bluuebunny/crossref_metadata_2025 huggingface dataset:
Crystal structure of the IL-2 signaling complex: Paradigm for a heterotrimeric cytokine receptor
Authors: Stauber Deborah J. , Debler Erik W. , Horton Patricia A. , Smith Kendall A. , Wilson Ian A.
Published: February 2006

IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2Rα, IL-2Rβ, and γc. Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3.0 Å resolution. The quaternary structure is consistent with a stepwise assembly from IL-2/IL-2Rα to IL-2/IL-2Rα/IL-2Rβ to IL-2/IL-2Rα/IL-2Rβ/γc. The IL-2Rα subunit forms the largest of the three IL-2/IL-2R interfaces, which, together with the high abundance of charge–charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2Rα with IL-2 at the cell surface. Surprisingly, IL-2Rα makes no contacts with IL-2Rβ or γc, and only minor changes are observed in the IL-2 structure in response to receptor binding. These findings support the principal role of IL-2Rα to deliver IL-2 to the signaling complex and act as regulator of signal transduction. Cooperativity in assembly of the final quaternary complex is easily explained by the extraordinarily extensive set of interfaces found within the fully assembled IL-2 signaling complex, which nearly span the entire length of the IL-2Rβ and γcsubunits. Helix A of IL-2 wedges tightly between IL-2Rβ and γcto form a three-way junction that coalesces into a composite binding site for the final γcrecruitment. The IL-2/γcinterface itself exhibits the smallest buried surface and the fewest hydrogen bonds in the complex, which is consistent with its promiscuous use in other cytokine receptor complexes.
A large family of ancient repeat elements in the human genome is under strong selection
Authors: Kamal Michael , Xie Xiaohui , Lander Eric S.
Published: February 2006

Although conserved noncoding elements (CNEs) constitute the majority of sequences under purifying selection in the human genome, they remain poorly understood. CNEs seem to be largely unique, with no large families of similar elements reported to date. Here, we search for CNEs among the ancestral repeat classes in the human genome and report the discovery of a large CNE family containing >900 members. This family belongs to the MER121 class of repeats. Although the MER121 family members show considerable sequence variation among one another, the individual copies show striking conservation in orthologous locations across the human, dog, mouse, and rat genomes. The element is also present and conserved in orthologous locations in the marsupial, but its genome-wide dispersal postdates the divergence from birds. The comparative genomic data indicate that MER121 does not encode a family of either protein-coding or RNA genes. Although the precise function of these elements remains unknown, the evidence suggests that this unusual family may play a cis-regulatory or structural role in mammalian genomes.
Role of estrogen receptor β in colonic epithelium
Authors: Wada-Hiraike Osamu , Imamov Otabek , Hiraike Haruko , Hultenby Kjell , Schwend Thomas , Omoto Yoko , Warner Margaret , Gustafsson Jan-Åke
Published: February 2006

Several papers report that the colon is one of the tissues regulated by estrogen receptor (ER)β. To better understand the physiological role of ERβ in colonic tissue, we have compared morphology, proliferation, and differentiation of colonic epithelium in ERβ
−/−
mice and WT littermates. BrdUrd labeling revealed that the number of proliferating cells was higher in ERβ
−/−
mice and that the migration of labeled cells toward the luminal surface was faster in ERβ
−/−
mice than in WT littermates. Additionally, in the absence of ERβ, there was a decrease in apoptosis, which was measured by immunohistochemical staining of cleaved caspase-3. The state of differentiation of the colonic epithelial cells was studied by using epithelial markers. In ERβ
−/−
mice, there was a significant decrease in the expression of the differentiation marker cytokeratin (CK)20 and in the cellular adhesion molecules α-catenin (an adherens junction protein) and plectin (a hemidesmosomal protein). These changes were also evident by electron microscopy as abnormalities in tight junctions and in the number and shape of desmosomes in ERβ
−/−
mice. These findings suggest a role for ERβ in the organization and architectural maintenance of the colon. Furthermore, our results indicate that the rapidly proliferating cells of the colonic epithelium in ERβ
−/−
mice are lost by increased shedding and not by increased apoptosis. In this way, hyperproliferative cells that lack ERβ do not form hyperplastic lesions and do not accumulate in the superficial epithelium.
Distributed Time Division Pattern Formation for Wireless Communication Networks
Authors: Sekiyama Kosuke , Kubo Yuki , Fukunaga Shigeru , Date Masaaki
Published: February 2006

This paper proposes a novel communication timing control for wireless sensor networks, named Phase Diffusion Time Division method. This is based on the mutual synchronization of coupled phase oscillatory dynamics with a stochastic adaptation, according to the history of collision frequency in communication nodes. Through local and fully distributed interactions in the communication network, the coupled phase dynamics self-organizes an efficient time division pattern of the communication so that the network reduces the collision frequency by diffusion of the phase pattern, while it sustains sufficient throughput of the communications. We introduce the built-in virtual node dynamics model for sensor device, to implement impulse signal based interactions. This method is designed for applications in a regular grid model of the wireless network, but it can be extended to an irregular grid model as simulation results illustrate, where the proposed method outperforms CSMA method in the efficiency.
Clique Size in Sensor Networks with Key Pre-Distribution Based on Transversal Design
Authors: Chakrabarti Dibyendu , Maitra Subhamoy , Roy Bimal
Published: February 2006

Key pre-distribution is an important area of research in Distributed Sensor Networks (DSN). Two sensor nodes are considered connected for secure communication if they share one or more common secret key(s). It is important to analyse the largest subset of nodes in a DSN where each node is connected to every other node in that subset (i.e., the largest clique). This parameter (largest clique size) is important in terms of resiliency and capability towards efficient distributed computing in a DSN. In this paper, we concentrate on the schemes where the key pre-distribution strategies are based on transversal design and study the largest clique sizes. We show that merging of blocks to construct a node provides larger clique sizes than considering a block itself as a node in a transversal design.
Human antibodies induce arthritis in mice deficient in the low-affinity inhibitory IgG receptor FcγRIIB
Authors: Petkova Stefka B. , Konstantinov Konstantin N. , Sproule Thomas J. , Lyons Bonnie L. , Awwami Moheeb Al , Roopenian Derry C.
Published: February 2006

Rheumatoid arthritis (RA) is a complex autoimmune disease with a poorly understood pathogenesis. The disease is associated with polyclonal B cell activation and the production of autoantibodies (autoAbs), but there is a longstanding controversy as to whether such Abs contribute to, or are secondary to, the pathogenesis of RA. To address the potential pathogenicity of human RA–associated Abs, we developed a passive transfer model involving mice deficient in the low-affinity inhibitory Fc receptor, FcγRIIB. We report that plasma or serum from patients with active RA can induce inflammation and histological lesions in FcγRIIB−/− mice consistent with arthritis, and that this pathogenic activity is caused by the immunoglobulin G–rich fraction. Our results suggest that humoral autoimmunity can contribute directly to autoimmune arthritis, and that FcγRIIB−/− mice are a promising model to evaluate the arthritogenic potential of human autoAbs.
The extension of the progressive aspect in Black South African English
Authors: Van Rooy Bertus
Published: February 2006

Abstract:  The extension of the progressive aspect to stative verbs has been identified as a characteristic feature of New Varieties of English across the world, including the English of black South Africans (BSAfE). This paper examines the use of the progressive aspect in BSAfE, by doing a comparative analysis of three corpora of argumentative student writing representing BSAfE (an outer circle variety), inner circle English and German Learner English as an example of expanding circle English. A comprehensive discussion of the meaning of the progressive aspect in English leads to the definition of a prototype, alongside various extensions and elaborations of the meaning of the construction. Nine attributes of the progressive are identified, which are used to analyse the data. On the basis of the co‐occurrence of the attributes, 17 uses of the progressive construction are identified, most of which are consistent with grammatical descriptions of standardised inner circle varieties, but some not. When the three corpora are compared, the BSAfE data show very different ways of using the progressive construction that are not related to the core senses of the progressive aspect, but instead display a kind of continuous aspect without temporal immediacy. It is suggested that the progressive construction is used in a way consistent with the persistitive aspect of the Bantu languages, a type of imperfective that emphasises mainly the long duration and incompleteness of a stative or durative verb. The expanding circle data, on the other hand, appear very similar to the inner circle data, except for a tendency to put the progressive construction to a slightly more limited range of uses.
Requests in a South African variety of English
Authors: Kasanga Luanga A.
Published: February 2006

Abstract:  The main assumption in this article is that the pragmatics of the variety of South African English commonly referred to as black South African English (BSAE) have been shaped, over time, by educated bilinguals, through a transfer of features from African languages. Transfer of syntactic forms, now firmly established in the variety, is evidenced by, among other things, the preferred use of forms dispreferred in requesting formulae in the native varieties of English. To test the hypothesis of transfer of forms into English for the same requesting functions as in Sesotho sa Leboa (Northern Sotho), an African language of South Africa, use was made of a contrastive study, using ethnographic notebook data of BSAE and DCT (discourse completion task)‐elicited requests in both languages and acceptability judgements on ‘politeness’ in the African language. The results of a pragmatico‐syntactic analysis, which found a mismatch between knowledge about and use of appropriate speech act formulae in the native form of English, (1) confirm the hypothesis of a transfer of strategies from L1 to L2 over time in the speech of educated bilinguals which shaped BSAE; (2) suggest the influence of ‘cultural rules’(because contact of languages involves contact of cultures) in shaping the pragmatics of BSAE, on the basis of which the ‘Cultural Difference Hypothesis’ is proposed; and (3) concur with the emerging conclusion of the institutionalization of BSAE as an indigenized variety of English.
The core and periphery of world Englishes: a corpus‐based exploration
Authors: Nelson Gerald
Published: February 2006

Abstract: This paper is concerned with the ‘common core’ of world Englishes. This is defined as the set of features and characteristics which all varieties have in common. It is also concerned with the ‘periphery’, that is, those features which are unique to individual varieties, and are not shared with any other variety. The study is based on comparisons of wordlists from electronic corpora of six varieties, and it attempts to examine the core and periphery of these in both quantitative and qualitative terms. It offers a measure of the relative sizes of the core and periphery, and goes on to compare the core and periphery in terms of their grammar and morphology. The core is found to be grammatically conditioned to a much greater degree than the periphery, which in turn results in very striking morphological differences between the two.
Is alcopop consumption in Switzerland associated with riskier drinking patterns and more alcohol‐related problems?
Authors: Wicki Matthias , Gmel Gerhard , Kuntsche Emmanuel , Rehm Jürgen , Grichting Esther
Published: February 2006

Objectives To examine (a) whether consumers of alcopops compared to consumers of other alcoholic beverages but not alcopops have riskier drinking patterns and more alcohol‐related consequences (e.g. truancy, scuffles, problems with parents) and (b) whether the amount of alcopops consumed is associated independently with risky drinking patterns and alcohol‐related consequences over and above those associated with the amount of other alcoholic beverages consumed.

Sample As part of the ESPAD international study, a cross‐sectional national representative sample of 5444 drinkers aged 13–16 years was interviewed by means of an anonymous, self‐report questionnaire administered in a classroom setting.

Results Earlier initiation of consumption, more frequent risky single occasion drinking (RSOD), and a higher likelihood of negative consequences for consumers than for non‐consumers of alcopops were due mainly to higher overall consumption. Other alcoholic beverages had similar effects, and whether the same amount of alcohol was consumed as alcopops or as any conventional alcoholic beverage made no difference.

Conclusions Alcopops in Switzerland do not seem to be linked to specific riskier drinking patterns or consequencesper se. Like all alcoholic beverages, they add to the problems caused by drinking and seem to be consumed in addition to conventional alcoholic beverages without replacing them. As the alcohol industry will continue to launch new beverages, prevention targeting alcohol consumption in general might be more effective than focusing on new beverages only.
Bioinformatic analysis of expressed sequence tags derived from a compatible Alternaria brassicicola–Brassica oleracea interaction
Authors: CRAMER ROBERT A. , LA ROTA C. MAURICIO , CHO YANGRAE , THON MICHAEL , CRAVEN KELLY D. , KNUDSON DENNIS L. , MITCHELL THOMAS K. , LAWRENCE CHRISTOPHER B.
Published: February 2006

Alternaria brassicicola is a necrotrophic fungal pathogen that causes black spot disease on members of the Brassicaceae plant family. In order to identify candidate fungal pathogenicity genes and characterize a compatible host response, a suppression subtractive hybridization (SSH) cDNA library enriched for A. brassicicola and Brassica oleracea genes expressed during the interaction was created, along with a fungal cDNA library representing genes expressed during nitrogen starvation (NS). A total of 3749 and 2352 expressed sequence tags (ESTs) were assembled into 2834 and 1264 unisequence sets for the SSH and NS libraries, respectively. We compared two methods to identify the origins (plant vs. fungal) of ESTs in the SSH library using different classification procedures, with and without the availability of a database representing the A. brassicicola whole genome sequence and Brassicaceae‐specific genes. BLASTX analyses of the 2834 unisequence set using the GenBank non‐redundant database identified 114 fungal genes. Further BLASTN analyses of the genes with unidentifiable origin using a database consisting of the 1264 fungal unisequence set from the nitrogen‐starved library identified 94 additional fungal genes. By contrast, BLASTN analyses of the same SSH unisequence set using a partially assembled A. brassicicola whole genome draft sequence identified a total of 310 unisequenes of fungal origin. Our results indicated that even a small number of organism‐specific EST sequences can be very helpful to identify pathogen genes in a library derived from infected tissue, partially overcoming the limitation of the public databases for little studied organisms. However, using the whole genome draft sequence of A. brassicicola we were able to identify approximately 30% more fungal genes in the SSH library than without utilizing this resource. The putative role of specific fungal and plant genes identified in this study in a compatible interaction is discussed.
The effects of changing temperature correction factors on measures of acidity calculated from gastric and oesophageal pH recordings
Authors: GARDNER J. D. , YOUNG W. , SLOAN S. , ROBINSON M. , MINER P. B.
Published: February 2006

Background  Recently, Medtronic notified customers that new correction factors should be used for their Slimline and Zinetics24 single‐use, internal‐standard pH catheters.

Aim and Methods  We selected 24‐h recordings of oesophageal and gastric pH with the Zinetics24 from our archives for five healthy subjects and for five gastro‐oesophageal reflux disease subjects who were studied at baseline and again after 8 days of treatment with a proton‐pump inhibitor. All pH values obtained with the old correction factors were rescaled using the new correction factors. Values for median pH, integrated acidity and time pH ≤ 4 were then calculated from pH values with old and new correction factors.

Results  The new correction factors changed values for median pH, integrated acidity and time pH ≤ 4. Values for median pH and integrated acidity changed in a predictable, proportionate way, whereas values for time pH ≤ 4 did not.

Conclusions  The new correction factors will not change the interpretation of previously published results with median pH or integrated acidity. In contrast, values for time ≤4 cannot be converted in an obvious way with the new correction factors. Instead, the raw pH data will need to be rescaled and values for time pH ≤ 4 recalculated using the rescaled pH data.
Systematic review: adherence issues in the treatment of ulcerative colitis
Authors: KANE S. V.
Published: February 2006

Ulcerative colitis is a chronic inflammatory and debilitating disease requiring lifelong treatment. First‐line therapy for ulcerative colitis is 5‐aminosalicylic acid, which suffers from poor patient adherence outside the clinical trial setting.

Formulations to deliver 5‐aminosalicylic acid to the disease activity site, both orally and topically, are often inconvenient and require multiple daily dosing. Such regimens can interfere with normal life and reduce the overall quality of life, negatively impacting on treatment adherence and leading to poorer long‐term outcomes. These include increased morbidity with an elevated risk of symptomatic relapse, possible greater risk of colorectal cancer and higher overall costs of care.

Ulcerative colitis patients cite treatment regimen complexity, tablet quantity and dose frequency as key negative influencers of adherence. Solutions to these issues include addressing patient concerns, simplifying daily regimens and utilizing new formulations such as micropellet and multimatrix oral formulations, rectal gel and once‐daily suppository formulations.

This review examines the prevalence and impact of non‐adherence to 5‐aminosalicylic acid therapy among patients with ulcerative colitis, as well as drug delivery strategies that may enhance dosing regimens to improve patient acceptability, adherence and long‐term clinical outcomes. It is a combination of understanding patient behaviour, recognizing signs of non‐adherent behaviour and utilizing management strategies to change behaviour that will improve patient outcomes.
Primary care physician perceptions of non‐steroidal anti‐inflammatory drug and aspirin‐associated toxicity: results of a national survey
Authors: CHEY W. D. , ESWAREN S. , HOWDEN C. W. , INADOMI J. M. , FENDRICK A. M. , SCHEIMAN J. M.
Published: February 2006

Aim  To assess primary care physician perceptions of non‐steroidal anti‐inflammatory drug (NSAID) and aspirin‐associated toxicity.

Methods  A group of gastroenterologists and internal medicine physicians created a survey, which was administered via the Internet to a large number of primary care physicians from across the US.

Results  One thousand primary care physicians participated. Almost one‐third of primary care physicians recommended 325 mg rather than 81 mg of aspirin/day for cardioprotection. Fifty‐nine percent thought enteric‐coated or buffered aspirin reduced the risk of upper gastrointestinal (GI) bleeding. Seventy‐six percent believed that Helicobacter pylori infection increased the risk of NSAID ulcers but fewer than 25% tested NSAID users for this infection. More than two‐thirds were aware that aspirin co‐therapy decreased the GI safety benefits of the cyclo‐oxygenase 2 selective NSAIDs. However, 84% felt that aspirin with a cyclo‐oxygenase 2 selective NSAID was safer than aspirin with a non‐selective NSAID. When presented a patient at high risk for NSAID‐related GI toxicity, almost 50% of primary care physicians recommended a proton pump inhibitor and cyclo‐oxygenase 2 selective NSAID.

Conclusions  This survey has identified areas of misinformation regarding the risk–benefit of NSAIDs and aspirin and the utilization of gastroprotective strategies. Further education on NSAIDs for primary care physicians is warranted.
Comparative study of characteristics and disease management between subjects with frequent and occasional gastro‐oesophageal reflux symptoms
Authors: BRETAGNE J. F. , HONNORAT C. , RICHARD‐MOLARD B. , CAEKAERT A. , BARTHÉLEMY P.
Published: February 2006

Background  Little is known about the distinctive characteristics of subjects with frequent (at least weekly) and occasional gastro‐oesophageal reflux symptoms.

Aim  To compare the characteristics and disease management of subjects complaining of at least weekly and less frequent gastro‐oesophageal reflux symptoms.

Methods  Population‐based postal survey carried out in France in 2003 among a representative sample of 8000 subjects.

Results  The prevalence of frequent and occasional gastro‐oesophageal reflux symptoms was 7.8% and 23.4%, respectively. Compared to subjects with occasional gastro‐oesophageal reflux symptoms, those with frequent symptoms were older, suffered from more severe symptoms and felt greater impact on daily living, despite a slightly shorter duration of symptoms. These subjects more often sought medical advice. Most of them had treated the last episode of symptoms primarily with a proton‐pump inhibitor and less often with antacids/alginates. The degree of treatment satisfaction was lower in subjects with frequent gastro‐oesophageal reflux symptoms, in relation to a more frequently observed persistence of symptoms irrespective of the medication used except for proton‐pump inhibitors.

Conclusions  This survey suggests that subjects complaining of frequent or occasional gastro‐oesophageal reflux symptoms constitute two distinctive groups. Despite greater healthcare use, the former group shows a lower level of satisfaction with disease management. Nevertheless, a substantial subset of subjects with occasional symptoms also complained of impaired health‐related quality of life and sought health care.
Anaesthetic implications of uterine artery embolisation in management of massive obstetric haemorrhage
Authors: Sundaram R. , Brown A. G. , Koteeswaran S. K. , Urquhart G.
Published: February 2006

The latest triennial report on maternal deaths has recommended the consideration of uterine artery embolisation in management of cases of massive obstetric haemorrhage. We have been using interventional radiology to manage both expected and unanticipated postpartum bleeding in our centre. Three case reports are presented to highlight the value of this technique and issues relating to the anaesthetic and postoperative management of these patients are discussed.
Effect‐site targeted patient‐controlled sedation with propofol: comparison with anaesthetist administration for colonoscopy
Authors: Stonell C. A. , Leslie K. , Absalom A. R.
Published: February 2006

Patient‐controlled sedation (PCS) allows patients to match their sedation requirement to perceived discomfort. The significant delay in onset of sedation may be overcome with effect‐site steered target controlled infusion, but previously only trials in volunteers have been carried out. We therefore conducted a randomised, double‐blind controlled trial comparing effect‐site steered propofol PCS with anaesthetist‐administered propofol sedation in 40 patients presenting for colonoscopy. The initial effect‐site target in the PCS group was 0.8 μg.ml−1, increment was 0.1 μg.ml−1 and lockout was 3 min. Patient and endoscopist satisfaction and operating conditions were similar between the two groups. PCS patients were sedated more slowly (13 [7.1] vs. 3 [1.1] min; p < 0.0001) and less deeply (minimum BIS value: 71 [16] vs. 58 [15]; p = 0.13) than anaesthetist‐administered propofol sedation patients. More of the latter patients were hypotensive, but all patients had similar recollection of events during the procedure and similar quality of recovery.
Paediatric caudal extradural catheterisation: an evaluation of a purpose designed equipment set
Authors: Bhandal N. , Rogers R. , Berg S. , Mason D. G.
Published: February 2006

Using a purpose designed set of equipment, the Caudal Extradural Catheter Tray, Oxford Set (B Braun Medical Ltd, Sheffield, UK) we have evaluated the ease of cannulation of the caudal space, and the subsequent success in threading extradural catheters and obtaining satisfactory analgesia via the caudal route. The set was evaluated in 91 children (age range: 1 day to 10 years). Cannulation of the caudal space was achieved in all patients, and catheterisation of the extradural space was successful in 96.7% of patients. Postoperative analgesia was satisfactory in 95% of children who had continuous extradural analgesia. There were no major complications or neurological sequelae associated with using the set. We found the Caudal Extradural Catheter Tray provides the necessary equipment to perform extradural anaesthesia and analgesia safely and successfully in children of a wide age range.
Use of a gum elastic bougie to facilitate blind nasotracheal intubation in children: a series of three cases
Authors: Arora M. K. , Karamchandani K. , Trikha A.
Published: February 2006

Management of a difficult paediatric airway is challenging, and the unavailability of a paediatric fibreoptic bronchoscope, a common limitation in developing countries, adds to these difficulties. Children with bilateral temporomandibular joint ankylosis have limited mouth opening and therefore direct laryngoscopy and intubation is not usually possible. In the absence of sophisticated fibreoptic equipment, blind nasal intubation remains the only non‐surgical option for control of the airway. Blind nasal intubation in paediatric anaesthesia is difficult. We describe a novel method of blind nasal intubation in paediatric patients using a gum elastic bougie. We have used this method successfully in three patients in whom tracheal intubation using a conventional blind nasal approach was unsuccessful. In view of its reliability and the absence of any soft tissue injury, we propose the use of this novel technique as an alternative to conventional blind nasal intubation, when more sophisticated fibreoptic equipment is not available.
Ciprofibrate increases paraoxonase activity in patients with metabolic syndrome
Authors: Paragh György , Seres Ildikó , Harangi Mariann , Erdei Annamária , Audikovszky Mária , Debreczeni Lóránd , Kovácsay Anna , Illyés László , Pados Gyula
Published: February 2006

Aims

Diabetic dyslipidaemia with decreased high‐density lipoprotein‐cholesterol (HDL‐C) concentration plays a key role in enhanced atherosclerosis. The antioxidant effect of HDL is due to the influence of human paraoxonase 1 (PON1) and several authors have described decreased activity of this enzyme in Type 2 diabetics and subjects with metabolic syndrome. The goal of this study was to examine the effect of daily ciprofibrate on serum PON1 and lipoprotein concentrations in patients with metabolic syndrome.

Methods

Fifty‐one patients with metabolic syndrome were enrolled into the study. We examined the effect of 100 mg day−1 ciprofibrate treatment on lipid concentrations, oxidized low‐density lipoprotein (LDL), PON1 concentrations and activity. We also investigated the calculated size of LDL‐cholesterol (LDL‐C).

Results

During the 3‐month study, it was observed that following treatment with ciprofibrate, the serum triglyceride concentration decreased significantly (from 2.76 ± 0.9 mmol l−1 to 2.27 ± 1.6 mmol l−1; −18%; P < 0.001), while HDL‐C increased significantly (from 0.95 ± 0.2 mmol l−1 to 1.2 ± 0.3 mmol l−1; 26%; P < 0.001). The oxidatively modified LDL‐C concentration decreased significantly (from 137 ± 19 U l−1 to 117 ± 20 U l−1; P < 0.001), while HDL‐associated apolipoprotein A1 significantly increased (from 1.35 ± 0.2 g l−1 to 1.75 ± 0.3 g l−1; P < 0.001). The LDL‐C/LDL‐apoB ratio, which reflects the size of LDL, increased significantly (from 0.96 ± 0.05 to 1.05 ± 0.06; P < 0.05). Serum PON1 activity was significantly elevated (from 108 ± 34 U l−1 to 129 ± 31 U l−1; P < 0.05), while standardized values for HDL‐C remained significantly unchanged (PON1/HDL‐C) (from 114 ± 21 to 107 ± 20; NS).

Conclusion

Three months of treatment with ciprofibrate favourably affected the lipid profile, increased LDL resistance to oxidation and improved antioxidant status by increasing serum paraoxonase activity in these patients.
Comparison of the pharmacokinetics, pharmacodynamics and tolerability of tezosentan between caucasian and Japanese subjects
Authors: Dingemanse Jasper , Gunawardena Kulasiri A. , van Giersbergen Paul L. M.
Published: February 2006

Aim

To investigate the pharmacokinetics, pharmacodynamics and tolerability of the dual endothelin receptor antagonist tezosentan in caucasian and Japanese subjects.

Methods

Twelve subjects of each ethnic origin were treated in a double‐blind, randomized design with sequential 3‐h infusions of 2.5, 5.0, 12.5 and 25 mg h−1, or placebo. Vital signs, ECG and adverse events were recorded and blood samples collected for determination of plasma concentrations of tezosentan and endothelin‐1 (ET‐1).

Results

Tezosentan was well tolerated in both ethnic groups with no clinically significant differences in laboratory measurements, ECG parameters and vital signs. The plasma concentration–time profiles of tezosentan were described by a three‐compartment model with half‐lives of approximately 5 min, 41 min and 3.6 h. Mean clearance and volume of distribution were approximately 35 l h−1 and 20 l, respectively. Differences in the means (95% confidence intervals) between ethnic groups in these two parameters were 6.0 l h−1 (−1.3, 13.3) and 4.3 l (−1.3, 9.9), respectively. Baseline ET‐1 concentrations were similar but increases in response to tezosentan were greater in caucasian than in Japanese subjects. An indirect response model described the relationship between tezosentan and ET‐1 plasma concentrations. The mean concentrations inhibiting 50% of ET‐1 clearance (IC50) in caucasian and Japanese subjects were 243 and 227 ng ml−1, respectively, with a difference in the means of 28.6 ng ml−1 (−52.7, 110).

Conclusions

The data in healthy subjects suggest that caucasian and Japanese patients can be treated with a similar dosing regimen of tezosentan.
Induction of P‐glycoprotein in lymphocytes by carbamazepine and rifampicin: the role of nuclear hormone response elements
Authors: Owen Andrew , Goldring Chris , Morgan Paul , Park B. Kevin , Pirmohamed Munir
Published: February 2006

Aims

Carbamazepine (CBZ) is an inducer of cytochrome P450 enzymes, which have been implicated in many drug interactions. However, for immunosuppressant and anti‐HIV drugs, whose main site of action is the lymphocyte, induction of P‐glycoprotein (Pgp) may also be important. In this study, we have investigated whether CBZ acts as an inducer of Pgp in lymphocytes.

Methods

Pgp expression was assessed by flow cytometry and real‐time reverse transcriptase‐polymerase chain reaction using lymphocytes from four healthy subjects after incubation with therapeutic concentrations of CBZ, using rifampicin as a positive control. Binding to DR‐4 elements in theMDR1promoter was assessed by electrophoretic mobility shift assay (EMSA) and a luciferase‐reporter construct.

Results

CBZ increasedMDR1mRNA expression at 6 h by 3.7‐fold [95% confidence interval (CI) 0, 7.6) when compared with controls. CBZ increased lymphocyte Pgp expression at 72 h by 7.6‐fold (95% CI 2.1, 13.2) over control values. EMSA revealed a 2.1‐fold (95% CI 1.5, 2.7) increased binding to the DR‐4 element of CBZ when compared with control values. Activation of the DR‐4 element was confirmed using reporter constructs. Rifampicin also had similar effects in all experiments.

Conclusions

Carbamazepine induces Pgp in a manner comparable to rifampicin, by increasing binding to the DR4 element. This has implications for interactions involving drugs whose site of action is the lymphocyte.
Plethysmography and impulse oscillometry assessment of tiotropium and ipratropium bromide; a randomized, double‐blind, placebo‐controlled, cross‐over study in healthy subjects
Authors: Singh D. , Tal‐Singer R. , Faiferman I. , Lasenby S. , Henderson A. , Wessels D. , Goosen A. , Dallow N. , Vessey R. , Goldman M.
Published: February 2006

Aims

Spirometry, plethysmography and impulse oscillometry (IOS) measure different aspects of lung function. These methods have not been compared for their ability to assess long‐ and short‐acting anticholinergic agents. We therefore performed a double‐blind, placebo‐controlled, four‐way cross‐over study in 30 healthy subjects.

Methods

Single doses of tiotropium bromide (Tio) 54 and 18 mcg, ipratropium bromide (IB) 40 mcg and placebo were administered. Specific conductance (sGaw), total lung capacity (TLC), inspiratory capacity (IC) and residual volume (RV) were measured using plethysmography, while IOS measured resistance (R5–25) and reactance (RF and X5). Pulmonary function was measured for 26 h post dose.

Results

Tio caused significant improvements in sGaw, forced expiratory voume in 1 s (FEV1), maximum mid‐expiratory flow (MMEF) and R5–R25 at time points up to 26 h, with no clear differences between doses. IB improved the same parameters, but only up to 8 h. The weighted mean change (0–24 h) caused by Tio 54 mcg compared with placebo for FEV1 was 240 ml (95% confidence interval 180, 300), while for sGaw the ratio of geometric means (Tio compared with placebo) was 1.35 (1.28, 1.41). Neither drug caused consistent statistically significant changes in RF, forced vital capacity, TLC or IC over 26 h. RV was significantly improved from 8 to 24 h by Tio 54 mcg only.

Conclusions

In addition to spirometry, IOS resistance measurements and sGaw can distinguish between the effects of long‐ and shortacting anticholinergic effects in healthy subjects.
Retrospective analysis of opioid prescriptions in cancer patients in a northern Italian Region
Authors: Chinellato Alessandro , Terrazzani Gianni , Debetto Patrizia , Zambon Paola , Guzzinati Stefano , Walley Tom , Giusti Pietro
Published: February 2006

We evaluated patterns of use of opioids in palliative care across one region in Italy by cross‐referencing a cancer registry with unique patient identifiers, with prescription databases. There were 90 803 patients in the registry, of whom 39 597 died during the study period. Only 8539 (21%) of these were prescribed opioids at the time of their death. Prescribed daily doses of oral morphine used (45 mg) and of buprenorphine (0.71 mg) were low compared with injected morphine (28.6 mg, equivalent to approximately 90 mg of oral morphine) and especially with doses of transdermal fentanyl (1.13 mg, equivalent to approximately 180 mg morphine). The reasons for this acceptance of transdermal fentanyl and reluctance to use oral morphine are unclear, but it seems that more effort in educating healthcare professionals and patients about the use of morphine would be useful. The use of more detailed prescribing data such as prescribed or received daily doses can add to our understanding of headline prescribing data.
High glucose levels enhance platelet activation: involvement of multiple mechanisms
Authors: Sudic Dzana , Razmara Masoud , Forslund Mikael , Ji Qiushang , Hjemdahl Paul , Li Nailin
Published: February 2006

Diabetes mellitus (DM) and hyperglycaemia are associated with platelet activation. The present study was designed to investigate how high glucose levels influence platelet function. Fasting human blood was incubated with different concentrations of d‐glucose (5, 15 and 30 mmol/l) and other sugars without or with in vitro stimuli. Platelet activation was monitored by whole blood flow cytometry. High glucose levels enhanced adenosine diphosphate (ADP)‐ and thrombin receptor‐activating peptide (TRAP)‐induced platelet P‐selectin expression, and TRAP‐induced platelet fibrinogen binding. Similar effects were seen with 30 mmol/l l‐glucose, sucrose and galactose. Hyperglycaemia also increased TRAP‐induced platelet‐leucocyte aggregation. Protein kinase C (PKC) blockade did not counteract the enhancement of platelet P‐selectin expression, but abolished the enhancement of TRAP‐induced platelet fibrinogen binding by hyperglycaemia. Superoxide anion scavenging by superoxide dismutase (SOD) attenuated the hyperglycaemic enhancement of platelet P‐selectin expression, but did not counteract the enhancement of TRAP‐induced platelet fibrinogen binding. Hyperglycaemia did not alter platelet intracellular calcium responses to agonist stimulation. Blockade of cyclo‐oxygenase (COX), phosphotidylinositol‐3 (PI3) kinase, or nitric oxide synthase, or the addition of insulin did not influence the effect of hyperglycaemia. In conclusion, high glucose levels enhanced platelet reactivity to agonist stimulation through elevated osmolality. This occurred via superoxide anion production, which enhanced platelet P‐selectin expression (secretion), and PKC signalling, which enhanced TRAP‐induced fibrinogen binding (aggregablity).
Promoter hypermethylation of the retinoic acid receptor β2 gene is frequent in acute myeloid leukaemia and associated with the presence of CBFβ–MYH11 fusion transcripts
Authors: Rethmeier Anita , Aggerholm Anni , Olesen Lene Hyldahl , Juhl‐Christensen Caroline , Nyvold Charlotte Guldborg , Guldberg Per , Hokland Peter
Published: February 2006

Silencing of the putative tumour suppressor gene retinoic acid receptorβ2 (RARβ2) caused by aberrant promoter hypermethylation has been identified in several solid tumours. In order to evaluate the extent of RARβ2 hypermethylation and transcription in acute myeloid leukaemia (AML) at diagnosis, 320 patients were investigated by bisulphite‐denaturing gradient gel electrophoresis and mRNA transcription levels were analysed in 61 of these by quantitative real‐time polymerase chain reaction. The results were compared with demographic‐ and molecular data from the patients. While RARβ2 was unmethylated in 10/10 bone marrow and 7/7 blood samples from healthy individuals, the gene was hypermethylated in 43% of the AML patients. The RARβ2 degree of promoter methylation differed between and within individuals, and the mRNA transcription levels of the gene varied inter‐individually by a factor of 4000. A significant inverse correlation between promoter hypermethylation and gene expression could be established (t‐test, P = 0·019). Comparison of methylation data with a series of other molecular alterations in the same patient materials revealed a correlation between hypermethylation of the RARβ2 promoter and the presence of CBF‐MYH11 fusion transcripts (P < 0·01). Our data suggest that RARβ2 promoter methylation is frequent in AML and may co‐operate with the expression of CBF‐MYH11 fusion transcripts in leukaemogenesis.
2D data modelling by electrical resistivity tomography for complex subsurface geology
Authors: Cardarelli E. , Fischanger F.
Published: February 2006

A new tool for two‐dimensional apparent‐resistivity data modelling and inversion is presented. The study is developed according to the idea that the best way to deal with ill‐posedness of geoelectrical inverse problems lies in constructing algorithms which allow a flexible control of the physical and mathematical elements involved in the resolution.

The forward problem is solved through a finite‐difference algorithm, whose main features are a versatile user‐defined discretization of the domain and a new approach to the solution of the inverse Fourier transform.

The inversion procedure is based on an iterative smoothness‐constrained least‐squares algorithm. As mentioned, the code is constructed to ensure flexibility in resolution. This is first achieved by starting the inversion from an arbitrarily defined model. In our approach, a Jacobian matrix is calculated at each iteration, using a generalization of Cohn's network sensitivity theorem. Another versatile feature is the issue of introducing a priori information about the solution. Regions of the domain can be constrained to vary between two limits (the lower and upper bounds) by using inequality constraints. A second possibility is to include the starting model in the objective function used to determine an improved estimate of the unknown parameters and to constrain the solution to the above model. Furthermore, the possibility either of defining a discretization of the domain that exactly fits the underground structures or of refining the mesh of the grid certainly leads to more accurate solutions. Control on the mathematical elements in the inversion algorithm is also allowed. The smoothness matrix can be modified in order to penalize roughness in any one direction. An empirical way of assigning the regularization parameter (damping) is defined, but the user can also decide to assign it manually at each iteration.

An appropriate tool was constructed with the purpose of handling the inversion results, for example to correct reconstructed models and to check the effects of such changes on the calculated apparent resistivity.

Tests on synthetic and real data, in particular in handling indeterminate cases, show that the flexible approach is a good way to build a detailed picture of the prospected area.
Second‐order interpolation of later‐arrival traveltimes
Authors: Vanelle Claudia , Dettmer Jan , Gajewski Dirk
Published: February 2006

The performance of a 3D prestack migration of the Kirchhoff type can be significantly enhanced if the computation of the required stacking surface is replaced by an efficient and accurate method for the interpolation of diffraction traveltimes. Thus, input traveltimes need only be computed and stored on coarse grids, leading to considerable savings in CPU time and computer storage. However, interpolation methods based on a local approximation of the traveltime functions fail in the presence of triplications of the wavefront or later arrivals. This paper suggests a strategy to overcome this problem by employing the coefficients of a hyperbolic traveltime expansion to locate triplications and correct for the resulting errors in the interpolated traveltime tables of first and later arrivals.
Influenza A Viruses Upregulate Neutrophil Toll‐Like Receptor 2 Expression and Function
Authors: Lee R. M. , White M. R. , Hartshorn K. L.
Published: February 2006

Neutrophils are involved in the initial host response to influenza A virus (IAV) infection and exhibit both activation and depressed function after exposure to the virus. We demonstrate that IAV causes rapid upregulation of Toll‐like receptor 2 (TLR2) expression on neutrophils. The neutrophil agonists, formyl‐methylpleucyl‐alanine (fMLP), C5a and lipopolysaccharide did not alter neutrophil TLR2 expression, whereas PMA and the microbial TLR2 ligands, peptidoglycan (PGN) and zymosan, reduced it. To determine the functional significance of IAV‐induced increase in TLR2 expression, IAV‐treated neutrophils were exposed to PGN, Staphylococcus aureus (S. aureus) and zymosan. Pretreatment with IAV resulted in significantly increased uptake of S. aureus and zymosan and accelerated neutrophil apoptosis when combined with S. aureus. IAV‐treated cells generated significantly more H2O2 in response to PGN. These results indicate that IAV increases neutrophil surface expression of TLR2 and modulates functional responses to ligands that bind TLR2. These findings may clarify IAV‐induced perturbation of neutrophil functions in vivo.
Hydrogen Peroxide Increases Interleukin‐12 p40/p70 Molecular Ratio and Induces Th2‐Predominant Responses in Mice
Authors: Obata F. , Hoshino A. , Toyama A.
Published: February 2006

To investigate the influence of oxidative stress on the immune response, mice were injected with H2O2, and peritoneal macrophages were isolated and stimulated in vitro with lipopolysaccharide (LPS). H2O2 significantly augmented both interleukin (IL)‐12p40 and IL‐12p70 production and increased the p40/p70 molecular ratio. This was confirmed by mRNA analysis, which showed that H2O2 increased LPS‐induced mRNA expression of both IL‐12p40 and IL‐12p35 subunits with an increased p40/p35 ratio. Analysis of anti‐ovalbumin (OVA) antibodies revealed that H2O2 injection significantly increased the production of type 2 helper T cell (Th2)‐associated antibody classes [immunoglobulin (Ig)E and IgG1] but not a Th1‐associated antibody class (IgG2a). To confirm the Th2‐predominant immune response, we analyzed the profile of cytokine production by spleen T cells of OVA‐immunized and H2O2‐injected mice. H2O2 significantly increased the production of IL‐4 but not that of interferon‐γ. Together, these results suggest that H2O2‐induced overproduction of IL‐12p40 promotes the Th2‐predominant response through increased production of IL‐12p40‐homodimers, which could serve as an antagonist of the Th1‐inducing cytokine IL‐12p70.
The Direct Pathway of Human T‐Cell Allorecognition is not Tolerized by Stimulation with Allogeneic Peripheral Blood Mononuclear Cells Irradiated with High‐Dose Ultraviolet Ba
Authors: Wallgren A. C. , Alder J. , Andersson B. , Karlsson‐Parra A. , Bäcker A. E.
Published: February 2006

Transfusions of high‐dose (≥10,000 Joule/m2) ultraviolet‐B (UVB)‐irradiated allogeneic leukocytes in rodent models have been shown to induce immunologic tolerance that is mediated by allospecific regulatory CD4+ T cells. Whether these regulatory T cells recognize alloantigens through the direct or indirect pathway of allorecognition is controversial. Here, we demonstrate that the proliferative response obtained in standard primary mixed leukocyte reactions (MLRs) with human peripheral blood mononuclear cells (PBMCs) reflected a CD4+ T‐cell‐dependent direct pathway of allorecognition and that high‐dose UVB irradiation of PBMCs totally inhibited their capacity to induce a proliferative alloresponse. Re‐stimulation with γ‐irradiated PBMCs from the same allogeneic donor (secondary MLR) elicited a proliferative and Th1‐deviated response that was similar to the response induced in unprimed PBMCs. Finally, high‐dose UVB was found to induce a rapid and massive apoptosis of irradiated PBMCs. Collectively, these data indicate that leukocytes irradiated with high‐dose UVB are unable to prime for unresponsiveness or immune deviation in T cells directly recognizing allogeneic major histocompatibility complex molecules. Because it is well‐established that antigens within transfused apoptotic cells are captured by resident tolerogenic spleen dendritic cells, we propose that tolerance induced by transfusions of high‐dose UVB‐irradiated leukocytes primarily involve T cells indirectly recognizing alloantigens.