Protein 4.1R-deficient mice are viable but have erythroid membrane skeleton abnormalities

A diverse family of protein 4.1R isoforms is encoded by a complex gene on human chromosome 1. Although the prototypical 80-kDa 4.1R in mature erythrocytes is a key component of the erythroid membrane skeleton that regulates erythrocyte morphology and mechanical stability, little is known about 4.1R function in nucleated cells. Using gene knockout technology, we have generated mice with complete deficiency of all 4.1R protein isoforms. These 4.1R-null mice were viable, with moderate hemolytic anemia but no gross abnormalities. Erythrocytes from these mice exhibited abnormal morphology, lowered membrane stability, and reduced expression of other skeletal proteins including spectrin and ankyrin, suggesting that loss of 4. 1R compromises membrane skeleton assembly in erythroid progenitors. Platelet morphology and function were essentially normal, indicating that 4.1R deficiency may have less impact on other hematopoietic lineages. Nonerythroid 4.1R expression patterns, viewed using histochemical staining for lacZ reporter activity incorporated into the targeted gene, revealed focal expression in specific neurons in the brain and in select cells of other major organs, challenging the view that 4.1R expression is widespread among nonerythroid cells. The 4.1R knockout mice represent a valuable animal model for exploring 4.1R function in nonerythroid cells and for determining pathophysiological sequelae to 4.1R deficiency.     

Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872)

MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered intravenously to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance. The range of values for the pharmacokinetic parameters were as follows: clearance, 0.26 to 0.51 ml/min/kg; half-life, 5.2 to 7.6 h; and distributive volume, 0.11 to 0.27 liters/kg. The level of protein binding of MK-0991 was determined to be 96% in mouse and human serum. The compound exhibited high affinities for human serum albumin and at least two lipid components. The rationale for the selection of MK-0991 as a drug development candidate was based on its two- to threefold superior pharmacokinetic performance in chimpanzees over the performance of an otherwise equivalent analog, L-733,560. Once-daily dosing for MK-0991 is indicated by a graphical comparison of levels in the circulations of chimpanzees and mice. In a study of the pharmacokinetics of MK-0991 in mouse tissue, the organs were assayed following intraperitoneal administration. The area under the concentration-versus-time curves (AUC) segregated the tissues into three exposure categories relative to plasma. The tissues with greater exposure than that for plasma were liver (16 times), kidney (3 times), and large intestine (2 times). The exposure for small intestine, lung, and spleen were equivalent to that for plasma. Organs with lower levels of exposure were the heart (0.3 times that for plasma), thigh (0.2 times), and brain (0.06 times). Kinetically, drug was cleared more slowly from all tissues than from plasma, indicating that terminal-phase equilibrium had not been achieved by 24 h. Thus, some measure of accumulation is predicted for all tissues. Single daily doses of MK-0991 should provide adequate systemic levels of fungicidal activity as a result of its long half-life pharmacokinetics, wide distribution, and slowly accumulating concentrations in tissue.     

Barley varieties for finishing steers: II. Ruminal characteristics and rate, site, and extent of digestion

Four ruminally and abomasally cannulated steers were used to evaluate the effects of barely variety on rate, site, and extent of digestion of high-concentrate diets. The treatments compared were 1) corn, 2) Gunhilde barley (GUN), Harrington barley (HAR), and 4) Medallion barley (MED). Diets were balanced to be isocaloric and isonitrogenous. Ruminal OM digestion was greater (P = .04) in steers fed corn than in those fed GUN, HAR, and MED (61.9 vs average 53.7%). No differences (P > .10) were seen in ruminal starch digestion (average 92.8%) or in starch flow to the abomasum (average 199 g/d) between diets. Total tract digestion of starch was greater (P = .09) in steers fed barley than in those fed corn (average 98.6 vs 95.7%). Total and nonammonia N presented to the abomasum were greater (P < .05) for steers fed HAR and GUN than for those fed MED and corn. Microbial N flow was lowest (P = .01) in corn-fed steers, highest in steers fed GUN and HAR, and intermediate in steers fed MED. Microbial efficiency was 59% greater (P = .03) in steers fed barley than in steers consuming corn. Ruminal acetate: propionate was lower (P = .002) in steers fed corn and HAR than in those fed GUN and MED. Compared to GUN, HAR, and MED barleys, corn had a lower (P < .03) rate (-.11 vs average -.47) and extent (15 h; 70.3 vs average 98.1%) of in situ starch disappearance. Differences in digestive characteristics found between barley varieties may contribute to differences in animal performance.     

Membrane fatty acid analysis of Antarctic bacteria

The removal of most ceramic brackets is accomplished by specially designed pliers that apply some form of tensile or shear force to the tooth surface. While the shear and tensile bond strengths for ceramic brackets in vitro have been reported, a simulation of the actual force application when using sharp-edged debonding pliers to debond a bracket has not. The purpose of this study is to determine the effectiveness and the force levels generated by the use of both the wide and the narrow blades in the debonding of ceramic brackets. The present findings indicate that the narrow blades effectively debonded ceramic brackets with a significantly lower mean debonding force (120 kg/cm2) than the wider blades (150 kg/cm2). The surface area of the blade in contact with the bracket-adhesive interface is less for the narrow blade (2.0 mm) than for the wide blade (3.2 mm). This relatively smaller contact area is sufficient to debond a bracket at a significantly lower debonding force.     

Anticonvulsant drug concentrations in epileptic patients

Using Wistar stain male rats, it has been shown that 2 atmospheric pressures associated with oxygen saturation, together or singly for 90 minutes daily for successive 46 days, resulted in no significant change on the ratio of testes to body weight. No significant change was observed in the incorporation of 3H-thymidine into testes and pituitary glands between the pressure-treated groups and the control group.