bluuebunny/crossref_metadata_2025_split huggingface dataset:
Models of prophylaxis
Authors: BERNTORP ERIK , FISCHER KATHELIJN , MINERS ALEC 
Published: June 2012

Summary. Long‐term, continuous prophylaxis for haemophilia began at a modest scale during the 1950s and 1960s in Sweden and The Netherlands. In the face of high cost and impediments to the performance of longitudinal, well‐designed studies, it was decades before prophylaxis was considered to be the best practice in countries that could afford the cost. In 2007 and 2011, the only prospective randomized studies ever performed confirmed what large cohort studies in Europe had long since shown. Today, focus is on when to start prophylaxis, dosing and when/if to stop. Retrospective comparisons of the Swedish and Dutch cohorts, where different strategies have been used, indicate that a costly, high‐dose regimen improves outcome, but not dramatically. A prospective comparison is now underway. Treatment, clinical outcome, clotting factor consumption and socioeconomic parameters will be compared between the two strategies. Results are expected to provide greater insight into the long‐term consequences of the different prophylactic treatment strategies.The economic justification for prophylaxis has been addressed in several studies with varying results. While the majority (implicitly) suggest that prophylaxis is not cost effective at conventional willingness to pay for additional units in health thresholds, their results vary markedly. Closer inspection suggests that the primary reasons results differ include different definitions of prophylaxis, clotting factor price, discount rates, choice of outcome measures and time horizon.
Assessing acute coronary syndrome patients' cardiac‐related beliefs, motivation and mood over time to predict non‐attendance at cardiac rehabilitation
Authors: Herber Oliver R. , Jones Martyn C. , Smith Karen , Johnston Derek W. 
Published: June 2012

AbstractAimThis research protocol describes and justifies a study to assess patients' cardiac‐related beliefs (i.e. illness representations, knowledge/misconceptions, cardiac treatment beliefs), motivation and mood over time to predict non‐attendance at a cardiac rehabilitation programme by measuring weekly/monthly changes in these key variables.BackgroundHeart disease is the UK's leading cause of death. Evidence from meta‐analyses suggests that cardiac rehabilitation facilitates recovery following acute cardiac events. However, 30–60% of patients do not attend cardiac rehabilitation. There is some evidence from questionnaire studies that a range of potentially modifiable psychological variables including patients' cardiac‐related beliefs, motivation and mood may influence attendance.DesignMixed‐methods.MethodsIn this study, during 2012–2013, electronic diary data will be gathered weekly/monthly from 240 patients with acute coronary syndrome from discharge from hospital until completion of the cardiac rehabilitation programme. This will identify changes and interactions between key variables over time and their power to predict non‐attendance at cardiac rehabilitation. Data will be analysed to examine the relationship between patients' illness perceptions, cardiac treatment beliefs, knowledge/misconceptions, mood and non‐attendance of the cardiac rehabilitation programme. The qualitative component (face‐to‐face interviews) seeks to explore why patients decide not to attend, not complete or complete the cardiac rehabilitation programme.DiscussionThe identification of robust predictors of (non‐)attendance is important for the design and delivery of interventions aimed at optimizing cardiac rehabilitation uptake. Funding for the study was granted in February 2011 by the Scottish Government Chief Scientist Office (CZH/4/650).
Genetically diverse but with surprisingly little geographical structure: the complex history of the widespread herb Carex nigra (Cyperaceae)
Authors: Jiménez‐Mejías Pedro , Luceño Modesto , Lye Kåre Arnstein , Brochmann Christian , Gussarova Galina 
Published: June 2012

AbstractAim  Based on extensive range‐wide sampling, we address the phylogeographical history of one of the most widespread and taxonomically complex sedges in Europe, Carex nigra s. lat. We compare the genetic structure of the recently colonized northern areas (front edge) and the long‐standing southern areas (rear edge), and assess the potential genetic basis of suggested taxonomic divisions at the rank of species and below.Location  Amphi‐Atlantic, central and northern Europe, circum‐Mediterranean mountain ranges, central Siberia, Himalayas.Methods  A total of 469 individuals sampled from 83 populations, covering most of the species’ range, were analysed with amplified fragment length polymorphism (AFLP) and chloroplast DNA (cpDNA) markers. Bayesian clustering, principal coordinates analysis, and estimates of diversity and differentiation were used for the analysis of AFLP data. CpDNA data were analysed with statistical parsimony networks and maximum parsimony and Bayesian inference of phylogenetic trees.Results  Overall genetic diversity was high, but differentiation among populations was limited. Major glacial refugia were inferred in the Mediterranean Basin and in western Russia; in addition, there may have been minor refugia in the North Atlantic region. In the southern part of the range, we found high levels, but geographically quite poorly structured genetic diversity, whereas the levels of genetic diversity varied among different areas in the north. North American populations were genetically very similar to the European populations.Main conclusions  The data are consistent with extensive gene flow, which has obscured the recent history of the taxon. The limited differentiation in the south probably results from the mixing of lineages expanding from several local refugia. Northward post‐glacial colonization resulted in a leading‐edge pattern of low diversity in the Netherlands, Belgium, Scotland and Iceland, whereas the observed high diversity levels in Fennoscandia suggest broad‐fronted colonization from the south as well as from the east. The patterns found in the American populations are consistent with post‐glacial colonization, possibly even with anthropogenic introduction from Europe. Our data also suggest that the tussock‐forming populations of C. nigra, often referred to as a distinct species (Carex juncella), represent an ecotype that has originated repeatedly from different populations with creeping rhizomes.
Effects of flunixin meglumine and ketoprofen on mediator production inex vivoandin vitromodels of inflammation in healthy dairy cows
Authors: DONALISIO C. , BARBERO R. , CUNIBERTI B. , VERCELLI C. , CASALONE M. , RE G 
Published: June 2012

Donalisio, C., Barbero, R., Cuniberti, B., Vercelli, C., Casalone, M., Re, G. Effects of flunixin meglumine and ketoprofen on mediator production inex vivoandin vitromodels of inflammation in healthy dairy cows.J. vet. Pharmacol. Therap. 36, 130–139.In this study,ex vivoassays were carried out in dairy cows to evaluate the anti‐inflammatory effects of two nonsteroidal anti‐inflammatory drugs: ketoprofen (KETO) and flunixin meglumine (FM). Twelve healthy Holstein dairy cattle were randomly allocated to two groups (n=6): group 1 received FM and group 2 received KETO at recommended therapeutic dosages. The anti‐inflammatory effects of both drugs were determined by measuring the production of coagulation‐induced thromboxane B2(TXB2), lipopolysaccharides (LPS) (10 μg/mL)‐induced prostaglandin E2(PGE2), and calcium ionophore (60 μm)‐induced leukotrien B4(LTB4). Cytokine production was assessed by measuring tumor necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ) and interleukin‐8 (CXCL8) concentrations after incubation in the presence of 10 μg/mL LPS. The IC50of FM and KETO was determinedin vitroby determining the concentration of TXB2and PGE2in the presence of scalar drug concentrations (10−9–10−3 m). Both FM and KETO inhibited the two COX isoforms in vitro, but showed a preference for COX‐1. FM and KETO showed similar anti‐inflammatory effects in the cow.
Pharmacokinetics and dose selection of a novel, long‐acting transdermal fentanyl solution in healthy laboratory Beagles
Authors: FREISE K. J. , SAVIDES M. C. , RIGGS K. L. , OWENS J. G. , NEWBOUND G. C. , CLARK T. P. 
Published: June 2012

Freise, K.J., Savides, M.C., Riggs, K.L., Owens, J.G., Newbound, G.C., Clark, T.P. Pharmacokinetics and dose selection of a novel, long‐acting transdermal fentanyl solution in healthy laboratory Beagles.J. vet. Pharmacol. Therap.35(Suppl. 2), 21–26.A novel, transdermal fentanyl solution (TFS) was developed that delivers sustained concentrations of fentanyl for days following a single application. The pharmacokinetics following a single topical dose was examined. Eighteen adult Beagle dogs were divided into three groups of six dogs (3M, 3F). Each group was administered a single dose of 1.3 (25), 2.6 (50), or 5.2 mg/kg (100 μL/kg) of TFS. The dose was applied to the clipped, ventral abdominal skin using a 1‐mL tuberculin syringe. Immediately following dosing, collars were placed on each dog through 72 h to prevent direct licking of the application site. Serial jugular venous blood samples were collected at 0 (predosing), 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 240, 336, 408, and 504 h after dosing and assayed for plasma fentanyl concentration. Fentanyl was rapidly detected following application with a mean absorption lag time (tlag) of 0.333 h in the 1.3 mg/kg group and 0 in the other two groups. The mean Cmaxincreased with dose and were 2.28, 2.67, and 4.71 ng/mL in the 1.3, 2.6 and 5.2 mg/kg dose groups, respectively. Mean terminal half‐lives were 53.7, 69.6, and 103 h in the 1.3, 2.6, and 5.2 mg/kg dose groups, respectively. The mean AUC0‐LLOQfrom lowest to highest dose groups were 157, 268, and 645 ng·h/mL and were dose proportional with aR2value of 0.9818. Adverse reactions were limited to the highest dose group and included sedation (four of six dogs) and decreased food and water intake (one dog). A dose of 2.6 mg/kg (50 μL/kg) is proposed for further development studies based on the lack of adverse events that were observed compared to the 5.2 mg/kg group and a more rapid onset of action and longer duration of action compared to the 1.3 mg/kg group.
The effectiveness of a long‐acting transdermal fentanyl solution compared to buprenorphine for the control of postoperative pain in dogs in a randomized, multicentered clinical study
Authors: LINTON D. D. , WILSON M. G. , NEWBOUND G. C. , FREISE K. J. , CLARK T. P. 
Published: June 2012

Linton, D. D., Wilson, M. G., Newbound, G. C., Freise, K. J., Clark, T. P. The effectiveness of a long‐acting transdermal fentanyl solution compared to buprenorphine for the control of postoperative pain in dogs in a randomized, multicentered clinical study. J. vet. Pharmacol. Therap.35 (Suppl. 2), 53–64.A prospective, double‐blinded, positive‐controlled, multicenter, noninferiority clinical study was conducted to evaluate the safety and effectiveness of a long‐acting transdermal fentanyl solution (TFS) for the control of postoperative pain. Four hundred forty‐five client‐owned dogs of various breeds were randomly assigned to receive a single dose of TFS (2.6 mg/kg [∼50 μL/kg]) (N = 223) applied 2–4 h prior to surgery or buprenorphine (20 μg/kg) (N = 222) administered intramuscularly 2–4 h prior to surgery and every 6 h through 90 h. There were 159 (35.7%) males and 286 (64.3%) females ranging from 0.5 to 16 years of age and 3 to 98.5 kg enrolled. Pain was scored using the modified Glasgow Composite Pain Scale with an a priori dropout criteria of ≥8 (20 maximum score). The one‐sided upper 95% confidence interval of the mean difference between fentanyl and buprenorphine treatment failures was 5.6%, which was not greater than the a priori selected margin difference of 15%. Adverse events attributed to either treatment were minimal in impact and were approximately equal between groups. Sustained plasma fentanyl concentrations provided by a single pre‐emptive dose of TFS are safe and effective and are noninferior to repeated injections of buprenorphine in controlling postoperative pain over 4 days. This long‐acting fentanyl formulation provides veterinarians with a novel, registered option for the control of postoperative pain in dogs that improves dosing compliance and potentially mitigates the disadvantages of oral, parenteral, and patch delivered opioids.
Naloxone reversal of an overdose of a novel, long‐acting transdermal fentanyl solution in laboratory Beagles
Authors: FREISE K. J. , NEWBOUND G. C. , TUDAN C. , CLARK T. P. 
Published: June 2012

Freise, K. J., Newbound, G. C., Tudan, C., Clark, T. P. Naloxone reversal of an overdose of a novel, long‐acting transdermal fentanyl solution in laboratory Beagles. J. vet. Pharmacol. Therap. 35 (Suppl. 2), 45–51.Opioid overdose in dogs is manifested by clinical signs such as excessive sedation, bradycardia, and hypothermia. The ability of two different intramuscular (i.m.) naloxone reversal regimens to reverse the opioid‐induced effects of a fivefold overdose of long‐acting transdermal fentanyl solution was evaluated in dogs. Twenty‐four healthy Beagles were administered a single 13 mg/kg dose (fivefold overdose) of transdermal fentanyl solution and randomized to two naloxone reversal regimen treatment groups, hourly administration for 8 h of 40 (n = 8) or 160 μg/kg i.m. (n = 16). All dogs were sedated and had reduced body temperatures and heart rates (HRs) prior to naloxone administration. Both dosage regimens significantly reduced sedation (P < 0.001), and the 160 μg/kg naloxone regimen resulted in a nearly threefold lower odds of sedation than that of the 40 μg/kg i.m. naloxone regimen (P < 0.05). Additionally, naloxone significantly increased the mean body temperatures and HR (P < 0.001), although the 160 μg/kg regimen increased body temperature and HR more (P < 0.05). However, the narcotic side effects of fentanyl returned within 1–3 h following termination of the naloxone dosage regimens. The opioid‐induced effects of an overdose of transdermal fentanyl solution can be safely and effectively reversed by either 40 or 160 μg/kg i.m. naloxone administered at hourly intervals.
The margin of safety of a single application of transdermal fentanyl solution when administered at multiples of the therapeutic dose to laboratory dogs
Authors: SAVIDES M. C. , POHLAND R. C. , WILKIE D. A. , ABBOTT J. A. , NEWBOUND G. C. , FREISE K. J. , CLARK T. P. 
Published: June 2012

Savides, M. C., Pohland, R. C., Wilkie, D. A., Abbott, J. A., Newbound, G. C., Freise, K. J., Clark, T. P. The margin of safety of a single application of transdermal fentanyl solution when administered at multiples of the therapeutic dose to laboratory dogs.J. vet. Pharmacol. Therap.35(Suppl. 2), 35–43.Previous studies have demonstrated that a single, topical application of a novel, long‐acting transdermal fentanyl solution provides analgesic fentanyl concentrations for at least 4 days. The objective of this study was to describe the margin of safety following application at multiples of the therapeutic dose. Twenty‐four laboratory dogs were administered a single placebo or 1×, 3×, or 5× multiple of the dose of 2.6 mg/kg (50 μL/kg) to the ventral abdominal skin and observed for 14 days. Plasma fentanyl concentrations increased in proportion to dose. Adverse reactions in the 1× group were transient and included a low prevalence (≤33%) of mild sedation, reduced food intake, modest weight loss, and minimal reductions in heart rate and rectal temperature. Moderate to severe sedation emerged in the 3× and 5× groups, which was associated with a dose‐limiting reduction in food and water intake, necessitating maintenance fluid replacement for the first 2 days following application. Also observed in the higher‐dose groups were an increased prevalence of abnormal stools and transient lens opacities. All abnormal health observations were completely resolved prior to necropsy on day 14, and there were no histological abnormalities identified. These data support the safe use of the 1× dose and describe the outcome of an overdose of up to 5× dose in the absence of opioid reversal.
Pharmacokinetics and the effect of application site on a novel, long‐acting transdermal fentanyl solution in healthy laboratory Beagles
Authors: FREISE K. J. , NEWBOUND G. C. , TUDAN C. , CLARK T. P. 
Published: June 2012

Freise, K. J., Newbound, G. C., Tudan, C., Clark, T. P. Pharmacokinetics and the effect of application site on a novel, long‐acting transdermal fentanyl solution in healthy laboratory Beagles.J. vet. Pharmacol. Therap.35(Suppl. 2), 27–33.Application of transdermal drugs to different anatomical sites can result in different absorption characteristics. The pharmacokinetics (PKs) and bioequivalence of a single 2.6 mg/kg (50 μL/kg) dose of a novel, long‐acting transdermal fentanyl solution were determined when applied topically to the ventral abdominal or dorsal interscapular skin of 40 healthy laboratory Beagles. The PKs were differentiated by a more rapid initial absorption of fentanyl from the dorsal application site. Mean plasma fentanyl concentrations remained above 0.6 ng/mL from 4 to 96 h in the dorsal application group and from 8 to 144 h in the ventral application group. Bioequivalence analysis demonstrated that the sites were not equivalent; the 90% confidence intervals of the ratio of the geometric means for both the maximum concentration (Cmax) and the area under the curve (AUC) were not contained within the 80–125% interval. TheCmaxwas 2.34 ± 1.29 (mean ± standard deviation) and 2.02 ± 0.84 ng/mL for the ventral and dorsal application groups, respectively. The terminal elimination half‐lives (t1/2) for both groups were similar with values of 137 ± 58.9 and 117 ± 59.6 h for the ventral and dorsal application site groups, respectively. A mean absorption rate of ≥2 μg · kg/h was maintained from 2 to 144 h following dorsal application and from 2 to 264 h following ventral application. These results suggest that transdermal fentanyl solution could be applied as a single dose to the dorsal scapular area 2–4 h prior to surgery with analgesia lasting a minimum of 4 days.
The history and pharmacology of fentanyl: relevance to a novel, long‐acting transdermal fentanyl solution newly approved for use in dogs
Authors: KUKANICH B. , CLARK T. P. 
Published: June 2012

KuKanich, B., Clark, T. P. The history and pharmacology of fentanyl: relevance to a novel, long‐acting transdermal fentanyl solution newly approved for use in dogs.J. vet. Pharmacol. Therap.35(Suppl. 2), 3–19.Fentanyl is a potent mu opioid receptor agonist that was discovered to identify an improved human health analgesic over morphine, an opioid frequently associated with histamine‐release, bradycardia, hyper‐ or hypotension, and prolonged postoperative respiratory depression. Historically, the pharmacological features of fentanyl have been described primarily through the study of the human approved fentanyl citrate formulation. In conscious dogs, fentanyl has a wide margin of safety, possesses minimum effects on the cardiovascular and respiratory systems, and is readily reversible. Other pharmacological features include sedation, mild reductions in body temperature, and dose‐dependent reduction in food intake. The short duration of effect of available fentanyl citrate solutions has limited its clinical use to perioperative injections or constant rate infusions (CRIs). To extend the analgesic effect, additional fentanyl delivery technologies have been developed for human health including the fentanyl patch that has been used in an extra‐label manner in dogs. Beyond the slow onset and variability in fentanyl delivery, several additional disadvantages have precluded common use of patches in dogs. The recent approval of long‐acting transdermal fentanyl solution for dogs provides a new approach for sustained delivery of fentanyl for the control of postoperative pain in dogs. It has a rapid onset of action, prolonged duration, and mitigates the disadvantages of oral, parenteral, and patch‐delivered opioids. The availability of a safe and effective approved opioid in dogs may allow further optimization of postoperative analgesia in this species. The objective of this review is to summarize the history and pharmacology of fentanyl and to integrate information about the newly approved long‐acting transdermal fentanyl solution.
Genetic basis of local adaptation and flowering time variation in Arabidopsis lyrata
Authors: LEINONEN PÄIVI H. , REMINGTON DAVID L. , LEPPÄLÄ JOHANNA , SAVOLAINEN OUTI 
Published: June 2012

AbstractUnderstanding how genetic variation at individual loci contributes to adaptation of populations to different local environments is an important topic in modern evolutionary biology. To date, most evidence has pointed to conditionally neutral quantitative trait loci (QTL) showing fitness effects only in some environments, while there has been less evidence for single‐locus fitness trade‐offs. At QTL underlying local adaptation, alleles from the local population are expected to show a fitness advantage. Cytoplasmic genomes also can have a role in local adaptation, but the role of cytonuclear interactions in adaptive differentiation has remained largely unknown. We mapped genomic regions underlying adaptive differentiation in multiple fitness components and flowering time in diverged populations of a perennial plant Arabidopsis lyrata. Experimental hybrids for this purpose were grown in natural field conditions of the parental populations in Norway and North Carolina (NC), USA, and in the greenhouse. We found QTL where high fitness and early flowering were associated with local alleles, indicating a role of different selection pressures in phenotypic differentiation. At two QTL regions, a fitness component showing local adaptation between the parental populations also showed signs of putative fitness trade‐offs. Beneficial dominance effects of conditionally neutral QTL for different fitness components resulted in hybrid vigour at the Norwegian site in the F2 hybrids. We also found that cytoplasmic genomes contributed to local adaptation and hybrid vigour by interacting with nuclear QTL, but these interactions did not show evidence for cytonuclear coadaptation (high fitness of local alleles combined with the local cytoplasm).