bluuebunny/crossref_metadata_2025 huggingface dataset:
Multipoint identity-by-descent computations for single-point polymorphism and microsatellite maps
Authors: Hinrichs Anthony L , Bertelsen Sarah , Bierut Laura J , Dunn Gerald , Jin Carol H , Kauwe John S , Suarez Brian K
Published: January 2006

We used the LOKI software to generate multipoint identity-by-descent matrices for a microsatellite map (with 31 markers) and two single-nucleotide polymorphism (SNP) maps to examine information content across chromosome 7 in the Collaborative Study on the Genetics of Alcoholism dataset. Despite the lower information provided by a single SNP, SNP maps overall had higher and more uniform information content across the chromosome. The Affymetrix map (578 SNPs) and the Illumina map (271 SNPs) provided almost identical information. However, increased information has a computational cost: SNP maps require 100 times as many iterations as microsatellites to produce stable estimates.
Simulation-based homozygosity mapping with the GAW14 COGA dataset on alcoholism
Authors: Libiger Ondrej , Schork Nicholas J
Published: January 2006

Background

We have developed a simulation-based approach to the analysis of shared homozygous chromosomal segments and have applied it to data on allele sharing among alcoholics in a single Collaborative Study on the Genetics of Alcoholism pedigree. Our assessment of sharing involved the use of a single-nucleotide polymorphism (SNP) marker map provided by Affymetrix.

Results

All 11 affected individuals in the selected pedigree shared 2 copies of an allele at 4 adjacent SNPs in a region on chromosome 5. Via simulation, we determined that the probability that such sharing is caused by mere chance is less than 0.0000001. After correcting for undocumented inbreeding, this probability rose to 0.0016. The probability that the shared segment emanates from a single ancestor and is unrelated to the affection status is less than 0.0000001 in the corrected pedigree. Haplotype association analysis and a search for a protective locus using unaffected individuals yielded no significant results.

Conclusion

Homozygosity mapping results on chromosome 5 provide suggestive evidence of the region's role as one that may harbor a genetic determinant of alcoholism. Furthermore, the probabilities of chance homozygous allele sharing for the original and for the inbreeding-corrected pedigree provide insight into the impact that inbreeding can have on such calculations.
Effects of Melatonin in Perimenopausal and Menopausal Women: Our Personal Experience
Authors: BELLIPANNI G , DI MARZO F , BLASI F , DI MARZO A
Published: January 2006

The purpose of this clinical trial on possible effects of nocturnal MEL administration in perimenopausal women was to find if MEL by itself modifies levels of hormones and produces changes of any kind, independently of age (42–62 years of age) and the stage of the menstrual cycle. It is accepted that a close link exists between the pineal gland, MEL, and human reproduction and that a relationship exists between adenohypophyseal and steroid hormones and MEL during the ovarian cycle, perimenopause, and menopause. Subjects took a daily dose of 3 mg synthetic melatonin or a placebo for 6 months. Levels of melatonin were determined from five daily saliva samples taken at fixed times. Hormone levels were determined from blood samples three times over the 6‐month period. Our results indicate that a cause‐effect relationship between the decline of nocturnal levels of MEL and onset of menopause may exist. The follow up controls show that MEL abrogates hormonal, menopause‐related neurovegetative disturbances and restores menstrual cyclicity and fertility in perimenopausal or menopausal women. At present we assert that the six‐month treatment with MEL produced a remarkable and highly significant improvement of thyroid function, positive changes of gonadotropins towards more juvenile levels, and abrogation of menopause‐related depression.
Effects of Insulin Treatment without and with Recurrent Hypoglycemia on Hypoglycemic Counterregulation and Adrenal Catecholamine-Synthesizing Enzymes in Diabetic Rats
Authors: Inouye Karen E. , Yue Jessica T. Y. , Chan Owen , Kim Tony , Akirav Eitan M. , Park Edward , Riddell Michael C. , Burdett Elena , Matthews Stephen G. , Vranic Mladen
Published: January 2006

Untreated diabetic rats show impaired counterregulation against hypoglycemia. The blunted epinephrine responses are associated with reduced adrenomedullary tyrosine hydroxylase (TH) mRNA levels. Recurrent hypoglycemia further impairs epinephrine counterregulation and is also associated with reduced phenylethanolamine N-methyltransferase mRNA. This study investigated the adaptations underlying impaired counterregulation in insulin-treated diabetic rats, a more clinically relevant model. We studied the effects of insulin treatment on counterregulatory hormones and adrenal catecholamine-synthesizing enzymes and adaptations after recurrent hypoglycemia. Groups included: normal; diabetic, insulin-treated for 3 wk (DI); and insulin-treated diabetic exposed to seven episodes (over 4 d) of hyperinsulinemic-hypoglycemia (DI-hypo) or hyperinsulinemic-hyperglycemia (DI-hyper). DI-hyper rats differentiated the effects of hyperinsulinemia from those of hypoglycemia. On d 5, rats from all groups were assessed for adrenal catecholamine-synthesizing enzyme levels or underwent hypoglycemic clamps to examine counterregulatory responses. Despite insulin treatment, fasting corticosterone levels remained increased, and corticosterone responses to hypoglycemia were impaired in DI rats. However, glucagon, epinephrine, norepinephrine, and ACTH counterregulatory defects were prevented. Recurrent hypoglycemia in DI-hypo rats blunted corticosterone but, surprisingly, not epinephrine responses. Norepinephrine and ACTH responses also were not impaired, whereas glucagon counterregulation was reduced due to repeated hyperinsulinemia. Insulin treatment prevented decreases in basal TH protein and increased PNMT and dopamine β-hydroxylase protein. DI-hypo rats showed increases in TH, PNMT, and dopamine β-hydroxylase. We conclude that insulin treatment of diabetic rats protects against most counterregulatory defects but not elevated fasting corticosterone and decreased corticosterone counterregulation. Protection against epinephrine defects, both without and with antecedent hypoglycemia, is associated with enhancement of adrenal catecholamine-synthesizing enzyme levels.
Frizzled5/8 is required in secondary mesenchyme cells to initiate archenteron invagination during sea urchin development
Authors: Croce Jenifer , Duloquin Louise , Lhomond Guy , McClay David R. , Gache Christian
Published: January 2006

Wnt signaling pathways play key roles in numerous developmental processes both in vertebrates and invertebrates. Their signals are transduced by Frizzled proteins, the cognate receptors of the Wnt ligands. This study focuses on the role of a member of the Frizzled family, Fz5/8, during sea urchin embryogenesis. During development, Fz5/8 displays restricted expression, beginning at the 60-cell stage in the animal domain and then from mesenchyme blastula stage, in both the animal domain and a subset of secondary mesenchyme cells (SMCs). Loss-of-function analyses in whole embryos and chimeras reveal that Fz5/8 is not involved in the specification of the main embryonic territories. Rather, it appears to be required in SMCs for primary invagination of the archenteron, maintenance of endodermal marker expression and apical localization of Notch receptors in endodermal cells. Furthermore,among the three known Wnt pathways, Fz5/8 appears to signal via the planar cell polarity pathway. Taken together, the results suggest that Fz5/8 plays a crucial role specifically in SMCs to control primary invagination during sea urchin gastrulation.
Mutation Scanning of the RET Protooncogene Using High-Resolution Melting Analysis
Authors: Margraf Rebecca L , Mao Rong , Highsmith W Edward , Holtegaard Leonard M , Wittwer Carl T
Published: January 2006

Background: Single-base pair missense mutations in exons 10, 11, 13, 14, 15, and 16 of the RET protooncogene are associated with the autosomal dominant multiple endocrine neoplasia type 2 (MEN2) syndromes: MEN2A, MEN2B, and familial medullary thyroid carcinoma. The current widely used approach for RET mutation detection is sequencing of the exons.

Methods: Because RET mutations are rare and the majority are heterozygous mutations, we investigated RET mutation detection by high-resolution amplicon melting analysis. This mutation scanning technique uses a saturating double-stranded nucleic acid binding dye, LCGreen®, and the high-resolution melter, HR-1™, to detect heterozygous and homozygous sequence variations. Mutant genotypes are distinguished from the wild-type genotype by an altered amplicon melting curve shape or position.

Results: Samples of 26 unique RET mutations, 4 nonpathogenic polymorphisms, or the wild-type genotype were available for this study. The developed RET mutation-scanning assay differentiated RET sequence variations from the wild-type genotype by altered derivative melting curve shape or position. A blinded study of 80 samples (derived from the 35 mutant, polymorphism, or wild-type samples) demonstrated that 100% of RET sequence variations were differentiated from wild-type samples. For exons 11 and 13, the nonpathogenic polymorphisms could be distinguished from the pathogenic RET mutations. Some RET mutations could be directly genotyped by the mutation scanning assay because of unique derivative melting curve shapes.

Conclusion: RET high-resolution amplicon melting analysis is a sensitive, closed-tube assay that can detect RET protooncogene sequence variations.
Interchangeability of Measurements of Total and Free Prostate-Specific Antigen in Serum with 5 Frequently Used Assay Combinations: An Update
Authors: Stephan Carsten , Klaas Moritz , Müller Christian , Schnorr Dietmar , Loening Stefan A , Jung Klaus
Published: January 2006

Background: The comparability of total and free prostate-specific antigen (tPSA and fPSA) results among commercial PSA assays has been suggested to be improved by calibration to WHO PSA reference materials and the development of equimolar-response assays. To characterize the current situation, we assessed 5 frequently used commercial assay combinations for tPSA and fPSA regarding the interchangeability of the PSA values and the ratio of fPSA to tPSA (%fPSA), equimolar characteristics, and diagnostic accuracy.

Methods: Sera from 314 patients with prostate cancer (PCa) and 282 men with no evidence of prostate cancer (NPCa) were measured with tPSA and fPSA assays from Abbott (AxSYM), Beckman Coulter (Access), Diagnostic Products Corporation (Immulite 2000), and Roche (Elecsys 2010) and with tPSA and complexed PSA (cPSA) assays from Bayer (ADVIA Centaur).

Results: Method comparisons (Passing and Bablok regressions; Bland–Altman plots) showed assay-dependent results for tPSA, fPSA, and %fPSA. With the Access tPSA values taken as 100%, tPSA concentrations varied from 87% (AxSYM and ADVIA Centaur) to 115% (Immulite), leading to different numbers of patients classified according to the commonly recommended tPSA cutoffs for performing a biopsy. Different %fPSA values also led to assay-dependent ROC analysis results, a finding that shows the importance for the diagnostic accuracy.

Conclusion: Interchangeability of tPSA, fPSA, and %fPSA values obtained by commercial PSA assays remains inadequate, but attention to this issue may minimize the misinterpretation of PSA results obtained by different assays.
Comparison of Solution‐Based versus Laser Ablation Inductively Coupled Plasma Mass Spectrometry for Analysis of Larval Fish Otolith Microelemental Composition
Authors: Ludsin Stuart A. , Fryer Brian J. , Gagnon Joel E.
Published: January 2006

Otolith microchemistry has become a widely used tool for fisheries‐based research in marine systems. However, its application to systems without well‐defined juvenile nursery areas in which distinct otolith elemental signatures can develop (i.e., most freshwater systems) remains limited. In large part, this deficiency is due to unsuitable protocols for reliably processing and analyzing small otoliths of larvae. Herein, we evaluate the abilities of solution‐based (SO) and laser ablation (LA) inductively coupled plasma mass spectrometry (ICPMS) to quantify the otolith elemental composition of larval yellow perch Perca flavescens captured in three distinct spawning locations in Lake Erie (USA–Canada). Analysis of otolith pairs by each technique demonstrated that both SO‐ and LA‐ICPMS could be used to reliably quantify the more abundant elements, such as Sr and Ba. Magnesium and zinc, analyzed by use of both SO‐ and LA‐ICPMS, also met the criteria for inclusion in our analyses (i.e., the coefficients of variation of standards were <10.5%, and over 90% of samples were above detection limits at a single location). Upon closer inspection of the data, however, we found that estimates of Mg and Zn were only reliable for LA‐ICPMS. Estimates of these two elements using SO‐ICPMS were unrealistically high, probably owing to contamination during the otolith dissolution and handling phases. We also found that LA‐ICPMS provided more precise estimates than did SO‐ICPMS for nearly all elements explored, but LA‐ICPMS was somewhat limited by high limits of detection for some elements. Despite these differences, both techniques could accurately discriminate among larvae produced in different Lake Erie spawning locations, primarily because of the significant variation in Sr among larval otoliths. Ultimately, although both methods are appropriate for analysis of otoliths from larvae, we recommend the use of LA‐ICPMS in future otolith microchemical applications involving larvae.
Examining the Relationship Between Bone Mineral Density and Fracture Risk Reduction During Pharmacologic Treatment of Osteoporosis
Authors: Divittorio Gino , Jackson Kirk L. , Chindalore Vishala L. , Welker Weston , Walker J. Bryan
Published: January 2006

Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes the patient to an increased risk for fracture. Elements of bone strength include bone mineralization, architecture, turnover, size, and bone mineral density (BMD). Measurement of BMD is the most readily available, noninvasive method for assessing osteoporotic fracture risk and is used by the World Health Organization for diagnostic purposes. Because low BMD is predictive of increased fracture risk, it was believed that changes in BMD during pharmacologic therapy for osteoporosis would strongly predict observed fracture risk reductions. We examined the relationship between changes in BMD and reduction in fracture risk during pharmacologic therapy in postmenopausal women with osteoporosis. The correlation between BMD increases and fracture risk reduction during treatment is not consistent; larger increases in BMD do not necessarily correlate with greater reductions in fracture risk. Multiple factors, in addition to BMD, appear to contribute to the increased bone strength and decreased fracture risk achieved with approved drug therapies for osteoporosis. Until the exact relationship of these factors is fully understood, clinicians should continue to evaluate drug efficacy for osteoporosis based on the fracture risk reductions from well‐designed clinical trials.
Monte Carlo Simulation in the Evaluation of Susceptibility Breakpoints: Predicting the Future: Insights from the Society of Infectious Diseases Pharmacists
Authors: Ambrose Paul G.
Published: January 2006

Appropriate treatment with antimicrobials involves factors we cannot control. Factors such as interpatient variability in drug exposure, the minimum inhibitory concentration (MIC) of the infecting pathogen, and the patient's clinical status clearly affect the therapeutic response. Despite these uncertainties, we can estimate the probability of attaining a successful therapeutic outcome in the context of factors that are within our control. Chief among these are drug, dose, and the dosing interval. One way to predict the probability of a positive therapeutic outcome is through the use of an integrated pharmacokinetic‐pharmacodynamic stochastic model. Pharmacokinetic‐pharmacodynamic target attainment analyses using Monte Carlo simulation to integrate interpatient variability in drug exposure, drug potency, and in vivo exposure targets predictive of positive therapeutic outcomes are influencing antibacterial susceptibility breakpoints at home and abroad. The consequences of this paradigm shift are far reaching, affecting the commercial concerns of drug and susceptibility testing device manufacturers, perceptions about antimicrobial resistance, and ultimately patient care decisions.
Ranolazine, a Novel Agent for Chronic Stable Angina
Authors: Gaffney Sarah M.
Published: January 2006

One of the first signs of ischemic heart disease may manifest as chronic stable angina, a mismatch between oxygen supply and demand. With more than approximately 16.5 million people each year having stable angina, development of new therapies to help control this disease state are warranted. Ranolazine, a novel agent exerting its effect through a partial fatty oxidase inhibitor, is one of the first new drugs in more than 20 years to be developed for chronic stable angina. Working through enzymatic modulation, instead of altering myocardial hemodynamics, ranolazine appears to be effective. An overview of chronic stable angina is provided, the American College of Cardiology–American Heart Association (ACC‐AHA) current pharmacologic treatment guidelines are reviewed, and the mechanism of action of ranolazine is explored. Finally, the major clinical trials supporting its place in medical therapy are discussed. Additional clinical trials are under way to further elucidate ranolazine's exact role in the treatment of chronic stable angina. From results of the existing phase III clinical trials, however, the most beneficial potential role of ranolazine in the treatment algorithm of chronic stable angina appears to be as adjunctive therapy to the recommended ACC‐AHA treatment modalities.
Management of Star Fruit–Induced Neurotoxicity and Seizures in a Patient with Chronic Renal Failure
Authors: Wang Yu‐Chin Lily , Liu Ber‐Ming , Supernaw Robert B. , Lu Yu‐Hong , Lee Ping‐Yu
Published: January 2006

An 84‐year‐old Asian woman with hypertension and chronic renal failure was evaluated for incoherent speech, followed by intermittent interruptions of consciousness, and then status epilepticus after ingesting one star fruit (Averrhoa carambola) each day for 3 days. Conventional first‐line anticonvulsants and hemodialysis were administered without significant control of the patient's seizures. Treatment was started with propofol, an intravenous agent that induces anesthesia with rapid onset and elimination from the central nervous system; this resulted in complete control of the seizures. Propofol may be an effective alternative when dialysis and conventional first‐line anticonvulsants are unsuccessful in treating the symptoms of neurotoxicity.
Disposition of Two Oral Formulations of Cyclosporine in Pediatric Patients Receiving Hematopoietic Stem Cell Transplants
Authors: Dupuis L. Lee , Taylor Tracey , Saunders E. Fred
Published: January 2006

Study Objectives. To compare the disposition of cyclosporine after the administration of two oral formulations to children undergoing hematopoietic stem cell transplantation, and to evaluate the relationship between whole blood cyclosporine concentrations during the dosing interval and the area under the whole blood concentration‐time curve.

Design. Prospective, descriptive, crossover study.

Setting. Hematopoietic stem cell transplantation unit in a tertiary‐quaternary university‐affiliated pediatric hospital.

Patients. Twenty‐four pediatric patients aged 0.5–16.9 years undergoing allogeneic hematopoietic stem cell transplantation.

Intervention. The modified oral formulation of cyclosporine was given on the first day (divided as two doses), and a single identical dose of the original oral formulation was given on the morning of the second day.

Measurements and Main Results. Blood samples were obtained at 0, 0.5, 1.25, 2, 4, 6, 9, and 12 hours after the morning dose from the lumen of the central venous catheter not previously used for intravenous cyclosporine administration. Cyclosporine concentration‐time data were analyzed by using noncompartmental methods. Mean ± SD maximum concentrations were significantly higher after administration of the modified form than after administration of the original form (594.9 ± 349.7 vs 483.0 ± 363.0 μg/L, p=0.003), as was the area under the concentration‐time curve from 0–12 hours (AUC0–12; 3432 ± 1563 vs 3144 ± 1780 μg/L•hr, p=0.022). For both formulations, cyclosporine concentrations at 4 hours after administration were most strongly correlated with the AUC0–12. Unlike that of the original formulation, the trough cyclosporine concentration of the modified form had the weakest relationship with AUC (Spearman ρ coefficient 0.584, p=0.003).

Conclusion. Cyclosporine absorption is lower in children undergoing hematopoietic stem cell transplantation than in children receiving solid organ transplants. Dosage adjustment for the modified formulation based on trough concentration may not be appropriate because its relationship with the AUC was weak. The link between pharmacokinetic parameters and clinical outcomes, such as graft‐versus‐host disease, must be further studied.
Osmol Gap as a Surrogate Marker for Serum Propylene Glycol Concentrations in Patients Receiving Lorazepam for Sedation
Authors: Barnes Brian J. , Gerst Christopher , Smith Jennifer R. , Terrell Andrea R. , Mullins Michael E.
Published: January 2006

Study Objectives. To correlate serum propylene glycol concentration with osmol gap, serum lactate concentration, and amount of propylene glycol administered to mechanically ventilated patients receiving continuous infusions of lorazepam (80% propylene glycol by weight), and to characterize the prevalence of hyperosmolality and range of serum propylene glycol concentrations in this patient population.

Design. Prospective, controlled, observational study.

Setting. Adult surgical and cardiothoracic intensive care units (ICUs) of a 1200‐bed, urban, tertiary care, teaching hospital.

Patients. Sixty‐four consecutively enrolled intensive care patients requiring mechanical ventilation and pharmacologic sedation.

Intervention. Thirteen patients received continuous infusions of high‐dose lorazepam (≥ 6 mg/hr) for a minimum of 36 hours, and 26 received continuous infusions of low‐dose lorazepam (2–5.99 mg/hr) for 36 hours. Twenty‐five control patients received sedatives that did not contain propylene glycol.

Measurements and Main Results. Serum propylene glycol and lactate concentrations, osmolality, and basic metabolic profiles were obtained 72–108 hours after ICU admission. Clinical data, drug administration, and severity of illness scores were recorded. Osmol gap and the amount of propylene glycol administered before serum sampling predicted propylene glycol concentrations (r2=0.692, p<0.05). Osmol gap alone also predicted serum propylene glycol concentrations (r2=0.532, p<0.05). Serum lactate concentrations did not correlate with serum propylene glycol concentrations. Unlike the low‐dose and control patients, eight (62%) of 13 high‐dose patients had osmol gaps above 10. All 13 high‐dose patients had serum propylene glycol concentrations previously associated with toxicity.

Conclusion. Osmol gap can be used as a surrogate marker for serum propylene glycol concentration. In critically ill patients receiving lorazepam for sedation, an osmol gap above 10 was associated with concentrations previously reported to cause toxicity.
Antibiotic Selection and Resistance Issues with Fluoroquinolones and Doxycycline Against Bioterrorism Agents
Authors: Brouillard Jason E. , Terriff Colleen M. , Tofan Andreea , Garrison Mark W.
Published: January 2006

Bacillus anthracis (anthrax), Yersinia pestis (plague), Francisella tularensis (tularemia), Coxiella burnetti (Q fever), and Brucella sp (brucellosis) are all potential bioterrorism agents. Their known virulence, potential lethality, and ability to develop resistance to known antibiotic treatments make these pathogens particularly dangerous. We reviewed the scientific literature by searching MEDLINE databases and published abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America from 1989–2005 for studies of each of these biologic agents with the specific aim of examining whether doxycycline or a fluoroquinolone should be stockpiled for mass‐scale postexposure prophylaxis. An evidence‐based approach was used to determine whether doxycycline or fluoroquinolones were efficacious (both in vitro and in vivo) against these biologic agents and to examine these drugs' respective susceptibility patterns and differences in cost, based on available data. Little published data are available on these pathogens, and much of the data are from studies that used older strains obtained from patient or animal sources in outbreaks decades ago. Doxycycline appears to show comparable minimum inhibitory concentrations to those of the fluoroquinolone class in most clinical and in vitro studies, perhaps with the exception of inhalation plague. Studies also suggest that development of antibiotic resistance is less likely to occur with doxycycline. Doxycycline is several‐fold less expensive than most fluoroquinolones and appears to have similar efficacy in most scenarios based on clinical case studies and established Clinical and Laboratory Standards Institute (formerly known as the National Committee for Clinical Laboratory Standards) breakpoints for staphylococci. Therefore, doxycycline should be considered as a first‐line antibiotic in the management of bioterrorism agents.
Pharmacoeconomic Modeling of Nesiritide versus Dobutamine for Decompensated Heart Failure
Authors: Gerhard Tobias , Zineh Issam , Winterstein Almut G. , Hartzema Abraham G.
Published: January 2006

Study Objective. To model the cost‐effectiveness of nesiritide compared with dobutamine in patients with decompensated heart failure.

Design. Cost‐effectiveness analysis.

Measurements and Main Results. A decision tree model was derived from randomized clinical trial data and data from a previously published economic study. Four cost‐effectiveness analyses were performed: analysis 1—full probabilistic analysis, repeatedly sampled probabilities for 6‐month mortality and hospital readmission from distributions based on 95% confidence intervals (CIs); analysis 2—best‐case nesiritide analysis, used the limiting values of the 95% CI favorable to nesiritide; analysis 3—best‐case dobutamine analysis, used the limiting values of the 95% CI favorable to dobutamine; and analysis 4—replicated the previously published cost‐effectiveness study and served as a methodologic control. Fifty‐one consecutive Monte Carlo simulations for cohorts of 1000 hypothetical patients were performed for each analysis. Incremental cost, incremental effectiveness, and incremental cost‐effectiveness ratios (ICERs) were calculated for nesiritide versus dobutamine. Analysis 1 showed a mean ICER of $767/life‐year gained for nesiritide versus dobutamine (incremental cost $251 ± $290, incremental effectiveness 0.33 ± 0.22 yr). The 95% confidence region surrounding this point estimate spanned all four quadrants of the incremental cost‐effectiveness scatterplot, suggesting inconclusive results. Nesiritide was the dominant treatment strategy in analysis 2 (incremental cost −$734 ± $106, incremental effectiveness 1.19 ± 0.07 yrs), whereas dobutamine was dominant in analysis 3 (incremental cost $1242 ± $73, incremental effectiveness −0.57 ± 0.05 yr). Analysis 4 was comparable to the previously published cost‐effectiveness analysis (incremental cost −$77 ± $87, incremental effectiveness 0.48 ± 0.05 yr).

Conclusions. Based on available randomized clinical trial data, nesiritide did not exhibit robust economic superiority over dobutamine. When incorporating the uncertainty (i.e., 95% CIs) in clinical effectiveness as reported in available clinical trial data into the economic analysis, either nesiritide or dobutamine may be the dominant treatment (i.e., more effective at lower cost) for the studied population. Economic analyses of nesiritide and any comparator must account for uncertainty in estimates of cost as well as in clinical effectiveness.
Evaluation of a Sex‐Based Difference in the Pharmacokinetics of Digoxin
Authors: Lee Lois S. , Chan Lingtak‐Neander
Published: January 2006

Study Objective. To determine whether a sex‐based difference in digoxin pharmacokinetics exists in patients receiving long‐term digoxin therapy for chronic heart failure or atrial fibrillation.

Design. Single‐center, retrospective review of medical records.

Setting. University‐based teaching hospital and outpatient clinic.

Patients. Sixty‐seven adults (32 men, 35 women) with chronic heart failure or atrial fibrillation who were receiving digoxin therapy.

Measurements and Main Results. Serum digoxin concentrations and daily digoxin doses were obtained from patients' medical records. Daily doses were adjusted for patients' actual and ideal body weight and body mass index (BMI). The ratio between the serum digoxin concentration and each of the adjusted daily doses of digoxin was compared between men and women. The mean ± SD serum digoxin concentration was 0.85 ± 0.51 ng/ml for men compared with 1.02 ± 0.51 ng/ml for women. Mean ± SD unadjusted doses of digoxin were 0.180 ± 0.063 and 0.164 ± 0.059 mg/day for men and women, respectively; the difference was not statistically significant. Ratios of serum digoxin concentration to daily digoxin doses did not differ by sex when doses were estimated with actual or ideal weight. Only the ratio of the digoxin concentration to the BMI‐adjusted dose was significantly different between men and women (0.14 ± 0.09 and 0.19 ± 0.11, respectively, p<0.05).

Conclusion. Sex‐based differences in digoxin pharmacokinetics were absent when actual or ideal body weight was used. However, the ratio of serum digoxin concentration to daily digoxin dose adjusted for BMI differed by sex. Because digoxin is distributed to lean body mass, use of the BMI could have overadjusted body weight, leading to inaccurate pharmacokinetic assumptions and calculations. The pharmacokinetics of digoxin do not appear to differ by sex.
Comparative Safety and Efficacy of Urokinase and Recombinant Tissue Plasminogen Activator for Peripheral Arterial Occlusion: A Meta‐Analysis
Authors: Sander Stephen , White C. Michael , Coleman Craig I.
Published: January 2006

Study Objective. To evaluate differences in the efficacy and safety of recombinant tissue plasminogen activator (rt‐PA) and urokinase in the treatment of peripheral arterial occlusion.

Design. Systematic review and meta‐analysis of prospective comparative trials.

Data Source. PubMed/MEDLINE database from 1966‐October 2004.

Conclusion. Urokinase was less effective than rt‐PA in successfully lysing acute peripheral arterial occlusion, but it was associated with lower rates of total and minor bleeding. Overall, rt‐PA was a reasonable substitute for urokinase, now that urokinase has been removed from the market in the United States. However, judicious monitoring for minor bleeding is necessary
Impact of a Piperacillin‐Tazobactam Shortage on Antimicrobial Prescribing and the Rate of Vancomycin‐Resistant Enterococci and Clostridium difficile Infections
Authors: Mendez Marisa N. , Gibbs Laurel , Jacobs Richard A. , McCulloch Charles E. , Winston Lisa , Guglielmo B. Joseph
Published: January 2006

Study Objective. To evaluate the impact of a shortage of piperacillintazobactam in the United States in 2002 on antimicrobial prescribing and associated rates of vancomycin‐resistant enterococci (VRE) and Clostridium difficile infections.

Design. Retrospective chart review.

Setting. University‐affiliated medical center.

Measurements and Main Results. Microbiologic reports, patient demographics, and antimicrobial utilization were evaluated for patients admitted 6 months before the shortage (March 1‐August 31, 2001) and for 6 months during the shortage (March 1‐August 31, 2002). Significant increases in usage of alternative β‐lactamase inhibitor combinations, cefepime, levofloxacin, vancomycin, clindamycin, and metronidazole were observed during the shortage; in contrast, a significant decrease in the use of ceftriaxone took place. No change in the rate of VRE infection was observed from before to during the piperacillin‐tazobactam shortage. However, a paradoxical 47% decrease in the rate of C. difficile colitis was documented during the shortage. Subsequent multivariate analyses suggested the reduced use of ceftriaxone and increased use of levofloxacin, but not the reduced use of piperacillin‐tazobactam, correlated with the decreased rate of C. difficile infections.

Conclusion. The piperacillin‐tazobactam shortage was associated with significant changes in antimicrobial prescribing, which resulted in a significant reduction in the rate of C. difficile but not VRE infections.
Pharmacotherapy for Idiopathic Pulmonary Arterial Hypertension During the Past 25 Years
Authors: Hackman Anna M. , Lackner Thomas E.
Published: January 2006

Objective. To review the current pharmacotherapy for idiopathic pulmonary arterial hypertension (IPAH).

Methods. A search of the primary literature was conducted by using MEDLINE, the National Institutes of Health medical research Web site (www.clinicaltrials.gov), and the United States Food and Drug Administration's Center for Drug Evaluation and Research Web site (www.fda.govcder).

Results. Until the early 1980s, conventional therapy for IPAH consisted of anticoagulation, diuretics, digitalis extracts, and supplemental oxygen, yet the 5‐year mortality rate remained at 66%. Calcium channel blocker therapy was introduced with the hope that it would improve survival in patients with IPAH, but it was found to be effective in only approximately 25% of patients. In 1996, intravenous epoprostenol was the first drug to show long‐term benefit on hemodynamics, exercise capacity, and survival. However, administration of epoprostenol requires a permanently indwelling central venous catheter, and tachyphylaxis is common, necessitating continuous dosage escalations. Subsequently, treprostinil, a prostacyclin analog of epoprostenol that can be administered by continuous subcutaneous infusion, was introduced, followed by aerosolized iloprost, a prostacyclin analog for inhalation. An increasing understanding of the multiple pathogeneses of IPAH led to the discovery of another target for drug therapy, and bosentan, an orally administered agent, became the first endothelin‐receptor antagonist approved for treatment of IPAH. Most recently, the phosphodiesterase inhibitor, sildenafil, has received approval from the United States Food and Drug Administration for the treatment of IPAH.

Conclusion. Recently developed pharmacotherapies offer greater effectiveness and safety than traditional agents for the treatment of IPAH.
Combating Influenza with Antiviral Therapy in the Pediatric Population
Authors: Townsend Kara A. , Eiland Lea S.
Published: January 2006

Influenza viruses are accountable for annual epidemics worldwide that result in significant morbidity and mortality. In preschool and school‐aged children, prospective surveillance of influenza demonstrates yearly infection rates of 15–42%. Children can easily transmit the virus to other children, to employees in day‐care and school settings, and to family members. Two classes of antiviral drugs, the adamantine derivatives (amantadine, rimantadine) and neuraminidase inhibitors (zanamivir and oseltamivir), have been approved for treatment and prophylaxis of influenza in the pediatric population. Duration of clinical symptoms decreases and daily activities are resumed sooner when therapy is begun within 48 hours of the onset of influenza symptoms. Mechanism of action, adverse effects, and development of resistant variants differ between the two drug classes. To our knowledge, head‐to‐head clinical trials between the classes and involving the neuraminidase inhibitors are nonexistent. Antiviral agents do not replace the annual influenza vaccine, and clinical trials indicate that amantadine, rimantadine, zanamivir, and oseltamivir are safe and effective for administration in the pediatric population.
Asian Oral-Facial Cleft Birth Prevalence
Authors: Cooper Margaret E. , Ratay Jessica S. , Marazita Mary L.
Published: January 2006

Objective:

To determine the clefting birth prevalence among Asian populations, specifically Chinese and Japanese, using raw counts from nonoverlapping published studies of Asian populations, and to investigate whether Asian clefting rates have been interpreted accurately as being up to twice the Caucasian rate.

Design:

A literature review of articles giving raw counts of clefting in Asian populations, primarily Japanese and Chinese.

Main Outcome Measures:

Where possible, clefts were identified by the patients’ ethnicity, country of origin, cleft type, syndromic status, and birth status.

Results:

Prevalence rates of cleft lip with or without cleft palate per 1000 live births are reported. Syndromic plus nonsyndromic cleft lip with or without cleft palate: Chinese, 1.30; Japanese, 1.34; Other Asian, 1.47; and total, 1.33. Nonsyndromic cleft lip with or without cleft palate: Chinese, 1.20; Japanese, 1.18; Other Asian, 1.22; and total, 1.19.

Conclusions:

Overall, Chinese and Japanese live birth prevalence rates for nonsyndromic cleft lip with or without cleft palate, based on the published reports of birth prevalence, are significantly lower than the oft-quoted rate of 2 per 1000 for Asians. The apparent reason for the discrepancy is that many published prevalence rates included all pregnancies (live births plus pregnancy losses) and do not distinguish between syndromic and nonsyndromic clefts or between cleft palate alone and cleft lip with or without cleft palate. These results demonstrate that it is extremely important for current population-based studies of clefts to include careful delineation of population groups, syndromes, cleft type, and birth status.
Fluctuating asymmetry and condition in golden shiner (Notemigonus crysoleucas) and channel catfish (Ictalurus punctatus) reared in sublethal concentrations of isopropyl methylphosphonic acid
Authors: Green Chris C. , Lochmann Steve E.
Published: January 2006

Fluctuating asymmetry (FA; small, random differences between the left and right sides of a bilateral character) has been related to embryological stress during development. Some populations exhibit positive relations between FA and exposure to toxicants during development. The United States has agreed to demilitarize chemical warfare agents in accordance with the Chemical Weapons Convention Treaty. Isopropyl methylphosphonic acid (IMPA), the main hydrolysis product of sarin, could be introduced accidentally into the environment during demilitarization. The present study examined the use of FA as a biomarker of developmental stress caused by sublethal exposures to IMPA. A suite of morphometric and meristic traits were measured in two fish species exposed to IMPA. Significant differences were found in composite FA among groups of channel catfish (Ictalurus punctatus) exposed to sublethal concentrations of IMPA during development. No differences were found in composite FA among groups of golden shiner (Notemigonus crysoleucas) exposed to IMPA. No relation was found between individual relative condition and FA in channel catfish or golden shiner.
Metal blood levels and hematological characteristics in wood mice (Apodemus sylvaticus L.) along a metal pollution gradient
Authors: Rogival Damien , Scheirs Jan , De Coen Wim , Verhagen Ron , Blust Ronny
Published: January 2006

The present study evaluated whether blood could be used as a nondestructive tool for monitoring metal exposure and related hematological effects in wood mice (Apodemus sylvaticus L.) living along a metal pollution gradient. Soil concentrations of arsenic, cadmium, copper, lead, silver, and zinc decreased with distance from the emission source. Blood levels of cadmium and lead differed significantly among sites, whereas those of the other metals did not. Blood levels of cadmium and lead correlated with soil concentrations of cadmium and lead, respectively. No such significant relationships were found for the other measured metals. Hematocrit levels decreased in wood mice from the most polluted site (45.96% ± 0.53% [mean ± standard error]) compared to the reference site (48.04% ± 0.47%). A negative correlation between hematocrit and blood levels of cadmium and lead was found. Erythrocyte count, leukocyte count, hemoglobin concentration, mean corpuscular hemoglobin (average wt of hemoglobin in a red blood cell in pg), and lysozyme activity did not differ among study sites. Mean corpuscular volume (average volume of a red blood cell in μm3) and mean corpuscular hemoglobin concentration (average proportion of hemoglobin in a red blood cell as a %) differed among study sites but showed no relationship with metal exposure. We conclude that whole blood from mice can be used for nondestructive monitoring of the exposure to nonessential metals under natural conditions. The present results indicate that decreased hematocrit levels may be an early warning signal for a negative impact of metal exposure on the oxygen-transport capacity of blood in wood mice in their natural environment.
Flows of dioxins and furans in coastal food webs: Inverse modeling, sensitivity analysis, and applications of linear system theory
Authors: Saloranta Tuomo M. , Andersen Tom , Næs Kristoffer
Published: January 2006

Rate constant bioaccumulation models are applied to simulate the flow of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in the coastal marine food web of Frierfjorden, a contaminated fjord in southern Norway. We apply two different ways to parameterize the rate constants in the model, global sensitivity analysis of the models using Extended Fourier Amplitude Sensitivity Test (Extended FAST) method, as well as results from general linear system theory, in order to obtain a more thorough insight to the system's behavior and to the flow pathways of the PCDD/Fs. We calibrate our models against observed body concentrations of PCDD/Fs in the food web of Frierfjorden. Differences between the predictions from the two models (using the same forcing and parameter values) are of the same magnitude as their individual deviations from observations, and the models can be said to perform about equally well in our case. Sensitivity analysis indicates that the success or failure of the models in predicting the PCDD/F concentrations in the food web organisms highly depends on the adequate estimation of the truly dissolved concentrations in water and sediment pore water. We discuss the pros and cons of such models in understanding and estimating the present and future concentrations and bioaccumulation of persistent organic pollutants in aquatic food webs.
A pollution-monitoring pilot study involving contaminant and biomarker measurements in the Seine Estuary, France, using zebra mussels (Dreissena polymorpha)
Authors: Minier Christophe , Abarnou Alain , Jaouen-Madoulet Agnès , Le Guellec Anne-Marie , Tutundjian Renaud , Bocquené Gilles , Leboulenger François
Published: January 2006

Zebra mussel (Dreissena polymorpha) is an invasive species that has proliferated in European and North American rivers and lakes during the last century. In this study, D. polymorpha has been used to provide information on contamination levels and biological effects in the Seine Estuary (France). The bivalves accumulated polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) to a high degree with values reaching 800 ng/g dry weight for PCBs (sum of 20 congeners), and 1,000 ng/g dry weight of PAHs (sum of 14 compounds) in the whole body. These values are among the highest reported of PCBs and, to a lesser extent, of PAHs in other contaminated areas in the world. Toxic equivalent quantities of PCBs and PAHs detected in zebra mussels varied from 20 to 40 pg dioxin equivalents/g dry weight for PCBs and up to 120 ng benzo[a]pyrene equivalents/g dry weight for PAHs, indicating a high potential risk for animals feeding on them. Biological impacts, such as altered condition index, decreased lysosomal stability, and high levels of multixenobiotic resistance (MXR) proteins also were detected in mussels living downstream of Rouen, the main city of the Seine Estuary. Taken together, these results indicate that the Seine Estuary is a heavily polluted area with the potential to cause deleterious health effects in some endogenous living organisms. This study also shows that chemical and biological measurements bring different but complementary results that can help diagnose environmental health.
Nondestructive pollution exposure assessment in the european hedgehog (Erinaceus europaeus): III. hair as an indicator of endogenous organochlorine compound concentrations
Authors: D'Havé Helga , Scheirs Jan , Covaci Adrian , Schepens Paul , Verhagen Ron , De Coen Wim
Published: January 2006

Concentrations of organochlorine persistent pollutants were investigated in tissues of the European hedgehog (Erinaceus europaeus). Road kills and carcasses from wildlife rescue centers were used to characterize organochlorine compound tissue distribution and tissue profile dissimilarities (hair, liver, kidney, muscle, and adipose tissue). The most important contaminants were polychlorinated biphenyls (PCBs), chlordanes (CHLs), and DDTs, with median concentrations of 75, 5.1, and 1.4 ng/g liver wet weight, respectively. Median levels for the remaining compounds—hexachlorobenzene (HCB), hexachlorocyclohexanes (HCHs), and octachlorostyrene—were less than 0.5ng/gliver wet weight. Compared to results with other mammalian wildlife, the present results indicate that hedgehogs may accumulate considerable concentrations of organochlorine compounds. Polychlorinated biphenyls and HCB preferably accumulated in liver and muscle tissue. Concentrations of DDTs and HCHs were highest in muscle tissue and hair, respectively. Octachlorostyrene and CHL levels were predominant in liver. The observed positive relationships between concentrations in hair and internal tissues for PCBs, DDTs, HCB, HCHs, and CHLs (0.49 < r < 0.91) and for several individual PCB, DDT, and CHL compounds (0.31 < r < 0.76) indicate the usefulness of hair as a biomonitoring tool of organochlorine compounds. Multivariate profile analyses revealed a higher dominance of less-persistent compounds (p,p′-DDT, α-HCH, and PCBs 95, 101, and 149) in hair compared to internal tissues. The present study demonstrates the suitability of hedgehog hair as a nondestructive biomonitoring tool regarding pollution with organochlorine compounds and the promising role of the hedgehog as a mammalian indicator species of pollution in terrestrial environments.