bluuebunny/crossref_metadata_2025_split huggingface dataset:
Applications of Fuzzy Regression in Actuarial Analysis
Authors: De Andrés Sánchez Jorge , Terceño Gómez Antonio 
Published: November 2003

AbstractIn this article, we propose several applications of fuzzy regression techniques for actuarial problems. Our main analysis is motivated, on the one hand, by the fact that several articles in the financial and actuarial literature suggest using fuzzy numbers to model interest rate uncertainty but do not explain how to quantify these rates with fuzzy numbers. Likewise, actuarial literature has recently focused some of its attention in analyzing the Term Structure of Interest Rates (TSIR) because this is a key instrument for pricing insurance contracts. With these two ideas in mind, we show that fuzzy regression is suitable for adjusting the TSIR and discuss how to apply a fuzzy TSIR when pricing life insurance contracts and property‐liability policies. Finally, we reflect on other actuarial applications of fuzzy regression and develop with this technique the London Chain Ladder Method for obtaining Incurred But Not Reported Reserves.
Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations
Authors: Allabi Aurel C. , Gala Jean‐Luc , Desager Jean‐Pierre , Heusterspreute Michel , Horsmans Yves 
Published: November 2003

Aims  To investigate the distribution of cytochrome P450 2C9 (CYP2C9) and 2C19 (CYP2C19) genotype frequencies in the Beninese and Belgian Caucasian populations.Methods  Beninese (n = 111) and Belgian (n = 121) were genotyped for CYP2C9*2, *3, *4, *5, and *11 as well as for CYP2C19*2 and*3.Results  The distribution of alleles was: CYP2C9*1: 95.5 vs. 82.2% (P < 0.001); CYP2C9*2: 0 vs. 10% (P < 0.001); CYP2C9*3: 0 vs. 7.4% (P < 0.01); CYP2C9*4: both 0%; CYP2C9*5: 1.8 vs. 0% (P = 0.05); and CYP2C9*11: 2.7 vs. 0.4% (P < 0.05). The frequencies of the CYP2C19*2 allele were 13 vs. 9.1%, respectively. CYP2C19*3 was not detected in either population. The 95% confidence intervals for the differences of frequencies of CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, CYP2C9*11, CYP2C19*1, CYP2C19*2 and CYP2C19*3 between  Belgian  and  Beninese  were  7%,  19%;  − 14%,  − 6%;  − 11%, − 4%; − 1%, 1%; 0%, 4%; 0%, 5%; − 10%, 2%; − 2%, 10%; − 1%; respectively. The distributions of CYP2C9 genotypes in the Beninese and Belgian individuals were: CYP2C9*1/*1: 91 vs. 67% (P < 0.00001); CYP2C9*1/*2: 0 vs. 18.2% (P < 0.0001); CYP2C9*1/*3: 0 vs. 11.6% (P < 0.001); CYP2C9*1/*5: 3.6 vs. 0% (P = 0.05); CYP2C9*1/*11: 5.4 vs. 0.8% (P = 0.05); CYP2C9*2/*3: 0 vs. 1.6% (NS); CYP2C9*3/*3: 0 vs. 0.8% (NS). The distributions of CYP2C19 genotypes between these ethnic groups were: CYP2C19*1/*1: 73.9 vs. 83.5% (NS); CYP2C19*1/*2: 26.1 vs. 14.9% (P < 0.05); CYP2C9*2/*2: 0 vs. 1.6% (NS).Conclusions  Differences of allele frequencies between Beninese and Belgian populations were statistically significant for CYP2C9*2, *3, *5 and *11, but not for CYP2C9*4 or for CYP2C19*2 and *3.
Bioavailability of dexmedetomidine after extravascular doses in healthy subjects
Authors: Anttila Markku , Penttilä Jani , Helminen Antti , Vuorilehto Lauri , Scheinin Harry 
Published: November 2003

Aim  To determine the absolute bioavailability of extravascularly administered dexmedetomidine, a novel a2‐adrenoceptor agonist, in healthy subjects.Methods  Single 2 µg kg−1 doses of dexmedetomidine were given intravenously, intramuscularly, perorally and buccally (where the solution is not swallowed) to 12 healthy male subjects. The drug concentration‐time data were analysed using linear one‐compartment (buccal and peroral data), or two‐compartment modelling (intravenous data), or noncompartmental methods (intramuscular data).Results  Mean (95% CI) absolute bioavailability after peroral, buccal and intramuscular administration was 16% (12–20%), 82% (73–92%) and 104% (96–112%), respectively.Conclusion  Dexmedetomidine is well absorbed systemically through the oral mucosa, and therefore buccal dosing may provide an effective, noninvasive route to administer the drug.
Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first‐pass metabolism, CYP2D6 genotype and formulation‐dependent bioavailability
Authors: Kerbusch Thomas , Wählby Ulrika , Milligan Peter A. , Karlsson Mats O. 
Published: November 2003

Aims  A model describing the population pharmacokinetics of darifenacin and its hydroxylated metabolite was developed from a combined analysis of 18 studies. The relationships between explanatory covariates and pharmacokinetic parameters were explored.Methods  Plasma concentration data from 337 individuals were pooled from 17 Phase 1 studies (median 28/33 darifenacin/metabolite observations per healthy subject), and one Phase 2 study (median 7/7 darifenacin/metabolite observations per subject) encompassing one intravenous and five different oral formulations (1–45 mg).Results  Non‐linear Mixed Effects Models (NONMEM Version VI) described both the population pharmacokinetics of darifenacin and its hydroxylated metabolite with a two‐compartment disposition model with first order absorption. The values (mean ± standard error of the mean) for clearance (CL) and volume of distribution of the central compartment were 40.2 ± 2.0 l h−1 and 34.7 ± 4.6 l h−1, respectively, in a typical male CYP2D6 homozygote‐extensive metabolizer (Hom‐EM). The absolute bioavailability (F) of darifenacin in a Hom‐EM after doses of 7.5, 15 or 30 mg extended release formulation (CR) was 15, 19 and 25%, respectively. Factors influencing F were formulation (70–110% higher for CR compared with immediate release following equivalent daily doses), CYP2D6 genotype [heterozygote‐extensive metabolizers (Het‐EM) and poor metabolizers (PM) experienced 40 and 90%, respectively, higher exposure than Hom‐EM irrespective of dose administered] and saturable first‐pass metabolism (dose nonlinearity 1.05–1.43‐fold). Race affected F, which was 56% lower in Japanese males. The CYP3A4 inhibitors ketoconazole and erythromycin increased F to approximately 100% and ketoconazole decreased CL by 67.5%. CL was 31% lower in females and 10% lower at night. Formulation affected the metabolite absorption/formation rate. Ketoconazole and erythromycin administration resulted in a decrease of 61.2 and 28.8% in exposure to the metabolite, respectively. The covariates race, gender and circadian rhythm accounted for only approximately half of the variability in the estimated exposures to darifenacin.Conclusions  The pooled analysis provided a descriptive integration of all characteristics and covariates of the pharmacokinetics of darifenacin and its metabolite, enabling interpolation and extrapolation of these key factors.
The pharmacokinetics and safety of intravenous voriconazole – a novel wide‐spectrum antifungal agent
Authors: Purkins Lynn , Wood Nolan , Greenhalgh Katie , Eve Malcolm D. , Oliver Stuart D. , Nichols Don 
Published: November 2003

Aims  Voriconazole is a new triazole with broad‐spectrum antifungal activity against clinically significant and emerging pathogens. These studies evaluated the pharmacokinetics and safety of intravenous voriconazole in healthy male volunteers.Methods  Two single‐blind, placebo‐controlled studies were conducted. In Study A, 12 subjects were randomized to voriconazole (3 mg kg−1) or placebo, administered once daily on days 1 and 12, and every 12 h on days 3–11. In Study B, 18 subjects were randomized to voriconazole or placebo, with voriconazole being administered as a loading dose at 6 mg kg−1 twice on day 1, then at 3 mg kg−1 twice daily on days 2–9, and once at 3 mg kg−1 on day 10.Results  In both studies, the plasma concentrations of voriconazole increased rapidly following the initiation of dosing. Minimum observed plasma concentration (Cmin) values at steady state were above the in vitro minimum inhibitory concentrations (MICs) for most fungal pathogens (Cmin > 0.8 µg ml−1). The use of a loading dose in Study B resulted in a shorter time to steady‐state Cmin values than was observed in Study A. Values of the final day plasma pharmacokinetic parameters in Studies A and B were similar: maximum observed plasma concentration (Cmax) 3621 and 3063 ng ml−1; areas under the plasma concentration–time curve from time zero to the end of the dosing interval (AUCτ) 16 535 and 13 245 ng·h  ml−1, and terminal elimination phase half‐lives (t1/2) 6.5 and 6.7 h, respectively. On multiple dosing, voriconazole accumulated (AUCτ accumulation ratio 2.53–3.17, Study A) at a level that was not predictable from single‐dose data. The mean concentration–time profiles for voriconazole in saliva were similar to those in plasma. Multiple doses of voriconazole were well tolerated and no subject discontinued from either study. Seven cases of possibly drug‐related visual disturbance were reported in three subjects (Study B).Conclusions  Administration of a loading dose of 6 mg kg−1 i.v. voriconazole on the first day of treatment followed by 3 mg kg−1 i.v. twice daily achieves steady state by the third day of dosing. This dosage regimen results in plasma levels of the drug that rapidly exceed the minimum inhibitory concentrations (MICs) against important fungal pathogens, including Aspergillus spp.
No clinically significant effect of erythromycin or azithromycin on the pharmacokinetics of voriconazole in healthy male volunteers
Authors: Purkins Lynn , Wood Nolan , Ghahramani Parviz , Kleinermans Diane , Layton Gary , Nichols Don 
Published: November 2003

Aims  The antibiotic erythromycin is a potent inhibitor of cytochrome P450 CYP3A4 metabolism. As CYP isozymes, including CYP3A4, are involved in the metabolism of the new triazole voriconazole, this study investigated the effects of multiple‐dose erythromycin or azithromycin on the steady‐state pharmacokinetics of voriconazole in healthy male subjects.Methods  In an open, randomized, parallel‐group, single‐centre study, 30 healthy male subjects aged 20–41 years received oral voriconazole 200 mg twice daily for 14 days plus either erythromycin (1 g twice daily on days 8–14), azithromycin (500 mg once daily on days 12–14) or placebo (twice daily on days 8–14). Only morning doses were administered on day 14. Plasma concentrations of voriconazole were measured up to 12 h postdose on days 7 and 14, and plasma pharmacokinetic parameters were calculated. Adverse events and standard laboratory test results were recorded before and throughout the study.Results  Comparison of the voriconazole Cmax day 14/day 7 ratio for the voriconazole + erythromycin group with that of the voriconazole + placebo group yielded a ratio of 107.7%[90% confidence interval (CI) 90.6, 128.0]; for the voriconazole + azithromycin group, the ratio was 117.5% (90% CI 98.8, 139.7). Comparison of the voriconazole AUCτ day 14/day 7 ratios of the voriconazole + erythromycin and voriconazole + azithromycin groups with that of the voriconazole + placebo group showed ratios of 101.2% (90% CI 89.1, 114.8) and 107.9% (90% CI 95.1, 122.4), respectively. For voriconazole tmax, the differences between the day 14–day 7 calculations for the voriconazole + erythromycin or the voriconazole + azithromycin groups and that of the voriconazole + placebo group were − 0.2 h (90% CI − 0.8, 0.3) and − 0.1 h (90% CI − 0.7, 0.5), respectively. None of these changes was considered clinically relevant. The study drugs were well tolerated by subjects in all groups; the most common study drug‐related adverse events were visual disturbances, reported in all groups, and abdominal pain, present in the voriconazole + erythromycin group.Conclusions  Coadministration of erythromycin or azithromycin does not affect the steady‐state pharmacokinetics of voriconazole in a clinically relevant manner in healthy male subjects.
Stages of activation of hepatic stellate cells: effects of ellagic acid, an inhibiter of liver fibrosis, on their differentiation in culture
Authors: Buniatian G. H. 
Published: November 2003

Abstract. To further explore that hepatic stellate cell (HSC) activation results in physiological protection against environmental insult, the profile of differentiation of HSC has been examined upon treatment with ellagic acid (EA), a plant‐derived antioxidant that shows multiple protective effects during liver disease. Sparse rat liver cell cultures were grown in media containing EA (3, 6, 30 and 100 µg/ml) and, as controls, without EA, and inspected until day 7 in culture. The cells were double‐labelled with antibodies against glial fibrillary acidic protein (GFAP) and smooth muscle alpha‐actin (SMAA), marker proteins of quiescent and activated HSC, respectively. In EA‐free culture conditions, the quiescent (SMAA−/GFAP+) HSC transiently acquired a semi‐activated (SMAA+/GFAP+), phenotype and were further transformed into activated (SMAA+/GFAP−), pleomorphic HSC. Up to a concentration of 30 µg/ml, EA induced an early synthesis of SMAA in all HSC and inhibited their morphologic differentiation and individual growth throughout the culture period. At a concentration of 6 µg/ml, EA supported the semi‐activated (SMAA+/GFAP+) phenotype of HSC throughout the culture period, whereas treatment with high EA concentrations (30 µg/ml) resulted in an early loss of GFAP expression. In conclusion: (i) the uniform response of HSC to EA by mild activation adds functional significance to cellular features preceding the transformation of HSC to myofibroblasts; (ii) the high sensitivity of HSC to EA treatment suggests their involvement in any mechanisms of protection by this antioxidant; (iii) the maintenance of HSC morphology might be one of the factors playing a role in the prevention or slowing down of liver fibrosis; (iv) because the effects of EA are concentration‐ and time‐dependent, an arbitrary usage of this antioxidant is a matter of potential concern; (v) the various patterns of HSC activation observed might correspond to distinct activities of these cells, which, in turn, might lead to different outcomes of liver fibrosis.
High levels of extra‐group paternity in a population of Australian magpiesGymnorhina tibicen: evidence from microsatellite analysis
Authors: Hughes J. M. , Mather P. B. , Toon A. , Ma J. , Rowley I. , Russell E. 
Published: November 2003

AbstractBreeding systems vary widely in birds, from monogamous pairs through to complex group systems where subordinates assist breeding individuals to rear young each season. The Australian magpie varies geographically both in plumage patterns and social organization. Some populations of both eastern and western plumage forms are plural breeders with group size varying from three to over 15 mature individuals. This study used variation at microsatellite loci to determine the level of extra‐group paternity in a population of the western form near Perth in Western Australia. Extra‐group paternity was the highest recorded for any bird species to date (82%) and indicates that few offspring within a territory are sired by the social partner of the female. In addition, the data indicated that nearly 10% of juveniles were not the genetic offspring of any female within their territory, suggesting some intraspecific brood parasitism. Taken together, these findings are remarkable considering the highly territorial nature of the species and the extent of territorial defence practised by all members of the group towards extra‐group conspecifics during daylight hours.
Environmentally related patterns of reproductive modes in the aphid Myzus persicae and the predominance of two ‘superclones’ in Victoria, Australia
Authors: Vorburger Christoph , Lancaster Melanie , Sunnucks Paul 
Published: November 2003

AbstractAsexual organisms that naturally coexist with sexual relatives may hold the key to understanding the maintenance of sex and recombination, a long‐standing problem in evolutionary biology. This situation applies to the peach‐potato aphid, Myzus persicae, in southeastern Australia where cyclical parthenogens form mixed populations with obligate parthenogens. We collected M. persicae from several areas across Victoria, genotyped them at seven microsatellite loci and experimentally determined their reproductive mode. The geographic distribution of reproductive modes was correlated with two environmental variables that differentially affect obligate and cyclical parthenogens; obligate parthenogens were less frequent in areas with cold winters because they cannot produce frost‐resistant eggs while cyclical parthenogens were limited by the availability of their primary host, peach, on which sexual reproduction takes place. Clonal diversity increased with the proportion of cyclical parthenogens in a sample because they tended to have unique microsatellite genotypes, whereas many obligate parthenogens were copies of the same genotype. Two obligately asexual genotypes stood out as being very abundant and widespread, one constituting 24% and the other 17.4% of the entire collection. Both of these highly successful genotypes were present in the majority of all collection sites. Genetic population structure was weak, albeit significant, with a multilocus FST of only 0.021 when samples were reduced to only one representative of each genotype. Interestingly, obligate parthenogens were, on average, more heterozygous and exhibited larger allele size differences between the two alleles at individual loci than cyclical parthenogens. This striking pattern could result from hybridization, for which we have no evidence, or may reflect the previously proposed model of biased mutational divergence of microsatellite alleles within asexual aphid lineages.
Pedigree‐based assignment tests for reversing coyote (Canis latrans) introgression into the wild red wolf (Canis rufus) population
Authors: Miller Craig R. , Adams Jennifer R. , Waits Lisette P. 
Published: November 2003

AbstractThe principal threat to the persistence of the endangered red wolf (Canis rufus) in the wild is hybridization with the coyote (Canis latrans). To facilitate idengification and removal of hybrids, assignment tests are developed which use genotype data to estimate identity as coyote, 1/4, 1/2, 3/4 or full red wolf. The tests use genotypes from the red wolves that founded the surviving population and the resulting pedigree, rather than a contemporary red wolf sample. The tests are evaluated by analysing both captive red wolves at 18 microsatellite loci, and data simulated under a highly parameterized, biologically reasonable model. The accuracy of assignment rates are generally high, with over 95% of known red wolves idengified correctly. There are, however, tradeoffs between ambiguous assignments and misassignments, and between misidengifying red wolves as hybrids and hybrids as red wolves. These result in a compromise between limiting introgression and avoiding demographic losses. The management priorities and level of introgression determine the combination of test and removal strategy that best balances these tradeoffs. Ultimately, we conclude that the use of the assignment tests has the capacity to arrest and reverse introgression. To our knowledge, the presented approach is novel in that it accounts for genetic drift when the genotypes under analysis are temporally separated from the reference populations to which they are being assigned. These methods may be valuable in cases where reference databases for small populations have aged substantially, pedigree information is available or data are generated from historical samples.
Rangewide phylogeography of a bird‐dispersed Eurasian shrub: contrasting Mediterranean and temperate glacial refugia
Authors: Hampe A. , Arroyo J. , Jordano P. , Petit R. J. 
Published: November 2003

AbstractWe studied the phylogeography of alder buckthorn (Frangula alnus), a bird‐dispersed shrub or small tree distributed over most of Europe and West Asia and present in three of the four main refugia of West Palaearctic temperate woody plants: the Iberian Peninsula, the Balkans and Anatolia. A total of 78 populations from 21 countries were analysed for chloroplast DNA variation using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP), and 21 different haplotypes were distinguished. We found a very strong overall population differentiation (GST = 0.81) and phylogeographical structure, and a sharp contrast between the haplotype‐rich refugia and the almost completely uniform area of postglacial colonization. The haplotype network comprises three lineages made up of haplotypes from the Iberian Peninsula, Anatolia with the Caucasus, and temperate Europe. The Iberian and the Anatolian branches represent parts of a major lineage that spans over the whole northern Mediterranean Basin and some neighbouring areas and probably dates back to the Tertiary. Many haplotypes of this lineage are distributed locally and most populations are fixed for a single haplotype; these populations have apparently been very stable since their establishment, experiencing negligible gene flow and few mutations. The temperate European lineage consists of one very widespread and abundant plus six locally distributed haplotypes. Four of them are located in Southeast Europe, the putative refugium of all extant temperate European populations. Contrary to populations from Iberia and Anatolia,F. alnuspopulations from the southeastern European refugium have most genetic variation within populations. Bird‐mediated seed dispersal has apparently allowed not only a very rapid postglacial expansion ofF. alnusbut also subsequent regular seed exchanges between populations of the largely continuous species range in temperate Europe. In contrast, the disjunctF. alnuspopulations persisting in Mediterranean mountain ranges seem to have experienced little gene flow and have therefore accumulated a high degree of differentiation, even at short distances. Populations from the southern parts of the glacial refugia have contributed little to the postglacial recolonization of Europe, but their long‐term historical continuity has allowed them to maintain a unique store of genetic variation.
Primary sex ratios in birds: problems with molecular sex identification of undeveloped eggs
Authors: Arnold Kathryn E. , Orr Kate J. , Griffiths Richard 
Published: November 2003

AbstractSex allocation studies seek to ascertain whether mothers manipulate offspring sex ratio prior to ovulation. To do so, DNA for molecular sexing should be collected as soon after conception as possible, but instead neonates are usually sampled. Here, we aim to identify and quantify some of the problems associated with using molecular techniques to identify the sex of newly laid avian eggs. From both fertilized and unfertilized chicken (Gallus gallus) eggs, we sampled (1) the blastoderm/disc, (2) vitelline membrane and (3) a mixture of (1) and (2). Thus, we replicated scenarios under which contaminated samples are taken and/or unfertilized eggs are not identified as such and are sampled. We found that two commonly used molecular sexing tests, based on the CHD‐1 genes, differed in sensitivity, but this did not always predict their ability to sex egg samples. The vitelline membrane was a considerable source of maternal and probably paternal contamination. Fertile eggs were regularly assigned the wrong sex when vitelline membrane contaminated the blastoderm sample. The membrane of unfertilized eggs was always female, i.e. maternal DNA had been amplified. DNA was amplified from 47 to 63% of unfertilized blastodiscs, even though it was highly unlikely that DNA from a single haploid cell could be amplified reliably using these polymerase chain reaction (PCR) techniques. Surprisingly, the blastodiscs were identified as both males and females. We suggest that in these cases only maternal DNA was amplified, and that ‘false’ males, Z not ZZ, were detected. This was due to the reduced ability of both sets of primers to anneal to the W chromosome compared to the Z chromosome at low DNA concentrations. Overall, our data suggested that estimates of primary sex ratios based on newly laid eggs will be appreciably inaccurate.