bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of an Adverse Drug Reaction Electronic Reporting System Integrated into a Hospital Information System
Authors: Ortega Ana , Aguinagalde Aránzazu , Lacasa Carlos , Aquerreta Irene , Fernández-Benítez Margarita , Fernández Luis M 
Published: September 2008

Background: Adverse drug reaction (ADR) spontaneous reporting is the primary method of postmarketing drug surveillance: although it is an important part of postmarketing drug surveillance, it is underused. Before 2004, almost no ADRs were reported in our 400-bed hospital. As an electronic hospital information system was available in our hospital, we developed a tool (ADR-RS-IHIS) for ADR reporting integrated into the hospital information system to facilitate reporting through easy use, automatic input of certain information, increased accessibility, real-time review, and intervention. Objective: To analyze the efficacy of the ADR-RS-IHIS in increasing ADR reporting to the national drug surveillance system, propose and implement improvements to increase ADR reporting, and evaluate the impact of these improvements, Methods: Every ADR reported through the ADR-RS-IHIS was evaluated retrospectively. Two study phases for evaluating ADR-RS-IHIS efficacy were identified. Phase I took place April 2004-August 2006; in April 2006, an interim analysis was performed to propose improvements. Phase II took place September 2006-April 2007 for evaluation of the impact made by the proposed improvements. Efficacy in the phase I and improvement impact on phase II were measured as the number of ADRs reported to the national drug surveillance system Results: The rate of ADRs reported per month to the national system increased from 0 before 2004 to 0.91 in phase I and 1.62 in phase II (2.25 if delayed reporting was considered). Improvement measures included: allowing nurses to report ADRs in the same way as physicians and pharmacists, automatic form filling of certain information from the electronic hospital information system, easier ADR report analysis, and automatic notification to the allergy department regarding suspected allergies. Conclusions: An ADR reporting system integrated into the electronic hospital information system is effective for increasing the number of ADRs reported to the national drug surveillance system. Allowing nurses to report ADRs in a manner similar to that of physicians and pharmacists, as well as automatic entry of certain data into the form, contributes to the improvement of the system.
Incremental Drug Treatment Cost in HIV-Positive Patients in Industry-Sponsored Clinical Trials
Authors: Perrín Rosario Santolaya , López Fernando J García 
Published: September 2008

Background: Drugs used in clinical trials supported by the pharmaceutical industry are supplied free of charge by the companies. However, maintenance of treatment with those drugs when the trials have finished can generate extra cost for patients who participated in the trials. Objective: To assess whether HIV-infected patients' participation in clinical trials results in drug cost savings or increases. Methods: An analysis of alt antiretrovirals dispensed to HIV-infected outpatients prior to, during, and after their participation in clinical trials in a university hospital during a 2-year period was conducted. Only patients who completed the trial during the study period were included. The following outcomes were measured: (1) cost saved (difference between cost per day during the trial and cost per day before study entry), (2) cost generated (difference between cost per day at the end of the trial and cost per day before study entry), (3) balance between cost saved and cost generated, and (4) number of days that a patient received a drug once the trial was finished to generate cost, considering costs saved. All data were extracted from the hospital pharmacy database. A stratified analysis by type of clinical trial (ordinary or expanded use) was undertaken. Results: Data from 61 patients were analyzed. The cost of drug therapy during patient participation in a clinical trial was lower than the cost prior to inclusion. Therefore, mean drug savings of $10.38 (US) per patient day resulted (95% CI –5.9 to 14.84), The mean cost generated was $8.74 per patient day (95% CI 3.95 to 13.52). Conclusions: A patient's participation in a clinical trial or expanded-access clinical trial generated extra cost once the trial had finished because the cost of drug therapy was higher at the end of the study. In our study, the daily drug costs saved during the trial were similar to the daily drug costs generated.
Trastuzumab-Induced Hepatotoxicity
Authors: Srinivasan Sridhar , Parsa Venkata , Liu Chin Y , Fontana Joseph A 
Published: September 2008

Objective: To report a case of probable trastuzumab-induced hepatotoxicity. Case Summary: A 54-yoar-old African American woman presented with locally advanced right-sided breast cancer that was found to be strongly positive for human epidermal growth factor receptor 2 (HER2) by fluorescence in situ hybridization. She was treated with neoadjuvant chemotherapy with 4 cycles of dose-dense doxorubicin and cyclophosphamide. Laboratory test results, including liver function tests (LFTs), were normal at that time. Therapy consisting of weekly doses of paditaxel 80 mg/m2 and a loading dose of trastuzumab 4 mg/kg for the first week and 2 mg/kg weekly thereafter was started. Alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels began to increase after the initial dose; the levels were significantly elevated after the fifth cycle. Paclitaxel was withheld, and trastuzumab was continued, as there were no prior reported cases of trastuzumab-induced hepatotoxicity at that time. Other possible etiologies for the elevated enzyme levels, including metastasis to the liver, were excluded. The patient continued to receive trastuzumab for a total of 8 weeks; it was discontinued at that time because enzyme levels continued to increase. When trastuzumab was discontinued, enzyme levels returned to normal. Subsequently, surgical resection of the cancer was performed. The patient's lymph nodes wore found to be involved and, because of the high risk of disease recurrence, she was re-challenged with trastuzumab, LFTs showed enzyme levels rising again and trastuzumab was discontinued after 2 cycles, with subsequent normalization of the levels. She was then treated with weekly paclitaxel and her LFT values continued to be in the near-normal range. Discussion: There were no comorbidities in this patient and, on initiation of trastuzumab, her liver enzyme levels were normal. The levels became elevated after initiation of trastuzumab, normalized after its discontinuation, and increased upon rechallenge. According to a validated drug-induced hepatotoxicity scale, trastuzumab was the probable cause of hepatotoxicity in this patient. Conclusions: Livor enzyme levels must be closely monitored in patients receiving trastuzumab. To our knowledge, this is the first report of trastuzumab-induced hepatotoxicity requiring discontinuation of the drug.
Compatibility and Aerosol Characteristic of Formoterol Fumarate Mixed with Other Nebulizing Solutions
Authors: Akapo Samuel , Gupta June , Martinez Eloisa , McCrea Chithra , Ye Liwen , Roach Mark 
Published: September 2008

Background: Patients with chronic obstructive pulmonary disease (COPO) are often given admixtures of nebulizable drugs to minimize the time of administration in treatment regimens. Objective: To evaluate the physicochemical compatibility and aerodynamic characteristics of formoterol fumarate 20 μg/2 mL when mixed or sequentially nebulized with budesonide inhalation suspension 0.5 mg/2 mL, ipratropium bromide 0.5 mg/2.5 mL, cromolyn sodium 20 mg/2 mL, or acetylcysteine 10% (100 mg/mL). Methods: The admixtures were prepared in triplicate and analyzed for physicochemical compatibility at 0, 15, 30, and 60 minutes after mixing at room temperature. Physical compatibility was determined by visual examination and measurements of pH, osmolality, and turbidity. Chemical stability was evaluated using compendial or in-house-validated high-performance liquid chromatography (HPLC) assay methods. The aerodynamic characteristics of the admixtures or sequentially nebulized drugs were determined from aerosols generated from a Pari LC Plus nebulizer, using an 8-stage cascade impactor followed by HPLC analysis of the deposited drug. Results: The admixtures remained clear, colorless solutions with no precipitation. except for cloudiness observed in the formoterol/budesonide combination due to budesonide suspension. The pH, osmolality, and turbidity for all admixtures were within the initial values (=3%), and there were no significant changes (=2%) in potency of the active components throughout the 1-hour study period. Due to increased drug volume or reconcentration in the nebulizer cup, the respirable fraction/delivered dose increased significantly (p < 0.05) for the mixed or sequentially nebulized drug Howover, the fine particle fraction (FPF), mass median aerodynamic diameter, and geometric standard deviation generally remained unchanged for all admixtures, with the exception of FPF for the formoterol/budesonide combination. Conclusions: Our results indicate that admixtures of formoterol with budesonide, ipratropium, cromolyn, or acetylcysteine are physically and chemically compatible. However, admixing or sequential nebulization significantly increased the amount of drug delivered compared with single drug nebulization. The clinical implications of the in vitro data in patients with COPD have not been determined.
End Joining atCaenorhabditis elegansTelomeres
Authors: Lowden Mia Rochelle , Meier Bettina , Lee Teresa Wei-sy , Hall Julie , Ahmed Shawn 
Published: September 2008

AbstractCritically shortened telomeres can be subjected to DNA repair events that generate end-to-end chromosome fusions. The resulting dicentric chromosomes can enter breakage–fusion–bridge cycles, thereby impeding elucidation of the structures of the initial fusion events and a mechanistic understanding of their genesis. Current models for the molecular basis of fusion of critically shortened, uncapped telomeres rely on PCR assays that typically capture fusion breakpoints created by direct ligation of chromosome ends. Here we use independent approaches that rely on distinctive features of Caenorhabditis elegans to study the frequency of direct end-to-end chromosome fusion in telomerase mutants: (1) holocentric chromosomes that allow for genetic isolation of stable end-to-end fusions and (2) unique subtelomeric sequences that allow for thorough PCR analysis of samples of genomic DNA harboring multiple end-to-end fusions. Surprisingly, only a minority of end-to-end fusion events resulted from direct end joining with no additional genome rearrangements. We also demonstrate that deficiency for the C. elegans Ku DNA repair heterodimer does not affect telomere length or cause synthetic effects in the absence of telomerase.
Patterns of Amino Acid Evolution in the Drosophila ananassae Chimeric Gene, siren, Parallel Those of Other Adh-Derived Chimeras
Authors: Shih Hung-Jui , Jones Corbin D 
Published: September 2008

Abstract
siren1 and siren2 are novel alcohol dehydrogenase (Adh)-derived chimeric genes in the Drosophila bipectinata complex. D. ananassae, however, harbors a single homolog of these genes. Like other Adh-derived chimeric genes, siren evolved adaptively shortly after it was formed. These changes likely shifted the catalytic activity of siren.
Domain-Specific Regulation of Recombination inCaenorhabditis elegansin Response to Temperature, Age and Sex
Authors: Lim Jaclyn G Y , Stine Rachel R W , Yanowitz Judith L 
Published: September 2008

AbstractIt is generally considered that meiotic recombination rates increase with temperature, decrease with age, and differ between the sexes. We have reexamined the effects of these factors on meiotic recombination in the nematode Caenorhabditis elegans using physical markers that encompass &gt;96% of chromosome III. The only difference in overall crossover frequency between oocytes and male sperm was observed at 16°. In addition, crossover interference (CI) differs between the germ lines, with oocytes displaying higher CI than male sperm. Unexpectedly, our analyses reveal significant changes in crossover distribution in the hermaphrodite oocyte in response to temperature. This feature appears to be a general feature of C. elegans chromosomes as similar changes in response to temperature are seen for the X chromosome. We also find that the distribution of crossovers changes with age in both hermaphrodites and females. Our observations indicate that it is the oocytes from the youngest mothers—and not the oldest—that showed a different pattern of crossovers. Our data enhance the emerging hypothesis that recombination in C. elegans, as in humans, is regulated in large chromosomal domains.
Pnc1p-Mediated Nicotinamide Clearance Modifies the Epigenetic Properties of rDNA Silencing in Saccharomyces cerevisiae
Authors: McClure Julie M , Gallo Christopher M , Smith Daniel L , Matecic Mirela , Hontz Robert D , Buck Stephen W , Racette Frances G , Smith Jeffrey S 
Published: September 2008

Abstract
The histone deacetylase activity of Sir2p is dependent on NAD+ and inhibited by nicotinamide (NAM). As a result, Sir2p-regulated processes in Saccharomyces cerevisiae such as silencing and replicative aging are susceptible to alterations in cellular NAD+ and NAM levels. We have determined that high concentrations of NAM in the growth medium elevate the intracellular NAD+ concentration through a mechanism that is partially dependent on NPT1, an important gene in the Preiss–Handler NAD+ salvage pathway. Overexpression of the nicotinamidase, Pnc1p, prevents inhibition of Sir2p by the excess NAM while maintaining the elevated NAD+ concentration. This growth condition alters the epigenetics of rDNA silencing, such that repression of a URA3 reporter gene located at the rDNA induces growth on media that either lacks uracil or contains 5-fluoroorotic acid (5-FOA), an unusual dual phenotype that is reminiscent of telomeric silencing (TPE) of URA3. Despite the similarities to TPE, the modified rDNA silencing phenotype does not require the SIR complex. Instead, it retains key characteristics of typical rDNA silencing, including RENT and Pol I dependence, as well as a requirement for the Preiss–Handler NAD+ salvage pathway. Exogenous nicotinamide can therefore have negative or positive impacts on rDNA silencing, depending on the PNC1 expression level.
Lethal Mutagenesis of Bacteria
Authors: Bull James J , Wilke Claus O 
Published: September 2008

Abstract
Lethal mutagenesis, the killing of a microbial pathogen with a chemical mutagen, is a potential broad-spectrum antiviral treatment. It operates by raising the genomic mutation rate to the point that the deleterious load causes the population to decline. Its use has been limited to RNA viruses because of their high intrinsic mutation rates. Microbes with DNA genomes, which include many viruses and bacteria, have not been considered for this type of treatment because their low intrinsic mutation rates seem difficult to elevate enough to cause extinction. Surprisingly, models of lethal mutagenesis indicate that bacteria may be candidates for lethal mutagenesis. In contrast to viruses, bacteria reproduce by binary fission, and this property ensures their extinction if subjected to a mutation rate &gt;0.69 deleterious mutations per generation. The extinction threshold is further lowered when bacteria die from environmental causes, such as washout or host clearance. In practice, mutagenesis can require many generations before extinction is achieved, allowing the bacterial population to grow to large absolute numbers before the load of deleterious mutations causes the decline. Therefore, if effective treatment requires rapid population decline, mutation rates ≫0.69 may be necessary to achieve treatment success. Implications for the treatment of bacteria with mutagens, for the evolution of mutator strains in bacterial populations, and also for the evolution of mutation rate in cancer are discussed.
Chromosome Segmental Dosage Analysis of Maize Morphogenesis Using B–A–A Translocations
Authors: Sheridan William F , Auger Donald L 
Published: September 2008

Abstract
The B–A–A translocations have enabled us to simultaneously assess the possible dosage-sensitive interactions of two nonhomologous chromosome segments in affecting maize plant development. Maize B–A–A translocations contain segments of two nonhomologous essential A chromosomes in tandem arrangement attached to a segment of the long arm of a supernumerary B chromosome. By utilizing the frequent nondisjunction of the B centromere at the second pollen mitosis we produced plants containing an extra copy of the two A chromosome segments. We compared these hyperploid plants with nonhyperploid plants by measuring leaf width, plant height, ear height, internode length, stalk circumference, leaf length, and tassel-branch number in 20 paired families that involved one of the chromosome arms 1S, 1L, 4L, 5S, and 10L. One or more of the seven measured traits displayed dosage sensitivity among 17 of the 20 B–A–A translocations, which included the involvement of chromosome arms 2L, 3L, 5L, 6L, and 7L. The most obvious effect of an increased dosage of the B–A–A translocation was a significant decrease in the traits in the hyperploid plants. These effects may be either the additive effects of hyperploidy for the two chromosome segments or a result of gene interaction between them.
FST andQST Under Neutrality
Authors: Miller Judith R , Wood Bryan P , Hamilton Matthew B 
Published: September 2008

AbstractA commonly used test for natural selection has been to compare population differentiation for neutral molecular loci estimated by FST and for the additive genetic component of quantitative traits estimated by QST. Past analytical and empirical studies have led to the conclusion that when averaged over replicate evolutionary histories, QST = FST under neutrality. We used analytical and simulation techniques to study the impact of stochastic fluctuation among replicate outcomes of an evolutionary process, or the evolutionary variance, of QST and FST for a neutral quantitative trait determined by n unlinked diallelic loci with additive gene action. We studied analytical models of two scenarios. In one, a pair of demes has recently been formed through subdivision of a panmictic population; in the other, a pair of demes has been evolving in allopatry for a long time. A rigorous analysis of these two models showed that in general, it is not necessarily true that mean QST = FST (across evolutionary replicates) for a neutral, additive quantitative trait. In addition, we used finite-island model simulations to show there is a strong positive correlation between QST and the difference QST − FST because the evolutionary variance of QST is much larger than that of FST. If traits with relatively large QST values are preferentially sampled for study, the difference between QST and FST will also be large and positive because of this correlation. Many recent studies have used tests of the null hypothesis QST = FST to identify diversifying or uniform selection among subpopulations for quantitative traits. Our findings suggest that the distributions of QST and FST under the null hypothesis of neutrality will depend on species-specific biology such as the number of subpopulations and the history of subpopulation divergence. In addition, the manner in which researchers select quantitative traits for study may introduce bias into the tests. As a result, researchers must be cautious before concluding that selection is occurring when QST ≠ FST.
A Genome-Scan Method to Identify Selected Loci Appropriate for Both Dominant and Codominant Markers: A Bayesian Perspective
Authors: Foll Matthieu , Gaggiotti Oscar 
Published: September 2008

Abstract
Identifying loci under natural selection from genomic surveys is of great interest in different research areas. Commonly used methods to separate neutral effects from adaptive effects are based on locus-specific population differentiation coefficients to identify outliers. Here we extend such an approach to estimate directly the probability that each locus is subject to selection using a Bayesian method. We also extend it to allow the use of dominant markers like AFLPs. It has been shown that this model is robust to complex demographic scenarios for neutral genetic differentiation. Here we show that the inclusion of isolated populations that underwent a strong bottleneck can lead to a high rate of false positives. Nevertheless, we demonstrate that it is possible to avoid them by carefully choosing the populations that should be included in the analysis. We analyze two previously published data sets: a human data set of codominant markers and a Littorina saxatilis data set of dominant markers. We also perform a detailed sensitivity study to compare the power of the method using amplified fragment length polymorphism (AFLP), SNP, and microsatellite markers. The method has been implemented in a new software available at our website (http://www-leca.ujf-grenoble.fr/logiciels.htm).
Secondary Mutations Correct Fitness Defects inToxoplasma gondiiWith Dinitroaniline Resistance Mutations
Authors: Ma Christopher , Tran Johnson , Li Catherine , Ganesan Lakshmi , Wood David , Morrissette Naomi 
Published: September 2008

AbstractDinitroanilines (oryzalin, trifluralin, ethafluralin) disrupt microtubules in protozoa but not in vertebrate cells, causing selective death of intracellular Toxoplasma gondii parasites without affecting host cells. Parasites containing α1-tubulin point mutations are dinitroaniline resistant but show increased rates of aberrant replication relative to wild-type parasites. T. gondii parasites bearing the F52Y mutation were previously demonstrated to spontaneously acquire two intragenic mutations that decrease both resistance levels and replication defects. Parasites bearing the G142S mutation are largely dependent on oryzalin for viable growth in culture. We isolated 46 T. gondii lines that have suppressed microtubule defects associated with the G142S or the F52Y mutations by acquiring secondary mutations. These compensatory mutations were α1-tubulin pseudorevertants or extragenic suppressors (the majority alter the β1-tubulin gene). Many secondary mutations were located in tubulin domains that suggest that they function by destabilizing microtubules. Most strikingly, we identified seven novel mutations that localize to an eight-amino-acid insert that stabilizes the α1-tubulin M loop, including one (P364R) that acts as a compensatory mutation in both F52Y and G142S lines. These lines have reduced dinitroaniline resistance but most perform better than parental lines in competition assays, indicating that there is a trade-off between resistance and replication fitness.