bluuebunny/crossref_metadata_2025_split huggingface dataset:
Micafungin
Authors: Carver Peggy L 
Published: September 2004

OBJECTIVE To review the pharmacology, mycology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of micafungin, an echinocandin antifungal agent. DATA SOURCES A MEDLINE search, restricted to English language, was conducted from 1978 to November 2003. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America from 1996 to 2003 and information available through the manufacturer's Web site. STUDY SELECTION AND DATA EXTRACTION In vitro and preclinical studies, as well as Phase II and III clinical trials, were evaluated to summarize the clinical efficacy and safety of micafungin. All published and unpublished trials and abstracts citing micafungin were selected. DATA SYNTHESIS Micafungin has shown in vitro activity against many yeasts and a variety of molds. Micafungin can be administered only parenterally. Efficacy has been illustrated in open noncomparative studies of esophageal candidiasis in HIV-infected patients and in comparative trials as antifungal prophylaxis in patients undergoing hematopoietic stem-cell transplantation. Adverse events appear mild and limited; the most commonly reported adverse events include hyperbilirubinemia, nausea, and diarrhea. CONCLUSIONS Micafungin has activity against Aspergillus spp. and a variety of Candida spp., including azole-resistant strains. Micafungin demonstrates efficacy in the treatment of esophageal candidiasis in HIV-infected patients and appears superior to fluconazole as antifungal prophylaxis in patients undergoing hematopoietic stem-cell transplantation. Based on case reports and in vitro efficacy, micafungin may prove to be a clinically useful agent in the treatment of other fungal diseases; however, these indications await the results of clinical trials.
Impact of Fluconazole Administration on Outcomes in Critically Ill Patients
Authors: Garrelts James C , Schroeder Todd R , Harrison Paul B 
Published: September 2004

BACKGROUND Serious infections caused by Candida spp. are an increasingly important cause of morbidity and mortality in critically ill patients. It is unclear which patients will benefit from therapy and at what point to institute treatment. OBJECTIVE To evaluate the impact of administration of fluconazole therapy in critically ill trauma patients on mortality, length of hospital stay, incidence of deep-seated fungal infection, and positive fungal cultures from any site. METHODS We conducted a retrospective, matched case—control study of 116 critically ill surgical trauma patients who did or did not receive fluconazole. Patients were followed until hospital discharge or death. A consecutive sample of 58 patients who received fluconazole was selected. A parallel group of patients was evaluated, from which 58 were matched with fluconazole-treated patients based on age (± 5 y), gender, and APACHE II score (± 3). RESULTS The groups of patients were well matched, with the exception of central venous catheter placement and broad-spectrum antibiotic use. We found no difference between groups in hospital mortality (21% vs 26%; p = 0.661) or incidence of deep-seated fungal infection (0% vs 2%; p = NS). However, patients receiving fluconazole had a significantly longer stay in both the intensive care unit (ICU) (18 ± 13 vs 7 ± 11 days; p < 0.001) and hospital (25 ± 15 vs 9 ± 11 days; p < 0.001). Fluconazole patients were significantly more likely to have Candida cultured from sites associated with colonization (43% vs 2%; p < 0.001), possibly explaining why they received fluconazole. CONCLUSIONS We were unable to detect a benefit from use of fluconazole in our surgical trauma patient population. Isolation of Candida from the mouth or throat alone, in the absence of correlating clinical signs of infection, should not lead to initiation of fluconazole therapy. Fluconazole use should be reserved for carefully selected patients in the trauma ICU setting.
Urinary Tract Infections During Pregnancy
Authors: Le Jennifer , Briggs Gerald G , McKeown Anna , Bustillo Gerardo 
Published: September 2004

OBJECTIVE To provide a comprehensive review of urinary tract infections (UTIs) during pregnancy. All aspects of UTIs, including epidemiology, pathogenesis, resistance, clinical features, diagnosis, treatment, and prevention, were reviewed. DATA SOURCES MEDLINE (1966–August 2003) and Cochrane Library searches were performed using the key search terms urinary tract infection, pyelonephritis, cystitis, asymptomatic bacteriuria, and resistance. STUDY SELECTION AND DATA EXTRACTION All article abstracts were evaluated for relevance. Only articles pertaining to pregnancy were included. The majority of published literature were review articles; the number of original clinical studies was limited. DATA SYNTHESIS UTIs are the most common bacterial infections during pregnancy. They are characterized by the presence of significant bacteria anywhere along the urinary tract. Pyelonephritis is the most common severe bacterial infection that can lead to perinatal and maternal complications including premature delivery, infants with low birth weight, fetal mortality, preeclampsia, pregnancy-induced hypertension, anemia, thrombocytopenia, and transient renal insufficiency. Enterobacteriaceae account for 90% of UTIs. The common antibiotics used are nitrofurantoin, cefazolin, cephalexin, ceftriaxone, and gentamicin. CONCLUSIONS Therapeutic management of UTIs in pregnancy requires proper diagnostic workup and thorough understanding of antimicrobial agents to optimize maternal outcome, ensure safety to the fetus, and prevent complications that lead to significant morbidity and mortality in both the fetus and the mother.
The Changing Face of Antibiotic Prescribing: The Mutant Selection Window
Authors: Epstein Benjamin J , Gums John G , Drlica Karl 
Published: September 2004

OBJECTIVE To describe the mutant selection window, discuss supporting evidence and limitations, and suggest potential applications for clinical practice. DATA SOURCES A MEDLINE search (1990–December 2003) of the English-language literature was conducted using the key words antibiotic, antimicrobial, resistance, mutant, selection window, prevention, MPC, and MSW in various combinations. Original investigations and reviews evaluating the mutant selection window, including abstracts and proceedings, were considered for inclusion. Published articles were also cross-referenced, and experts were contacted to locate additional pertinent data. STUDY SELECTION AND DATA EXTRACTION All data sources identified were evaluated and all information deemed relevant was included. DATA SYNTHESIS Until recently, physicians have had few ways to preserve antimicrobials from resistance other than by prescribing the agents less often. The mutant selection window hypothesis may modify this paradigm by shifting the focus to dosing strategies that reduce the growth of resistant mutants. Conventional dosing strategies have been formulated on the likelihood of curing an individual patient. Unfortunately, doses that cure patients appear to enrich resistant subpopulations of bacteria, thus promoting resistance. Antimicrobial—pathogen combinations can be identified that minimize mutant selection and cure patients while possibly restricting the progression of resistance. CONCLUSIONS The mutant selection window hypothesis provides a framework for considering the contribution of dosing to resistance, and it offers ideas for restricting the enrichment of resistant mutants and antimicrobial resistance.
Lumiracoxib Does Not Affect Methotrexate Pharmacokinetics in Rheumatoid Arthritis Patients
Authors: Hartmann Stefan N , Rordorf Christiane M , Milosavljev Slavica , Branson Janice M , Chales Gérard H , Juvin Robert R , Lafforgue Pierre , Le Parc Jean Marie , Tavernier Christian G , Meyer Olivier C 
Published: September 2004

BACKGROUND Methotrexate and nonsteroidal antiinflammatory drugs are frequently coadministered in the treatment of rheumatoid arthritis (RA). OBJECTIVE To evaluate the effect of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor, on methotrexate pharmacokinetics and short-term safety in patients with RA. METHODS This multicenter, randomized, double-blind, placebo-controlled crossover study enrolled 18 patients (mean age 49.1 y) with stable RA. Patients were randomized to receive methotrexate 7.5–15 mg orally once weekly plus either lumiracoxib 400 mg/day or placebo for 7 days. Patients then received the other treatment combination for an additional 7 days. Serial blood and urine were collected for 24 hours after the methotrexate dose on day 1 (methotrexate alone) and days 8 and 15 (combination treatment). RESULTS Plasma methotrexate pharmacokinetics (AUC0–t, maximum concentration [Cmax], time to Cmax) and methotrexate protein binding were similar for methotrexate alone (108.0 ng•h/mL, 26.7 ng/mL, 1.5 h, and 57.1%, respectively), methotrexate/lumiracoxib (110.2 ng•h/mL, 27.5 ng/mL, 1.0 h, and 53.7%, respectively), and methotrexate/placebo (101.8 ng•h/mL, 22.6 ng/mL, 1.0 h, and 57.0%, respectively). Similarly, no clinically significant difference was found in the urinary excretion of methotrexate. Mean exposure to the 7–OH metabolite was lower when methotrexate was given with lumiracoxib compared with placebo, shown by a reduction in AUC and Cmax, although similar amounts of the metabolite were recovered in urine following both lumiracoxib and placebo. Coadministration of methotrexate and lumiracoxib was well tolerated. CONCLUSIONS Lumiracoxib had no significant effect on the pharmacokinetics, protein binding, or urinary excretion of coadministered methotrexate in patients with RA.
Recombinant Factor VIIa for Refractory Bleeding Following Orthotopic Heart Transplantation
Authors: Flynn Jeremy D , Pajoumand Mehrnaz , Camp Phillip C , Jahania M Salik , Ramaiah Chand , Akers Wendell S 
Published: September 2004

OBJECTIVE To report a case of successful use of recombinant factor VIIa (rFVIIa) for the treatment of refractory bleeding in a patient undergoing orthotopic heart transplantation. Case Summary A 57-year-old white male with idiopathic cardiomyopathy was taken to the operating room for explantation of his left-ventricular assist device and orthotopic heart transplantation. He experienced excessive generalized oozing that required transfusions of multiple units of blood products and significant amounts of Cellsaver (washed red blood cells via autotransfusion) without achieving adequate hemostasis. After ruling out any obvious surgical sources of bleeding and attempting to correct all coagulation deficiencies, the clinicians administered rFVIIa 90 μg/kg. The oozing rapidly declined to a negligible level, chest tubes and sternal wires were placed, and the chest was closed. The patient was on minimal inotropic support and was transferred to the intensive care unit in stable condition. DISCUSSION Cardiac surgery is often associated with significant disruption of the coagulation system, particularly in high-risk patients, such as those undergoing removal of a ventricular assist device and subsequent orthotopic heart transplantation. This can lead to life-threatening bleeding that can require multiple hemostatic agents and significant transfusions to restore hemostasis. Recently, rFVIIa has been utilized as an alternative to massive transfusion for treatment of refractory bleeding in several patient populations, including some cardiac surgery patients. CONCLUSIONS rFVIIa appears to be a viable option as rescue therapy for treatment of refractory bleeding following orthotopic heart transplantation. Despite the anecdotal success of rFVIIa in this setting, further clinical research is needed.
Brain-Derived Neurotrophic Factor Regulates the Onset and Severity of Motor Dysfunction Associated with Enkephalinergic Neuronal Degeneration in Huntington's Disease
Authors: Canals Josep M. , Pineda José R. , Torres-Peraza Jesús F. , Bosch Miquel , Martín-Ibañez Raquel , Muñoz M. Teresa , Mengod Guadalupe , Ernfors Patrik , Alberch Jordi 
Published: September 2004

The mechanism that controls the selective vulnerability of striatal neurons in Huntington's disease is unclear. Brain-derived neurotrophic factor (BDNF) protects striatal neurons and is regulated by Huntingtin through the interaction with the neuron-restrictive silencer factor. Here, we demonstrate that the downregulation of BDNF by mutant Huntingtin depends on the length and levels of expression of the CAG repeats in cell cultures. To analyze the functional effects of these changes in BDNF in Huntington's disease, we disrupted the expression ofbdnfin a transgenic mouse model by cross-matingbdnf+/ -mice with R6/1 mice. Thus, we compared transgenic mice for mutant Huntingtin with different levels of BDNF. Using this double mutant mouse line, we show that the deficit of endogenous BDNF modulates the pathology of Huntington's disease. The decreased levels of this neurotrophin advance the onset of motor dysfunctions and produce more severe uncoordinated movements. This behavioral pathology correlates with the loss of striatal dopamine and cAMP-regulated phosphoprotein-32-positive projection neurons. In particular, the insufficient levels of BDNF cause specific degeneration of the enkephalinergic striatal projection neurons, which are the most affected cells in Huntington's disease. This neuronal dysfunction can specifically be restored by administration of exogenous BDNF.Therefore, the decrease in BDNF levels plays a key role in the specific pathology observed in Huntington's disease by inducing dysfunction of striatal enkephalinergic neurons that produce severe motor dysfunctions. Hence, administration of exogenous BDNF may delay or stop illness progression.
Significance Tests and Weighted Values for AFLP Similarities, Based on Arabidopsis in Silico AFLP Fragment Length Distributions
Authors: Koopman Wim J M , Gort Gerrit 
Published: September 2004

AbstractMany AFLP studies include relatively unrelated genotypes that contribute noise to data sets instead of signal. We developed: (1) estimates of expected AFLP similarities between unrelated genotypes, (2) significance tests for AFLP similarities, enabling the detection of unrelated genotypes, and (3) weighted similarity coefficients, including band position information. Detection of unrelated genotypes and use of weighted similarity coefficients will make the analysis of AFLP data sets more informative and more reliable. Test statistics and weighted coefficients were developed for total numbers of shared bands and for Dice, Jaccard, Nei and Li, and simple matching (dis)similarity coefficients. Theoretical and in silico AFLP fragment length distributions (FLDs) were examined as a basis for the tests. The in silico AFLP FLD based on the Arabidopsis thaliana genome sequence was the most appropriate for angiosperms. The G + C content of the selective nucleotides in the in silico AFLP procedure significantly influenced the FLD. Therefore, separate test statistics were calculated for AFLP procedures with high, average, and low G + C contents in the selective nucleotides. The test statistics are generally applicable for angiosperms with a G + C content of ∼35–40%, but represent conservative estimates for genotypes with higher G + C contents. For the latter, test statistics based on a rice genome sequence are more appropriate.
Sex-Specific Meiotic Drive and Selection at an Imprinted Locus
Authors: Úbeda Francisco , Haig David 
Published: September 2004

Abstract
We present a one-locus model that breaks two symmetries of Mendelian genetics. Whereas symmetry of transmission is breached by allowing sex-specific segregation distortion, symmetry of expression is breached by allowing genomic imprinting. Simple conditions for the existence of at least one polymorphic stable equilibrium are provided. In general, population mean fitness is not maximized at polymorphic equilibria. However, mean fitness at a polymorphic equilibrium with segregation distortion may be higher than mean fitness at the corresponding equilibrium with Mendelian segregation if one (or both) of the heterozygote classes has higher fitness than both homozygote classes. In this case, mean fitness is maximized by complete, but opposite, drive in the two sexes. We undertook an extensive numerical analysis of the parameter space, finding, for the first time in this class of models, parameter sets yielding two stable polymorphic equilibria. Multiple equilibria exist both with and without genomic imprinting, although they occurred in a greater proportion of parameter sets with genomic imprinting.
Maximum-Likelihood Estimation of Rates of Recombination Within Mating-Type Regions
Authors: Takebayashi Naoki , Newbigin Ed , Uyenoyama Marcy K 
Published: September 2004

AbstractFeatures common to many mating-type regions include recombination suppression over large genomic tracts and cosegregation of genes of various functions, not necessarily related to reproduction. Model systems for homomorphic self-incompatibility (SI) in flowering plants share these characteristics. We introduce a method for the exact computation of the joint probability of numbers of neutral mutations segregating at the determinant of mating type and at a linked marker locus. The underlying Markov model incorporates strong balancing selection into a two-locus coalescent. We apply the method to obtain a maximum-likelihood estimate of the rate of recombination between a marker locus, 48A, and S-RNase, the determinant of SI specificity in pistils of Nicotiana alata. Even though the sampled haplotypes show complete allelic linkage disequilibrium and recombinants have never been detected, a highly significant deficiency of synonymous substitutions at 48A compared to S-RNase suggests a history of recombination. Our maximum-likelihood estimate indicates a rate of recombination of perhaps 3 orders of magnitude greater than the rate of synonymous mutation. This approach may facilitate the construction of genetic maps of regions tightly linked to targets of strong balancing selection.
Application of Coalescent Methods to Reveal Fine-Scale Rate Variation and Recombination Hotspots
Authors: Fearnhead Paul , Harding Rosalind M , Schneider Julie A , Myers Simon , Donnelly Peter 
Published: September 2004

Abstract
There has been considerable recent interest in understanding the way in which recombination rates vary over small physical distances, and the extent of recombination hotspots, in various genomes. Here we adapt, apply, and assess the power of recently developed coalescent-based approaches to estimating recombination rates from sequence polymorphism data. We apply full-likelihood estimation to study rate variation in and around a well-characterized recombination hotspot in humans, in the β-globin gene cluster, and show that it provides similar estimates, consistent with those from sperm studies, from two populations deliberately chosen to have different demographic and selectional histories. We also demonstrate how approximate-likelihood methods can be used to detect local recombination hotspots from genomic-scale SNP data. In a simulation study based on 80 100-kb regions, these methods detect 43 out of 60 hotspots (ranging from 1 to 2 kb in size), with only two false positives out of 2000 subregions that were tested for the presence of a hotspot. Our study suggests that new computational tools for sophisticated analysis of population diversity data are valuable for hotspot detection and fine-scale mapping of local recombination rates.
Comparative Mapping of a Major Aluminum Tolerance Gene in Sorghum and Other Species in the Poaceae
Authors: Magalhaes Jurandir V , Garvin David F , Wang Yihong , Sorrells Mark E , Klein Patricia E , Schaffert Robert E , Li Li , Kochian Leon V 
Published: September 2004

Abstract
In several crop species within the Triticeae tribe of the grass family Poaceae, single major aluminum (Al) tolerance genes have been identified that effectively mitigate Al toxicity, a major abiotic constraint to crop production on acidic soils. However, the trait is quantitatively inherited in species within other tribes, and the possible ancestral relationships between major Al tolerance genes and QTL in the grasses remain unresolved. To help establish these relationships, we conducted a molecular genetic analysis of Al tolerance in sorghum and integrated our findings with those from previous studies performed in crop species belonging to different grass tribes. A single locus, AltSB, was found to control Al tolerance in two highly Al tolerant sorghum cultivars. Significant macrosynteny between sorghum and the Triticeae was observed for molecular markers closely linked to putatively orthologous Al tolerance loci present in the group 4 chromosomes of wheat, barley, and rye. However, AltSB was not located within the homeologous region of sorghum but rather mapped near the end of sorghum chromosome 3. Thus, AltSB not only is the first major Al tolerance gene mapped in a grass species that does not belong to the Triticeae, but also appears to be different from the major Al tolerance locus in the Triticeae. Intertribe map comparisons suggest that a major Al tolerance QTL on rice chromosome 1 is likely to be orthologous to AltSB, whereas another rice QTL on chromosome 3 is likely to correspond to the Triticeae group 4 Al tolerance locus. Therefore, this study demonstrates a clear evolutionary link between genes and QTL encoding the same trait in distantly related species within a single plant family.