Role of P-selectin cytoplasmic domain in granular targeting in vivo and in early inflammatory responses

P-selectin is an adhesion receptor for leukocytes expressed on activated platelets and endothelial cells. The cytoplasmic domain of P-selectin was shown in vitro to contain signals required for both the sorting of this protein into storage granules and its internalization from the plasma membrane. To evaluate in vivo the role of the regulated secretion of P-selectin, we have generated a mouse that expresses P-selectin lacking the cytoplasmic domain (DeltaCT mice). The deletion did not affect the sorting of P-selectin into alpha-granules of platelets but severely compromised the storage of P-selectin in endothelial cells. Unstored P-selectin was proteolytically shed from the plasma membrane, resulting in increased levels of soluble P-selectin in the plasma. The DeltaCT-P-selectin appeared capable of mediating cell adhesion as it supported leukocyte rolling in the mutant mice. However, a secretagogue failed to upregulate leukocyte rolling in the DeltaCT mice, indicating an absence of a releasable storage pool of P-selectin in the endothelium. Furthermore, the neutrophil influx into the inflamed peritoneum was only 30% of the wild-type level 2 h after stimulation. Our results suggest that different sorting mechanisms for P-selectin are used in platelets and endothelial cells and that the storage pool of P-selectin in endothelial cells is functionally important during early stages of inflammation.     

Impact of multiple antenatal doses of betamethasone on growth and development of mice offspring

OBJECTIVE: Our purpose was to determine in a randomized, placebo-controlled manner whether multiple antenatal doses of betamethasone affect long-term growth and development of exposed mouse offspring. STUDY DESIGN: Sixty pregnant CD-1 mice received either two, four, or eight antepartum doses of 0.1 mg betamethasone or placebo. Perinatal outcomes, growth, and development of the offspring were compared in a blinded manner. Variables were compared by analysis of variance or chi 2 testing. RESULTS: Betamethasone-exposed subjects gained less weight during pregnancy and were delivered of fewer live pups, with fewer male survivors and lower birth weights. These trends were dose related. Growth measurements were similar after the neonatal period. No differences in functional development and physical maturation in the offspring were noted. The reproductive capability, perinatal outcomes, and growth and development of the second-generation offspring were unaffected by betamethasone exposure. CONCLUSION: Multiple antenatal dosings of betamethasone, reaching toxic levels, did not have an impact on the long-term growth and development of the surviving mouse offspring.     

Developmentally regulated gene expression of thrombomodulin in postimplantation mouse embryos

Embryonic lethality of thrombomodulin-deficient mice has indicated an essential role for this regulator of blood coagulation in murine development. Here, the embryonic expression pattern of thrombomodulin was defined by surveying beta-galactosidase activity in a mouse strain in which the reporter gene was placed under the regulatory control of the endogenous thrombomodulin promoter via homologous recombination in embryonic stem cells. The murine trophoblast was identified as a previously unrecognized anatomical site where TM expression is conserved between humans and mice and may exert a critical function during postimplantation development. Targeted reporter gene expression in mesodermal precursors of the endothelial cell lineage defined thrombomodulin as an early marker of vascular differentiation. Analysis of the thrombomodulin promoter in differentiating ES cells and in transgenic mice provided evidence for a disparate and cell type-specific gene regulatory control mechanism in the parietal yolk sac. The thrombomodulin promoter as defined in this study will allow the targeting of gene expression to the parietal yolk sac of transgenic mice and the initiation of investigations into the role of parietal endoderm in placental function.     

Compensatory education: Effective or ineffective?

Measured the effectiveness of a college level compensatory program for Black disadvantaged students relative to aspiration, motivation, and academic levels as compared to advantaged students at the University of Detroit. Ss were 169 undergraduates, 98% of whom were Black; controls were 152 predominantly White undergraduates. Ss had lower levels of aspiration, motivation, and academic achievement in each year of college. However, the disadvantaged group reduced the gap between initial disparities on the criterion measures for the independent variables measured when compared to the control group. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dynamic Programming Approach to Unit Commitment

A field-proven dynamic programming formulation of the unit commitment problem is presented. This approach features the classification of generating units into related groups so as to minimize the number of unit combinations which must be tested without precluding the optimal path. Programming techniques are described which maximize efficiency. Considerations are discussed which determine when generating units must be evaluated and when they may be ignored. The heuristic procedures described in this paper are concerned with supplying all apriori information to the program thereby minimizing its execution time. Results are presented from field testing on a medium size utility. Composite generating unit formulation is described for the economic allocation of constrained fuel to a group of units.     

Short communication: Use of a digital refractometer in assessing immunoglobulin G concentrations in colostrum and the first 5 transition milkings in an Irish dairy herd

Transition milk is a source of immunoglobulin G (IgG) and could potentially be used to provide calves with passive immunity, when the IgG concentration is ≥50 g/L. Assessment of IgG concentrations in transition milk would be required before feeding and could be conducted using cow-side tests such as refractometers. Currently, limited information is available on the ability of refractometers to assess transition milk quality. We hypothesized that digital refractometry could be used to provide an accurate cow-side assessment of IgG concentrations in colostrum and transition milk, and IgG concentration in colostrum and one or more transition milking in an Irish herd is >50 g/L. The objectives of this study were to determine the IgG concentrations in colostrum and first, second, third, fourth, and fifth transition milk, and determine the utility of a digital refractometer in assessing quality of colostrum and transition milk produced by cows in a pasture-based dairy production system. A convenient sample of 75 dairy cows were enrolled. Colostrum and transition milk IgG concentrations were determined by radial immunodiffusion and refractometry. Sensitivity and specificity of the refractometer were determined and cut-off points that maximized sensitivity and specificity were determined using receiver operating characteristic curves. Median (range) IgG concentrations in colostrum and first, second, third, fourth, and fifth milking were 99.6, 43.5, 12.5, 5.3, 1.9, and 1.8 g/L, respectively. The sensitivity (0.8–1) of digital refractometry in identifying samples with low IgG concentrations in colostrum, first, second, and third transition milk was acceptable. In contrast, digital refractometry was not useful for assessing IgG concentrations in the fourth and fifth milking due to low IgG concentrations.     

Placebo-controlled comparison between a single dose and a multidose of betamethasone in accelerating lung maturation of mice offspring

OBJECTIVE: Our purpose was to determine, in a placebo-controlled manner with a mouse model, whether a multidose of betamethasone is more beneficial than a single dose in accelerating fetal lung maturation. STUDY DESIGN: Ninety gravid CD-1 mice were randomly assigned to 1 of 3 groups (n = 30) to receive either a placebo (0.25 mL subcutaneously) or betamethasone (0.1 mg subcutaneously) as a single dose on gestational day 14 or as a multidose twice daily on gestational day 14 and 15. Ten pregnancies in each group were terminated at gestational day 16.5 to observe the neonatal breathing pattern (scale 0 to 5; 5 is unlabored breathing) and the lung histologic findings (scale 0 to 5; 5 is alveolar budding). The lungs of the offspring belonging to the remaining 20 pregnancies in each group were removed and weighed at postnatal day 1, 3, 5, or 120. RESULTS: Fetuses exposed to a multidose of betamethasone displayed a higher breathing score at gestational day 16.5 than either to a single dose or to the placebo (mean score 4.6 vs 3.8 or 1.3; P <. 001). Alveolar development was greater after exposure to a multidose of betamethasone than after a single dose or after a placebo (mean score 4.4 vs 3.5 or 1.6; P <.001). The lung weights at gestational day 16.5 were less after a multidose of betamethasone than after a single dose of either betamethasone or a placebo (18.3 +/- 1.0 g vs 21.4 +/- 1.3 g or 23.3 +/- 1.3 g; P <.02). The lung/body weight ratio was similarly affected. This reduced weight of the lungs persisted postnatally into adulthood. CONCLUSIONS: With a CD-1 mouse model, a multidose of antenatal betamethasone accelerated fetal lung maturation more than after a single dose but was accompanied with a decrease in lung weight that persisted into adulthood.     

The relationship between cardiac function and neuropsychological status among heart transplant candidates

Psychological dependence was induced in rats by a 1-year intermittent exposure to intoxicating doses of ethanol, and recorded by the rat's ability to later take the same dose of ethanol independent of the offered concentration. Citalopram (10 or 40 mg/kg/day) was given for 3 weeks with ethanol available only the first and the last day; 10 mg/kg had no effect. On the first treatment day 40 mg/kg decreased ethanol intake. On the last treatment day 40 mg/kg had no effect. The following week the ethanol intake was higher than before the treatment in the 40 mg/kg group. During the four posttreatment weeks the ethanol intake of the 40 mg/kg group dropped significantly. Citalopram was retested 18 weeks after the first treatment during 1 week, with continuous access to ethanol; 10 mg/kg had no effect and 40 mg/kg decreased ethanol intake at day 1, reaching a minimum in day 3. A tolerance to this effect was seen at the end of the week. Thus, in this model an acute dose of citalopram can decrease ethanol intake, but tolerance to this effect develops when citalopram is given both with and without access to ethanol.