the comparison of serum cobalamin to urinary MMA levels, and other basic hematologic data. MMA levels are a good indication of cobalamin distribution and function since they are directly related to a cobalamin-dependent metabolic pathway. With rapid, reliable quantitation by mass spectrometry, urinary MMA can now be a useful clinical test.     

Neutrophil elastase produces 52-kD and 30-kD glucocorticoid receptor fragments in the cytosol of human leukemia cells

Characterization of glucocorticoid receptors in leukemia cells is important to understand mechanisms of glucocorticoid resistance but has been impeded by receptor fragmentation in cytosol extracts. We recently found that formation of 52- and 30-kilodalton (kD) glucocorticoid receptor fragments in cytosol of leukemia cells is due to proteolysis and is blocked by diisopropylfluorophosphate (DFP). In the present study, we identify a 28-kD serine protease in cytosol of leukemia cells that binds [3H]DFP and correlates with the formation of 52- and 30-kD receptor fragments. This protease is immunoprecipitated by antiserum to neutrophil elastase. Limited digestion of [3H]dexamethasone-21-mesylate- labeled receptors by purified neutrophil elastase produces 52- and 30- kD receptor fragments. Receptor fragmentation in the cytosol of leukemia cells in inhibited by methoxysuccinyl-alanyl-alanyl-prolyl- valyl-chloromethylketone, a highly specific inhibitor of neutrophil elastase. The addition of as few as 5% neutrophils to a lymphoid cell suspension provides sufficient elastase to produce receptor fragmentation. Our findings indicate that neutrophil elastase is responsible for receptor fragmentation in the cytosol of leukemia cells. The neutrophil elastase may be endogenous to the leukemia cells or may come from neutrophils that contaminate leukemia cell suspensions.