bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose‐dependent systemic exposure of albendazole metabolites in lambs
Authors: ALVAREZ L. , SUÁREZ G. , CEBALLOS L. , MORENO L. , LANUSSE C.
Published: August 2011

Alvarez, L., Suárez, G., Ceballos, L., Moreno, L., Lanusse, C. Dose‐dependent systemic exposure of albendazole metabolites in lambs. J. vet. Pharmacol. Therap. 35, 365–372.

The gastrointestinal absorption of most drugs follows a first‐order kinetics, whereby a constant fraction of the total drug is absorbed in each equal time interval. Although this related absorption principle is applicable to the most of the therapeutically used drugs, it remains unclear for poorly water‐soluble compounds such as the benzimidazole anthelmintics in ruminants. The goal of the current work was to characterize the albendazole (ABZ) metabolites plasma disposition kinetics after ABZ administration at different dosages to nematode‐infected lambs. Eighteen Corriedale lambs artificially infected with a resistant Haemonchus contortus strain were allocated into three groups and intraruminally treated with ABZ at either 5 (ABZ5), 15 (ABZ15) or 45 (ABZ45) mg/kg. Blood samples were collected up to 120 h post‐treatment, and the collected plasma was analysed by high‐performance liquid chromatography. The estimated pharmacokinetic parameters were statistically compared using parametric and nonparametric tests. None of the animals involved in the current trial showed any adverse events during the study. While ABZ parent drug was not recovered in the bloodstream, the area under the concentration vs time curve (AUC) of the active ABZ‐sulphoxide (ABZSO) metabolite increased significantly (P < 0.05) from 21.0 (ABZ5) up to 158.6 (ABZ15) and 389.7 μg·h/mL (ABZ45), which indicates some type of nonproportionality in the relationship between dose level and drug systemic exposure. The overall kinetic disposition of the inactive sulphone metabolite did not change after treatment at threefold the therapeutic ABZ dosage. However, significantly (P < 0.05) higher AUC, Cmax and mean residence time values were observed after the administration of the highest dosage level. The higher dosages accounted for a significantly (P < 0.05) enhancement of the ABZSO peak plasma concentration, which were obtained at delayed times post‐treatment. High correlations between AUC0‐LOQ and Cmax and nematode counts were observed, with Spearman’s coefficients of −0.83 and −0.84, respectively. The results obtained in the current experiment show that increasing the dose of ABZ in sheep is clearly associated with enhanced plasma ABZ metabolites exposure. The data showed a nonproportionality on the gastrointestinal absorption of ABZ in nematode‐infected lambs.
Microbial influence on erosion, grain transport and bedform genesis in sandy substrates under unidirectional flow
Authors: HAGADORN JAMES W. , MCDOWELL CONOR
Published: August 2011

Interpreting the physical dynamics of ancient environments requires an understanding of how current‐generated sedimentary structures, such as ripples and dunes, are created. Traditional interpretations of these structures are based on experimental flume studies of unconsolidated quartz sand, in which stepwise increases in flow velocity yield a suite of sedimentary structures analogous to those found in the rock record. Yet cyanobacteria, which were excluded from these studies, are pervasive in wet sandy environments and secrete sufficient extracellular polysaccharides to inhibit grain movement and markedly change the conditions under which sedimentary structures form. Here, the results of flume experiments using cyanobacteria‐inoculated quartz sand are reported which demonstrate that microbes strongly influence the behaviour of unconsolidated sand. In medium sand, thin (ca 0·1 to 0·5 mm thick) microbial communities growing at the sediment–water interface can nearly double the flow velocity required to produce the traditional sequence of ripple→dune→plane‐bed lamination bedforms. In some cases, these thin film‐like microbial communities can inhibit the growth of ripples or dunes entirely, and instead bed shear stresses result in flip‐over and rip‐up structures. Thicker (ca≥1 mm thick) microbial mats mediate terracing of erosional edges; they also, foster transport of multi‐grain aggregates and yield a bedform progression consisting of flip‐overs→roll‐ups→rip‐ups of bound sand.
Nocardia infection in kidney transplant recipients: case report and analysis of 66 published cases
Authors: Yu X. , Han F. , Wu J. , He Q. , Peng W. , Wang Y. , Huang H. , Li H. , Wang R. , Chen J.
Published: August 2011

X. Yu, F. Han, J. Wu, Q. He, W. Peng, Y. Wang, H. Huang, H. Li, R. Wang, J. Chen. Nocardia infection in kidney transplant recipients: case report and analysis of 66 published cases. Transpl Infect Dis 2011: 13: 385–391. All rights reserved

Abstract: Nocardiosis is a rare but life‐threatening opportunistic infection, especially in immune compromised patients, including kidney transplant recipients. Primary pulmonary infection is the most common clinical pattern, and can easily result in disseminated Nocardia infection if treatment therapy is not adequate at the beginning. In this article, we report a new case of disseminated nocardiosis (lungs, skin, and pericardium) after renal allograft transplantation. We also review the English literature published from 1980 to 2010 and analyze the clinical characteristics of nocardiosis in kidney transplant recipients.
Insights into the Structure and Function of Membrane Polypeptides Carrying Blood Group Antigens
Authors: Cartron J.P. , Bailly P. , Van Kim C. Le , Cherif‐Zahar B. , Matassi G. , Bertrand O. , Colin Y.
Published: August 2011

In recent years, advances in biochemistry and molecular genetics have contributed to establishing the structure of the genes and proteins from most of the 23 blood group systems presently known. Current investigations are focusing on genetic polymorphism analysis, tissue‐specific expression, biological properties and structure‐function relationships. On the basis of this information, the blood group antigens were tentatively classified into five functional categories: (i) transporters and channels, (ii) receptors for exogenous ligands, viruses, bacteria and parasites, (iii) adhesion molecules, (iv) enzymes and, (v) structural proteins. This review will focus on selected blood groups systems (RH, JK, FY, LU, LW, KEL and XK) which are representative of these classes of molecules, in order to illustrate how these studies may bring new information on common and variant phenotypes and for understanding both the mechanisms of tissue specific expression and the potential function of these antigens, particularly those expressed in nonerythroid lineage.
Stem Cell Biology for the Transfusionist
Authors: Lansdorp P.M.
Published: August 2011

The limited life‐span of most blood cells requires continuous production of cells which in adults may exceed 1012 cells/day. This impressive production of cells (˜ 4.1015 cells over a life time) is achieved by the proliferation and differentiation of committed progenitor cells which themselves are derived from a population of pluripotent stem cells with self‐renewal potential. In adults, the large majority of stem cells are found in the bone marrow among cells with a CD34+CD38‐ phenotype. Interestingly, small but significant numbers of such cells can be found in the circulation. The frequency of circulating CD34+CD38‐ cells can be dramatically increased by treatment with certain compounds including cytokines. Such “mobilized” peripheral blood stem cells have become an important alternative to bone marrow in stem cell transplantation procedures primarily because engraftment is more rapid. The latter is almost certainly related to the increased numbers of primitive CD34+CD38‐ cells capable of engrafting the bone marrow in blood versus bone marrow stem cell grafts [1]. Paradoxically, the large majority of “candidate” stem cells in adult bone marrow are quiescent cells. One possibility is that stem cells, like other somatic cells, have only a limited replicative potential (<100 divisions). This hypothesis is supported by two key observations and the consideration that, in theory, 52 divisions can yield 4.1015 cells. First, it was shown that “candidate” stem cells purified from fetal and adult tissue display marked functional differences in turn‐over time and the ability to produce cells with stem cell properties [2]. Secondly, these functional differences were found to correlate with a measurable loss of telomere repeats [3], despite the presence of low but readily detectable levels of telomerase in all purified cell fractions [4,5]. In order to address questions about the role of telomeres in normal and malignant hematopoiesis, we developed quantitative fluorescence in situ hybridization [6]. With this technique the length of telomere repeats at individual chromosome ends can be reliably estimated using optical density measurements from digital images of metaphase chromosomes after fluorescence in situ hybridization with directly labeled (CCCTAA)3 ‐ Peptide Nucleic Acid probe [6,7]. Furthermore, we recently showed that this method can be adapted to measure the total telomere repeat content of cells by flow cytometry [8].

Here some issues in studies of hematopoietic stem cells are discussed in relation to rapidly accumulating information about telomere biology.
Epidemiology of the Hepatitis C Virus
Authors: Ebeling F.
Published: August 2011

According to WHO estimations, about 3 % of the world population may be infected with the hepatitis C virus. The relative prevalences of subtypes of this virus vary in different geographic areas. The main known routes of transmission are parenteral; intravenous drug abuse, contaminated injection devices and receipt of unscreened blood. Sexual, vertical, household and nosocomial transmissions may occur, but seem to be rare. The risk of screened blood or blood products is now almost eliminated, but unscreened blood is a considerable risk in areas where screening is economically not possible. The future impact of this virus is greatly dependent on the trends in intravenous drug use as well as the possible emergence of increased late morbidity among present asymptomatic carriers during the next decades.
In Vitro and in Vivo Properties of Various Types of Platelets
Authors: Rebulla P.
Published: August 2011

The most popular procedures used to prepare platelet concentrates (PC) can be categorized into methods using platelet rich plasma (PRP) obtained by soft centrifugation of whole blood units, methods using buffy coats (BC) obtained by hard centrifugation of whole blood units, and apheresis procedures. The main feature that differentiates apheresis PC from whole blood unit derived PC is that apheresis reduces the number of donors necessary to support a recipient, although the advantages related to this feature have not been conclusively documented. From the biochemical point of view, a limited number of comparative studies and a large series of non‐comparative studies indicate that differences in PC obtained with different protocols depend more on the performance of the production laboratory rather than the preparative approach – PRP, BC or apheresis – itself. Similarly, the clinical effectiveness of PC seems to depend more on PC age, storage modalities and recipient's conditions rather than primarily on the method of PC preparation. Despite the basic differences in the three preparative approaches, all methods share a number of key elements that are necessary pre‐requisites for a successful platelet transfusion therapy: minimization of the risk of bacterial contamination by careful donor skin disinfection and temperature control during PC production and storage; protection of aerobic metabolism during PC storage; laboratory quality control including at least pH and volume determinations, platelet and white cell counts and visual inspection of the swirling phenomenon at time of release. Future directions in the field of PC production include the development of new products such as infusible platelet membranes, thrombospheres, thrombo‐ erythrocytes and reconstituted freeze‐dried platelets.
Novel Diagnostic and Therapeutic Strategies with Genetically Engineered Human Antibodies
Authors: Ouwehand W.H. , Watkins N.
Published: August 2011

Human antibodies can be generated by recombinant technology. The human immunoglobulin repertoire can be tapped in an effective manner by the so called V gene phage display technology. Using this technique the genes encoding the variable domains of an antibody of interest can be captured from the B cell repertoire. With these V genes tailor‐made immune recognition molecules can be obtained by a ‘design and build’ strategy. These novel developments will lead to the introduction of a manifold of antibody based therapies into the clinic in coming decades. Recombinant antibody technology also provides unique opportunities to study the molecular structure of antibody variable domains against blood cell antigens. Such studies might possibly lead to the development of new therapies for antibody mediated blood cell destruction.
Complement Regulation
Authors: Meri S. , Jarva H.
Published: August 2011

Because of its strong potential for generating inflammation and causing tissue destruction the complement system has to be kept strictly under control. Cells of the host need special protection against the cytolytic complement system. This paper will describe how inappropriate activation of complement in the fluid phase is prevented and how viable human blood cells defend themselves against being destroyed and cleared away by the complement system. Since disturbances in complement regulation occasionally result in disease a brief reference will be made to two of the syndromes caused by complement regulator deficiency, hereditary angioedema (HAE) and paroxysmal nocturnal hemoglobinuria (PNH).
Complement and Biocompatibility
Authors: Mollnes T.E.
Published: August 2011

Blood contact with foreign surfaces induces a certain degree of activation of the defence systems including complement. Recent data using complement specific inhibitors have shown that complement is not only associated with, but in fact contributes to the whole body inflammatory reaction seen as a complication of cardiopulmonary bypass (artificial surfaces) and is responsible for the hyperacute rejection of xenografts (foreign endothelium). Complement activation products, particularly the terminal SC5b‐9 complex (TCC), is a sensitive indicator of bioincompatibility. Modifications of the artificial surfaces by coating with heparin improves both coagulation and complement compatibility. The use of specific complement inhibitors in general improves biocompatibility both of artificial materials and foreign endothelium.
Use of HLA‐ and HPA ‐ Matched Platelets in Alloimmunized Patients
Authors: Kekomäki R.
Published: August 2011

Refractoriness for platelet transfusion is mostly due to clinical factors but may also be caused by alloimmunization. Use of leukocyte‐depleted blood cells for transfusions of patients with hematological diseases has reduced if not eliminated HLA‐alloimmunization. HLA‐antibodies reduce the survival time of incompatible platelets complicating seriously the platelet transfusion support in at least 5% of patients. If consecutive transfusions of HLA matched platelets also fail without identifiable clinical causes, HPA‐alloimmunization may have occurred. Platelets from donors phenotyped for both HLA and HPA may produce good platelet count increments and allow optimal treatment of the basic disease despite broad spectrum alloimmunization. Additional crossmatching of phenotyped platelets with patient serum may be needed to circumvent platelet‐specific antibodies of unknown specificity.
A Comparison of in Vitro Tests for predicting the Severity of Haemolytic Disease of the Fetus and Newborn
Authors: Hadley A.G
Published: August 2011

Haemolytic disease of the newborn (HDN) is characterized by the presence of IgG antibodies in the maternal circulation which cause haemolysis in the fetus by crossing the placenta and sensitizing red cells for destruction by macrophages in the fetal spleen. Numerous serological, quantitative and cellular assays have been developed to predict the severity of HDN. These assays all measure and/or characterize alloantibodies in the maternal circulation. Quantitative assays which accurately measure antibody levels correlate with disease severity better than serological assays which are inherently less precise. Nevertheless, high antibody levels are found in some cases of mild HDN and relatively low antibody levels are found in some severe cases. This suggests that disease severity is influenced by factors in addition to antibody concentration. These factors remain to be fully elucidated but may include the subclass and glycosylation of maternal antibodies, the structure, site density, maturational development and tissue distribution of blood group antigens, the efficiency of IgG transport to the fetus, the functional maturity of the fetal spleen, polymorphisms which affect Fc receptor function, and the presence of HLA‐related inhibitory antibodies. Cellular assays which are sensitive to factors affecting antibody function have therefore been developed in an attempt to improve the prediction of disease severity. Although these assays are cumbersome, there are now sufficient data to suggest that some cellular assays, when used as part of a structured approach to diagnostic testing, may provide clinically‐useful information to complement serological and quantitative assays.
Requirements for the Electronic Crossmatch
Authors: Judd W. John
Published: August 2011

With the integration of laboratory information systems into transfusion services, it is now possible to develop standard operating procedures (SOPs) for an electronic crossmatch (EXM) to replace the immediate‐spin crossmatch for detecting ABO incompatibility between the blood sample submitted for pre‐ transfusion testing and the donor unit selected for transfusion. Essential to the safety of an EXM are requirements that: 1) the computer contains logic to prevent assignment and release of ABO incompatible blood; 2) no clinically significant antibodies are detected in the recipient's serum/plasma and there is no record of previous detection of such antibodies; 3) there are concordant results of at least two determinations of the recipient's ABO type on record, one of which is from a current sample; 4) critical elements of the system have been validated on‐site; and, 5) there are mechanisms to verify the correct entry of data prior to release of blood.

EXM procedures are in use in at least 10 North American facilities, Scandinavia, Hong Kong and Australia. Some provide blood at remote sites lacking laboratory services. Experience has shown that a combination of properly programmed computer software and carefully developed SOPs can provide a safe and efficient means of detecting ABO incompatibility without performing a serological crossmatch.
From Serological to Computer Crossmatching in Nine Hospitals
Authors: Georgsen J. , Kristensen T.
Published: August 2011

In 1991 it was decided to reorganise the transfusion service of the County of Funen. The aims were to standardise and improve the quality of blood components, laboratory procedures and the transfusion service and to reduce the number of outdated blood units. Part of the efficiency gains was reinvested in a dedicated computer system making it possible – among other things – to change the cross‐match procedures from serological to computer cross‐matching according to the ABCD‐concept. This communication describes how this transition was performed in terms of laboratory techniques, education of personnel as well as implementation of the computer system and indicates the results obtained.

The Funen Transfusion Service has by now performed more than 100.000 red cell transfusions based on ABCD‐cross‐matching and has not encountered any problems. Major results are the significant reductions of cross‐match procedures, blood grouping as well as the number of outdated blood components.
The French Hæmovigilance System
Authors: Noel L. , Debeir J. , Cosson A.
Published: August 2011

Hæmovigilance was part of the reform of the French transfusion system. The hæmovigilance network is now operational with approximately 4600 transfusion incidents reported annually. Immediate incidents observed within 8 days after transfusion account for 85 % of the reports. A cause cannot be identified in 41% of these, usually concerning minor clinical incidents with transient fever and /or shivers. An allergic reaction is described in 31% of transfusion reactions. Immunological conflicts account for 18% and bacteria associated transfusion reactions for 6%. The importance of bacteria associated transfusion reactions, the first identified cause of death associated with transfusion is one of the findings of hæmovigilance. Improvement in the hæmovigilance systems aims at obtaining better descriptions of transfusion incidents, standardisation of severity and imputability assessment and definitions of denominators such as the actual number of recipients. Delayed incidents will ultimately provide a true vision of post transfusion immunisation and infection The improvement of hæmovigilance now considered as part of transfusion medicine practice is a continuous process.
CD34+ Subset and Tumor Cell Quantitation by Flow Cytometry — Step Toward Quality Assessment of Autografts in B Cell Malignancies
Authors: Johnsen H.E. , Rasmussen T. , Knudsen L.M.
Published: August 2011

To day it is possible to predict the probability of fast engraftment based on a very simple flow cytometry standard analysis of CD34+ cells as documented by the 28 laboratories within the NSCL‐G. However, the risk for delayed platelet engraftment still needs to be predicted in clinical practice for patients receiving less than 10 times 106 CD34+ cells/kg. Here we present data from our center supporting that identification by double staining of uncommitted (CD34+/CD38‐) and lineage specific (CD34+/CD61+) progenitors may allow us to predict patients at high risk for prolonged platelet recovery.

Following high dose therapy more than 30% of patients with haematological malignancies do suffer from disease recurrence within the first 3–6 months following high dose therapy. Today there are strong indications that such patients may have been transplanted with an autograft contaminated with a high number of potentially malignant B cells. Here we present a novel methodology for quantitation of blood circulating tumor cells by combining flowcytometry, cell sorting, limiting dilution and single cell RT‐PCR. Such methodology has documented mobilization of clonal B cells following priming of the peripheral blood stem cell harvest and it can be used to identify minor populations and predict the efficacy of patient specific purging strategy.

Consequently, quality assessment of autografts may include techniques which can predict fast three lineage engraftment as well as the risk for prolonged platelet recovery and can identify the group of patients/autografts with a strong contamination of potential tumor cells with a risk of early relapse The future supportive cell therapy may depend upon improvements of such technologies and strategies including the selective administration of lineage specific growth factors e.g. trombopoietin as well as patient specific controlled purging strategies.
Targeted Superantigens for Immunotherapy of Haematopoietic Tumours
Authors: Tötterman T.H. , Gidlöf C. , Ragnarsson L. , Högbom E. , Lindeberg M. , von der Lehr N. , Einarsson A. , Sœgaard M. , Kristensson K. , Kalland T. , Dohlsten M.
Published: August 2011

With the exception of childhood common acute lymphoblastic leukaemia (cALL), treatment of other hematopoietic B cell lineage tumours such as non‐ Hodgkin's lymphoma (B‐NHL), adult ALL and multiple myeloma (MM) is unsatisfactory. Similarly, the therapeutic outcome of acute and chronic myeloid leukaemia (AML, CML) is frequently dismal. At the same time, leukae‐ mia/lymphoma cells represent ideal targets for immunotherapy. The present review summarizes our preclinical experience with a novel type of cytotoxic T cell based immunotherapy for B‐lineage and myeloid tumours. Staphylococcal enterotoxin‐derived superantigens (SAgs) are among the most potent T cell activators known, linking the T cell receptor to HLA‐DR on natural target cells. SAgs were genetically engineered to reduce DR binding and were then fused to Fab parts of tumour‐directed monoclonal antibodies (mAbs). Using these “targeted” SAgs, highly efficient lysis of B‐lineage (B‐NHL, B‐CLL, ALL, MM) and myeloid (AML, CML) tumour cells by T‐cells was achieved in vitro and in an animal model. We are entering an interesting era of innovative cancer therapy based on novel man‐made biotherapeutic agents.
Donor Selection: The Exclusion of High Risk Donors?
Authors: van den Burg P.J.M. , Vrielink H. , Reesink H.W.
Published: August 2011

Selection of donors is an important means to improve the overall safety of the blood supply. Since the AIDS epidemic emerged and after the introduction of sensitive screening tests for HIV, it became clear that blood donations given in the infectious ‘window’ period, formed the most important risk for recipients of blood products. Therefore, selection criteria became more and more stringent to exclude these high risk donors. Means to exclude high risk donors are non‐ remuneration, including a clear policy to provide no incentives which can be readily converted to cash, the avoidance of replacement donations, the discouragement of ‘HIV test seeking’ donors, education and information of donors about HIV and other blood‐borne infectious diseases and the in depth questioning about risk behaviour, orally as well as by questionnaires. Although this policy of donor selection is recognized by most blood centers in the world, the efficacy of this selection has not been well documented. Therefore in future, studies should be performed to base these selection criteria on evidence.
Response of Locusta migratoria tibetensis Chen (Orthoptera: Acrididae) to climate warming over the Tibetan plateau
Authors: Feng C. H. , Guo C. , Luo L. M. , Qin Z.
Published: August 2011

As a region with one of the most important terrestrial ecosystems, the Tibetan plateau is both sensitive to and vulnerable to climate warming. Locusta migratoria tibetensis Chen, an endemic species on the Tibetan plateau, is likely to be affected by climatic warming. In our studies, accumulated degree‐days (ADD) of L. Migratoria T.C. were calculated based on data from 90 weather stations over the Tibetan plateau from 1961 to 2005. Trend lines show that across weather stations, ADD increased at a rate of 1.17 DD/a during climate warming. The majority of weather stations (82.2%) showing increases in ADD were located towards the west of the Tibetan plateau. At higher elevations, the increase in the ratio of annual ADD to the station mean ADD was higher relative to those at lower elevations. A linear regression model between ADD and geographical position was established to create raster maps of ADD in ArcGIS 9.2. The area of potential locust distribution (APD) was estimated to be 42 420 km2, mostly distributed along major rivers on the Tibetan plateau. In warmer years, the APD increased sharply over study periods. A new area of potential distribution would appear in the north Tibetan plateau if the climate warming continued. In the south‐east Tibetan plateau, the locust would expand its range northwards or westwards along the river valleys, and the locust APD would also rise in elevation.
Application of complementary luminescent and fluorescent imaging techniques to visualize nuclear and cytoplasmic Ca2+ signalling during the in vivo differentiation of slow muscle cells in zebrafish embryos under normal and dystrophic conditions
Authors: Webb Sarah E , Cheung Chris CY , Chan Ching Man , Love Donald R , Miller Andrew L
Published: August 2011

1. Evidence is accumulating for a role for Ca2+ signalling in the differentiation and development of embryonic skeletal muscle.

2. Imaging of intact, normally developing transgenic zebrafish that express the protein component of the Ca2+‐sensitive complex aequorin, specifically in skeletal muscle, show that two distinct periods of spontaneous synchronised Ca2+ transients occur in the trunk: one at approximately 17.5–19.5 h post‐fertilization (h.p.f.; termed signalling period SP1) and the other after approximately 23 h.p.f. (termed SP2). These periods of intense Ca2+ signalling activity are separated by a quiet period.

3. Higher‐resolution confocal imaging of embryos loaded with the fluorescent Ca2+ reporter calcium green‐1 dextran shows that the Ca2+ signals are generated almost exclusively in the slow muscle cells, the first muscle cells to differentiate, with distinct nuclear and cytoplasmic components.

4. Here, we show that coincidental with the SP1 Ca2+ signals, dystrophin becomes localized to the vertical myoseptae of the myotome. Introduction of a dmd morpholino (dmd‐MO) resulted in no dystrophin being expressed in the vertical myoseptae, as well as a disruption of myotome morphology and sarcomere organization. In addition, the Ca2+ signalling signatures of dmd‐MO‐injected embryos or homozygous sapje mutant embryos were abnormal such that the frequency, amplitude and timing of the Ca2+ signals were altered compared with controls.

5. Our new data suggest that, in addition to a structural role, dystrophin may function in the regulation of [Ca2+]i during the early stages of slow muscle cell differentiation when the Ca2+ signals generated in these cells coincide with the first spontaneous contractions of the trunk.
Heaves, an asthma‐like disease of horses
Authors: LECLERE MATHILDE , LAVOIE‐LAMOUREUX ANOUK , LAVOIE JEAN‐PIERRE
Published: August 2011

Animal models have been developed to investigate specific components of asthmatic airway inflammation, hyper‐responsiveness or remodelling. However, all of these aspects are rarely observed in the same animal. Heaves is a naturally occurring disease of horses that combines these features. It is characterized by stable dust‐induced inflammation, bronchospasm and remodelling. The evaluation of horses during well‐controlled natural antigen exposure and avoidance in experimental settings allows the study of disease mechanisms in the asymptomatic and symptomatic stages, an approach rarely feasible in humans. Also, the disease can be followed over several years to observe the cumulative effect of repeated episodes of clinical exacerbation or to evaluate long‐term treatment, contrasting most murine asthma models. This model has shown complex gene and environment interactions, the involvement of both innate and adaptive responses to inflammation, and the contribution of bronchospasm and tissue remodelling to airway obstruction, all occurring in a natural setting. Similarities with the human asthmatic airways are well described and the model is currently being used to evaluate airway remodelling and its reversibility in ways that are not possible in people for ethical reasons. Tools including antibodies, recombinant proteins or gene arrays, as well as methods for sampling tissues and assessing lung function in the horse are constantly evolving to facilitate the study of this animal model. Research perspectives that can be relevant to asthma include the role of neutrophils in airway inflammation and their response to corticosteroids, systemic response to pulmonary inflammation, and maintaining athletic capacities with early intervention.
Evidence‐based practice: SLTs under siege or opportunity for growth? The use and nature of research evidence in the profession
Authors: McCurtin Arlene , Roddam Hazel
Published: August 2011

Background: Speech and language therapists are encouraged to be evidence‐based practitioners in contemporary clinical practice. This apparently signifies their commitment to ‘good’ practice. An examination of evidence‐based practice (EBP) and its adoption in clinical practice is therefore warranted.

Aims: This paper aims to explore EBP, specifically research evidence, as related to the field of speech and language therapy (SLT), using profession specific and cross‐disciplinary examples. It asks the reader to consider whether research evidence contributes positively to SLT practice, or adds to the demands placed on clinicians?

Methods & Procedures: A review of the literature on the nature and use of research evidence in the field of speech and language therapy and related health professions was undertaken using multiple databases (Cochrane, Medline, Cinahal, BioMed, Trip, Dare) and the following up of references provided within texts and articles. This paper asks the reader to consider the topic from the perspective of the nature of research produced, the barriers perceived, and the use of research evidence by SLTs and the allied health professions.

Outcomes & Results: The uptake of research evidence in the profession is similar to other health professions and continues to be problematic. There are multiple reasons why this is so, originating from both the nature and use of research.

Conclusions & Implications: Research evidence is one of the pillars of EBP. Despite problems with the nature and use of such evidence, it has a positive contribution to make to clinical practice as it provides for a scientific touchstone. However, it may be that the speech and language therapist and not the research evidence is the primary pivot upon which scientific practice is based.
Massive dominance of Epsilonproteobacteria in formation waters from a Canadian oil sands reservoir containing severely biodegraded oil
Authors: Hubert Casey R. J. , Oldenburg Thomas B. P. , Fustic Milovan , Gray Neil D. , Larter Stephen R. , Penn Kevin , Rowan Arlene K. , Seshadri Rekha , Sherry Angela , Swainsbury Richard , Voordouw Gerrit , Voordouw Johanna K. , Head Ian M.
Published: August 2011

The subsurface microbiology of an Athabasca oil sands reservoir in western Canada containing severely biodegraded oil was investigated by combining 16S rRNA gene‐ and polar lipid‐based analyses of reservoir formation water with geochemical analyses of the crude oil and formation water. Biomass was filtered from formation water, DNA was extracted using two different methods, and 16S rRNA gene fragments were amplified with several different primer pairs prior to cloning and sequencing or community fingerprinting by denaturing gradient gel electrophoresis (DGGE). Similar results were obtained irrespective of the DNA extraction method or primers used. Archaeal libraries were dominated by Methanomicrobiales (410 of 414 total sequences formed a dominant phylotype affiliated with a Methanoregula sp.), consistent with the proposed dominant role of CO2‐reducing methanogens in crude oil biodegradation. In two bacterial 16S rRNA clone libraries generated with different primer pairs, > 99% and 100% of the sequences were affiliated with Epsilonproteobacteria (n = 382 and 72 total clones respectively). This massive dominance of Epsilonproteobacteria sequences was again obtained in a third library (99% of sequences; n = 96 clones) using a third universal bacterial primer pair (inosine‐341f and 1492r). Sequencing of bands from DGGE profiles and intact polar lipid analyses were in accordance with the bacterial clone library results. Epsilonproteobacterial OTUs were affiliated with Sulfuricurvum, Arcobacter and Sulfurospirillum spp. detected in other oil field habitats. The dominant organism revealed by the bacterial libraries (87% of all sequences) is a close relative of Sulfuricurvum kujiense – an organism capable of oxidizing reduced sulfur compounds in crude oil. Geochemical analysis of organic extracts from bitumen at different reservoir depths down to the oil water transition zone of these oil sands indicated active biodegradation of dibenzothiophenes, and stable sulfur isotope ratios for elemental sulfur and sulfate in formation waters were indicative of anaerobic oxidation of sulfur compounds. Microbial desulfurization of crude oil may be an important metabolism for Epsilonproteobacteria indigenous to oil reservoirs with elevated sulfur content and may explain their prevalence in formation waters from highly biodegraded petroleum systems.
Early milestones in glucagon research
Authors: Lefèbvre P. J.
Published: August 2011

As an introduction to the Symposium, we have reviewed the early steps in glucagon research from its discovery in 1923 to the establishment of the basics of the physiology and pathophysiology of the hormone after the description of a sensitive and specific radioimmunoassay by Unger and his co‐workers in 1959.
Incretin hormones and the expanding families of glucagon‐like sequences and their receptors
Authors: Irwin D. M. , Prentice K. J.
Published: August 2011

Peptide hormones encoded by the proglucagon (Gcg) and glucose‐dependent insulinotropic polypeptide (Gip) genes are evolutionarily related glucagon‐like sequences and act through a subfamily of G‐protein‐coupled receptors. A better understanding of the evolutionary history of these hormones and receptors should yield insight into their biological functions. The availability of a large number of near‐complete vertebrate genome sequences is a powerful resource to address questions concerning the evolution of sequences; here, we utilize these resources to examine the evolution of glucagon‐like sequences and their receptors. These studies led to the discovery of novel genes for a glucagon receptor‐like receptor (Grlr) and a glucagon‐like sequence (exendin) in vertebrates. Both exendin and GRLR have ancient origins, early in vertebrate evolution, but have been lost on the ancestral lineage leading to extant mammals. We also show that exendin and GRLR are both expressed in the brain of the chicken and Xenopus tropicals, results that suggest that the products of these genes function in this tissue. The lack of exendin or Grlr genes in mammals suggests that other genes may have acquired the functions of exendin and Grlr during mammalian evolution.
Glucagon gene expression in the endocrine pancreas: the role of the transcription factor Pax6 in α‐cell differentiation, glucagon biosynthesis and secretion
Authors: Gosmain Y. , Cheyssac C. , Heddad Masson M. , Dibner C. , Philippe J.
Published: August 2011

The glucagon gene is expressed in α‐cells of the pancreas, L cells of the intestine and the hypothalamus. The determinants of the α‐cell‐specific expression of the glucagon gene are not fully characterized, although Arx, Pax6 and Foxa2 are critical for α‐cell differentiation and glucagon gene expression; in addition, the absence of the β‐cell‐specific transcription factors Pdx1, Pax4 and Nkx6.1 may allow for the glucagon gene to be expressed. Pax6, along with cMaf and MafB, binds to the DNA control element G1 which confers α‐cell specificity to the promoter and to G3 and potently activates glucagon gene transcription. In addition, to its direct role on the transcription of the glucagon gene, Pax6 controls several transcription factors involved in the activation of the glucagon gene such as cMaf, MafB and NeuroD1/Beta2 as well as different steps of glucagon biosynthesis and secretion. We conclude that Pax6 independently of Arx and Foxa2 is critical for α‐cell function by coordinating glucagon gene expression as well as glucagon biosynthesis and secretion.
Regulation of glucagon secretion by glucose: paracrine, intrinsic or both?
Authors: Walker J. N. , Ramracheya R. , Zhang Q. , Johnson P. R. V. , Braun M. , Rorsman P.
Published: August 2011

Glucagon secretion is regulated by glucose but the mechanisms involved remain hotly debated. Both intrinsic (within the α‐cell itself) and paracrine (mediated by factors released β‐ and/or δ‐cells) have been postulated. Glucagon secretion is maximally suppressed by glucose concentrations that do not affect insulin and somatostatin secretion, a finding that highlights the significance of intrinsic regulation of glucagon secretion. Experiments on islets from mice lacking functional ATP‐sensitive potassium channels (KATP‐channels) indicate that these channels are critical to the α‐cell's capacity to sense changes in extracellular glucose. Here, we review recent data on the intrinsic and paracrine regulation of glucagon secretion in human pancreatic islets. We propose that glucose‐induced closure of the KATP‐channels, via membrane depolarization, culminates in reduced electrical activity and glucagon secretion by voltage‐dependent inactivation of the ion channels involved in action potential firing. We further demonstrate that glucagon secretion measured in islets isolated from donors with type‐2 diabetes is reduced at low glucose and that glucose stimulates rather than inhibits secretion in these islets. We finally discuss the relative significance of paracrine and intrinsic regulation in the fed and fasted states and propose a unifying model for the regulation of glucagon secretion that incorporates both modes of control.
Comparison of longitudinal point‐of‐care and high‐performance liquid chromatography HbA1c measurements in a multi‐centre trial
Authors: Alleyn C. R. , Laffel L. M. B. , Volkening L. K. , Anderson B. J. , Nansel T. R. , Wysocki T. , Weissberg‐Benchell J
Published: August 2011

Diabet. Med. 28, 1525–1529 (2011)

Aims  Point‐of‐care HbA1c is routine in clinical practice. Comparison of point‐of‐care HbA1c against laboratory measurements across sites and over time is warranted.

Methods  One hundred and twenty‐one young persons with Type 1 diabetes from four centres provided 450 paired samples collected over 10 months for point‐of‐care HbA1c and central laboratory‐based high‐performance liquid chromatography (HPLC) HbA1c determinations. Change in HbA1c over time was assessed by difference from initial to final HbA1c and by growth modelling with annualized slope calculation. Change in HbA1c was categorized as improved (decrease of ≥ 0.5% or negative slope), no change (± 0.4% of initial HbA1c or slope = 0) or worsened (increase of ≥ 0.5% or positive slope).

Results  The 450 paired samples (median of four pairs/patient) were highly correlated (r = 0.97, P < 0.0001), as were time‐specific and site‐specific pairs (r = 0.94 to 0.98, P < 0.0001). Initial‐to‐final point‐of‐care HbA1c and HPLC HbA1c changes were 0.3 ± 1.1% (range −2.7 to 4.1) and 0.4 ± 1.2% (−3.9 to 4.5), respectively, with 21% of patients (n = 26) discordant for change categories. ΔHbA1c by point‐of‐care HbA1c vs. HPLC HbA1c differed across the HbA1c range and by ≥ 0.5% absolute difference in ΔHbA1c in 14 (54%) of the 26 patients discordant for HbA1c change categories. Mean annual HbA1c slope was 0.4 ± 1.5% (−5.4 to 4.8) for point‐of‐care HbA1c and 0.4 ± 1.6% (−6.9 to 5.2) for HPLC HbA1c, with 18% (n = 22 pairs) discordant for change categories.

Conclusions  Assessment of absolute HbA1c change may not be different for point‐of‐care HbA1c compared with HPLC HbA1c; however, misclassification of patients by discrete cut‐off values may occur with point‐of‐care HbA1c compared with HPLC HbA1c determinations.
Precision and accuracy of blood glucose measurements using three different instruments
Authors: Nowotny B. , Nowotny P. J. , Strassburger K. , Roden M.
Published: August 2011

Diabet. Med. 29, 260–265 (2012)

Aims  Assessment of insulin sensitivity by dynamic metabolic tests such as the hyperinsulinemic euglycemic clamp critically relies on the reproducible and fast measurement of blood glucose concentrations. Although various instruments have been developed over the last decades, little is known as to the accuracy and comparability. We therefore compared the best new instrument with the former gold standard instruments to measure glucose concentrations in metabolic tests.

Methods  Fasting blood samples of 15 diabetic and 10 healthy subjects were collected into sodium‐fluoride tubes, spiked with glucose (0, 2.8, 6.9 and 11.1 mmol/l) and measured either as whole blood (range 3.3–26.3 mmol/l) or following centrifugation as plasma (range 3.9–32.0 mmol/l). Plasma samples were analyzed in the YSI‐2300 STAT plus (YSI), EKF Biosen C‐Line (EKF) and the reference method, Beckman Glucose analyzer‐II (BMG), whole blood samples in EKF instruments with YSI as reference method.

Results  The average deviation of the EKF from the reference, BMG, was 3.0 ± 3.5% without any concentration‐dependent variability. Glucose measurements by YSI were in good agreement with that by BMG (plasma) and EKF (plasma and whole blood) up to concentrations of 13.13 mmol/l (0.5 ± 3.7%), but deviation increased to −6.2 ± 3.8% at higher concentrations. Precision (n = 6) was ±2.2% (YSI), ±3.9% (EKF) and ±5.2% (BMG).

Conclusions  The EKF instrument is comparable regarding accuracy and precision to the reference method BMG and can be used in metabolic tests, while the YSI showed a systematic shift at higher glucose concentrations. Based on these results we decided to replace BMG with EKF instrument in metabolic tests.
Motivating Employees to Work Beyond Retirement: A Multi‐Level Study of the Role of I‐Deals and Unit Climate
Authors: Bal P. Matthijs , De Jong Simon B. , Jansen Paul G. W. , Bakker Arnold B.
Published: August 2011

abstract

The present study investigates what role I‐deals (i.e. the idiosyncratic deals made between employees and their organization) play in the motivation of employees to continue working after retirement. We hypothesized two types of I‐deals (i.e. development and flexibility I‐deals) to be positively related to motivation to continue working. More specifically, we drew from continuity and personality theory to argue that the motivation to continue working is enhanced by I‐deals, because they fulfil people's needs for personalized work arrangements. Moreover, drawing from activity and disengagement theory it was hypothesized that two types of unit climate (i.e. accommodative and development climates) would moderate these relationships. Specifically, it was predicted that I‐deals would be positively related to motivation to continue working under conditions of low accommodative or high development climate. Results of a multi‐level study among 1083 employees in 24 units largely supported the above expectations; flexibility I‐deals related positively to motivation to continue working, and unit climate moderated the relation between development I‐deals and motivation to continue working.
The Development of Distrust
Authors: Vanderbilt Kimberly E. , Liu David , Heyman Gail D.
Published: August 2011

Preschool‐age children’s reasoning about the reliability of deceptive sources was investigated. Ninety 3‐ to 5‐year‐olds watched several trials in which an informant gave advice about the location of a hidden sticker. Informants were either helpers who were happy to give correct advice, or trickers who were happy to give incorrect advice. Three‐year‐olds tended to accept all advice from both helpers and trickers. Four‐year‐olds were more skeptical but showed no preference for advice from helpers over trickers, even though they differentiated between helpers and trickers on metacognitive measures. Five‐year‐olds systematically preferred advice from helpers. Selective trust was associated with children’s ability to make mental state inferences.
Nonlinear Growth Curves in Developmental Research
Authors: Grimm Kevin J. , Ram Nilam , Hamagami Fumiaki
Published: August 2011

Developmentalists are often interested in understanding change processes, and growth models are the most common analytic tool for examining such processes. Nonlinear growth curves are especially valuable to developmentalists because the defining characteristics of the growth process such as initial levels, rates of change during growth spurts, and asymptotic levels can be estimated. A variety of growth models are described beginning with the linear growth model and moving to nonlinear models of varying complexity. A detailed discussion of nonlinear models is provided, highlighting the added insights into complex developmental processes associated with their use. A collection of growth models are fit to repeated measures of height from participants of the Berkeley Growth and Guidance Studies from early childhood through adulthood.