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We consider an extension of Lagrangian relaxation methods for solving the total weighted tardiness scheduling problem on a single machine. First, we investigate a straightforward relaxation method and decompose it into upper and lower subproblems. For the upper subproblem we propose an alternative solving method in the form of a local search metaheuristic. We also introduce a scaling technique by arbitrary numbers to reduce the complexity of the problem and confront it with greatest common divisor scaling. Next, we propose a novel alternative relaxation approach based on aggregating constraints. We discuss the properties and implementation of this new approach and a technique to further reduce its computational complexity. We perform a number of computer experiments on instances based on the OR-Library generation scheme to illustrate and ascertain the numerical properties of the proposed methods. The results indicate that for larger instances the proposed alternative relaxation and scaling approaches have a much better convergence rate with little to no decrease in solution quality. The results also show that the proposed local-search metaheuristic is a viable alternative to the existing solving methods.

Human skin is commonly colonized and infected by Staphylococcus aureus. Exactly how these organisms are sensed by keratinocytes has not been clearly delineated. Using a combination of metabolic and transcriptomic methodologies, we found that S. aureus infection is sensed as a metabolic stress by the hypoxic keratinocytes. This induces HIF1α signaling, which promotes IL-1β production and stimulates aerobic glycolysis to meet the metabolic requirements of infection. We demonstrate that staphylococci capable of glycolysis, including WT and agr mutants, readily induce HIF1α responses. In contrast, Δpyk glycolytic mutants fail to compete with keratinocytes for their metabolic needs. Suppression of glycolysis using 2-DG blocked keratinocyte production of IL-1β in vitro and significantly exacerbated the S. aureus cutaneous infection in a murine model. Our data suggest that S. aureus impose a metabolic stress on keratinocytes that initiates signaling necessary to promote both glycolysis and the proinflammatory response to infection.

Abstract Background Simultaneous measurement of gene expression on a genomic scale can be accomplished using microarray technology or by sequencing based methods. Researchers who perform high throughput gene expression assays often deposit their data in public databases, but heterogeneity of measurement platforms leads to challenges for the combination and comparison of data sets. Researchers wishing to perform cross platform normalization face two major obstacles. First, a choice must be made about which method or methods to employ. Nine are currently available, and no rigorous comparison exists. Second, software for the selected method must be obtained and incorporated into a data analysis workflow. Results Using two publicly available cross-platform testing data sets, cross-platform normalization methods are compared based on inter-platform concordance and on the consistency of gene lists obtained with transformed data. Scatter and ROC-like plots are produced and new statistics based on those plots are introduced to measure the effectiveness of each method. Bootstrapping is employed to obtain distributions for those statistics. The consistency of platform effects across studies is explored theoretically and with respect to the testing data sets. Conclusions Our comparisons indicate that four methods, DWD, EB, GQ, and XPN, are generally effective, while the remaining methods do not adequately correct for platform effects. Of the four successful methods, XPN generally shows the highest inter-platform concordance when treatment groups are equally sized, while DWD is most robust to differently sized treatment groups and consistently shows the smallest loss in gene detection. We provide an R package, CONOR, capable of performing the nine cross-platform normalization methods considered. The package can be downloaded at http://alborz.sdsu.edu/conor and is available from CRAN.

Gabapentin (GPT) is an antiepileptic drug that was approved in 1993 for use in the management of neurotrophic pain and as an adjunctive therapy for refractory partial seizure in humans. It is also being tested in veterinary medicine as an adjunctive medication in the treatment of pain due to laminitis, neuropathic, or chronic pain. Gabapentin is readily available by prescription and even on the internet; therefore, it has the potential of being used in racehorses to mask pain. It is for this reason that a sensitive liquid chromatography-tandem mass spectrometry method has now been developed for the analysis of GPT in equine plasma and for studying the pharmacokinetic and pharmacodynamic profiles of GPT in the horse. Sample preparation was by rapid protein precipitation with acetonitrile. Analyte separation was achieved on a reversed-phase ACE C(18) column and analyzed by a hybrid triple-quadrupole linear ion trap mass spectrometer in positive electrospray ionization mode. Limits of detection, quantification, and confirmation of GPT were 1, 10, and 20 ng/mL, respectively. Calibration curve showed excellent linearity within the 10-2500 ng/mL range (r(2) > 0.999). Intra- and interday precision defined by coefficient of variation was <10%. Intra- and interday accuracy (bias %) was within 90-110%. Measurement uncertainty estimation was 8.6%. The method has been successfully used in the analysis of GPT in equine plasma following its administration to research horses for pharmacokinetic studies and in routine forensic analysis for doping control in racehorses in the State of Pennsylvania.

Objective: To investigate the pharmacokinetics of fentanyl administered transdermally and IV in sheep., Animals: 21 adult female sheep., Procedures: Fentanyl was administered IV to 6 healthy sheep. Transdermal fentanyl patches (TFPs) were applied to 15 sheep 12 hours prior to general anesthesia and surgery. Seria blood samples were collected for 18 hours after IV injection and 84 hours after TFP application. Fentanyl concentrations were quantified via liquid chromatography-mass spectrometry, and pharmacokinetic values were estimated., Results: All sheep completed the study without complications. Following a dose of 2.5 g/kg administered IV, the half-life was 3.08 hours (range, 2.20 to 3.36 hours), volume of distribution at steady state was 8.86 L/kg (range, 5.55 to 15.04 L/kg), and systemic clearance was 3.62 L/kg/h (range, 2.51 to 5.39 L/kg/h). The TFPs were applied at a mean dose of 2.05 g/kg/h. Time to maximum plasma concentration and maximal concentration were 12 hours (range, 4 to 24 hours) and 1.30 ng/mL (range, 0.62 to 2.73 ng/mL), respectively. Fentanyl concentrations were maintained at >0.5 ng/mL for 40 hours after TFP application., Conclusions and Clinical Relevance: IV administration of fentanyl resulted in a short half-life. Application of a TFP resulted in stable blood fentanyl concentrations in sheep.

A sensitive liquid chromatographic-tandem mass spectrometric method was developed and validated for screening, quantification, and confirmation of phenylbutazone and oxyphenbutazone in equine plasma. Analytes were recovered from plasma by liquid-liquid extraction followed by separation in a reversed-phase column and identification by mass spectrometry with selected reaction monitoring in negative electrospray ionization mode. Extraction recovery for both analytes was >80%. Limits of detection, quantification, and confirmation for both analytes were 0.01 microg/mL (S/N>or= 3), 0.05 microg/mL, and 0.05 microg/mL, respectively. The assay with d9-labeled phenylbutazone as internal standard (IS) was linear over a range of 0.05-20 microg/mL (r2>0.995). Intra- and interday precision in terms of coefficient of variation was less than 15%. Intra- and interday accuracy (bias%) was within 80-120%. Hemolysis of red blood cells decreased analyte signal intensity but did not affect quantification results because an isotope-labeled IS was used. Analytes were stable in plasma for 24 h at room temperature, 9 days at 4 degrees C, and 45 days at -20 degrees C and -70 degrees C. The method was successfully used in screening, quantification, and confirmation of phenylbutazone in post-competition plasma samples obtained from racehorses. The method is simple, rapid, and reliably reproducible.

Objective: To investigate the pharmacokinetics and behavioral effects of aminorex administered IV and PO in horses., Animals: 7 Thoroughbreds., Procedures: In a cross-over design, aminorex (0.03 mg/kg) was administered IV or PO. Plasma and urinary aminorex concentrations were determined via liquid chromatography- mass spectrometry., Results: Decrease of aminorex from plasma following IV administration was described by a 3-compartment pharmacokinetic model. Median (range) values of alpha, beta, and gamma half-lives were 0.04 (0.01 to 0.28), 2.30 (1.23 to 3.09), and 18.82 (8.13 to 46.64) hours, respectively. Total body and renal clearance, the area under the plasma time curve, and initial volume of distribution were 37.26 (28.61 to 56.24) mL x min/kg, 1.25 (0.85 to 2.05) mL x min/kg, 13.39 (8.82 to 17.37) ng x h/mL, and 1.44 (0.10 to 3.64) L/kg, respectively. Oral administration was described by a 2-compartment model with first-order absorption, elimination from the central compartment, and distribution into peripheral compartments. The absorption half-life was 0.29 (0.12 to 1.07) hours, whereas the beta and gamma elimination phases were 1.93 (1.01 to 3.17) and 23.57 (15.16 to 47.45) hours, respectively. The area under the curve for PO administration was 10.38 (4.85 to 13.40) ng.h/mL and the fractional absorption was 81.8% (33.8% to 86.9%)., Conclusions and Clinical Relevance: Aminorex administered IV had a large volume of distribution, initial rapid decrease, and an extended terminal elimination. Following PO administration, there was rapid absorption, rapid initial decrease, and an extended terminal elimination. At a dose of 0.03 mg/kg, the only effects detected were transient and central in origin and were observed only following IV administration.

Objective: To determine pharmacokinetics and excretion of phenytoin in horses., Animals: 6 adult horses., Procedure: Using a crossover design, phenytoin was administered (8.8 mg/kg of body weight, IV and PO) to 6 horses to determine bioavailability (F). Phenytoin also was administered orally twice daily for 5 days to those same 6 horses to determine steady-state concentrations and excretion patterns. Blood and urine samples were collected for analysis., Results: Mean (+/- SD) elimination half-life following a single IV or PO administration was 12.6+/-2.8 and 13.9+/-6.3 hours, respectively, and was 11.2+/-4.0 hours following twice-daily administration for 5 days. Values for F ranged from 14.5 to 84.7%. Mean peak plasma concentration (Cmax) following single oral administration was 1.8+/-0.68 microg/ml. Steady-state plasma concentrations following twice-daily administration for 5 days was 4.0+/-1.8 microg/ml. Of the 12.0+/-5.4% of the drug excreted during the 36-hour collection period, 0.78+/-0.39% was the parent drug phenytoin, and 11.2+/-5.3% was 5-(phydroxyphenyl)-5-phenylhydantoin (p-HPPH). Following twice-daily administration for 5 days, phenytoin was quantified in plasma and urine for up to 72 and 96 hours, respectively, and p-HPPH was quantified in urine for up to 144 hours after administration. This excretion pattern was not consistent in all horses., Conclusions and Clinical Relevance: Variability in F, terminal elimination-phase half-life, and Cmax following single or multiple oral administration of phenytoin was considerable. This variability makes it difficult to predict plasma concentrations in horses after phenytoin administration.

Objective: To compare the pharmacokinetics of penicillin G and procaine in racehorses following i.m. administration of penicillin G procaine (PGP) with pharmacokinetics following i.m. administration of penicillin G potassium and procaine hydrochloride (PH)., Animals: 6 healthy adult mares., Procedure: Horses were treated with PGP (22,000 units of penicillin G/kg of body weight, i.m.) and with penicillin G potassium (22,000 U/kg, i.m.) and PH (1.55 mg/kg, i.m.). A minimum of 3 weeks was allowed to elapse between drug treatments. Plasma and urine penicillin G and procaine concentrations were measured by use of high-pressure liquid chromatography., Results: Median elimination phase half-lives of penicillin G were 24.7 and 12.9 hours, respectively, after administration of PGP and penicillin G potassium. Plasma penicillin G concentration 24 hours after administration of penicillin G potassium and PH was not significantly different from concentration 24 hours after administration of PGP. Median elimination phase half-life of procaine following administration of PGP (15.6 hours) was significantly longer than value obtained after administration of penicillin G potassium and PH (1 hour)., Conclusions and Clinical Relevance: Results suggest that i.m. administration of penicillin G potassium will result in plasma penicillin G concentrations for 24 hours after drug administration comparable to those obtained with administration of PGP Clearance of procaine from plasma following administration of penicillin G potassium and PH was rapid, compared with clearance following administration of PGP.