bluuebunny/crossref_metadata_2025 huggingface dataset:
Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism
Authors: Kornev Alexandr P. , Haste Nina M. , Taylor Susan S. , Ten Eyck Lynn F.
Published: November 2006

The surface comparison of different serine–threonine and tyrosine kinases reveals a set of 30 residues whose spatial positions are highly conserved. The comparison between active and inactive conformations identified the residues whose positions are the most sensitive to activation. Based on these results, we propose a model of protein kinase activation. This model explains how the presence of a phosphate group in the activation loop determines the position of the catalytically important aspartate in the Asp-Phe-Gly motif. According to the model, the most important feature of the activation is a “spine” formation that is dynamically assembled in all active kinases. The spine is comprised of four hydrophobic residues that we detected in a set of 23 eukaryotic and prokaryotic kinases. It spans the molecule and plays a coordinating role in activated kinases. The spine is disordered in the inactive kinases and can explain how stabilization of the whole molecule is achieved upon phosphorylation.
A common pumiliotoxin from poison frogs exhibits enantioselective toxicity against mosquitoes
Authors: Weldon Paul J. , Kramer Matthew , Gordon Scott , Spande Thomas F. , Daly John W.
Published: November 2006

Neotropical poison frogs (Dendrobatidae) contain a variety of lipophilic alkaloids in their diffusely distributed cutaneous glands, including a major class of compounds known as pumiliotoxins. Pumiliotoxins are highly toxic and are believed to protect frogs against predators. Their potential activity against ectoparasites, however, has not been investigated. We tested female yellow fever mosquitoes (
Aedes aegypti
) for responses to 8-hydroxy-8-methyl-6-(2′-methylhexylidene)-1-azabicyclo[4.3.0]nonane, designated pumiliotoxin 251D [PTX (+)-251D], a skin alkaloid present in all genera of dendrobatids and in other anurans, and to its unnatural enantiomer, PTX (−)-251D. Both enantiomers of PTX 251D presented on silicone feeding membranes reduced landing and feeding by
A. aegypti
, but PTX (+)-251D did so at lower concentrations. PTX (+)-251D also induced toxicosis, shown when mosquitoes failed to fly off membranes. Similarly, mosquitoes confined with copper wires coated with PTX (+)-251D exhibited greater latencies to fly off the substrate and a higher incidence of leg autotomy than did those confined with the (−)-enantiomer. Our results on the contact toxicities of PTX 251D enantiomers parallel those reported for mice injected with them. The presentation of serial dilutions of PTX (+)-251D to
A. aegypti
revealed a minimum toxic concentration of 0.1 μg/cm
2
. This value is substantially lower than that estimated for the cutaneous abundance of this compound in some frogs, an observation consistent the function of PTX 251D in anuran chemical defense against ectoparasitic arthropods.
Pattern locator: a new tool for finding local sequence patterns in genomic DNA sequences
Authors: Mrázek Jan , Xie Shaohua
Published: November 2006

Summary: We present a new tool for finding local sequence patterns in long DNA sequences. The program, Pattern Locator, uses an intuitive syntax for pattern description, and provides more flexibility than existing programs by allowing combinations of specific nucleotide sequences, direct and inverted repeats, variable length tandem repeats of subpatterns, and a specified number of errors in any part of the pattern.

Availability: The program is available for download and as a web service accessible through a CGI interface at . The source code is written in C and distributed under the GNU General Public License.

Contact:  mrazek@uga.edu
Mutations in the palm region of a plus-strand RNA virus polymerase result in attenuated phenotype
Authors: Gallei Andreas , Widauer Simone , Thiel Heinz-Jürgen , Becher Paul
Published: November 2006

The three-dimensional structure of RNA-dependent RNA polymerases (RdRps) is highly conserved among RNA viruses. In a previous study, a unique set of mutant strains of Bovine viral diarrhea virus was obtained, encompassing either a genomic deletion of six codons or duplications of between 1 and 45 codons; these mutations affect different parts of the palm region, the most conserved part of RdRps containing the catalytic centre. In the present study, a detailed characterization of the RdRp mutant viruses was performed, demonstrating different degrees of a small-plaque phenotype in cell culture, correlating with significantly reduced viral RNA synthesis and delayed virus replication. Taken together, the results of this study demonstrate a surprising flexibility within the palm region of a plus-strand RNA virus RdRp, resulting in viral attenuation in vitro. This interesting insight into an essential viral protein may have implications for the development of vaccines and attenuated viral vectors.
Immunological characterization of abnormal prion protein from atypical scrapie cases in sheep using a panel of monoclonal antibodies
Authors: Gretzschel Anja , Buschmann Anne , Langeveld Jan , Groschup Martin H.
Published: November 2006

After the implementation of an active surveillance programme for scrapie in sheep in the EU, the number of diagnosed classical scrapie cases rose sharply and a novel kind of so-called atypical scrapie case was discovered. These atypical scrapie cases display unusual features concerning the distribution of the abnormal prion protein (PrPSc) in the brain, a distinct electrophoretic profile of PrPSc and an inconsistent reaction pattern in the currently used rapid tests. In this report, PrPSc of two German atypical sheep scrapie cases was characterized by epitope mapping using a panel of 18 monoclonal antibodies that were directed against epitopes located throughout the prion protein. This analysis suggests that PrPSc derived from atypical scrapie cases and treated with proteinase K is largely composed of an 11 kDa fragment (previously referred to as the 12 kDa band) and of polymeric fragments thereof. The 11 kDa band corresponds to a prion protein fragment spanning approximately aa 90–153 and may therefore represent a novel PrPSc type.
Ovine prion protein variant A136R154L168Q171 increases resistance to experimental challenge with bovine spongiform encephalopathy agent
Authors: Goldmann Wilfred , Houston Fiona , Stewart Paula , Perucchini Matteo , Foster James , Hunter Nora
Published: November 2006

Susceptibility and incubation periods of transmissible spongiform encephalopathies, such as scrapie in sheep, are modulated by the PrP gene. The standard model of association between ovine PrP genetics and classical scrapie susceptibility is based on PrP genotypes with respect to codons 136, 154 and 171, e.g. alanine–arginine–glutamine (ARQ). It is demonstrated here that a proline to leucine substitution in codon 168 of the ovine PrP protein gene is associated with increased resistance to experimental bovine spongiform encephalopathy (BSE) inoculation. The ARL168Q PrP allele was found in heterozygous ARP168Q/ARL168Q sheep that have so far survived intravenous BSE challenge three times longer than BSE-challenged homozygous ARP168Q/ARP168Q sheep, which develop disease in around 700 days. In contrast, the L141F polymorphism does not appear to be associated with susceptibility to intravenous BSE challenge.
Passage of chronic wasting disease prion into transgenic mice expressing Rocky Mountain elk (Cervus elaphus nelsoni) PrPC
Authors: LaFauci Giuseppe , Carp Richard I. , Meeker Harry C. , Ye Xuemin , Kim Jae I. , Natelli Michael , Cedeno Marisol , Petersen Robert B. , Kascsak Richard , Rubenstein Richard
Published: November 2006

Chronic wasting disease (CWD) of elk (Cervus elaphus nelsoni) and mule deer (Odocoileus hemionus) is one of three naturally occurring forms of prion disease, the others being Creutzfeldt–Jakob disease in humans and scrapie in sheep. In the last few decades, CWD has spread among captive and free-ranging cervids in 13 US states, two Canadian provinces and recently in Korea. The origin of the CWD agent(s) in cervids is not known. This study describes the development of a transgenic mouse line (TgElk) homozygous for a transgene array encoding the elk prion protein (PrPC) and its use in propagating and simulating CWD in mice. Intracerebral injection of one mule deer and three elk CWD isolates into TgElk mice led to disease with incubation periods of 127 and 95 days, respectively. Upon secondary passage, the incubation time was reduced to 108 and 90 days, respectively. Upon passage into TgElk mice, CWD prions (PrPSc) maintained the characteristic Western blot profiles seen in CWD-affected mule deer and elk and produced histopathological modifications consistent with those observed in the natural disease. The short incubation time observed on passage from cervid to mouse with both mule deer and elk CWD brain homogenates and the demonstrated capacity of the animals to propagate (mouse to mouse) CWD agents make the TgElk line a valuable model to study CWD agents in cervid populations. In addition, these results with this new transgenic line suggest the intriguing hypothesis that there could be more than one strain of CWD agent in cervids.
Pseudorabies virus particles lacking tegument proteins pUL11 or pUL16 incorporate less full-length pUL36 than wild-type virus, but specifically accumulate a pUL36 N-terminal fragment
Authors: Michael Kathrin , Böttcher Sindy , Klupp Barbara G. , Karger Axel , Mettenleiter Thomas C.
Published: November 2006

Proteins of the virion tegument of alphaherpesviruses are involved in protein–protein interactions, which play important roles in virus morphogenesis. Seven single-gene deletion mutants of Pseudorabies virus were analysed for alterations in the overall composition of the virion beyond the loss of the targeted protein. The UL36 protein (pUL36) was present in equal amounts in wild-type virions and mutants lacking pUL21, pUL49, pUL51, pUS3 or pUS8. Virions lacking pUL11 or pUL16 incorporated less full-length pUL36 than wild-type particles, but contained increased amounts of an N-terminal fragment of pUL36 that is present only in traces in wild-type virus and the other mutants.
Proteolytic maturation of replicase polyprotein pp1a by the nsp4 main proteinase is essential for equine arteritis virus replication and includes internal cleavage of nsp7
Authors: van Aken Danny , Zevenhoven-Dobbe Jessika , Gorbalenya Alexander E. , Snijder Eric J.
Published: November 2006

The positive-stranded RNA genome of the arterivirus Equine arteritis virus (order Nidovirales) encodes the partially overlapping replicase polyproteins pp1a (1727 aa) and pp1ab (3175 aa). Previously, three viral proteinases were reported to cleave these large polyproteins into 12 non-structural proteins (nsps). The chymotrypsin-like viral main proteinase residing in nsp4 is responsible for eight of these cleavages. Processing of the C-terminal half of pp1a (the nsp3–8 region) was postulated to occur following either of two alternative proteolytic pathways (the ‘major’ and ‘minor’ pathways). Here, the importance of these two pathways was investigated by using a reverse-genetics system and inactivating each of the cleavage sites by site-directed mutagenesis. For all of these pp1a cleavage sites, mutations that prevented cleavage by the nsp4 proteinase were found to block or severely inhibit EAV RNA synthesis. Furthermore, our studies identified a novel nsp4 cleavage site (Glu-1575/Ala-1576) that is located within nsp7 and is conserved in arteriviruses. The N-terminal nsp7 fragment (nsp7α) derived from this cleavage was detected in lysates of both EAV-infected cells and cells transiently expressing pp1a. Mutagenesis of the novel cleavage site in the context of an EAV full-length cDNA clone proved to be lethal, underlining the fact that the highly regulated, nsp4-mediated processing of the C-terminal half of pp1a is a crucial event in the arterivirus life cycle.
Detection of the prototype of a potential novel genus in the family Papillomaviridae in association with canine epidermodysplasia verruciformis
Authors: Tobler Kurt , Favrot Claude , Nespeca Gilles , Ackermann Mathias
Published: November 2006

Epidermodysplasia verruciformis (EV) is a rare human genetic predisposition to develop flat warts, some of which subsequently undergo cancer transformation. Some human papillomaviruses (HPVs), i.e. HPV 5 and 8, have been associated with cancer development as a sequela of EV. As similar diseases have been observed in dogs, it was hypothesized that unknown canine papillomaviruses (CPVs) may exist and that they may be present in cases of canine EV. Consequently, DNA was extracted from a malignant lesion of a dog with EV and circular DNA was amplified by multiple-primed rolling-circle amplification (RCA). Indeed, sequence determination and analysis of the RCA-amplified and cloned DNA from a malignant canine EV lesion resulted in the detection and primary description of a third CPV (CPV3). Typical papillomavirus genes were identified, with deduced amino acid similarities ranging from 20 to 57 % for E1, E2, E6, E7, L1 and L2, respectively. According to the sequence of the L1 gene, which is used for papillomavirus classification, the new isolate meets the majority of criteria needed to declare detection of a novel genus among the papillomaviruses. Thus, CPV3 may represent the prototype of this novel genus. As the novel virus was found in a dog in association with lesions reminiscent of human EV, it should be interesting to test in the future whether this condition can be reproduced in experimental animals. If such were the case, a new model for EV could be established.
Murine gammaherpesvirus-68 glycoprotein B presents a difficult neutralization target to monoclonal antibodies derived from infected mice
Authors: Gillet Laurent , Gill Michael B. , Colaco Susanna , Smith Christopher M. , Stevenson Philip G.
Published: November 2006

Persistent viruses disseminate from immune hosts. They must therefore resist neutralization by antibody. Murine gammaherpesvirus-68 (MHV-68) represents an accessible model with which to address how resistance to neutralization is achieved and how overcoming it might improve infection control. The MHV-68 glycoprotein B (gB), like that of other herpesviruses, is a virion protein that is essential for infectivity. As such, it presents a potential neutralization target. In order to test whether virus-induced antibodies reduce virion infectivity by binding to gB, monoclonal antibodies (mAbs) were derived from MHV-68-infected mice. gB-specific mAbs were common, but only an IgM specific for the gB N terminus reduced virion infectivity significantly. It inhibited MHV-68 entry into BHK-21 cells at a post-binding step that was linked closely to membrane fusion. Reducing the mAb to IgM monomers compromised neutralization severely, suggesting that a pentameric structure was crucial to its function. Antibody treatment never blocked BHK-21 cell infection completely and blocked the infection of NMuMG epithelial cells hardly at all. Virions saturated with antibody also remained infectious to mice. Thus, the MHV-68 gB presents at best a very difficult target for antibody-mediated neutralization.
High levels of retroperitoneal fibromatosis (RF)-associated herpesvirus in RF lesions in macaques are associated with ORF73 LANA expression in spindleoid tumour cells
Authors: Bruce A. Gregory , Bakke Angela M. , Bielefeldt-Ohmann Helle , Ryan Jonathan T. , Thouless Margaret E. , Tsai Che-Chung , Rose Timothy M.
Published: November 2006

Two distinct lineages of rhadinoviruses related to Kaposi's sarcoma (KS)-associated herpesvirus (KSHV; Human herpesvirus 8), the causative agent of KS, have been identified. In macaques, the RV1 lineage is represented by retroperitoneal fibromatosis (RF) herpesvirus (RFHV), the homologue of KSHV, whilst the RV2 lineage is represented by rhesus rhadinovirus (RRV), a more distantly related virus. Real-time quantitative PCR was used to estimate the loads of RV1 and RV2 rhadinoviruses in simian acquired immunodeficiency syndrome-associated RF (SAIDS-RF), a neoplasm of macaques with similarities to AIDS-associated KS. Both RV1 and RV2 rhadinoviruses were detected in macaques with RF. The RV1 loads were 220- to 4300-fold higher in RF tumours than in spleen, showing a strong tumour association (mean loads of 1 800 000 vs 2900 copies per 106 cells in tumours and spleen, respectively). In contrast, RV2 loads in the RF tumours were 100-fold lower than RV1 loads and showed similar levels in tumours and spleen (mean loads of 16 000 vs 24 000 copies per 106 cells, respectively). Immunostaining with antibodies reactive against RFHV ORF73 latency-associated nuclear antigen (LANA) showed intense nuclear staining of the spindleoid RF tumour cells. Correlation of viral load and the number of LANA-positive cells indicated that RF tumour cells contained multiple copies of the RFHV genome per cell. This pattern of infectivity is similar to that seen in KS tumours latently infected with KSHV. Our study demonstrates similarities in the biology of KSHV and RFHV and supports a role for RFHV in the aetiology of SAIDS-RF.
Human-specific insertions and deletions inferred from mammalian genome sequences
Authors: Chen Feng-Chi , Chen Chueng-Jong , Li Wen-Hsiung , Chuang Trees-Juen
Published: November 2006

It has been suggested that insertions and deletions (indels) have contributed to the sequence divergence between the human and chimpanzee genomes more than do nucleotide changes (3% vs. 1.2%). However, although there have been studies of large indels between the two genomes, no systematic analysis of small indels (i.e., indels ≤ 100 bp) has been published. In this study, we first estimated that the false-positive rate of small indels inferred from human–chimpanzee pairwise sequence alignments is quite high, suggesting that the chimpanzee genome draft is not sufficiently accurate for our purpose. We have therefore inferred only human-specific indels using multiple sequence alignments of mammalian genomes. We identified >840,000 “small” indels, which affect >7000 UCSC-annotated human genes (>11,000 transcripts). These indels, however, amount to only ∼0.21% sequence change in the human lineage for the regions compared, whereas in pseudogenes indels contribute to a sequence divergence of 1.40%, suggesting that most of the indels that occurred in genic regions have been eliminated. Functional analysis reveals that the genes whose coding exons have been affected by human-specific indels are enriched in transcription and translation regulatory activities but are underrepresented in catalytic and transporter activities, cellular and physiological processes, and extracellular region/matrix. This functional bias suggests that human-specific indels might have contributed to human unique traits by causing changes at the RNA and protein level.
A model-based approach to capture genetic variation for future association studies
Authors: Eyheramendy Susana , Marchini Jonathan , McVean Gilean , Myers Simon , Donnelly Peter
Published: November 2006

Genome-wide association studies are still constrained by the cost of genotyping. For this reason, the selection of a reduced set of markers or tags able to capture a significant proportion of the genetic variation is an important aspect of these studies. Most tagging SNP selection methods have been successful in capturing the genetic variation of the data from which the tags have been chosen. However, when these tags are used in an independent data set, a significant proportion of the remaining SNPs (non-tags) are not captured and, in most cases, there is no information on which SNPs are captured. We propose to use a probabilistic model to predict the non-tags based on a set of tags, as a way to capture genetic variation. An important advantage of this method is that it directly predicts the genotype of the non-tags with which we can test for association with the phenotype and which could help to elucidate the location of genes responsible for increasing disease susceptibility. Additionally, this method provides an estimate of the probabilities with which the predictions are made, which reflects the confidence of the probabilistic model. We also propose new methods to select the tagging SNPs. We empirically show by using HapMap data that our approach is able to capture significantly more genetic variation than methods based solely on a pairwise LD measure.
Results of a prospective randomised multicentre controlled trial comparing a new 2‐L ascorbic acid plus polyethylene glycol and electrolyte solution vs. sodium phosphate solution in patients undergoing elective colonoscopy
Authors: BITOUN A. , PONCHON T. , BARTHET M. , COFFIN B. , DUGUÉ C. , HALPHEN M. ,   ON BEHALF OF THE NORCOL GROUP
Published: November 2006

Background  Elective colonoscopy is used increasingly to screen at risk patients for colonic malignancy. Bowel preparation quality is a critical factor for successful screening. Preparations used include high doses of potent laxatives, e.g. sodium phosphate solution or high volume polyethylene glycol. Because of constraints and limited patient acceptability, there remains a need for a more acceptable bowel preparation with at least equivalent cleansing to existing preparations.

Aim  To determine if a 2‐L polyethylene glycol solution with electrolytes and ascorbic acid (polyethylene glycol + ascorbic acid) produces equivalent bowel cleansing to sodium phosphate solution, and is acceptable to patients and well tolerated.

Methods  This was a single blind, parallel group, equivalence study comparing polyethylene glycol + ascorbic acid with sodium phosphate solution in 352 patients undergoing elective colonoscopy. A blinded, independent expert scored a video recording of each colonoscopy. Patients completed a questionnaire reporting acceptability of the bowel preparation process.

Results  Clinically successful bowel preparation was reported in 72.5% of cases prepared using polyethylene glycol + ascorbic acid and in 63.9% of cases prepared using sodium phosphate solution (treatment difference +8.6%, 95% confidence interval −2.3%, +19.4%). The new solution was well accepted and better tolerated than sodium phosphate solution.

Conclusions  The new 2‐L solution of polyethylene glycol + ascorbic acid was at least as efficacious as sodium phosphate solution with comparable efficacy and a better tolerability profile.
Budesonide treatment is associated with increased bile acid absorption in collagenous colitis
Authors: BAJOR A. , KILANDER A. , GÄLMAN C. , RUDLING M. , UNG K.‐A.
Published: November 2006

Background  Bile acid malabsorption is frequent in collagenous colitis and harmful bile acids may play a pathophysiological role. Glucocorticoids increase ileal bile acid transport. Budesonide have its main effect in the terminal ileum.

Aims  To evaluate whether the symptomatic effect of budesonide is linked to increased uptake of bile acids.

Methods  Patients with collagenous colitis were treated with budesonide 9 mg daily for 12 weeks. Prior to and after 8 weeks of treatment, the 75SeHCAT test, an indirect test for the active uptake of bile acid‐s, measurements of serum 7α‐hydroxy‐4‐cholesten‐3‐one, an indicator of hepatic bile acid synthesis, and registration of symptoms were performed.

Results  The median 75SeHCAT retention increased from 18% to 35% (P < 0.001, n = 25) approaching the values of healthy controls (38%). The 7α‐hydroxy‐4‐cholesten‐3‐one values decreased significantly among those with initially high synthesis (from 36 to 23 ng/mL, P = 0.04, n = 9); however, for the whole group the values were not altered (19 ng/mL vs. 13 ng/mL, P = 0.23, N.S., n = 19).

Conclusion  The normalization of the 75SeHCAT test and the reduction of bile acid synthesis in patients with initially high synthetic rate, suggests that the effect of budesonide in collagenous colitis may be in part due to decreased bile acid load on the colon.
Safety, tolerability and pharmacokinetics of higher‐dose mizoribine in healthy male volunteers
Authors: Stypinski Daria , Obaidi Mohammad , Combs Michelle , Weber Meg , Stewart Adrian J. , Ishikawa Hiroaki
Published: November 2006

Aims

Mizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at ≥0.5 but <3 µg ml−1. It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2–5 mg kg−1 day−1. The safety, tolerability and pharmacokinetics from two clinical trials of higher‐dose mizoribine treatments in healthy male volunteers are presented.

Methods

Forty‐eight healthy White male nonsmokers participated in two randomized, double‐blind, placebo‐controlled trials: 32 in a single‐dose study (3, 6, 9 and 12 mg kg−1) and 16 in a multiple‐dose study [6 mg kg−1 day−1 once daily for 5 days or twice daily (12 mg kg−1 day−1) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed.

Results

The safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg−1 day−1) in the multiple‐dose study. Orally administered mizoribine reached peak concentrations within 2–3 h and was eliminated mostly via the kidney (65–100% of dose) with a 3‐h half‐life. Only the 12 mg kg−1 day−1 group achieved trough concentrations that were within the therapeutic window.

Conclusions

Based on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6–12 mg kg−1 day−1 range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.
The influence of CYP2D6 phenotype on the clinical response of nebivolol in patients with essential hypertension
Authors: Lefebvre Jean , Poirier Luc , Poirier Paul , Turgeon Jacques , Lacourciere Yves
Published: November 2006

What is already known about this subject

• The variability in drug metabolism has been recognized as an important factor in the occurrence of adverse effects or lack of therapeutic efficacy.

• The metabolism of the third‐generation β1‐receptor antagonist nebivolol has been shown to be highly dependent on cytochrome P450 2D6 enzymatic activity in preclinical studies.

What this study adds

• This paper assesses the role of a cytochrome P450 2D6 gene defect on the antihypertensive response to nebivolol in a clinical setting.

• Despite significant differences in drug disposition, the chronic administration of nebivolol produced similar efficacy and tolerability in hypertensive patients either characterized as poor or extensive metabolizers of the drug.

• The study offers insight into the relative contribution of nebivolol enantiomers in systemic blood pressure control.

Aims

Nebivolol is a β1‐adrenergic receptor antagonist with vasodilating properties used in the treatment of hypertension. It is administered as a racemic mixture (D‐ and L‐nebivolol) and is highly metabolized by the cytochrome P‐450 2D6 (CYP2D6). The purpose of this study was to determine the role of CYP2D6 phenotypes on the efficacy and tolerability of nebivolol during chronic administration to patients with essential hypertension.

Methods

Two hundred and eighteen patients were genotyped and phenotyped for CYP2D6 activity, allowing to find and match 14 poor metabolizers (PMs) with 23 extensive metabolizers (EMs). Patients took rac‐nebivolol 5 mg daily for 12 weeks. Blood pressure (BP), heart rate, adverse events, plasma levels of the two enantiomers D‐ and L‐nebivolol and their corresponding hydroxymetabolites were assessed.

Results

The metabolic disposition of nebivolol was enantioselective and highly influenced by CYP2D6 phenotypes. Mean steady‐state plasma concentrations of D‐ and L‐nebivolol were 10‐ and 15‐fold greater in PMs than in EMs, respectively (P < 0.0001). Despite these differences in the pharmacokinetics of nebivolol, EMs and PMs displayed similar BP responses. Mean reductions in sitting systolic and diastolic BPs were −11/−10 ± 9/4 mmHg in EMs and −11/−9 ± 10/5 mmHg in PMs. Side‐effects were mild to moderate and not different between groups.

Conclusion

Polymorphisms in the gene encoding CYP2D6 significantly influenced the metabolism of nebivolol, but not its antihypertensive efficacy and tolerability. The similar clinical response between EMs and PMs could be explained by the contribution of active hydroxylated metabolites of nebivolol to its antihypertensive actions in EMs.
National outpatient medication profiling: medications associated with outpatient fractures in community‐dwelling elderly veterans
Authors: French Dustin D. , Campbell Robert , Spehar Andrea , Rubenstein Laurence Z. , Branch Laurence G. , Cunningham Francesca
Published: November 2006

What is already known about this subject

• Polypharmacy, to include a subissue of potentially inappropriate prescribing, in community‐dwelling elderly is widespread.

• The objective of this study was to identify the magnitude of problematic outpatient drug prescribing and its potential association as a risk factor for injuries.

What this study adds

• This is the first national study of outpatient injuries in elderly veterans.

• The results are consistent with previous published literature highlighting the risks associated with prescribing central nervous system drugs in the elderly.

Aims

The primary objective of this retrospective case–control study in an elderly veteran population was to assess the impact of specific medications with recognized side‐effects that increase the risk of a fall and were prescribed prior to fractures treated in the outpatient setting compared with patients treated for nonspecific chest pain.

Methods

Two national Veterans Health Administration (VHA) databases were used to identify 17 273 unique patients, aged ≥65 years, treated in outpatient settings with a fracture in fiscal year 2005, and for whom we could link to all of their outpatient prescriptions (809 536). For comparison, we identified other elderly patients with outpatient clinic visits for nonspecific chest pain (N = 62 331) for whom we could link with their 2 987 394 outpatient prescriptions. We categorized the fall‐related medications as drugs that primarily affect the cardiovascular (CVS), the central nervous (CNS) or the muscular skeletal system (MSS).

Results

Significant differences in the two patient groups occurred in the CNS category. Approximately 41% of the patients with fracture‐coded encounters were prescribed CNS drugs compared with 31% of the patients in the comparison group (P < 0.0003). Finally, the use of muscle relaxants in the MSS category was significantly higher in the fracture group than in the nonspecific chest pain group.

Conclusions

Studies using administrative data can foster the development of more proactive pharmacovigilance systems and assist in formulary refinement, particularly in countries with national healthcare systems that have integrated patient data. Particular attention and monitoring of elderly patients taking CNS medications may be important for injury prevention.
Adherence to chronic cardiovascular therapies: persistence over the years and dose coverage
Authors: Poluzzi Elisabetta , Strahinja Petar , Vaccheri Alberto , Vargiu Antonio , Silvani Maria Chiara , Motola Domenico , Marchesini Giulio , De Ponti Fabrizio , Montanaro Nicola
Published: November 2006

What is already known about this subject

• Cardiovascular diseases are the major cause of premature death in most Western countries.

• Drug treatment, along with diet and lifestyle changes, is the mainstay of prevention and is effective provided that it is maintained over time.

• Treatments with antihypertensives or lipid‐lowering agents are known to be affected by a high rate of early withdrawal.

What this study adds

Four classes of drugs for cardiovascular prevention were studied, and they showed different patterns of use:

• Poor adherence to antihypertensive and lipid‐lowering therapies, probably due to poor perception of risk and a too early start of pharmacological treatment.

• Higher adherence to oral hypoglycaemic agents and nitrates, which are used in conditions where disease awareness and the consequences of stopping medication favour compliance.

Aim

To evaluate adherence to chronic cardiovascular drug treatments, in terms of long‐term persistence and dose coverage.

Methods

General practice prescription data of antihypertensives, lipid‐lowering agents, oral hypoglycaemic agents and nitrates were collected over a 5‐year period (1998–2002) in a Northern Italian district (Ravenna, 350 000 inhabitants). We selected subjects (>40 years) receiving at least one prescription of the above drugs in December 1999. For each patient, we documented the regimen at the time of selection and evaluated adherence to treatment during the following 3 years in terms of persistence (at least one prescription per year) and daily coverage (recipients of an amount of medication consistent with daily treatment).

Results

Fewer than 10% of the 32 068 selected subjects were naive to treatment. Antihypertensives were the most represented therapeutic category. Among patients already on treatment in December 1999, persistence was virtually complete, whereas >40% of naive patients withdrew within 1 year, except for nitrates. The rates of coverage were always much lower than the corresponding values of persistence. Coverage was significantly higher in older patients (χ2 for trend 69.41; P < 0.001), males (odds ratio 1.30; 95% confidence interval 1.25, 1.36) and users receiving more than one therapeutic category.

Conclusions

Lack of adherence to chronic cardiovascular treatments represents an important matter of concern: although most people continued treatment over the years, less than 50% received an amount of drugs consistent with daily treatment, thus jeopardizing the proved beneficial effects of available medications.
A mechanism‐based binding model for the population pharmacokinetics and pharmacodynamics of omalizumab
Authors: Hayashi Naoto , Tsukamoto Yuko , Sallas William M. , Lowe Philip J.
Published: November 2006

Aim

Omalizumab, a humanized IgG monoclonal antibody that binds to human immunoglobulin E (IgE), interrupts the allergic cascade in asthmatic patients. The aim was to compare simultaneously drug exposure and IgE biomarker responses in Japanese and White patient populations.

Methods

An instantaneous equilibrium drug–ligand binding and turnover population model was built from 202 Japanese patients. A posterior predictive evaluation for the steady‐state distributions of omalizumab and IgE was then carried out against 531 White patients.

Results

The mean parameters estimated from the Japanese patients were as follows: omalizumab clearance 7.32 ± 0.153 ml h−1, IgE clearance 71.0 ± 4.68 ml h−1 and the difference between that for omalizumab and the complex 5.86 ± 0.920 ml h−1, the volume of distribution for omalizumab and IgE 5900 ± 107 ml, and that for the complex 3630 ± 223 ml, the rate of IgE production 30.3 ± 2.04 µg h−1. Half‐lives of IgG (23 days) and IgE (2.4 days) were close to previous reports. The dissociation constant for binding, 1.07 nM, was similar to in vitro values. Clearance and volume of distribution for omalizumab varied with bodyweight, whereas the clearance and rate of production of IgE were predicted accurately by baseline IgE. Overall, these covariates explained much of the interindividual variability.

Conclusions

The predictiveness of the Japanese model was confirmed by Monte‐Carlo simulations for a White population, also providing evidence that the pharmacokinetics of omalizumab and IgE were similar in these two populations. Furthermore, the model enabled the estimation of not only omalizumab disposition parameters, but also the binding with and the rate of production, distribution and elimination of its target, IgE.
Inhibitor treatment in haemophilias A and B: summary statement for the 2006 international consensus conference
Authors: BERNTORP E. , SHAPIRO A. , ASTERMARK J. , BLANCHETTE V. S. , COLLINS P. W. , DIMICHELE D. , ESCURIOLA C. , HAY C. R. M. , HOOTS W. K. , LEISSINGER C. A. , NEGRIER C. , OLDENBURG J. , PEERLINCK K. , REDING M. T. , HART C.
Published: November 2006

Summary.  Participants in an international conference on the management of haemophilia patients with inhibitors developed a jointly authored summary of the findings and conclusions of the conference. Current knowledge of the genetic and immunologic mechanisms underlying inhibitor development was briefly summarized. Concerning the purported treatment‐related risk factors, conference participants commented on the limitations of the available evidence and the need for more rigorous prospective research in a fully genotyped population. Other clinical considerations discussed included the unproved utility of routine surveillance, the need for assay standardization, the management of acute bleeding and approaches to joint disease prophylaxis and immune tolerance induction (ITI). A number of issues were identified as needing further investigation in larger prospective studies, ideally through international cooperation. Such studies should enrol cohorts that have been scrupulously defined in terms of mutation status and treatment exposure. Finally, conference participants urged their colleagues to participate in the currently ongoing international trials of ITI.
The epidemiology of factor VIII inhibitors
Authors: HAY CHARLES R. M.
Published: November 2006

Summary.  Risk factors for inhibitor development include specific factor VIII (FVIII) genotypes, a family history of inhibitor development amongst first‐degree relatives, certain HLA haplotypes and non‐caucasian ethnicity. Patients with major FVIII deletions or rearrangements have a higher risk of inhibitor development than those with small deletions or missense mutations. Studies of HLA‐DR amongst northern European patients with the intron 22 inversion indicate that certain HLA haplotypes may also confer either increased or decreased inhibitor risk. However, although brothers of patients with inhibitor have a high risk of inhibitor development, concordance is not 100%, and other constitutional factors must also operate. Disputed risk factors for inhibitor development include early age at first FVIII exposure, the use of recombinant rather than plasma‐derived FVIII and product switching. Two studies suggest that inhibitor risk is increased by very early FVIII exposure (P = 0.03), but this is disputed by a third study; larger studies addressing the question are ongoing. Studies investigating the relative inhibitor risk of plasma‐derived vs. recombinant FVIII have been similarly inconclusive and will be reviewed. Other environmental or treatment variables such as concomitant infection or vaccination are suspected to influence inhibitor risk but have not yet been fully investigated.
Basic aspects of bypassing agents
Authors: NEGRIER C. , DARGAUD Y. , BORDET J. C.
Published: November 2006

Summary.  Bypassing agents consist of activated prothrombin complex concentrates (aPCC) and recombinant factor VIIa (rFVIIa). Their main utilization is for prevention and treatment of bleeding complications, which may occur in inhibitor‐developing haemophiliacs, although new indications for rFVIIa (e.g. trauma‐related and cerebral bleeds) are now under evaluation in clinical trials. The mechanisms of action for these agents are still not fully understood. The relative complexity of the composition of aPCC suggests the possibility of multiple modes of action for achieving haemostasis. Among those possibilities, the contributions of activated factor X and prothrombin have been demonstrated in recent years both in vitro and in animal models for the only aPCC which remains on the market. rFVIIa also exhibits a complex mode of action, improving coagulation through both tissue factor‐dependent and ‐independent pathways. The various mechanisms that occur at the cellular surfaces, particularly on the outer leaflet of the platelet membrane, primarily contribute to Xase complex formation and thrombin generation. The ways in which these agents affect the complex kinetics of fibrin formation at the site of vascular damage need further clarification, although significant progress has been achieved in the last 10 years. In addition, the ex vivo monitoring that would reflect achievement of haemostasis in vivo is still not standardized, although several attempts using thromboelastography, thrombin generation and the kinetics of fibrin formation have been initiated.
Novel therapies for immune tolerance in haemophilia A
Authors: COLLINS P. W.
Published: November 2006

Summary.  Standard treatment for an inhibitory antibody to factor VIII (FVIII) in a patient with severe congenital haemophilia A is to attempt to induce immune tolerance with high‐dose FVIII, either alone or in combination with immunosuppression. Patients in whom the inhibitor is not eradicated or who have prognostic features suggestive of a poor response may be suitable for experimental approaches to immune tolerance induction. The two options that are currently under investigation in clinical practice are anti‐CD20 antibody therapy using rituximab and the use of von Willebrand factor (VWF)‐containing FVIII concentrate in immune tolerance regimens. Immunomodulation with rituximab has been reported to eradicate inhibitors in some patients with severe haemophilia A who have previously failed standard immune tolerance. Similarly, some patients who have failed to be tolerised with high‐purity FVIII have been successfully treated with VWF‐containing concentrates. Neither of these treatment modalities is supported by controlled clinical trial data, and reported observational data require confirmation. Immunomodulation via interference with B‐cell/T‐cell interactions by blocking CD40/CD40 ligand or a gene therapy approach using FVIII peptides in IgG heavy chain transfected into B‐cell blasts has been reported to suppress inhibitors in animal models and may lead to clinically useful therapies. Further understanding of the aetiology of inhibitor formation and how FVIII leads to tolerance in some patients with an inhibitor may suggest further approaches in the future.
Urgent inhibitor issues: targets for expanded research
Authors: HOOTS W. K.
Published: November 2006

Summary.  Although up to 80% of high‐responding inhibitors in patients with severe factor VIII deficiency can be eliminated using heterogeneous regimens for immune tolerance induction, the residual morbidity in this population of haemophilic patients is far from trivial. There is an exigent need for focussed basic, translational and clinical research to extend our understanding of the pathogenesis of haemophilic inhibitor development. In this article, we identify four key research needs, including (i) whether presently available clotting factor concentrates (CFCs) have differential antigenicity, giving rise to clinically relevant immunogenicity; (ii) the interplay of quantitative and qualitative (e.g. age at first exposure) influences of CFCs as well as host–environmental factors (e.g. vaccination effects) on inhibitor development; (iii) the therapeutic role (if any) that concurrent immune tolerance with suppressive or immune‐competitive therapeutic strategies play in inhibitor eradication and (iv) pending any major therapeutic advances, alternative or enhanced strategies for treating acute haemorrhage and for preventing chronic haemorrhagic events in these patients.
Effectiveness of turning with unequal time intervals on the incidence of pressure ulcer lesions
Authors: Vanderwee K. , Grypdonck M. H. F. , De Bacquer D. , Defloor Tom
Published: November 2006

Title. Effectiveness of turning with unequal time intervals on the incidence of pressure ulcer lesions

Aim.  This paper reports a study investigating whether repositioning patients lying on a pressure‐reducing mattress alternately for 2 hours in a lateral position and 4 hours in a supine position reduces the incidence of pressure ulcers in comparison with repositioning every 4 hours.

Background.  Repositioning is commonly recognized as an effective preventive measure. Almost no research has been carried out so far on the necessary turning frequencies to prevent pressure ulcer lesions. The pressure is higher in a lateral than in a supine position.

Method.  A two‐arm randomized controlled trial was conducted in 16 Belgian elder care nursing homes. Patients with non‐blanchable erythema were randomly assigned to either an experimental or a control group. In the experimental group (n = 122), patients were repositioned alternately 2 hours in a lateral position and 4 hours in a supine position. In the control group (n = 113), patients were repositioned every 4 hours. The sitting protocol was identical in both groups. Pressure areas were observed daily and classified according to the four grades of the European Pressure Ulcer Advisory Panel.

Results.  In the experimental group, 16·4% patients developed a pressure ulcer lesion (grade 2–4), while 21·2% did so in the control group. The incidence was not statistically significantly different between the two groups (P = 0·40). The severity (P = 0·65) and location (P = 0·19) of pressure ulcer lesions, and the time to developing them (P = 0·29) were also similar in both groups. No patient developed a pressure ulcer at the hips. A considerable number of patients changed from a lateral to a supine position between the turning intervals.

Conclusion.  More frequent repositioning on a pressure‐reducing mattress does not necessarily lead to fewer pressure ulcer lesions and consequently cannot be considered as a more effective preventive measure.
Gender and the risk of falling: a sociological approach
Authors: Horton Khim
Published: November 2006

Title. Gender and the risk of falling: a sociological approach

Aim.  This paper reports a grounded theory study of the influence of gender on older people's perceptions of their risk of falling and their actions to prevent future falls.

Background.  The incidence and rates of falls among older people, including injurious falls, are of much international concern. The risk of falling remains a major concern for older people since it increases with age, with those aged 85 years and over at greatest risk. However, research using a sociological approach to the topic is limited.

Methods.  An exploratory design, with grounded theory analysis, was used. Data were collected during 2001 through in‐depth interviews with a convenience sample of 40 older people living in south east of England.

Findings.  Two core categories emerged: gendered meanings of risk and gendered responsibility. The social construction of the meaning of the risk of falling and of participants’ actions was gendered. Older men and women had specific ways of talking about their ‘risk’ and identifying the risk factors for falling. Older men perceived themselves as ‘responsible’ and ‘rational’ individuals who expected to reduce their own risk of falling. Older women's expectations of themselves and of their peers explained their tendency to blame themselves or others for their falls. These perceptions influenced the actions they took to prevent future falls.

Conclusion.  Nurses and other healthcare professionals need to take account of the gendered meanings attached to falling by older men and women when carrying out risk assessments and giving advice on fall prevention.