bluuebunny/crossref_metadata_2025 huggingface dataset:
The Influence of a Non-Occlusive Bi-Layer Composite Membrane on Skin Barrier Properties
Authors: Brazzelli V. , Berardesca E. , Rona C. , Borroni G.
Published: December 2007

The purpose of this placebo-controlled right-left intra-individual pre/post comparison study was to evaluate the efficacy of a new bi-layer composite membrane, composed of a layer of knitted cotton and a layer of semi-permeable polyurethane, developed in order to improve skin hydration. Eighteen healthy subjects entered the study. A T-shirt, dedicated to this study, was prepared and it was worn for 8 h, mimicking overnight wearing. Before and at the removal of the T-shirt an objective quantification of skin parameters was performed by measuring hydration, transepidermal water loss (TEWL) and skin surface pH, bilaterally, on the inner side of the forearm. Measurements were performed both at the interface between the skin and the bi-layer composite membrane or cotton and on the outer side of the membrane (to assess permeation of water and occlusive properties of the product) with and without a single application of a moisturizer. A statistically significant improvement of skin hydration, recorded on the stratum corneum underneath the bi-layer membrane versus cotton alone, was measured both with (p < 0.0001) and without application of the moisturizer (p < 0.002). TEWL was shown to decrease significantly on the side of the bi-layer membrane, if compared with cotton (p < 0.008), after application of the moisturizer. TEWL through the membrane showed no significant differences as compared to placebo, confirming the permeability of the fabric. Our data suggest that this bi-layer composite membrane can promote the hydration process of the stratum corneum, increasing the hydrating properties of the moisturizer agent.
Poly-N-Acetyl Glucosamine Nanofibers Regulate Endothelial Cell Movement and Angiogenesis: Dependency on Integrin Activation of Ets1
Authors: Vournakis John N. , Eldridge Juanita , Demcheva Marina , Muise-Helmericks Robin C.
Published: December 2007

Poly-N-acetyl glucosamine (pGlcNAc) nanofiber-derived materials effectively achieve hemostasis during surgical procedures. Treatment of cutaneous wounds with pGlcNAc in a diabetic mouse animal model causes marked increases in cell proliferation and angiogenesis. We sought to understand the effect of the pGlcNAc fibers on primary endothelial cells (EC) in culture and found that pGlcNAc induces EC motility. Cell motility induced by pGlcNAc fibers is blocked by antibodies directed against αVβ3 and α5β1 integrins, both known to play important roles in the regulation of EC motility, in vitroand in vivo. pGlcNAc treatment activates mitogen-activated protein kinase and increases Ets1, vascular endothelial growth factor (VEGF) and interleukin 1 (IL-1) expression. pGlcNAc activity is not secondary to its induction of VEGF; inhibition of the VEGF receptor does not inhibit the pGlcNAc-induced expression of Ets1 nor does pGlcNAc cause the activation of VEGF receptor. Both dominant negative and RNA interference inhibition of Ets1 blocks pGlcNAc-induced EC motility. Antibody blockade of integrin results in the inhibition of pGlcNAc-induced Ets1 expression. These findings support the hypothesis that pGlcNAc fibers induce integrin activation which results in the regulation of EC motility and thus in angiogenesis via a pathway dependent on the Ets1 transcription factor and demonstrate that Ets1 is a downstream mediator of integrin activation.
Insulin Activates ATP-Sensitive Potassium Channels via Phosphatidylinositol 3-Kinase in Cultured Vascular Smooth Muscle Cells
Authors: Yasui Sonoko , Mawatari Kazuaki , Kawano Takashi , Morizumi Ran , Hamamoto Akiko , Furukawa Hiroko , Koyama Kei , Nakamura Aki , Hattori Atsushi , Nakano Masayuki , Harada Nagakatsu , Hosaka Toshio , Takahashi Akira , Oshita Shuzo , Nakaya Yutaka
Published: December 2007

The effects of insulin on the vasculature are significant because insulin resistance is associated with hypertension. To increase the understanding of the effects of insulin on the vasculature, we analyzed changes in potassium ion transport in cultured vascular smooth muscle cells (VSMCs). Using the potential-sensitive fluorescence dye bis-(1,3-dibutylbarbituric acid)trimethine oxonol [DiBAC4(3)], we found that insulin induced membrane hyperpolarization after 2 min in A10 cells. Insulin-induced hyperpolarization was suppressed by glibenclamide, an ATP-sensitive potassium (KATP) channel blocker. Using a cell-attached patch clamp experiment, the KATP channel was activated by insulin in both A10 cells and isolated VSMCs from rat aortas, indicating that insulin causes membrane hyperpolarization via KATP channel activation. These effects were not dependent on intracellular ATP concentration, but wortmannin, a phosphatidylinositol 3-kinase (PI3-K) inhibitor, significantly suppressed insulin-induced KATP channel activation. In addition, insulin enhanced phosphorylation of insulin receptor, insulin receptor substrate (IRS)-1 and protein kinase B (Akt) after 2 min. These data suggest that KATP channel activation by insulin is mediated by PI3-K. Furthermore, using a nitric oxide synthase (NOS) inhibitor, we found that NOS might play an important role downstream of PI3-K in insulin-induced KATP channel activation. This study may contribute to our understanding of mechanisms of insulin resistance-associated hypertension.
Atherosclerotic Renal Artery Stenosis: Association with Emerging Vascular Risk Factors
Authors: Paraskevas Kosmas I. , Hamilton George , Cross Jenny M. , Mikhailidis Dimitri P.
Published: December 2007

Background: The established risk factors for atherosclerotic renal artery stenosis (ARAS) include hypertension, diabetes mellitus, dyslipidemia, obesity,smoking, old age and family history. In the last few years, several emerging risk factors have been proposed as predictors of ARAS, namely homocysteine, fibrinogen, C-reactive protein, lipoprotein(a) and creatinine. Methods: We searched Pubmed/Medline for studies investigating the prognostic value of each of these emerging risk factors in ARAS. Results: Creatinine and C-reactive protein seem to be the most promising predictors of ARAS, whereas the prognostic value of homocysteine, lipoprotein(a) and fibrinogen is not yet fully determined. Conclusion: The establishment of a definite role for these emerging risk factors could result in earlier recognition and/or better management of ARAS with potential regression/slowing down of progression of stenosis. Modifying these markers may also improve the therapeutic approach of the associated systemic atherosclerosis in these high-risk patients. Future trials should focus on the effect of different classes of drugs (e.g. statins and fibrates) on the levels of the emerging risk factors and the association with ARAS progression.
Utility of the Rapid B-Type Natriuretic Peptide Assay for Detection of Cardiovascular Problems in Newborn Infants with Respiratory Difficulties
Authors: Ko Hong Ki , Lee Jang Hoon , Choi Byung Min , Lee Jung Hwa , Yoo Kee Hwan , Son Chang Sung , Lee Joo Won
Published: December 2007

Background: Because the major problems of respiratory difficulties in newborn infants are due to cardiopulmonary problems, improving the early detection and referral of newborn infants with cardiovascular problems has been considered one of the primary goals of care in the neonatal intensive care unit. Objective: To evaluate whether rapid plasma B-type natriuretic peptide (BNP) assay could be used as a screening test to detect the cardiovascular problems in newborn infants with respiratory difficulties. Methods: We studied 73 newborn infants ≧34 weeks gestational age presenting with respiratory difficulties during the first few days after birth; they were divided into a cardiovascular problem group (CP group, n = 32) and a noncardiac problem group (NP group, n = 41) according to the presence of cardiovascular problems by clinical and/or echocardiographic studies in newborn infants with respiratory difficulties. Results: On admission, the median (25–75%) BNP concentration of the CP group was significantly higher than that of the NP group [1,038 (578–1,435) vs. 240 (118–388) pg/ml, p < 0.001]. The best cutoff BNP values for differentiating the CP group were 346.0, 421.0, 570.5 and 191.5 pg/ml within 18 h, at 18–36 h, at 36–60 h and after 60 h of life, respectively. Although the plasma BNP measurement was not a single confirmative test, it was found to have a high sensitivity and a high negative predictive value for rapidly ruling out serious cardiovascular problems in neonatal respiratory difficulties. Conclusion: A rapid plasma BNP assay may be useful for detection of cardiovascular problems in newborn infants with respiratory difficulties during the first few days after birth.
When Memory Challenges History: Public Contestation of the Past in Post-Suharto Indonesia
Authors:   Budiawan
Published: December 2007

Serving to legitimate the power of a political regime, official history is usually radically questioned as the regime collapses. Such is the case in Indonesia since the fall of Suharto in May 1998. Yet, unlike many other countries which have experienced transitions from authoritarian or totalitarian rule to democracy, post-Suharto Indonesia is witnessing an ambivalent critique of the official history, especially regarding the "September 30, 1965 affair" (the killing of six top Army officers by a regiment of Presidential guards which brought about Suharto's rise to power). On one hand, there is a public query over who masterminded the killings; on the other hand, there are reactionary responses towards the claims of victimization among ex-political prisoners associated with the September 30,1965 movement, as they articulate their experiences of the past tragedy. This paper attempts to explore the current controversy surrounding the official history of the September 30, 1965 affair through discussions of the paradox of memory, and the relationship between memory and history.
Johannes Kuchlinus, the 'Faithful Teacher': His Role in the Arminian Controversy and His Impact as a Theological Interpreter and Educator
Authors: Stanglin Keith
Published: December 2007

Johannes Kuchlinus (1546-1606) was a Reformed pastor in Amsterdam and the founding regent of the theological college at Leiden University. Modern scholarship has overlooked the impact he had during his tenure at the university. Part of his impact has to do with his ability to keep relative peace in the midst of a boiling faculty controversy between Jacobus Arminius and Franciscus Gomarus. His greatest influence, though, is seen in his work as an interpreter and teacher of the Heidelberg Catechism. His first-hand knowledge of the Catechism and one of its authors, Zacharias Ursinus, combined with his prominent position of training pastors, uniquely qualified him as a proponent of the Catechism in the low countries. The disputations on the catechetical topics that he composed for student defenses, a list of which appears at the conclusion of this article, not only comprise a vast wealth of material for further study of this figure who influenced a generation, but also represent another source for the "Leiden theology" during this controversial period.
Systemic Exposure and Urinary Cortisol Effects of Fluticasone Propionate Formulated With Hydrofluoroalkane in 4‐ to 11‐Year‐Olds With Asthma
Authors: Kim Kennet T. , Milgrom Henry , Yoon Y. Kellie , Levy Arde L. , Matz Paul , Welch Michae J. , Cahn Anthony , Collins Davi A. , Kathman Steven , Mehta Rashmi , Su Sheng‐Fang , Kunka Rober L.
Published: December 2007

The systemic exposure of fluticasone propionate with hydrofluoroalkane propellant compared with chlorofluorocarbon propellant and the effect of fluticasone propionate hydrofluoroalkane on 24‐hour urinary cortisol in children aged 4 to 11 years with asthma were evaluated. Study 1 was an open‐label, 2‐way crossover study in which 16 subjects were randomized to 7.5 days each of fluticasone propionate hydrofluoroalkane 88 μg twice a day or fluticasone propionate chlorofluorocarbon 88 μg twice a day. In study 2, 63 subjects received 13.5 days of placebo followed by 27.5 days of fluticasone propionate hydrofluoroalkane 88 μg twice a day. The main outcome measure for study 1 was the difference between fluticasone propionate hydrofluoroalkane and fluticasone propionate chlorofluorocarbon in fluticasone propionate AUClast (area under the plasma fluticasone propionate concentration–time curve from zero up to the last quantifiable plasma concentration), and for study 2, 24‐hour overnight urinary cortisol excretion. In study 1, fluticasone propionate systemic exposure was significantly lower (55%) with hydrofluoroalkane metered dose inhaler compared with chlorofluorocarbon metered dose inhaler. Study 2 showed no statistically significant changes in 24‐hour overnight urinary cortisol excretion and no relationship to fluticasone propionate systemic exposure at this dose. The results of these 2 studies showed that in children aged 4 to 11 years with asthma, fluticasone propionate hydrofluoroalkane has lower systemic exposure compared with chlorofluorocarbon and no hypothalamic–pituitary–adrenal axis effects as measured by 24‐hour urinary cortisol excretion.
Prasugrel, a New Thienopyridine Antiplatelet Drug, Weakly Inhibits Cytochrome P450 2B6 in Humans
Authors: Farid Nag A. , Payne Christophe D. , Ernest C. Steven , Li Y. Grace , Winters Kennet J. , Salazar Danie E. , Small Davi S.
Published: December 2007

Prasugrel, a thienopyridine prodrug, is hydrolyzed in vivo by esterases to a thiolactone followed by a single cytochrome P450 (CYP)‐dependent step to an active metabolite that is a potent inhibitor of adenosine diphosphate–induced platelet aggregation. This open‐label, multiple‐dose, 2‐period, fixed‐sequence study assessed CYP2B6 inhibition by prasugrel using bupropion as a probe substrate, where its active metabolite, hydroxybupropion, is almost exclusively formed by CYP2B6. Thirty healthy subjects received a single 150‐mg oral dose of sustained‐release bupropion. After a 7‐day washout, a 60‐mg prasugrel loading dose, followed by a 10‐mg daily maintenance dose for 10 days, was administered. Bupropion (150 mg) was given with prasugrel on day 7 of this phase. Prasugrel weakly inhibited CYP2B6 activity as it increased bupropion Cmaxand AUC0‐∞by 14% and 18%, respectively, and decreased hydroxybupropion Cmaxand AUC0‐∞by 32% and 23%. These results are consistent with patients receiving prasugrel not requiring dose adjustments when treated with drugs primarily metabolized by CYP2B6.
Childcare, choice and social class: Caring for young children in the UK
Authors: Vincent Carol , Braun Annette , Ball Stephen J .
Published: December 2007

This paper draws on the results of two qualitative research projects examining parental engagements with the childcare market in the UK. Both projects are located in the same two London localities. One project focuses on professional middle class parents, and the other on working class families, and we discuss the key importance of social class in shaping parents' differential engagement with the childcare market, and their understandings of the role childcare plays in their children's lives. We identify and discuss the different `circuits' of care available to and used by families living physically close to each other, but in social class terms living in different worlds. We also consider parents' relationships with carers, and their social networks. We conclude that, in order to fully understand childcare policies and practices and families' experiences of care, an analysis which encompasses social class and the workings of the childcare market is needed.
The UK's gamete donor `crisis' - a critical analysis
Authors: Blyth Eric , Frith Lucy
Published: December 2007

Since April 2005, individuals donating sperm, eggs or embryos for the treatment of others in the UK have been required to agree to the disclosure of their identity to any child conceived as a result of their donation on reaching the age of 18. The main arguments advanced against the removal of donor anonymity are: first, it is responsible for a dramatic decline in the number of donors; second, it causes particular problems for donors in egg sharing programmes; and third, that it will increase the unwillingness of parents of donor-conceived children to tell their children about their conception. This paper analyses these arguments and points to flaws in both the evidential base and the argumentative strategies of these claims. The authors argue for a proactive approach to donor recruitment that reflects the contemporary context for the provision of donor conception services in the UK.
Depressive Disorders Related to Female Reproductive Transitions
Authors: Serrano Elka , Warnock Julia “Jill” K.
Published: December 2007

Depression is rapidly becoming a major health concern. Recent estimates rank it as the fourth leading cause of disease burden worldwide, and its incidence is steadily increasing. Women have a risk of experiencing depressive illnesses that is twice that of men. Women with depression also typically experience greater functional impairment. The incidence of depression dramatically increases during the reproductive years, which correspond to ages 25 to 44 years. During this time frame, women may experience several reproductive milestones or transitional events such as menarche, the menstrual cycle, pregnancy, infertility, miscarriage, and perimenopause/menopause. These transitions evoke neuroendocrinologic changes that appear to influence the risk for depressive episodes. Common disorders associated with these hormonal fluctuations include premenstrual dysphoric disorder, postpartum depression, and depression in the perimenopausal transition. Although the specific pathophysiologic association is still unclear, evidence supports that these reproductive transitions influence the risk of depression in women.
Sulfonamide Allergy and Possible Cross-Reactivity
Authors: Kourlas Helen , Morey Susan
Published: December 2007

True allergic reactions are IgE-mediated immune reactions and are also termed type I reactions, where the spectrum of presentation may range from urticaria to severe anaphylactic shock. Currently, 3% of the patients who use sulfonamide antibiotics develop an allergic reaction, with the most common being the development of a maculopapular rash. Sulfonamides are chemical compounds that can be further divided into 3 groups based on differences in their structural makeup. Several cases reviewing the cross-reactivity between sulfonamide antibiotics and nonantibiotics have suggested an increased risk of cross-reactivity and therefore recommend other treatment strategies to avoid a possible anaphylactic reaction; however, other reports argue that patients with a history of sulfonamide allergy who received sulfonamide nonantibiotics did not experience any adverse reactions. Pertinent data extracted from these studies are reviewed and evaluated.
Income Health Inequalities Among Older Persons
Authors: Evans Gary W. , Wethington Elaine , Coleman Meredith , Worms Margo , Frongillo Edward A.
Published: December 2007

Objective: We examine whether the pervasive income gradient in health among senior citizens can be explained in part by multiple risk exposure. Method: A representative sample of 457 older persons ( M = 74.29 years) living independently at home were assessed in a longitudinal study. Health was assessed with a standard self-report index. Risks included loss of a loved one, caregiver burden, low housing quality, and low social integration. Results: The prospective link between income and subsequent health 2 years later is largely explained by exposure to a confluence of multiple risk factors during the 2-year period. These findings incorporate controls for negative affectivity. Discussion: Low-income, older persons are significantly more likely to have lost a loved one or close friend, be burdened by extensive caregiving demands for someone else, be more socially isolated, and live in lower quality housing. These risk exposures, in turn, largely account for the prospective link between income and health.
Secondary school teachers' conceptions of student information literacy
Authors: Williams Dorothy A. , Wavell Caroline
Published: December 2007

This paper describes empirical research examining secondary school teachers' conceptions of student information literacy and reflects on the implications for the development of information-literate students. The research was designed to be practitioner centred, focusing on curriculum-based information activities and the student learning process from the teacher perspective. The study took a broadly phenomenographic approach and data were collected through a series of group discussions and interviews with subject teachers. Teachers described student information literacy in terms of a variety of skills and processes which overlap with existing models and frameworks. However, significant differences from other models and definitions included the absence of defining the information need and knowledge building. Teachers' conceptions evolved during the study and were influenced by individual experiences and curriculum priorities. The study suggests that overemphasis on mechanistic skills development without local debate and understanding hinders the alignment of information literacy with independent and lifelong learning. A number of challenges are identified for the development of information literacy in UK secondary schools, not least the fact that information literacy was understood by teachers in isolation from the subject curriculum. The study also sheds light on possible reasons why students may not leave school as information-literate individuals.
Accounting for expertise: Wynne and the autonomy of the lay public actor
Authors: Durant Darrin
Published: December 2007

This paper argues that the public understanding of science has eliminated the understanding gap between experts and the public, but erected an ontological gap in its place. Experts are conceived of as unreflexive, but lay public actors as reflexive. To provide a concrete grounding for this claim, this paper offers a conceptual analysis of Brian Wynne's work on the public understanding of science. Wynne's work intersects theorizing about late modernity (explored via a comparison with Beck's and Giddens') and debates about the role of experts and the public in decision-making (explored via a comparison to Collins and Evans). I show that Wynne's work, as with Beck's and Giddens', and Collins and Evans', embodies different conceptions of lay actors. In Wynne's work ambivalence arises concerning whether social identities or social relationships ground the theoretical account. I suggest the tension arises because of the general desire of the social science analyst to preserve the autonomy of the lay actor.
School science and its controversies; or, whatever happened to scientific literacy?
Authors: Turner Steven
Published: December 2007

The 1980s saw the rise of the public understanding of science, as a movement and as a research field. The decade also saw the goal of K-12 science instruction reoriented toward the promotion of scientific literacy for all students. This paper explores the subsequent relationship of these two movements. It examines debates over K-12 science curricular reform, with particular focus on “civic scientific literacy,” the introduction of science, technology, and society (STS) issues into classrooms, and the gradual retreat from STS-oriented reforms. It discusses how those debates may have been influenced by findings from the public understanding of science, and argues that educational debates themselves provide an important resource for probing larger issues of public understanding.
CAM Competencies for the Health Professions
Authors: Kreitzer Mary Jo , Mann Doug , Lumpkin Michael
Published: December 2007

As consumer demand for complementary therapies has increased, so too has the public's expectation that health care professionals be knowledgeable about complementary and alternative medicine (CAM) and prepared to advise patients. In 2000, the National Institutes of Health National Center for Complementary and Alternative Medicine (NCCAM) began awarding competitive, 5-year educational grants to academic institutions committed to teaching CAM content to health professional students. Fifteen awards were made under this program. Five somewhat overlapping domains of competency have emerged: awareness of CAM therapies and practices, evidence base underlying CAM therapies, CAM skill development, self-awareness and self-care, and CAM models and systems. The NCCAM R-25 projects have demonstrated the value of defining competencies in a variety of ways that can usefully guide the allopathic learner toward the broader goals of informed integrative, patient-centered practice and enhanced self-care.
Low roughness thin diamond films produced at moderate temperatures using microwave plasma assisted chemical vapour deposition process
Authors: Jawid Askari S. , Lu F.
Published: December 2007

Diamond coatings on pure titanium substrates are of interest for tribological and biomedical implants; however, due to different thermal expansion coefficients of the two materials, the complex nature of the interlayer formed during diamond deposition, and the difficulty in achieving very high nucleation density, it is hard to deposit adherent thin diamond layers on titanium. The aim of this research work is to successfully produce smooth and well adherent diamond coatings on a pure Ti substrate using the microwave plasma chemical vapour deposition (MWPCVD) method. The effects of applying two kinds of gas mixtures (H2/CH4 and Ar/H2/CH4) during diamond deposition on the pure Ti substrate are studied. The morphology, surface roughness, diamond crystal orientation and purity are obtained by characterising the sample with field emission electron microscopy (FESEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and Raman spectroscopy respectively.
Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo
Authors: Edwards Claire M. , Edwards James R. , Lwin Seint T. , Esparza Javier , Oyajobi Babatunde O. , McCluskey Brandon , Munoz Steven , Grubbs Barry , Mundy Gregory R.
Published: December 2007

There is increasing evidence to suggest that the Wnt signaling pathway plays a critical role in the pathogenesis of myeloma bone disease. In the present study, we determined whether increasing Wnt signaling within the bone marrow microenvironment in myeloma counteracts development of osteolytic bone disease. C57BL/KaLwRij mice were inoculated intravenously with murine 5TGM1 myeloma cells, resulting in tumor growth in bone and development of myeloma bone disease. Lithium chloride (LiCl) treatment activated Wnt signaling in osteoblasts, inhibited myeloma bone disease, and decreased tumor burden in bone, but increased tumor growth when 5TGM1 cells were inoculated subcutaneously. Abrogation of β-catenin activity and disruption of Wnt signaling in 5TGM1 cells by stable overexpression of a dominant-negative TCF4 prevented the LiCl-induced increase in subcutaneous growth but had no effect on LiCl-induced reduction in tumor burden within bone or on osteolysis in myeloma-bearing mice. Together, these data highlight the importance of the local microenvironment in the effect of Wnt signaling on the development of myeloma bone disease and demonstrate that, despite a direct effect to increase tumor growth at extraosseous sites, increasing Wnt signaling in the bone marrow microenvironment can prevent the development of myeloma bone disease and inhibit myeloma growth within bone in vivo.
The inhibitory receptor LILRB1 modulates the differentiation and regulatory potential of human dendritic cells
Authors: Young Neil T. , Waller Edward C. P. , Patel Rashmi , Roghanian Ali , Austyn Jonathan M. , Trowsdale John
Published: December 2007

Dendritic cells (DCs) link innate and adaptive immunity, initiating and regulating effector cell responses. They ubiquitously express members of the LILR (ILT, LIR, CD85) family of molecules, some of which recognize self-HLA molecules, but little is known of their possible functions in DC biology. We demonstrate that the inhibitory receptor LILRB1 (ILT2, LIR1, CD85j) is selectively up-regulated during DC differentiation from monocyte precursors in culture. Continuous ligation of LILRB1 modulated cellular differentiation, conferred a unique phenotype upon the resultant cells, induced a profound resistance to CD95-mediated cell death, and inhibited secretion of cytokines IL-10, IL-12p70, and TGF-β. These features remained stable even after exposure of the cells to bacterial LPS. Ligated DCs exhibited poor stimulatory activity for primary and memory T-cell proliferative responses, but this was substantially reversed by blockade of CD80 or its preferred ligand CTLA-4, or by depleting CD4+ CD25+ CD127lo regulatory T cells. Our findings suggest that ligation of LILRB1 on DCs by self-HLA molecules may play a key role in controlling the balance between the induction and suppression of adaptive immune responses.
Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells
Authors: Chae Hee-Don , Lee Katherine E. , Williams David A. , Gu Yi
Published: December 2007

RhoH, a hematopoietic-specific and constitutively active member of the Rho guanosine triphosphatase (GTPase) family, has been implicated in the negative regulation of Rac GTPase-mediated signaling in hematopoietic cells. However, the molecular mechanisms underlying the functional interaction between RhoH and Rac in primary cells are poorly understood. Here we show that deletion of Rhoh in hematopoietic progenitor cells (HPCs) leads to increased stromal-derived factor-1α (SDF-1α)–induced chemotaxis and chemokinesis (random migration). The abnormally enhanced migration of Rhoh−/− HPCs is associated with increased Rac1 activity and translocation of Rac1 protein to the cell membrane, where it colocalizes with cortical filamentous-actin (F-actin) and lipid rafts. Expression of the dominant-negative mutant Rac1N17 inhibits the cortical F-actin assembly and chemotaxis of wild-type and Rhoh−/− HPCs to the same extent. Conversely, overexpression of RhoH in HPCs blocks the membrane translocation of Rac1–enhanced green fluorescence protein (EGFP) and active Rac1V12–EGFP proteins and impairs cortical F-actin assembly and chemotaxis in response to SDF-1α stimulation. Furthermore, we demonstrate that the subcellular localization and inhibitory function of RhoH in HPCs are regulated by C-terminal motifs, including a CKIF prenylation site. Together, we have identified an antagonistic role of RhoH in regulation of cortical F-actin assembly and chemotaxis via suppressing Rac1 membrane targeting and activation in primary HPCs.
High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia
Authors: von Stackelberg Arend , Hartmann Reinhard , Bührer Christoph , Fengler Rüdiger , Janka-Schaub Gritta , Reiter Alfred , Mann Georg , Schmiegelow Kjeld , Ratei Richard , Klingebiel Thomas , Ritter Jörg , Henze Günter
Published: December 2007

High-dose methotrexate (MTX) has been extensively used for treatment of acute lymphoblastic leukemia (ALL). To determine the optimal dose of MTX in childhood relapsed ALL, the ALL Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) Study Group performed this prospective randomized study. A total of 269 children with a first early/late isolated (n = 156) or combined (n = 68) bone marrow or any isolated extramedullary relapse (n = 45) of precursor B-cell (PBC) ALL (excluding very early marrow relapse within 18 months after initial diagnosis) were registered at the ALL-REZ BFM90 trial and randomized to receive methotrexate infusions at either 1 g/m2 over 36 hours (intermediate dose, ID) or 5 g/m2 over 24 hours (high dose, HD) during 6 (or 4) intensive polychemotherapy courses. Intensive induction/consolidation therapy was followed by cranial irradiation, and by conventional-dose maintenance therapy. Fifty-five children received stem-cell transplants. At a median follow-up of 14.1 years, the 10-year event-free survival probability was .36 (± .04) for the ID group (n = 141), and .38 (± .04) for the HD group (n = 128, P = .919). The 2 groups did not differ in terms of prognostic factors and other therapeutic parameters. In conclusion, methotrexate infusions at 5 g/m2 per 24 hours, compared with 1 g/m2 per 36 hours, are not associated with increased disease control in relapsed childhood PBC acute lymphoblastic leukemia.
Identification of two novel activities of the Wnt signaling regulator Dickkopf 3 and characterization of its expression in the mouse retina
Authors: Nakamura Rei EI , Hunter Dale D , Yi Hyun , Brunken William J , Hackam Abigail S
Published: December 2007

Background

The Wnt signaling pathway is a cellular communication pathway that plays critical roles in development and disease. A major class of Wnt signaling regulators is the Dickkopf (Dkk) family of secreted glycoproteins. Although the biological properties of Dickkopf 1 (Dkk1) and Dickkopf 2 (Dkk2) are well characterized, little is known about the function of the related Dickkopf 3 (Dkk3) protein in vivo or in cell lines. We recently demonstrated that Dkk3 transcripts are upregulated during photoreceptor death in a mouse model of retinal degeneration. In this study, we characterized the activity of Dkk3 in Wnt signaling and cell death.

Results

Dkk3 was localized to Müller glia and retinal ganglion cells in developing and adult mouse retina. Western blotting confirmed that Dkk3 is secreted from Müller glia cells in culture. We demonstrated that Dkk3 potentiated Wnt signaling in Müller glia and HEK293 cells but not in COS7 cells, indicating that it is a cell-type specific regulator of Wnt signaling. This unique Dkk3 activity was blocked by co-expression of Dkk1. Additionally, Dkk3 displayed pro-survival properties by decreasing caspase activation and increasing viability in HEK293 cells exposed to staurosporine and H2O2. In contrast, Dkk3 did not protect COS7 cells from apoptosis.

Conclusion

These data demonstrate that Dkk3 is a positive regulator of Wnt signaling, in contrast to its family member Dkk1. Furthermore, Dkk3 protects against apoptosis by reducing caspase activity, suggesting that Dkk3 may play a cytoprotective role in the retina.
Surface antigens and potential virulence factors from parasites detected by comparative genomics of perfect amino acid repeats
Authors: Fankhauser Niklaus , Nguyen-Ha Tien-Minh , Adler Joël , Mäser Pascal
Published: December 2007

Background

Many parasitic organisms, eukaryotes as well as bacteria, possess surface antigens with amino acid repeats. Making up the interface between host and pathogen such repetitive proteins may be virulence factors involved in immune evasion or cytoadherence. They find immunological applications in serodiagnostics and vaccine development. Here we use proteins which contain perfect repeats as a basis for comparative genomics between parasitic and free-living organisms.

Results

We have developed Reptile http://reptile.unibe.ch, a program for proteome-wide probabilistic description of perfect repeats in proteins. Parasite proteomes exhibited a large variance regarding the proportion of repeat-containing proteins. Interestingly, there was a good correlation between the percentage of highly repetitive proteins and mean protein length in parasite proteomes, but not at all in the proteomes of free-living eukaryotes. Reptile combined with programs for the prediction of transmembrane domains and GPI-anchoring resulted in an effective tool for in silico identification of potential surface antigens and virulence factors from parasites.

Conclusion

Systemic surveys for perfect amino acid repeats allowed basic comparisons between free-living and parasitic organisms that were directly applicable to predict proteins of serological and parasitological importance. An on-line tool is available at http://genomics.unibe.ch/dora.
Free-radical crosslinking of specific proteins alters the function of the egg extracellular matrix at fertilization
Authors: Wong Julian L. , Wessel Gary M.
Published: December 2007

All animal embryos begin development by modifying the egg extracellular matrix. This protein-rich matrix protects against polyspermy, microbes and mechanical stress via enzyme-dependent transformations that alter the organization of its constituents. Using the sea urchin fertilization envelope,a well-defined extracellular structure formed within minutes of fertilization,we examine the mechanisms whereby limited permeability is established within this matrix. We find that the fertilization envelope acquires a barrier filtration of 40,000 daltons within minutes of insemination via a peroxidase-dependent mechanism, with dynamics that parallel requisite production of hydrogen peroxide by the zygote. To identify the molecular targets of this free-radical modification, we developed an in vivo technique to label and isolate the modified matrix components for mass spectrometry. This method revealed that four of the six major extracellular matrix components are selectively crosslinked, discriminating even sibling proteins from the same gene. Thus, specific free-radical chemistry is essential for establishing the embryonic microenvironment of early development.
Risk and Return of Information Technology Initiatives: Evidence from Electronic Commerce Announcements
Authors: Dewan Sanjeev , Ren Fei
Published: December 2007

This paper takes an event study approach to jointly examine the wealth and risk effects associated with electronic commerce announcements, contributing to the emerging research on the riskiness of IT investments and the trade-off between risk and return in the information systems literature. We estimate a generalized event study model that allows for both systematic and unsystematic risk changes on data collected for electronic commerce announcements in the 1996–2002 time frame. A striking result emerging from our analysis is that wealth effects are not significant after controlling for contemporaneous risk changes. Both total and unsystematic risk show a significant postevent increase in 1998 and 2000, whereas systematic risk adjusts downward in 1996 and 2002. Put together, our results contribute to our nascent understanding of how IT initiatives affect the risk-return profile of the firm.
Editorial Note
Authors: Sambamurthy Vallabh
Published: December 2007

The performance of the journal is reviewed, and metrics for 2007 are presented. In addition, key editorial transitions are highlighted.
Modeling the Determinants and Effects of Creativity in Advertising
Authors: Smith Robert E. , MacKenzie Scott B. , Yang Xiaojing , Buchholz Laura M. , Darley William K.
Published: December 2007

Consumer perceptions of advertising creativity are investigated in a series of studies beginning with scale development and ending with comprehensive model testing. Results demonstrate that perceptions of ad creativity are determined by the interaction between divergence and relevance, and that overall creativity mediates their effects on consumer processing and response.
Improving Performance in Cyclic Production Systems by Using Forced Variable Idle Setup Time
Authors: Samaddar Subhashish , Whalen Thomas
Published: December 2007

In the early 1990s, research began to show that the Japanese production theory, which espouses reduction of machine setup time as a sure way to improve production performance, may be limited. Specifically, it was found that reduction in mean setup times without any change in variance can, paradoxically, increase waiting time and work in process (WIP) in a cyclic production system. Setup time variance was demonstrated to play a central role because of the paradoxes it produced with the resulting harm to effective capacity. Subsequently, explicit formulas were derived for determining whether adding fixed forced idle time (but holding variance constant) would reduce waiting time and, if so, the optimal amount of idle time to add. However, research to date has offered little guidance to reduce setup time variance to improve waiting time. We show that a greater reduction is achievable by adding a variable idle time that is a nonincreasing function of setup time and thereby reduce the combined setup time variance. We provide explicit procedures for finding the optimal variable idle time as a function of setup time when the latter follows any finite discrete distribution. We also show how to implement our policy and show that our approach can improve waiting time even when other currently known approaches cannot.
A Simple Staffing Method for Multiskill Call Centers
Authors: Pot Auke , Bhulai Sandjai , Koole Ger
Published: December 2007

We study a simple method for staffing in multiskill call centers. The method has short computation times and determines nearly optimal staffing levels. It is in both views competitive to other methods from the literature. Because of the fast and accurate performance of the method, many different scenarios can be analyzed, and our method can be used for both tactical and strategic capacity management decisions.
Inhibition of human μ-calpain by conformationally constrained calpastatin peptides
Authors: Pfizer José , Assfalg-Machleidt Irmgard , Machleidt Werner , Schaschke Norbert
Published: December 2007

The 27-mer peptide CP1B-[1–27] derived from exon 1B of calpastatin stands out among the known inhibitors for μ- and m-calpain due to its high potency and selectivity. By systematical truncation, a 20-mer peptide, CP1B-[4–23], was identified as the core sequence required to maintain the affinity/selectivity profile of CP1B-[1–27]. Starting with this peptide, the turn-like region Glu10(i)-Leu11(i+1)-Gly12(i+2)-Lys13(i+3) was investigated. Sequence alignment of subdomains 1B, 2B, 3B and 4B from different mammalians revealed that the amino acid residues in position i+1 and i+2 are almost invariably flanked by oppositely charged residues, pointing towards a turn-like conformation stabilized by salt bridge/H-bond interaction. Accordingly, using different combinations of acidic and basic residues in position i and i+3, a series of conformationally constrained variants of CP1B-[4–23] were synthesized by macrolactamization utilizing the side chain functionalities of these residues. With the combination of Glu(i)/Dab(i+3), the maximum of conformational rigidity without substantial loss in affinity/selectivity was reached. These results clearly demonstrate that the linear peptide chain corresponding to subdomain 1B reverses its direction in the region Glu10-Lys13 upon binding to μ-calpain, and thereby adopts a loop-like rather than a tight turn conformation at this site.
Heparinase selectively sheds heparan sulphate from the endothelial glycocalyx
Authors: Chappell Daniel , Jacob Matthias , Rehm Markus , Stoeckelhuber Mechthild , Welsch Ulrich , Conzen Peter , Becker Bernhard F.
Published: December 2007

A healthy vascular endothelium is coated by the endothelial glycocalyx. Its main constituents are transmembrane syndecans and bound heparan sulphates. This structure maintains the physiological endothelial permeability barrier and prevents leukocyte and platelet adhesion, thereby mitigating inflammation and tissue oedema. Heparinase, a bacterial analogue to heparanase, is known to attack the glycocalyx. However, the exact extent and specificity of degradation is unresolved. We show by electron microscopy, immunohistological staining and quantitative measurements of the constituent parts, that heparinase selectively sheds heparan sulphate from the glycocalyx, but not the syndecans.
A counterintuitive approach to treat enzyme deficiencies: use of enzyme inhibitors for restoring mutant enzyme activity
Authors: Fan Jian-Qiang
Published: December 2007

Pharmacological chaperone therapy is an emerging counterintuitive approach to treat protein deficiencies resulting from mutations causing misfolded protein conformations. Active-site-specific chaperones (ASSCs) are enzyme active-site directed small molecule pharmacological chaperones that act as a folding template to assist protein folding of mutant proteins in the endoplasmic reticulum (ER). As a result, excessive degradation of mutant proteins in the ER-associated degradation (ERAD) machinery can be prevented, thus restoring enzyme activity. Lysosomal storage disorders (LSDs) are suitable candidates for ASSC treatment, as the levels of enzyme activity needed to prevent substrate storage are relatively low. In addition, ASSCs are orally active small molecules and have potential to gain access to most cell types to treat neuronopathic LSDs. Competitive enzyme inhibitors are effective ASSCs when they are used at sub-inhibitory concentrations. This whole new paradigm provides excellent opportunity for identifying specific drugs to treat a broad range of inherited disorders. This review describes protein misfolding as a pathophysiological cause in LSDs and provides an overview of recent advances in the development of pharmacological chaperone therapy for the diseases. In addition, a generalized guidance for the design and screening of ASSCs is also presented.
Two Distinct Heterotypic Channels Mediate Gap Junction Coupling between Astrocyte and Oligodendrocyte Connexins
Authors: Orthmann-Murphy Jennifer L. , Freidin Mona , Fischer Esther , Scherer Steven S. , Abrams Charles K.
Published: December 2007

Genetic diseases demonstrate that the normal function of CNS myelin depends on connexin32 (Cx32) and Cx47, gap junction (GJ) proteins expressed by oligodendrocytes. GJs couple oligodendrocytes and astrocytes (O/A channels) as well as astrocytes themselves (A/A channels). Because astrocytes express different connexins (Cx30 and Cx43), O/A channels must be heterotypic, whereas A/A channels may be homotypic or heterotypic. Using electrophysiological and immunocytochemical approaches, we found that Cx47/Cx43 and Cx32/Cx30 efficiently formed functional channels, but other potential heterotypic O/A and A/A pairs did not. These results suggest that Cx30/Cx30 and Cx43/Cx43 channels mediate A/A coupling, and Cx47/Cx43 and Cx32/Cx30 channels mediate O/A coupling. Furthermore, Cx47/Cx43 and Cx32/Cx30 channels have distinct macroscopic and single-channel properties and different dye permeabilities. Finally, Cx47 mutants that cause Pelizaeus–Merzbacher-like disease do not efficiently form functional channels with Cx43, indicating that disrupted Cx47/Cx43 channels cause this disease.
Multiple Sites for Generation of Ectopic Spontaneous Activity in Neurons of the Chronically Compressed Dorsal Root Ganglion
Authors: Ma Chao , LaMotte Robert H.
Published: December 2007

In a chronically compressed dorsal root ganglion (CCD) in the rat, a model of foraminal stenosis and radicular pain in human, a subpopulation of neurons with functional axons exhibits spontaneous activity (SA) that originates within the ganglion. Intracellular electrophysiological recordings were obtained from the somata of neurons of the compressed ganglion bothin vitroandin vivo. The SA was classified into two types according to the presence (type I) or absence (type II) of subthreshold membrane potential oscillation. Neurons with type I SA had significantly higher somal excitability than those with type II SA. In most cases, depolarization of the membrane potential by current injection increased the discharge rates of type I - but not type II SA. Both types occasionally coexisted in the same neuron. Several lines of evidence suggested that the origin of SA in the DRG was most likely the soma for type I SA and the axon for type II. Therefore CCD neurons have multiple sites for generation of action potentials other than the terminal endings.In vivorecordings revealed the same two types of SA in a subpopulation of neurons with functionally characterized peripheral receptive fields. Thus, SA might not only produce spurious sensory input to the afferent pathways but also add to or block impulse transmission generated by natural stimulation of peripheral receptors. SA originating in the compressed ganglion is likely to interfere with sensory transmission in nociceptive and non-nociceptive neurons, thereby contributing to radicular pain, paresthesias, hyperalgesia and allodynia.