bluuebunny/crossref_metadata_2025 huggingface dataset:
Genotypic variability at the major histocompatibility complex (B and Rfp‐Y) in Camperos broiler chickens
Authors: Iglesias G. M. , Soria L. A. , Goto R. M. , Jar A. M. , Miquel M. C. , Lopez O. J. , Miller M. M.
Published: December 2004

Evidence for the importance of major histocompatibility complex (MHC) genotype in immunological fitness of chickens continues to accumulate. The MHC B haplotypes contribute resistance to Marek's and other diseases of economic importance. The Rfp‐Y, a second cluster of MHC genes in the chicken, may also contribute to disease resistance. Nevertheless, the MHC B and Rfp‐Y haplotypes segregating in broiler chickens are poorly documented. The Camperos, free‐range broiler chickens developed in Argentina, provide an opportunity to evaluate MHC diversity in a genetically diverse broiler stock. Camperos are derived by cross‐breeding parental stocks maintained essentially without selection since their founding. We analysed 51 DNA samples from the Camperos and their parental lines for MHC B and Rfp‐Y variability by restriction fragment pattern (rfp) and SSCP typing methods for B‐G, B‐F (class Ia), B‐Lβ (class II) and Y‐F (class Ib) diversity. We found evidence for 38 B‐G genotypes. The Camperos B‐G patterns were not shared with White Leghorn controls, nor were any of a limited number of Camperos B‐G gene sequences identical to published B‐G sequences. The SSCP assays provided evidence for the presence of at least 28 B‐F and 29 B‐Lβ genotypes. When considered together B‐F, B‐L, and B‐G patterns provide evidence for 40 Camperos B genotypes. We found even greater Rfp‐Y diversity. The Rfp‐Y class I‐specific probe, 163/164f, revealed 44 different rfps among the 51 samples. We conclude that substantial MHC B and Rfp‐Y diversity exists within broiler chickens that might be drawn upon in selecting for desirable immunological traits.
Origin of rabbit (Oryctolagus cuniculus) in China: evidence from mitochondrial DNA control region sequence analysis
Authors: Long J.‐R. , Qiu X.‐P. , Zeng F.‐T. , Tang L.‐M. , Zhang Y.‐P.
Published: December 2004

A fragment of mitochondrial DNA (mtDNA) control region (∼700 bp) was sequenced in 104 individuals from 20 breeds (three Chinese domestic breeds, five recently derived breeds and 12 introduced breeds) of domestic rabbits, Oryctolagus cuniculus. Nineteen sites were polymorphic, with 18 transitions and one insertion/deletion, and eight haplotypes (A1, A2, A3, A4, A5, A6, A7 and A8) were identified. Haplotype A1 was the most common and occurred in 89 individuals. In the 25 Chinese rabbits, only haplotype A1 was observed, while four haplotypes (A1, A3, A5 and A6) were found in 26 recently derived individuals. Haplotype A2 was shared by seven individuals among three introduced strains. The other six haplotypes accounted for 0.96–1.92% of the animals. Combined with the published sequences of European rabbits, a reduced median‐joining network was constructed. The Chinese rabbit mtDNAs were scattered into two clusters of European rabbits. These results suggest that the (so‐called) Chinese rabbits were introduced from Europe. Genetic diversity in Chinese rabbits was very low.
Phylogenies using mtDNA and SRY provide evidence for male‐mediated introgression in Asian domestic cattle
Authors: Kikkawa Y. , Takada T. , Sutopo  , Nomura K. , Namikawa T. , Yonekawa H. , Amano T.
Published: December 2004

Using nucleotide sequences of the mitochondrial DNA (mtDNA) cytochrome b and SRY genes, we examined the genetic status of two major groups of domestic cattle, the humpless taurine (Bos taurus) and humped zebu (B. indicus), using 10 cattle populations in Asia. Several sequence polymorphisms specific for each major group were found, although the frequency of these polymorphisms varied in each population. Six major mtDNA‐SRY composite types were observed. The Mishima, Mongolian, Korean, Chinese Yellow and Sri Lanka cattle populations had a full match between the mtDNA and SRY sequences, specifically the taurine/taurine type or zebu/zebu type. A non‐match type (zebu/taurine type) was found at a high frequency in the Bangladesh (83.4%) and Nepal populations (83.3%). Our results suggest that these non‐match type populations developed from genetic hybridization of different strains. Also, the domestication history of modern Asian domestic cattle could be explained by male‐mediated introgression. Additionally, our results suggest the occurrence of introgression of mtDNA from other Bibos or Poephagus species into native cattle populations. The existence of other mtDNA‐SRY composite types, such as the Bali‐zebu and yak‐zebu types in Indonesia (85.7%) and Nepal (16.7%), respectively, suggests that genetic introgression also occurred from other genera into domestic cattle during the process of domestication.
A consolidated linkage map for rainbow trout (Oncorhynchus mykiss)
Authors: Nichols K. M. , Young W. P. , Danzmann R. G. , Robison B. D. , Rexroad C. , Noakes M. , Phillips R. B. , Bentzen P. , Spies I. , Knudsen K. , Allendorf F. W. , Cunningham B. M. , Brunelli J. , Zhang H. , Ristow S. , Drew R. , Brown K. H. , Wheeler P. A. , Thorgaard G. H.
Published: December 2004

Androgenetic doubled haploid progeny produced from a cross between the Oregon State University and Arlee clonal rainbow trout (Oncorhynchus mykiss) lines, used for a previous published rainbow trout map, were used to update the map with the addition of more amplified fragment length polymorphic (AFLP) markers, microsatellites, type I and allozyme markers. We have added more than 900 markers, bringing the total number to 1359 genetic markers and the sex phenotype including 799 EcoRI AFLPs, 174 PstI AFLPs, 226 microsatellites, 72 VNTR, 38 SINE markers, 29 known genes, 12 minisatellites, five RAPDs, and four allozymes. Thirty major linkage groups were identified. Synteny of linkage groups in our map with the outcrossed microsatellite map has been established for all except one linkage group in this doubled haploid cross. Putative homeologous relationships among linkage groups, resulting from the autotetraploid nature of the salmonid genome, have been revealed based on the placement of duplicated microsatellites and type I loci.
Characterization of naturally processed and presented peptides associated with bovine major histocompatibility complex (BoLA) class II DR molecules
Authors: Sharif S. , Mallard B. A. , Wilkie B. N.
Published: December 2004

Differential regulation of genetic resistance to infectious disease may partially be explained by variation in the binding affinity and the repertoire of pathogen‐derived antigenic peptides associated with major histocompatibility complex (MHC) molecules. In this study, we investigated characteristics of peptides that bind to the bovine MHC allele BoLA‐DRB3*2703, which is associated with occurrence of clinical mastitis in Holstein dairy cattle, and assigned a putative peptide‐binding motif to this allele. This was achieved by in vitro expression of allele *2703 as well as a control allele, BoLA‐DRB3*1201 which is present at high frequency in Holsteins. Transfected cell lines alone (for allele *1201) or in combination with blood mononuclear cells from an animal homozygous for allele *2703 were used as the source of naturally processed and presented peptides. Subsequent to elution of peptides from BoLA‐DR+ cells, their sequences were determined by electrospray ionization mass spectrometry. Eluted peptides were between 13 and 20 amino acids long and the majority were in sets of overlapping sequences. These peptides were derived from intra‐ and extracellular proteins, as well as foreign proteins present in the culture medium. Some peptides had originated from molecular chaperones present in the endoplasmic reticulum, such as ER‐60 and GRP78, pointing to some degree of overlap and cross‐sampling between MHC class I and class II antigen presentation pathways. Consistent with reports of human and mouse MHC class II‐associated peptides, putative peptide‐binding motifs could be assigned to alleles *2703 and *1201, comprising a hydrophobic or an aromatic residue at relative position 1, a hydrophobic residue at position 4 and a small residue at position 6 of the eluted peptides. These findings provide the foundation for future studies of molecular mechanisms of MHC‐disease associations of cattle.
Mapping of porcine ESTs obtained from the anterior pituitary
Authors: Bertani G. R. , Johnson R. K. , Robic A. , Pomp D.
Published: December 2004

We report the physical mapping of porcine expressed sequence tags (ESTs) from anterior pituitary clones isolated by differential display PCR in a study using lines selected for reproduction. These ESTs were mapped using a somatic cell hybrid panel (SCHP) and a radiation hybrid panel (IMpRH) as follows (SCHP position, nearest marker on the RH map): SPARCL1 (8q23–q27, SSP1); ATF4 (5p11–p15, AC02); MEF2C [2(1/2q21)–(1/2q22), SW2134]; FTH1 (2p14–p17, SWR783); FRAP1 (6q22–q23, SW1355); PBP (14, SW2508); LOC92004 [13q23‐(1/2q41), CP]; and PGRMC1 [Xq22, SW1943]. All RH assignments were at LOD score >6.0 except for PGRMC1 at LOD score 5.4. ESTs TCP1 [12p11‐(2/3p13)], SF3B1 (15q23–q26) and Clock (8q11–q12) were assigned using only the SCHP. The map position of SPARCL1 coincides with a quantitative trait loci (QTL) for age at puberty found in the University of Nebraska selection lines. Physical mapping of ESTs reported in the present study contributes to characterization of the transcriptome of anterior pituitary of pigs, adds new information to the public database of the porcine genome expression map, and further develops the porcine–human comparative map.
Evaluation of the present breeding programme against copper toxicosis in Danish Bedlington terriers
Authors: Proschowsky H. F. , Olsen J. B. , Jepsen B. , Fredholm M.
Published: December 2004

A breeding programme to eradicate copper toxicosis in Danish Bedlington terriers has been established based on a DNA marker test. Genotyping of both parents is compulsory and after 1 January 2000, only homozygous non‐carriers are used for breeding. In this study, two groups of Bedlington terriers were genotyped at 18 microsatellite loci. One group represented the original population of Bedlington terriers before introducing the breeding programme (n = 23); the other represented a group of homozygous non‐carriers (n = 24) available for breeding after year 2000. Allele numbers, allele frequencies, observed heterozygosities (Ho), expected heterozygosities (He), locus‐specific coefficients of inbreeding (Fl) and Nei's genetic distance (D) was calculated. Individual coefficients of inbreeding (Fi) were calculated from the pedigrees and an assignment test was performed. Four rare alleles were lost in the group of homozygous non‐carriers. No significant differences were observed between the mean values of allele numbers,Ho, He, FlandFiof the two populations of dogs. Nei's genetic distance between the two populations was 0.06 and 88% of the homozygous non‐carriers were assigned correctly in the assignment test. The overall diversity of the breed was low (Ho = 0.41) and the breeders were advised to include the heterozygous carriers again.
Development of 50 gene‐associated microsatellite markers using BAC clones and the construction of a linkage map of swine chromosome 4
Authors: Fujishima‐Kanaya N. , Toki D. , Suzuki K. , Sawazaki T. , Hiraiwa H. , Iida M. , Hayashi T. , Uenishi H. , Wada Y. , Ito Y. , Awata T.
Published: December 2004

The development of informative polymorphic markers is essential for QTL mapping. We developed 50 microsatellite markers from BAC clones containing genes that were predicted to map swine chromosome 4 (SSC4) according to comparative analysis between human and swine chromosomes, and constructed a linkage map that consisted of 37 markers including 24 markers closely linked to genes in BAC clones. Microsatellite markers were developed by direct‐sequencing of BAC clones and our results demonstrated that this method was effective for developing microsatellite markers in specific regions on chromosomes. Effective development of microsatellite markers closely linked to genes can further accelerate the comparative studies of chromosomes between different species.
Cloning and characterization of the bovine EGR4 gene and evaluation as candidate gene for bovine spinal dysmyelination
Authors: Nissen P. H. , Thomsen B. , Offenberg H. , Thomsen P. D. , Bendixen C.
Published: December 2004

Genes of the early growth response (EGR) family encode transcription factors with a highly conserved DNA binding zinc finger domain, which regulate a variety of genes, e.g. late myelin genes. Here, the cloning, genomic structure and expression of the bovine orthologue of the EGR4 gene are reported. The gene consists of two exons and encodes a 482 amino acid protein with a Cys2His2 zinc finger structure. The predicted protein shares between 80 and 87% identity to mouse, rat and human EGR4 proteins and all four species share almost complete identity in the DNA‐binding domain. The bovine transcript is alternatively spliced by retaining intronic sequence, giving rise to two different mRNAs differing in three nucleotides and resulting in an extra alanine residue in the longer variant of the predicted protein. The gene was mapped by radiation hybrid (RH) mapping to markers on bovine chromosome 11. EGR4 transcripts were detected by reverse transcriptase polmerase chain reaction (RT‐PCR) in the frontal cortex and cerebellum, and a low expression level was also detected in the liver. The EGR4 gene was evaluated as a candidate gene for bovine spinal dysmyelination (BSD). Sequencing of the gene from a homozygous affected animal and a heterozygous carrier revealed a single base mutation that leads to an amino acid substitution at residue 322 in EGR4. Genotype analysis of this polymorphism in a pedigree segregating for BSD, as well as in a panel of different cattle breeds, and sequence analysis of the entire coding region suggested that the EGR4 is not the gene responsible for BSD. Furthermore, 87 animals of different cattle breeds were screened for single‐nucleotide polymorphisms (SNPs) resulting in the identification of two SNPs in EGR4.
Identification of quantitative trait loci for growth and carcass composition in cattle1
Authors: Casas E. , Keele J. W. , Shackelford S. D. , Koohmaraie M. , Stone R. T.
Published: December 2004

A genomic screening to detect quantitative trait loci (QTL) affecting growth, carcass composition and meat quality traits was pursued. Two hundred nineteen microsatellite markers were genotyped on 176 of 620 (28%) progeny from a Brahman × Angus sire mated to mostly MARC III dams. Selective genotyping, based on retail product yield (%) and fat yield (%), was used to select individuals to be genotyped. Traits included in the study were birth weight (kg), hot carcass weight (kg), retail product yield, fat yield, marbling score (400 = slight00 and 500 = small00), USDA yield grade, and estimated kidney, heart and pelvic fat (%). The QTL were classified as significant when the expected number of false positives (ENFP) was less than 0.05 (F‐statistic greater than 17.3), and suggestive when the ENFP was <1 (F‐statistic between 10.2 and 17.3). A significant QTL (F = 19; ENFP = 0.02) was detected for marbling score at centimorgan (cM) 54 on chromosome 2. Suggestive QTL were detected for fat yield at 50 cM, for retail product yield at 53 cM, and for USDA yield grade at 63 cM on chromosome 1, for marbling score at 56 cM, for retail product yield at 70 cM, and for estimated kidney, heart and pelvic fat at 79 cM on chromosome 3, for marbling score at 44 cM, for hot carcass weight at 49 cM, and for estimated kidney, heart and pelvic fat at 62 cM on chromosome 16, and for fat yield at 35 cM on chromosome 17. Two suggestive QTL for birth weight were identified, one at 12 cM on chromosome 20 and the other at 56 cM on chromosome 21. An additional suggestive QTL was detected for retail product yield, for fat yield, and for USDA yield grade at 26 cM on chromosome 26. Results presented here represent the initial search for quantitative trait loci in this family. Validation of detected QTL in other populations will be necessary.
Genetic markers applied in regression tree prediction models
Authors: Hizer S. E. , Wright T. M. , Garcia D. K.
Published: December 2004

Classification and regression tree (CART) modelling was used to determine infectious hypodermal and haematopoietic necrosis virus (IHHNV) resistance and susceptibility in Penaeus stylirostris. In a previous study, eight random amplified polymorphic DNA (RAPD) markers and viral load values using real‐time quantitative PCR were obtained and used as the training data set in order to create numerous regression tree models. Specifically, the genetic markers were used as categorical predictor variables and viral load values as the dependent response variable. To determine which model has the highest predictive accuracy for future samples, RAPD fingerprint data was generated from new Penaues stylirostris IHHNV resistant and susceptible individuals and used to test the regression models. The best performing tree was a four terminal node tree with three genetic markers as significant variables. Marker‐assisted breeding practices may benefit from the creation of regression tree models that apply genetic markers as predictive factors. To our knowledge this is the first study to use RAPD markers as predictors within a CART prediction model to determine viral susceptibility.
Mapping of bovine ovulation rate QTL; an analytical approach for three generation pedigrees
Authors: Arias J. , Kirkpatrick B.
Published: December 2004

Interval mapping was conducted for ovulation rate quantitative trait loci (QTL) using data from two related families from the United States Department of Agriculture, US Meat Animal Research Center twinning cattle herd. Both families are extended, three generation pedigrees from which records of sons, daughters and granddaughters were analysed. Both a method of analysis and results from that analysis are reported herein. Results from one of the two families (839802) were previously reported, but reanalysis here including the second, related family (839803) and a revised statistical model lessens support for the previously reported QTL. Results from interval mapping provided evidence for QTL in regions corresponding to those previously suggested for chromosomes 7 (chromosome‐wise P < 0.05) and 19 (chromosome‐wise P < 0.01) in the 839802 family, although statistical significance was reduced. In contrast to the previous report, evidence for a chromosome 5 QTL in the same family was greatly reduced while support for a QTL on chromosome 10 increased (chromosome‐wise P < 0.01). Analysis of data from the related 839803 family failed to replicate evidence of QTL observed on either chromosome 7 or chromosome 19 in the 839802 family.
Detection and characterization of SNPs useful for identity control and parentage testing in major European dairy breeds
Authors: Werner F. A. O. , Durstewitz G. , Habermann F. A. , Thaller G. , Krämer W. , Kollers S. , Buitkamp J. , Georges M. , Brem G. , Mosner J. , Fries R.
Published: December 2004

We propose the use of single nucleotide polymorphisms (SNPs) instead of polymorphic microsatellite markers for individual identification and parentage control in cattle. To this end, we present an initial set of 37 SNP markers together with a gender‐specific SNP for identity control and parentage testing in the Holstein, Fleckvieh and Braunvieh breeds. To obtain suitable SNPs, a total of 91.13 kb of random genomic DNA was screened yielding 531 SNPs. These, and 43 previously identified SNPs, were subjected to the following selection criteria: (1) the frequency of the minor allele must be larger than 0.1 in at least two of the three examined breeds, and (2) markers should not be linked closely. Allele frequencies were estimated by analysing sequencing traces of pooled DNA or by genotyping individual DNA samples. The selected SNP loci were physically mapped by radiation hybrid mapping or by fluorescence in situ hybridization, and tested against the neutral mutation hypothesis. The presented marker set theoretically allows probabilities of identity less than 10−13 for individual verification and exclusion powers exceeding 99.99% for parentage testing.
Power of exclusion for parentage verification and probability of match for identity in American kennel club breeds using 17 canine microsatellite markers
Authors: DeNise S. , Johnston E. , Halverson J. , Marshall K. , Rosenfeld D. , McKenna S. , Sharp T. , Edwards J.
Published: December 2004

DNA analysis of microsatellite markers has become a common tool for verifying parentage in breed registries and identifying individual animals that are linked to a database or owner. Panels of markers have been developed in canines, but their utility across and within a wide range of breeds has not been reported. The American Kennel Club (AKC) authorized a study to determine the power to exclude non‐parents and identify individuals using DNA genotypes of 17 microsatellite markers in two panels. Cheek swab samples were voluntarily collected at Parent Breed Club National Specialty dog shows and 9561 samples representing 108 breeds were collected, averaging 88.5 dogs per breed. The primary panel of 10 markers exceeded 99% power of exclusion for canine parentage verification of 61% of the breeds. In combination with the secondary panel of seven markers, 100% of the tested breeds exceeded 99% power of exclusion. The minimum probability match rate of the first panel was 3.6 × 10−5 averaged across breeds, and with the addition of the second panel, the probability match rate was 3.2 × 10−8; thus the probability of another random, unrelated dog with the same genotype is very low. The results of this analysis indicated that, on average, the primary panel meets the AKC's needs for routine parentage testing, but that a combination of 10–15 genetic markers from the two panels could yield a universal canine panel with enhanced processing efficiency, reliability and informativeness.
Development and linkage relationships for new microsatellite markers of the sea bass (Dicentrarchus labrax L.)
Authors: Chistiakov D. A. , Hellemans B. , Tsigenopoulos C. S. , Law A. S. , Bartley N. , Bertotto D. , Libertini A. , Kotoulas G. , Haley C. S. , Volckaert F. A. M.
Published: December 2004

Twenty‐eight polymorphic microsatellites were isolated from the sea bass, Dicentrarchus labrax, using a microsatellite enrichment protocol and selective hybridization with oligonucleotide probes. Analysis for these markers and 11 recently described microsatellites of D. labrax found linkage between 26 loci and revealed eight linkage groups.
Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects
Authors: Spina E. , Avenoso A. , Campo G. M. , Scordo M. G. , Caputi A. P. , Perucca E.
Published: December 2004

Aims The aim of the study was to characterize further the role of CYP3A4 in the metabolism of tricyclic antidepressants.

Methods The effect of oral ketoconazole (200 mg day−1 for 14 days) on the kinetics of a single oral dose of imipramine (100 mg) and desipramine (100 mg) was evaluated in two groups of six healthy male subjects.

Results Ketoconazole administration was associated with a decrease in imipramine apparent oral clearance (from 1.16±0.21 to 0.96±0.20 l h−1 kg−1, mean±s.d.; ‘of2\P<0.02), a prolongation in imipramine half‐life (from 16.7±3.3 to 19.2±5.4 h, ‘of2\P<0.05) and a decrease in area under the curve of metabolically derived desipramine (from 3507±1707 to 3180±1505 nmol l−1 h, P<0.05), whereas concentrations of 2‐hydroxy‐imipramine were unaffected. In the subjects given desipramine, no significant changes in desipramine and 2‐hydroxy‐desipramine kinetics were observed during ketoconazole treatment.

Conclusions These findings indicate that ketoconazole, a relatively specific inhibitor of CYP3A4, inhibits the N‐demethylation of imipramine without affecting the 2‐hydroxylation of imipramine and desipramine. This interaction, confirms that CYP3A4 plays a role in the demethylation of tricyclic antidepressants.
Eradication of ‘ooHelicobacter pylori‘ox : an objective assessment of current therapies
Authors: Penston J. G. , L McColl K. E.
Published: December 2004

The purpose of the present review was to determine objectively the optimal treatment for the eradication of H. pylori amongst the currently used regimens. A comprehensive literature search provided a data‐base relating to the following treatments: dual therapy with an anti‐secretory drug plus either amoxycillin or clarithromycin; standard triple therapy, with or without additional anti‐secretory drugs; proton pump inhibitor triple therapy; and H2‐receptor antagonist triple therapy. Emphasis was placed on intention‐to‐treat analyses of eradication rates using all of the available evidence. The criteria used to select the optimal treatment were efficacy (eradication rates), frequency of side‐effects, simplicity of the regimen (number of tablets per day and duration of treatment) and cost. The analysis showed that proton pump inhibitor triple therapy (that is, a proton pump inhibitor plus any two of amoxycillin, clarithromycin or a nitroimidazole) was the preferred treatment for the eradication of H. pylori. In particular, the 1‐week, low‐dose regimen with omeprazole plus clarithromycin plus tinidazole produced the highest eradication rates (>90%) with the lowest frequency of side‐effects and at only modest cost.
Effects of frusemide and hypoxia on the pulmonary vascular bed in man
Authors: Kiely David G. , Cargill Robert I. , Lipworth Brian J.
Published: December 2004

Aims Diuretic therapy is conventionally used to treat oedema in patients with hypoxic cor pulmonale. This condition is associated with activation of the renin angiotensin system (RAS) with elevated levels of angiotensin II (ANG II), a potent pulmonary pressor agent. We explored the hypothesis that RAS activation by diuretic therapy might therefore worsen hypoxic pulmonary vasoconstriction via the effects of ANG II on the pulmonary vascular bed.

Methods Eight normal volunteers were studied on 2 separate days. They either received 40 mg frusemide daily or placebo for 4 days and were then rendered hypoxaemic, by breathing an N2/O2 mixture for 20 min to achieve an SaO2 of 85–90% adjusted for a further 20 min to achieve an SaO2 of 75–80%. Pulsed wave doppler echocardiography was used to measure mean pulmonary artery pressure, cardiac output and hence pulmonary vascular resistance (PVR).

Results Plasma renin activity (PRA) was significantly (P<0.01) increased after prior treatment with frusemide compared with placebo at all time points. Prior treatment with frusemide significantly (P<0.05) increased PVR compared with placebo at baseline: 185±17 vs 132±10 dyn s cm−5 at an SaO2 of 85–90%: 291±18 vs 229±16 dyn s cm−5 and at SaO2 of 75–80%: 356±12 vs 296±17 dyn s cm−5 respectively. However, the delta‐PVR response to hypoxaemia was not significantly altered by frusemide compared with placebo. In contrast to its effect on the pulmonary vasculature prior treatment with frusemide did not significantly alter systemic haemodynamic parameters either at baseline or during hypoxia..

Conclusions Thus, prior treatment with frusemide increased baseline pulmonary vascular resistance and significantly augmented the hypoxaemic pulmonary vascular response in additive fashion. It is hypothesised that this effect of frusemide may be due to RAS activation with ANG II mediated pulmonary vasoconstriction.
Comparative effect of human soluble insulin and insulin aspart upon hypoglycaemia‐induced alterations in cardiac repolarization
Authors: Robinson Robert T. C. E. , Harris Nigel D. , Ireland Robert H. , Lindholm Anders , Heller Simon R.
Published: December 2004

Aims
  Sudden death in young diabetic patients has been associated with nocturnal hypoglycaemia perhaps as a result of cardiac dysrhythmias following abnormal cardiac repolarization during hypoglycaemia. It was therefore important to compare the effect of soluble human insulin (HI) and a rapid‐acting insulin analogue, insulin aspart (IAsp), on these aspects of cardiac function.

Methods
  A total of 17 healthy males underwent identical hyperinsulinaemic hypoglycaemic clamps with blood glucose maintained at 5 mm for 30 min and reduced to 2.5 mm after an additional 30 min. Subjects received either HI or IAsp on two different occasions separated by 4–6 weeks. Regular measurements were made of two measures of cardiac repolarization, QT dispersion and QTc as well as of counter‐regulatory hormones.

Results
  The blood glucose lowering effect did not differ between IAsp and HI and the clearance rates were similar (HI mean ± SD 1.24 ± 0.12 l h−1 kg−1, IAsp mean ± s.d. 1.22 ± 0.32 l h−1 kg−1). There were similar significant increases but no difference between treatments in QTc after hypoglycaemia induced by either IAsp or HI (480 ± 37 ms vs 480 ± 25 ms; NS). However, QT dispersion during hypoglycaemia was less pronounced with IAsp than with HI (92 ± 36 ms vs 107 ± 42 ms; P < 0.05). Plasma adrenaline increased significantly and similarly after both insulins (initial and final concentration, HI, 0.23 ± 0.01 to 4.87 ± 0.48 nm, P < 0.001, IAsp, 0.24 ± 0.01 to 4.99 ± 0.48 nm, P < 0.001). Serum potassium decreased significantly but by a similar amount between the groups (initial and final concentration, HI, 4.18 ± 0.3 to 4.2 ± 0.2 mm, P < 0.001, IAsp, 4.2 ± 0.3 to 4.2 ± 0.3 mm, P < 0.001).

Conclusions
  Soluble human insulin and insulin aspart had similar effects upon hypoglycaemia‐induced alterations in cardiac repolarization, presumably because the effects of both regular insulin and insulin aspart on the sympathoadrenal response and potassium concentration were the same.
The distribution and gender difference of CYP3A activity in Chinese subjects
Authors: Zhu Bing , Liu Zhao‐Qian , Chen Guo‐Lin , Chen Xiao‐Ping , Ou‐Yang Dong‐Sheng , Wang Lian‐Sheng , Huang Song‐Lin , Tan Zhi‐Rong , Zhou Hong‐Hao
Published: December 2004

Aims
To investigate the distribution of CYP3A activity in the Chinese population, and to test for gender‐related differences in CYP3A activity.

Methods
Using midazolam as a probe drug, CYP3A activity in 202 Chinese healthy subjects (104 men) was measured by plasma 1′‐hydroxymidazolam:midazolam (1′‐OH‐MDZ:MDZ) ratio at 1 h after oral administration of 7.5 mg midazolam. The different phases of the menstrual cycle including preovulatory, ovulatory and luteal phases of 66 women phenotyped with midazolam were recorded. The concentrations of 1′‐OH‐MDZ and MDZ in plasma were measured by HPLC

Results
A 13‐fold variation of CYP3A activity (log1′‐OH‐MDZ:MDZ: range −0.949–0.203) was shown. The CYP3A activity was normally distributed as indicated by the frequency distribution histogram, the probit plot and the Kolmogorov–Smirnov test (P > 0.05). The CYP3A activity of women was higher than that of men (median: −0.36 vs−0.43, P < 0.05; 95% CI for difference: −0.127, −0.012). There was a significant difference in CYP3A activity between the three phases of the menstrual cycle. The activity was highest in the preovulatory phase and decreased sequentially in the ovulatory and luteal phases (P < 0.05).

Conclusions
A normal distribution of CYP3A activity was observed in the Chinese population. The CYP3A activity is higher in female subjects than in males. CYP3A activity differed across the phases of the menstrual cycle.
Systemic bioactivity of intranasal triamcinolone and mometasone in perennial allergic rhinitis
Authors: Lee Daniel K. C. , Robb Fiona M. , Sims Erika J. , Currie Graeme P. , McFarlane Lesley C. , Lipworth Brian J.
Published: December 2004

Aims
To evaluate the systemic bioactivity of triamcinolone acetonide (TA) 220 µg or mometasone furoate (MF) 200 µg over 3 weeks in perennial allergic rhinitis.

Methods
Twenty‐seven patients received TA 220 µg or MF 200 µg once daily for 3 weeks with a 2 week placebo washout period prior to each randomized treatment. Measurements were made at baseline after each washout and after each randomized treatment, comprising overnight 10‐h urinary cortisol corrected for creatinine (OUCC), 08.00 h plasma cortisol and 08.00 h serum osteocalcin.

Results
There were no significant differences between baseline values prior to TA or MF, and for any outcome measures comparing randomized treatments to respective baseline values or comparing TA with MF. For OUCC compared with baseline, the geometric mean fold suppression (95% CI) was 1.02 (0.78, 1.33) for TA (2% decrease), 1.07 (0.80, 1.42) for MF (7% decrease), and 1.05 (0.79, 1.39) for TA vs MF (5% decrease).

Conclusions
Standard doses of TA or MF over 3 weeks showed no differences in systemic bioactivity markers compared with respective baseline values after placebo washout, and there were no differences between TA vs MF.
Pharmacokinetics and systemic effects of inhaled fluticasone propionate in chronic obstructive pulmonary disease
Authors: Singh S. D. , Whale C. , Houghton N. , Daley‐Yates P. , Kirby S. M. , Woodcock A. A.
Published: December 2004

Aims  We have previously shown that the systemic exposure to inhaled fluticasone propionate (FP) is reduced in asthmatics compared with healthy subjects. We have now compared its pharmacokinetics in patients suffering from chronic obstructive pulmonary disease (COPD, n = 10) and matched healthy subjects (n = 13).

Methods  A double‐blind, randomized, cross‐over study design was used. Plasma FP and serum cortisol were measured for 12 h after subjects received hydrofluoroalkane FP 1000 µg day−1 inhaled (via an MDI and spacer) for 7 days and following a single 1000‐µg intravenous dose.

Results  The pharmacokinetics differed in the two groups. After inhalation, geometric least square means were significantly lower in the COPD group for the plasma AUC (1961 vs 2996 pg ml−1 h−1 for COPD and controls, respectively; P = 0.03) and the Cmax (235 vs 421 pg ml−1 for COPD and controls, respectively; P = 0.03). Suppression of serum cortisol concentration over 12 h was greater in healthy controls. Weighted mean serum cortisol concentration (nmol l−1) in healthy subjects and COPD was 93 and 170, respectively (P = 0.03). The intravenous pharmacokinetic parameters for FP were comparable in the two groups, resulting in similar suppression of serum cortisol.

Conclusions  We conclude that the altered pharmacokinetics of inhaled fluticasone propionate in COPD caused less hypothalamic–pituitary–adrenal suppression than in healthy controls. This is further evidence that the systemic effects of inhaled corticosteroids should be assessed in patients and not healthy subjects.
Arylamine N‐acetyltransferase‐2 genotypes in the Thai population
Authors: Kukongviriyapan Veerapol , Prawan Auemduan , Tassaneyakul Wichittra , Aiemsa‐ard Jareerat , Warasiha Benjamart
Published: December 2004

Aims
  To determine the frequencies of the major arylamine‐ N‐acetyltransferase‐2 (NAT2) alleles in the Thai population.

Methods
  DNA samples from 235 Thai individuals were analysed by polymerase chain reaction with restriction fragment length polymorphism assays.

Results
  The frequency distribution of major NAT2 alleles, including NAT2*4, NAT2*5, NAT2*6 and NAT2*7 were 0.381 (95% CI 0.337, 0.426), 0.038 (0.023, 0.060), 0.326 (0.283, 0.370) and 0.204 (0.169, 0.244), respectively. When converted to phenotypes, the study population comprised 63.8% rapid acetylators and 36.2% slow acetylators.

Conclusions
  The pattern of NAT2 alleles of Thais is similar to those of many Asian populations, although the frequency of NAT2*4 is significantly lower and NAT2*7 is higher than that of Oriental populations.
Valproate overdose: a comparative cohort study of self poisonings
Authors: Isbister Geoffrey K. , Balit Corrine R. , Whyte Ian M. , Dawson Andrew
Published: December 2004

Aims  Based on individual case reports of massive overdoses, valproate is often regarded as having significant toxicity. This study aimed to describe the epidemiology of valproate poisoning and the spectrum of its clinical effects.

Methods  Consecutive valproate poisonings were identified and compared with other anticonvulsant overdoses and all other poisonings, from a prospective database of poisoning admissions presenting to a regional toxicology service. National prescription data for the same period were obtained.

Results  There were 79 patients with valproate poisoning from January 1991 to November 2001, 15 cases with valproate alone. Of the 15 cases, drowsiness occurred in two patients (both taking> 200 mg kg−1), vomiting occurred in four and tachycardia in five. In patients co‐ingesting other medications, moderate to severe effects were consistent with the co‐ingestants. There was one death not directly related to valproate. One patient had metabolic acidosis and thrombocytopaenia consistent with severe valproate toxicity. Comparison of valproate, carbamazepine, phenytoin and control groups showed that length of stay for both phenytoin and carbamazepine was significantly longer than for valproate (P < 0.0001), and there was a significantly increased risk of intensive care unit admission for carbamazepine vs valproate (OR 2.73; 95% CI 1.22, 6.28; P = 0.015). Although valproate prescriptions increased over the 10 years, there was relatively greater increase in the incidence of valproate poisoning. The odds of a valproate overdose in 1992 compared with carbamazepine were 0.29 (95% CI 0.07, 1.28; P = 0.141), but in 2001 were 2.73 (95% CI 1.38, 5.39; P = 0.004).

Conclusions  Valproate causes mild toxicity in the majority of cases. Massive overdoses of greater than 400 mg kg−1 can cause severe toxicity, but these are uncommon. The older anticonvulsants phenytoin and carbamazepine remain a greater problem than valproate in overdose.
An evaluation of short‐term corticosteroid response in perennial allergic rhinitis using histamine and adenosine monophosphate nasal challenge
Authors: Wilson Andrew M. , Sims Erika J. , Orr Linda C. , Robb Fiona , Lipworth Brian J.
Published: December 2004

Aims  To evaluate the role of AMP nasal challenge as a measure of short‐term treatment response in patients receiving intranasal corticosteroids. Adenosine monophosphate (AMP) challenge has been shown to be a good inflammatory surrogate in the lower airways, but it has not been properly evaluated as a nasal challenge test.

Methods  Fourteen patients with perennial allergic rhinitis (PAR) were randomized to receive 2 weeks treatment with placebo (PL) or 200 µg intranasal mometasone furoate (MF) once daily in a randomized single‐blind crossover study. AMP (25–800 mg ml−1) and histamine (0.25–8 mg ml−1) nasal challenge testing were performed after each treatment period with 30% decrease in minimal cross‐sectional area (MCA). Domiciliary symptom data were collected.

Results  There was a significant (P < 0.05) improvement in PC30 MCA and nasal volume with AMP but not with histamine comparing MF vs PL. This amounted to a 2.8 (95% CI 1.5, 4.0) and 0.7 (95% CI −0.5, 1.9) doubling‐dose change for AMP and histamine challenges, respectively. There were significant (P < 0.05) improvements in nasal symptoms and quality of life.

Conclusions  AMP nasal challenge using acoustic rhinometry may be a useful test to assess short‐term treatment response in patient with PAR.
A randomized, double‐blind crossover trial of paracetamol 1000 mg four times daily vs ibuprofen 600 mg: effect on swelling and other postoperative events after third molar surgery
Authors: Bjørnsson G. A. , Haanæs H. R. , Skoglund L. A.
Published: December 2004

Aims To evaluate the effect of a 3‐day regimen of ibuprofen 600 mg × 4 on acute postoperative swelling and pain and other inflammatory events after third molar surgery compared with a traditional regimen of paracetamol 1000 mg × 4.

Methods A controlled, randomized, double‐blind, cross‐over study where 36 patients (26 females, 10 males) with mean age 23 (range 19–27) years acted as their own controls. All patients were subjected to surgical removal of bilateral third molars. After one operation the patients received tablets of ibuprofen 600 mg × 4 for 3 days. After the other operation they received an identical regimen of paracetamol 1000 mg tablets. Swelling was objectively measured (mm) with a standardized face bow and the patients scored their pain intensity (PI) on a 100‐mm visual analogue scale.

Results There was no statistically significant difference between paracetamol and ibuprofen treatment with respect to effect on acute postoperative swelling. Swelling after paracetamol on the third postoperative day was 1.8% less than that after ibuprofen. Mean (95% CI) difference between treatments was −0.3 (−4.7, 4.1) mm. On the sixth postoperative day swelling after ibuprofen was 2.3% less than that after paracetamol. Mean (95% CI) between treatments was 0.2 (−2.4, 2.8) mm. There was   no   statistically   significant   difference   in   pain   intensity   between the paracetamol and the ibuprofen  regimen on the day of surgery.  The mean (95% CI) difference between the treatments for summed pain intensity on the day of surgery (SUMPI3.5−11) was 3.31 (−47.7, 54.3) mm. Two patients developed fibrinolysis of the blood clot (dry socket) after receiving ibuprofen while none did this after paracetamol treatment. There was no noticeable difference between treatments with respect to appearance of haematomas/ecchymoses or adverse effects which all were classified as mild to moderate.

Conclusions A 3‐day regimen of ibuprofen 600 mg × 4 daily does not offer any clinical advantages compared with a traditional paracetamol regimen 1000 mg × 4 daily with respect to alleviation of acute postoperative swelling and pain after third molar surgery.
Pharmacokinetics of ribavirin in combined interferon‐alpha 2b and ribavirin therapy for chronic hepatitis C virus infection
Authors: Tsubota Akihito , Hirose Yuichi , Izumi Namiki , Kumada Hiromitsu
Published: December 2004

Aims The aim of this study was to clarify the pharmacokinetics of ribavirin and interferon‐alpha (IFN‐α) 2b when administered in combination for 24 weeks and effects of pharmacokinetics of both on treatment outcome in chronic hepatitis C with genotype 1b and high viral load.

Methods In this multicentre open study, 27 patients received 2‐week daily induction therapy followed by 22‐week, three‐times‐a‐week maintenance therapy of intramuscular IFN‐α 2b at a dose of 6 million units and oral ribavirin at 400 mg twice daily for 24 weeks, and followed up for 24 weeks post‐treatment. Single‐ and multiple‐dose pharmacokinetic studies were assessed by serial measurements of serum concentrations of both compounds at weeks 1 and 24.

Results Five patients attained sustained virological response. Serum ribavirin concentrations asymptoted after 4–8 weeks of treatment in all patients. The steady‐state concentration correlated significantly with serum ribavirin clearance after multiple dosing (r = −0.875; 95% CI −0.932, −0.721; P < 0.001). Serum concentrations at weeks 4 and 8, Cmax and AUC(0,12 h) after multiple dosing and AUC(0,28 weeks) of ribavirin were significantly higher in sustained virological responders than in virological responders or nonresponders (P < 0.05, each). Increased Cmax and accumulation index of AUC(0,12 h) (median 10.5; 95% CI 6.4, 12.4), and prolonged washout half‐life after multiple dosing reflected accumulation and slow clearance of ribavirin from the tissue compartments.

Conclusions Continuous exposure and accumulation of ribavirin may be necessary for sustained virological response to combination therapy in chronic hepatitis C with genotype 1b and high viral load.
Olanzapine pharmacokinetics are similar in Chinese and Caucasian subjects
Authors: Sathirakul Korbtham , Chan Clark , Teng Leyan , Bergstrom Richard F. , Yeo Kwee Poo , Wise Stephen D.
Published: December 2004

Aim  To compare the pharmacokinetic profiles and dose proportionality of olanzapine in Chinese and Caucasian subjects.

Methods  Randomized, three‐period study with 12 Chinese and 12 Caucasian, healthy, male subjects administered 2.5, 5 and 10 mg olanzapine. Noncompartmental pharmacokinetic parameters were derived.

Results  No statistically significant racial differences in the weight‐normalized pharmacokinetic parameters were observed except for Vz/Fnorm, which was 17% lower at the 5‐ and 10‐mg dose in the Chinese group (95% confidence interval 8.49, 10.1 and 8.05, 9.73, respectively), compared with the Caucasian group (9.53, 12.8 and 9.39, 12.0, respectively). Olanzapine's pharmacokinetics were linear and dose proportional in both racial groups.

Conclusion  The pharmacokinetics of olanzapine are similar in both Chinese and Caucasian racial groups.
Effects of sex on the pharmacokinetic and pharmacodynamic properties of quinidine
Authors: El‐Eraky Hala , Thomas Simon H. L.
Published: December 2004

Aims   To investigate the source of the apparent increased susceptibility of women to develop QT interval prolongation and torsade de pointes after the administration of drugs that delay cardiac repolarization.

Methods   Plasma quinidine concentrations and electrocardiographic changes (QRS and QT intervals) were measured over 24 h following the administration of single oral doses of the QT prolonging drug quinidine (3 mg kg−1) and compared between 27 male and 21 female healthy volunteers.

Results   There were no significant differences between males and females in plasma quinidine concentrations or in calculated pharmacokinetic variables. Maximum quinidine concentrations in males and females were 997 ± 56 and 871 ± 57 ng ml−1, respectively (mean difference (−125, 95% confidence intervals (CI) −239, 11 ng ml−1, P = NS). Quinidine lengthened actual (QTa) and corrected (QTc) QT intervals and the QRS interval to a greater extent in females than males (P < 0.001 for each), but there were no significant sex differences detected in the effects of quinidine on the heart rate corrected JT interval. Maximum prolongation of QTc interval was observed 2 h after quinidine and was significantly greater in women (33 ± 16 vs 24 ± 17 ms, mean difference 9 ± 20 ms, 95% CI 3, 15, P = 0.037). At this time mean differences (95% CI) were 1.0 min−1 (−2.5, 4.4, P = NS) for heart rate, 5.5 ms (3.5, 7.6, P = 0.05) for the QRS and 3.4 ms (−2.5, 9.3, P = NS) for the JTc intervals.

Conclusions   Quinidine‐induced increases in QTc were larger in females, but no sex differences in quinidine pharmacokinetics were found. The disparity in prolongation of cardiac repolarization is thus due to a pharmacodynamic difference which appears more complex than simply an increase in repolarization delay in females.
Assessment of non‐steroidal anti‐inflammatory drug (NSAID) damage in the human gastrointestinal tract
Authors: James Martin W. , Hawkey Christopher J.
Published: December 2004

Aspirin is widely prescribed and confers considerable benefit to patients by reducing cardiovascular and cerebrovascular morbidity and mortality. Nonsteroidal anti‐inflammatory drugs (NSAIDs) are effective analgesics, antipyretics and reduce the inflammatory component in conditions such as rheumatoid arthritis. However, both agents are associated with an increased risk of gastrointestinal symptoms and the potentially serious consequences of gastroduodenal ulceration, bleeding and perforation. The introduction of highly selective cyclo‐oxygenase (COX)‐2 inhibitors or the coprescription gastroprotective agents with nonselective NSAIDs have offered strategies to reduce the incidence of such events. This review article analyzes the quantitative techniques that can be employed by clinical pharmacologists and the clinical studies performed to assess NSAID damage in the gastrointestinal tract.