bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenotypic variation in cardiovascular responses to acute hypoxic and hypercapnic exposure in mice
Authors: Campen Matthew J. , Tagaito Yugo , Li Jianguo , Balbir Alexander , Tankersley Clarke G. , Smith Phillip , Schwartz Alan , O’Donnell Christopher P.
Published: October 2004

The impact of genetic variation on cardiovascular responses to hypoxia and hypercapnia is not well understood. Therefore, we determined the acute changes in systemic arterial blood pressure (PSA) and heart rate (HR) in seven strains of commonly used inbred mice exposed to acute periods of hypoxia (10% O2), hypercapnia (5% CO2), and hypoxia/hypercapnia (10% O2 + 5% CO2) during wakefulness. Hypercapnia induced an essentially homogeneous response across strains, with PSA maintained at or slightly above baseline and with HR exhibiting a typical baroreceptor-mediated bradycardia. In contrast, exposure to hypoxia elicited a marked heterogeneity in cardiovascular responses between strains. The change in PSA during hypoxia ranged from maintenance of normotension in the FVB/J strain to profound hypotension of ∼30 mmHg in the DBA/2J strain. HR responses were highly variable between strains during hypoxia, and with the exception of the DBA/2J strain that exhibited significant bradyarrhythmias and consequent hypotension, the HR responses were unrelated to changes in PSA. The PSA response to combined hypoxia/hypercapnia represented a balance of the hypertension of hypercapnia and the hypotension of hypoxia in six of the seven strains. In the FVB/J strain, combined hypoxia/hypercapnia produced a hypertensive response that was greater than that of hypercapnia alone. These results suggest that genetic background affects the cardiovascular response to hypoxia, but not hypercapnia.
Coefficients of prolongations for symmetries of ODEs
Authors: Alfaro Ricardo , Schaeferle Jim
Published: October 2004

Sophus Lie developed a systematic way to solve ODEs. He found that
transformations which form a continuous group and leave a
differential equation invariant can be used to simplify the
equation. Lie′s method uses the infinitesimal generator of these
point transformations. These are symmetries of the equation
mapping solutions into solutions. Lie′s methods did not find
widespread use in part because the calculations for the
infinitesimals were quite lengthy, needing to calculate the
prolongations of the infinitesimal generator. Nowadays,
prolongations are obtained using Maple or Mathematica, and Lie′s
theory has come back to the attention of researchers. In general,
the computation of the coefficients of the (n)‐prolongation is
done using recursion formulas. Others have given methods that do
not require recursion but use Fréchet derivatives. In this
paper, we present a combinatorial approach to explicitly write the
coefficients of the prolongations. Besides being
novel, this approach was found to be useful by the authors for
didactical and combinatorial purposes, as we show in the examples.
Breeding synchrony does not affect extra-pair paternity in great reed warblers
Authors: von Schantz Torbjörn , Arlt Debora , Bensch Staffan , Hasselquist Dennis , Hansson Bengt
Published: October 2004

Breeding synchrony is hypothesised to influence the occurrence and frequency of extra-pair fertilisations (EPFs) in birds irrespective of the social mating system. The two proposed hypotheses make opposite predictions. (1) Synchronous breeding leads to a lower frequency of EPFs because males face a trade-off between mate guarding and obtaining additional matings via extra-pair copulations (EPCs) ('guarding constraint' hypothesis). (2) Synchronous breeding promotes EPFs because females are able to compare displaying males simultaneously, which provides them with more reliable cues for extra-pair mate choice ('mate assessment' hypothesis). In a study of great reed warblers (Acrocephalus arundinaceus) from 1987-1998, annual breeding was asynchronous and the frequency of EPFs was rather low (extra-pair young occurring in 6.4% of the broods). Within this population, however, there was no relationship between the frequency of EPFs and breeding synchrony, thus not favouring any of the two hypotheses. Contrary to assumptions of the hypotheses, mate guarding did not seem to constrain males from engaging in EPCs (disfavouring the 'guarding constraint' hypothesis), and females seem to have repeated opportunities to compare males irrespective of breeding synchrony (disfavouring the 'mate assessment' hypothesis). Our results suggest that breeding synchrony is not an important factor influencing patterns of EPFs in great reed warblers. The low frequency of EPFs may instead be explained by the socially polygynous mating system, where females are less constrained in their choice of a social male.
Effects of Fluvoxamine on Lansoprazole Pharmacokinetics in Relation to CYP2C19 Genotypes
Authors: Yasui‐Furukori Norio , Saito Masato , Uno Tsukasa , Takahata Takenori , Sugawara Kazunobu , Tateishi Tomonori
Published: October 2004

Lansoprazole is a substrate of CYP2C19 and CYP3A4. The aim of this study was to compare the inhibitory effects of fluvoxamine, an inhibitor of CYP2C19, on the metabolism of lansoprazole between CYP2C19 genotypes. Eighteen volunteers—of whom 6 were homozygous extensive metabolizers (EMs), 6 were heterozygous EMs, and 6 were poor metabolizers (PMs) for CYP2C19—received three 6‐day courses of either daily 50 mg fluvoxamine or placebo in a randomized fashion with a single oral 60‐mg dose of lansoprazole on day 6 in all cases. Plasma concentrations of lansoprazole and its metabolites, 5‐hydroxylansoprazole and lansoprazole sulfone, were monitored up to 24 hours after the dosing. During placebo administration, there was a significant difference in the area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐∞) of lansoprazole between CYP2C19 genotypes. Fluvoxamine treatment increased AUC0‐∞ of lansoprazole by 3.8‐fold (P < .01) in homozygous EMs and by 2.5‐fold (P < .05) in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in the fluvoxamine‐mediated percentage increase in the AUC0‐∞ of lansoprazole between CYP2C19 genotypes. The present study indicates that there are significant drug interactions between lansoprazole and fluvoxamine in EMs. CYP2C19 is predominantly involved in lansoprazole metabolism in EMs.
Human mesenchymal stem cells modulate allogeneic immune cell responses
Authors: Aggarwal Sudeepta , Pittenger Mark F.
Published: October 2004

Mesenchymal stem cells (MSCs) are multipotent cells found in several adult tissues. Transplanted allogeneic MSCs can be detected in recipients at extended time points, indicating a lack of immune recognition and clearance. As well, a role for bone marrow-derived MSCs in reducing the incidence and severity of graft-versus-host disease (GVHD) during allogeneic transplantation has recently been reported; however, the mechanisms remain to be investigated. We examined the immunomodulatory functions of human MSCs (hMSCs) by coculturing them with purified subpopulations of immune cells and report here that hMSCs altered the cytokine secretion profile of dendritic cells (DCs), naive and effector T cells (T helper 1 [TH1] and TH2), and natural killer (NK) cells to induce a more anti-inflammatory or tolerant phenotype. Specifically, the hMSCs caused mature DCs type 1 (DC1) to decrease tumor necrosis factor α (TNF-α) secretion and mature DC2 to increase interleukin-10 (IL-10) secretion; hMSCs caused TH1 cells to decrease interferon γ (IFN-γ) and caused the TH2 cells to increase secretion of IL-4; hMSCs caused an increase in the proportion of regulatory T cells (TRegs) present; and hMSCs decreased secretion of IFN-γ from the NK cells. Mechanistically, the hMSCs produced elevated prostaglandin E2 (PGE2) in co-cultures, and inhibitors of PGE2 production mitigated hMSC-mediated immune modulation. These data offer insight into the interactions between allogeneic MSCs and immune cells and provide mechanisms likely involved with the in vivo MSC-mediated induction of tolerance that could be therapeutic for reduction of GVHD, rejection, and modulation of inflammation. (Blood. 2005;105:1815-1822)
RhoH, a hematopoietic-specific Rho GTPase, regulates proliferation, survival, migration, and engraftment of hematopoietic progenitor cells
Authors: Gu Yi , Jasti Aparna C. , Jansen Michael , Siefring Jamie E.
Published: October 2004

Rho guanosine triphosphatases (GT-Pases) are recognized as critical mediators of signaling pathways regulating actin assembly, migration, proliferation, and survival in hematopoietic cells. Here, we have studied a recently identified hematopoietic-specific Rho GTPase, RhoH. Unlike most members of the Rho GTPase family, RhoH is GTPase deficient and does not cycle between GTP- and guanosine diphosphate (GDP)–bound forms, suggesting that regulation of RhoH expression may be critical in its activity. We found that RhoH is expressed in murine hematopoietic progenitor cells (HPCs) and fully differentiated myeloid and lymphoid lineages. In cytokine-stimulated HPCs, knockdown of RhoH expression via RNA interference stimulates proliferation, survival, and stromal cell-derived factor-1α (SDF-1α)–induced migration in vitro. Conversely, RhoH overexpression in these cells via retrovirus-mediated gene transfer is associated with impaired activation of Rac GTPases, reduced proliferation, increased apoptosis, and defective actin polymerization and chemotaxis. In vivo, HPCs with RhoH overexpression demonstrate defective hematopoietic reconstitution capability compared with control vector-transduced cells. Our results suggest that RhoH serves as a negative regulator of both growth and actin-based function of HPCs possibly via suppression of Rac-mediated signaling.
Platelet depletion by anti-CD41 (αIIb) mAb injection early but not late in the course of disease protects against Plasmodium berghei pathogenesis by altering the levels of pathogenic cytokines
Authors: van der Heyde Henri C. , Gramaglia Irene , Sun Guang , Woods Catherine
Published: October 2004

Accumulating evidence indicates that platelets play a critical role in the pathogenesis of experimental severe malaria (ESM) elicited by infection with Plasmodium berghei. Mice injected on day 1 of P berghei infection (early) with either anti-CD41 or anti-CD61 monoclonal antibodies (mAbs) exhibited significantly (P < .001) increased survival from ESM compared with infection controls, indicating that platelets function early in the disease. In contrast, groups of mice treated on days 4, 5, and 6 (late) with anti-CD41 mAb exhibited similar mortality as controls. Because platelet depletion by anti-CD41 mAb on day 4 of infection did not protect mice, and platelet adherence occurs on day 6, platelet adherence to endothelium is not required to mediate malarial pathogenesis. Few platelet microparticles were detected in the blood during the course of malaria, but large numbers of erythrocyte vesicles, microparticles, and debris were detected. The protective effect of early anti-CD41 mAb treatment was independent of the number of platelets, platelet microparticles, erythrocyte-platelet conjugates, and erythrocyte vesicles. Mice treated early with anti-CD41 mAb exhibited markedly altered cytokine production on day 4 of P berghei infection (increased interleukin 10 [IL-10], IL-1α, IL-6, interferon-γ [IFN-γ], and tumor necrosis factor α [TNF-α]; decreased IL-2) but no decline in coagulation factors compared with rat immunoglobulin G (IgG)–treated controls, indicating that platelets regulate the levels of pathogenic cytokines.
Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization
Authors: Selleri Carmine , Montuori Nunzia , Ricci Patrizia , Visconte Valeria , Carriero Maria Vincenza , Sidenius Nicolai , Serio Bianca , Blasi Francesco , Rotoli Bruno , Rossi Guido , Ragno Pia
Published: October 2004

We investigated the involvement of the urokinase-type plasminogen-activator receptor (uPAR) in granulocyte–colony-stimulating factor (G-CSF)–induced mobilization of CD34+ hematopoietic stem cells (HSCs) from 16 healthy donors. Analysis of peripheral blood mononuclear cells (PBMNCs) showed an increased uPAR expression after G-CSF treatment in CD33+ myeloid and CD14+ monocytic cells, whereas mobilized CD34+ HSCs remained uPAR negative. G-CSF treatment also induced an increase in serum levels of soluble uPAR (suPAR). Cleaved forms of suPAR (c-suPAR) were released in vitro by PBMNCs and were also detected in the serum of G-CSF–treated donors. c-suPAR was able to chemoattract CD34+ KG1 leukemia cells and CD34+ HSCs, as documented by their in vitro migratory response to a chemotactic suPAR-derived peptide (uPAR84-95). uPAR84-95 induced CD34+ KG1 and CD34+ HSC migration by activating the high-affinity fMet-Leu-Phe (fMLP) receptor (FPR). In addition, uPAR84-95 inhibited CD34+ KG1 and CD34+ HSC in vitro migration toward the stromal-derived factor 1 (SDF1), thus suggesting the heterologous desensitization of its receptor, CXCR4. Finally, uPAR84-95 treatment significantly increased the output of clonogenic progenitors from long-term cultures of CD34+ HSCs. Our findings demonstrate that G-CSF–induced upregulation of uPAR on circulating CD33+ and CD14+ cells is associated with increased uPAR shedding, which leads to the appearance of serum c-suPAR. c-suPAR could contribute to the mobilization of HSCs by promoting their FPR-mediated migration and by inducing CXCR4 desensitization.
Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation
Authors: Hanash Alan M. , Levy Robert B.
Published: October 2004

Allogeneic bone marrow transplantation (BMT) is a potentially curative treatment for both inherited and acquired diseases of the hematopoietic compartment; however, its wider use is limited by the frequent and severe outcome of graft-versus-host disease (GVHD). Unfortunately, efforts to reduce GVHD by removing donor T cells have resulted in poor engraftment and elevated disease recurrence. Alternative cell populations capable of supporting allogeneic hematopoietic stem/progenitor cell engraftment without inducing GVHD could increase numbers of potential recipients while broadening the pool of acceptable donors. Although unfractionated CD4+ T cells have not been shown to be an efficient facilitating population, CD4+CD25+ regulatory cells (T-reg's) were examined for their capacity to support allogeneic hematopoietic engraftment. In a murine fully major histocompatibility complex (MHC)-mismatched BMT model, cotransplantation of donor B6 T-reg's into sublethally conditioned BALB/c recipients supported significantly greater lineage-committed and multipotential donor progenitors in recipient spleens 1 week after transplantation and significantly increased long-term multilineage donor chimerism. Donor engraftment occurred without GVHD-related weight loss or lethality and was associated with tolerance to donor and host antigens by in vitro and in vivo analyses. Donor CD4+CD25+ T cells may therefore represent a potential alternative to unfractionated T cells for promotion of allogeneic engraftment in clinical hematopoietic cell transplantation. (Blood. 2005;105:1828-1836)
Meanings of being old and living with chronic obstructive pulmonary disease
Authors: Elofsson Linnéa Carling , Öhlén Joakim
Published: October 2004

The aim of this study was to achieve a deeper understanding of the meaning of the lived experiences of elderly persons who are severely ill with chronic obstructive pulmonary disease (COPD) and in need of everyday care. Narratives from dialogues with six persons were interpreted using phenomenological–hermeneutic methodology. The structural analyses showed severe problems in daily life due to old age with a decaying body and dialectic experiences of resignation–contentedness, loneliness–connectedness, and being homeless–being at home. The interpreted whole reveals that life, suffering and comfort must be understood as an interlaced experience where ageing is just as important as the experience of illness. These elderly people's concerns and problems due to old age, a decaying body and being severely ill with COPD call for palliative and comfort care and thus challenge all professionals involved in their care.
Sexuality in palliative care: patient perspectives
Authors: Lemieux Laurie , Kaiser Stefanie , Pereira Jose , Meadows Lynn M
Published: October 2004

This qualitative study investigated the meaning of sexuality to palliative patients. Face-to-face interviews were conducted with ten patients receiving care in a tertiary palliative care unit, a hospice or by palliative home care services in their homes. Several themes emerged. Emotional connection to others was an integral component of sexuality, taking precedence over physical expressions. Sexuality continues to be important at the end of life. Lack of privacy, shared rooms, staff intrusion and single beds were considered barriers to expressing sexuality in the hospital and hospice settings. Only one subject had previously been asked about sexuality as part of their clinical care, yet all felt that it should have been brought up, especially after the initial cancer treatments were completed. Home care nurses and physicians were seen as the appropriate caregivers to address this issue. Subjects unanimously mentioned that a holistic approach to palliative care would include opportunities to discuss the impact of their illness on their sexuality.
Cancer pain management in children
Authors: Mercadante Sebastiano
Published: October 2004

Unrelieved pain may have a major impact on the care of children with cancer. The type and severity of pain experienced by children with cancer varies from acute, procedure-related pain to progressive chronic pain associated with the progression of the disease or sequelae of treatment. Drugs are the mainstay of treatment. Regular pain assessments combined with appropriate analgesic administration at regular dosing intervals, adjunctive drug therapy for control of adverse effects and associated symptoms, and nonpharmacological interventions are recommended. Although standard dosing of opioids adequately treats most cancer pain in children, more complex treatment is required by a significant group. Strategies to improve analgesia include the use of epidural or intrathecal infusions of a combination of opioids and other adjuvants, or other regional anaesthesia techniques. Procedure-and treatment-related pain is an even greater problem than cancer pain. Recommendations have been published with regard to the monitoring and personnel required when children are sedated which aim to set the standard of care and minimize both physical discomfort or pain and negative psychological responses, by providing analgesia; and to maximize the potential for amnesia; and to control behaviour.
Metacognitive Experiences: Response to Commentaries
Authors: Schwarz Norbert
Published: October 2004

The stimulating commentaries by Huber (2004), Lee (2004), and Pham (2004) raised important questions. This response elaborates on some of their themes by addressing the assessment of naive theories, the role of expectations, the influence of metacognitive experiences on consumer choice, as well as parallels between different metacognitive experiences and moods. Receiving thoughtful and stimulating commentary from three of my favorite consumer researchers, whose work has influenced my own thinking, is a great privilege. In this response, I elaborate on some of the themes of their commentaries (Huber, 2004; Lee, 2004; Pham, 2004), although space constraints do not allow me to do full justice to their thoughts.
The rotavirus surface protein VP8 modulates the gate and fence function of tight junctions in epithelial cells
Authors: Nava Porfirio , López Susana , Arias Carlos F. , Islas Socorro , González-Mariscal Lorenza
Published: October 2004

Rotaviruses constitute a major cause of diarrhea in young mammals. Rotaviruses utilize different integrins as cell receptors, therefore upon their arrival to the intestinal lumen their integrin receptors will be hidden below the tight junction (TJ), on the basolateral membrane. Here we have studied whether the rotavirus outer capsid proteins are capable of opening the paracellular space sealed by the TJ. From the outermost layer of proteins of the rotavirus, 60 spikes formed of protein VP4 are projected. VP4 is essential for virus-cell interactions and is cleaved by trypsin into peptides VP5 and VP8. Here we found that when these peptides are added to confluent epithelial monolayers (Madin-Darby canine kidney cells), VP8 is capable of diminishing in a dose dependent and reversible manner the transepithelial electrical resistance. VP5 exerted no effect. VP8 can also inhibit the development of newly formed TJs in a Ca-switch assay. Treatment with VP8 augments the paracellular passage of non-ionic tracers, allows the diffusion of a fluorescent lipid probe and the apical surface protein GP135, from the luminal to the lateral membrane, and triggers the movement of the basolateral proteins Na+-K+-ATPase, ανβ3 integrin and β1 integrin subunit, to the apical surface. VP8 generates a freeze-fracture pattern of TJs characterized by the appearance of loose end filaments, that correlates with an altered distribution of several TJ proteins. VP8 given orally to diabetic rats allows the enteral administration of insulin, thus indicating that it can be employed to modulate epithelial permeability.
Bcr (breakpoint cluster region) protein binds to PDZ-domains of scaffold protein PDZK1 and vesicle coat protein Mint3
Authors: Malmberg Emily K. , Andersson Christian X. , Gentzsch Martina , Chen Jey H. , Mengos April , Cui Liying , Hansson Gunnar C. , Riordan John R.
Published: October 2004

The breakpoint cluster region protein (Bcr) is a large soluble oligomeric multidomain protein best known because of its involvement in chronic myelogenous leukemia (CML). A chromosomal translocation between its gene and that of the c-abl kinase (`Philadelphia chromosome') plays a major causative role in that malignancy. Thus most attention has been paid to the role of the protein in hemopoietic cells. However, Bcr is also expressed in other cell types including epithelia. Bcr is generally considered to be a cytoplasmic protein but in addition to its kinase and GTPase exchange and activating domains it contains potentially membrane-interacting pleckstrin homology and C2 domains as well as a PDZ-binding C terminus mediating an interaction with a PDZ-domain protein at intercellular junctions of epithelial cells. We have examined the ability of Bcr to interact with other epithelial PDZ proteins and found specific binding to both the apical PDZK1 protein and the Golgi-localized Mint3. The former is important in the organization of several apical functions and the latter in vesicular trafficking in the secretory pathway. Hence these findings extend the interactions and likely signaling impact of Bcr in epithelia from the cytosol to at least these two membrane compartments.
Localization of GDP-mannose transporter in the Golgi requires retrieval to the endoplasmic reticulum depending on its cytoplasmic tail and coatomer
Authors: Abe Masato , Noda Yoichi , Adachi Hiroyuki , Yoda Koji
Published: October 2004

The Saccharomyces cerevisiae GDP-mannose transporter (GMT) encoded by the essential gene VRG4/VIG4 is a member of the nucleotide-sugar transporter family in the Golgi apparatus. We examined GMT in the secretory mutant cells to investigate the mechanism of its localization in the Golgi. At the nonpermissive temperature, most GMT was found in the endoplasmic reticulum of sec23ts cells, which have defective COPII, and in the vacuole of sec21ts cells, which have defective COPI. The C-terminal hydrophilic peptide of GMT that is exposed to the cytosol binds to Ret2p, a subunit of the COPI coat. Mutant peptide derivatives that have lost a cluster of lysine in the vicinity of the transmembrane domain had reduced binding activity to Ret2p and the GMT with this sequence was delivered to the vacuole. Our results indicate that GMT escapes from delivery to the vacuole by recycling to the endoplasmic reticulum and retrieval requires the lysine-rich C-terminal tail that can bind to the COPI coat.
Differential regulation of keratinocyte chemokinesis and chemotaxis through distinct nicotinic receptor subtypes
Authors: Chernyavsky Alex I. , Arredondo Juan , Marubio Lisa M. , Grando Sergei A.
Published: October 2004

Nicotinergic agents can act as both chemokines and chemoattractants for cell migration. Epidermal keratinocytes both synthesize acetylcholine and use it as a paracrine and autocrine regulator of cell motility. To gain a mechanistic insight into nicotinergic control of keratinocyte motility, we determined types of nicotinic acetylcholine receptors and signaling pathways regulating keratinocyte chemokinesis and chemotaxis, using respective modifications of the agarose gel keratinocyte outgrowth assay. Random migration of keratinocytes was significantly (P<0.05) inhibited by hemicholinum-3, a metabolic inhibitor of acetylcholine synthesis, as well as by the α-conotoxins MII and AuIB, preferentially blocking α3-containing nicotinic acetylcholine receptors. The use of antisense oligonucleotides specific for nicotinic-acetylcholine-receptor subunits and knockout mice demonstrated pivotal role for the α3β2 channel in mediating acetylcholine-dependent chemokinesis. Signaling pathways downstream of α3β2 included activation of the protein-kinase-C isoform δ and RhoA-dependent events. The nicotinergic chemotaxis of keratinocytes was most pronounced towards the concentration gradient of choline, a potent agonist of α7 nicotinic acetylcholine receptor. The α7-preferring antagonist α-bungarotoxin significantly (P<0.05) diminished keratinocyte chemotaxis, further suggesting a central role for the α7 nicotinic acetylcholine receptor. This hypothesis was confirmed in experiments with anti-α7 antisense oligonucleotides and α7-knockout mice. The signaling pathway mediating α7-dependent keratinocyte chemotaxis included intracellular calcium, activation of calcium/calmodulin-dependent protein-kinase II, conventional isoforms of protein-kinase C, phosphatidylinositol-3-kinase and engagement of Rac/Cdc42. Redistribution of α7 immunoreactivity to the leading edge of keratinocytes upon exposure to a chemoattractant preceded crescent shape formation and directional migration. Application of high-resolution deconvolution microscopy demonstrated that, on the cell membrane of keratinocytes, the nicotinic acetylcholine receptor subunits localize with the integrin β1. The obtained results demonstrate for the first time that α3 and α7 nicotinic acetylcholine receptors regulate keratinocyte chemokinesis and chemotaxis, respectively, and identify signaling pathways mediating these functions, which has clinical implications for wound healing and control of cancer metastases.
Development of Danish Wind Power Market
Authors: Meyer Niels I.
Published: October 2004

The modern phase of Danish wind power started after the oil crisis in 1973. Based on long traditions of Danish wind power dating back to the beginning of the century a new commercial phase was initiated by small industrial entrepreneurs with support by the Danish government, the Danish Academy of Technical Sciences and green organizations.

During the eighties technological development resulted in increased cost efficiency, while the investment subsidies from the state were gradually phased out. Conflicts between utilities and wind power producers over tariffs and the costs of grid connections, then slowed down the penetration of wind power on the Danish market. In addition, many local municipalities were setting up administrative barriers for wind turbines.

These barriers were removed by government intervention in the early nineties when favourable feed-in tariffs were introduced together with easy access to the grid, simple procedures for construction allowances and priority to green electricity. As a result wind power was booming in the Danish home market and Danish turbines achieved a global market share of around 50%.

After a change of government in December 2001, however the Danish home market for wind power has more or less collapsed.
Greening of Nordic Electricity Industry: Policy Convergence and Diversity
Authors: Midttun Atle , Gundersen Mari Hegg , Koefoed Anne Louise
Published: October 2004

With a comparative focus on policy similarity and diversity, this article1 gives an overview of the main elements of electricity-related environmental policy in the Nordic countries, following the launching of a common electricity market in the 1990s.

The article points out that the electricity related environmental policy positions of the Nordic countries showed a noticeable lack of coordination in the 1990s. Nordic divergence is observed both in terms of general policy orientations and at the instrument and incentive levels, in spite of the pioneering development of a common integrated electricity market and ambitious environmental policy goals. The article then highlights how the recent Swedish “green” certificate market model has created a new momentum for market-based “greening” with a potential for stronger convergence in Nordic renewable energy policy.

In spite of signs of convergence, the article shows how the development of Nordic electricity-related environmental policy still contains considerable ambiguity: Unequal resource endowments, subject to simple resource-based interest formation, should indicate that there is little room for convergence in Nordic renewable energy policy. Shifting the environmental policy focus from existing technologies and resources to potential innovations, however provides a more open arena where the Nordic countries may see themselves served by the dynamic scope of a broader Nordic market based on a common policy approach, such as a green certificate market.

In explaining why the Nordic arena may be an interesting locus for common renewable energy policy, the article points out that small countries may need an “intermediary” arena to aggregate size and scope in order to generate a European momentum in regulatory competition with larger European states. Similarly, Nordic companies may consider the opportunity to gain first mover advantages by partnering with government as local experimentation may be seen as useful pilot experience. Together with the precedence of a common Nordic electricity market and the development of common market institutions, the aspiration to be in a stronger position to shape European policy provides arguments for collective Nordic solutions even under increased Europeanization of both market and policy making.
Economic Efficiency of Compulsory Green Electricity Quotas in Sweden
Authors: Kåberger Tomas , Sterner Thomas , Zamanian Max , Jürgensen Anna
Published: October 2004

Green certificates are not an efficient as a measure to correct for the effect of environmental external costs of fossil fuels and nuclear power. Nor are they efficient as a measure to create markets for new electricity supply technologies.

Removing subsidies and introducing environmental taxes on energy sources with undesired external effects more efficiently corrects for incurred environmental costs. It appears that guaranteed feed-in tariffs are a more efficient policy instrument to promote the industrialisation of technologies for new sustainable sources of electricity.

Alternatively, the certificate scheme could be reformed in a number of ways to improve performance. However decisions to change or abolish the instrument cannot be taken lightly since instrument stability is very important for the credibility of future policy.
Renewable Energy and Nature Conservation
Authors: Traube Klaus
Published: October 2004

The article refers to the EU targets of increasing the share of renewable energy sources in energy supply. The promotion of renewables for electricity generation, and the expanded use of biofuels for transport, is stipulated by various Directives. While EU member states started implementation, only few are on track to achieve their national targets.

A new phenomena is the opposition of environmentalists against renewables, which is exaggerated by the media. The author focusses on an actual controversy over wind power in Germany. The general conflict between the installation and expansion of renewable energy sources and nature conservation is then analysed. The article sketches possible lessons for further policy learning.
Three Decades of Renewable Electricity Policies in Germany
Authors: Lauber Volkmar , Mez Lutz
Published: October 2004

Of the large industrial countries, Germany is clearly leading with regard to new renewable energy sources, occupying the first rank in terms of installed wind energy capacity, and the second rank in photovoltaics. This capacity is not due to an exceptional natural resource base but to policy, despite the fact that this policy was conducted in a rather lukewarm fashion until 1997. This led to a remarkable expansion of this sector. The red-green coalition, in office since 1998, developed the vision of achieving 50 percent and more of electricity generated from RES by 2050, a goal that seems well accepted by the public but not by the established energy interests or the leaders of the conservative-liberal opposition, even though the cost appears to be comparatively modest.

The article gives a historical account of German RES-E policy since 1974 and focuses in particular on the evolution of “feed-in” legislation from 1990 to 2004. The first 15 years of RES-E policy after 1974 were devoted to R&D. Market creation measures only came into effect after 1988; of these, the Feed-In Law was the most important. During the 1990s, it barely managed to survive, but significant improvement occurred after the 1998 election; the new majority greatly strengthened RES-E support, particularly for photovoltaics and biomass. However, this legislation is still not fully accepted on both the domestic and the EU levels.
RNAi: Finding the elusive endonuclease
Authors: LINGEL ANDREAS , IZAURRALDE ELISA
Published: October 2004

RNA interference involves endonucleolytic cleavage of mRNAs at a site determined by complementary siRNAs. Initial cleavage leads to rapid degradation of the message, resulting in a corresponding reduction in the level of the encoded protein. Despite intensive study, the identity of the endonucleolytic activity (designated slicer) has remained obscure. Now, a combination of structural and biochemical analyses provide compelling evidence that human Argonaute2 (Ago2), a protein already known to be a key player in the RNAi pathway, is in fact the missing endonuclease.
Two distinct Staufen isoforms in Xenopus are vegetally localized during oogenesis
Authors: ALLISON RACHEL , CZAPLINSKI KEVIN , GIT ANNA , ADEGBENRO ELIZABETH , STENNARD FIONA , HOULISTON EVELYN , STANDART NANCY
Published: October 2004

Localization of mRNA is an important way of generating early asymmetries in the developing embryo. In Drosophila, Staufen is intimately involved in the localization of maternally inherited mRNAs critical for cell fate determination in the embryo. We show that double-stranded RNA-binding Staufen proteins are present in the oocytes of a vertebrate, Xenopus, and are localized to the vegetal cytoplasm, a region where important mRNAs including VegT and Vg1 mRNA become localized. We identified two Staufen isoforms named XStau1 and XStau2, where XStau1 was found to be the principal Staufen protein in oocytes, eggs, and embryos, the levels of both proteins peaking during mid-oogenesis. In adults, Xenopus Staufens are principally expressed in ovary and testis. XStau1 was detectable throughout the oocyte cytoplasm by immunofluorescence and was concentrated in the vegetal cortical region from stage II onward. It showed partial codistribution with subcortical endoplasmic reticulum (ER), raising the possibility that Staufen may anchor mRNAs to specific ER-rich domains. We further showed that XStau proteins are transiently phosphorylated by the MAPK pathway during meiotic maturation, a period during which RNAs such as Vg1 RNA are released from their tight localization at the vegetal cortex. These findings provide evidence that Staufen proteins are involved in targeting and/or anchoring of maternal determinants to the vegetal cortex of the oocyte in Xenopus. The Xenopus oocyte should thus provide a valuable system to dissect the role of Staufen proteins in RNA localization and vertebrate development.
The crystal structure of a high affinity RNA stem-loop complexed with the bacteriophage MS2 capsid: Further challenges in the modeling of ligand–RNA interactions
Authors: HORN WILF T. , CONVERY MÁIRE A. , STONEHOUSE NICOLA J. , ADAMS CHRIS J. , LILJAS LARS , PHILLIPS SIMON E.V. , STOCKLEY PETER G.
Published: October 2004

We have determined the structure to 2.8 Å of an RNA aptamer (F5), containing 2′-deoxy-2-aminopurine (2AP) at the −10 position, complexed with MS2 coat protein by soaking the RNA into precrystallised MS2 capsids. The −10 position of the RNA is an important determinant of binding affinity for coat protein. Adenine at this position in other RNA stem-loops makes three hydrogen bonds to protein functional groups. Substituting 2AP for the −10 adenine in the F5 aptamer yields an RNA with the highest yet reported affinity for coat protein. The refined X-ray structure shows that the 2AP base makes an additional hydrogen bond to the protein compared to adenine that is presumably the principal origin of the increased affinity. There are also slight changes in phosphate backbone positions compared to unmodified F5 that probably also contribute to affinity. Such phosphate movements are common in structures of RNAs bound to the MS2 T = 3 protein shell and highlight problems for de novo design of RNA binding ligands.
The PRC-barrel domain of the ribosome maturation protein RimM mediates binding to ribosomal protein S19 in the 30S ribosomal subunits
Authors: LÖVGREN J. MATTIAS , BYLUND GÖRAN O. , SRIVASTAVA MANOJ K. , LUNDBERG L.A. CARINA , PERSSON OLOF P. , WINGSLE GUNNAR , WIKSTRÖM P. MIKAEL
Published: October 2004

The RimM protein in Escherichia coli is associated with free 30S ribosomal subunits but not with 70S ribosomes. A ΔrimM mutant is defective in 30S maturation and accumulates 17S rRNA. To study the interaction of RimM with the 30S and its involvement in 30S maturation, RimM amino acid substitution mutants were constructed. A mutant RimM (RimM-YY→AA), containing alanine substitutions for two adjacent tyrosines within the PRC β-barrel domain, showed a reduced binding to 30S and an accumulation of 17S rRNA compared to wild-type RimM. The (RimM-YY→AA) and ΔrimM mutants had significantly lower amounts of polysomes and also reduced levels of 30S relative to 50S compared to a wild-type strain. A mutation in rpsS, which encodes r-protein S19, suppressed the polysome- and 16S rRNA processing deficiencies of the RimM-YY→AA but not that of the ΔrimM mutant. A mutation in rpsM, which encodes r-protein S13, suppressed the polysome deficiency of both rimM mutants. Suppressor mutations, found in either helices 31 or 33b of 16S rRNA, improved growth of both the RimM-YY→AA and ΔrimM mutants. However, they suppressed the 16S rRNA processing deficiency of the RimM-YY→AA mutant more efficiently than that of the ΔrimM mutant. Helices 31 and 33b are known to interact with S13 and S19, respectively, and S13 is known to interact with S19. A GST-RimM but not a GST-RimM(YY→AA) protein bound strongly to S19 in 30S. Thus, RimM likely facilitates maturation of the region of the head of 30S that contains S13 and S19 as well as helices 31 and 33b.
Use of Erythropoietin in Heart Failure Management
Authors: Caiola Krista , Cheng Judy WM
Published: October 2004

OBJECTIVE

To review the use of erythropoietin for anemia in heart failure (HF).

DATA SOURCES

Peer-reviewed articles in MEDLINE (1966–June 2004) were identified and citations from available articles were reviewed using the search terms anemia, erythropoietin, and heart failure.

DATA SYNTHESIS

Anemia worsens HF prognosis. Clinical studies in patients with New York Heart Association Class III/IV HF who had hemoglobin <12 mg/dL and were refractory to maximal medical management showed that erythropoietin improves symptoms. Larger scale studies with mortality endpoints are required to confirm the benefits.

CONCLUSIONS

In selected patients with severe, chronic HF, erythropoietin may be considered for functional improvement. However, routine use of this treatment strategy is not recommended until more data are available.
Acute Myocardial Infarction Associated with Albuterol
Authors: Fisher Alexander A , Davis Michael W , McGill Darryl A
Published: October 2004

OBJECTIVE

To report a case of acute myocardial infarction (AMI) following the use of albuterol (salbutamol) in a patient without preexisting coronary artery disease and to review the related literature.

CASE SUMMARY

An 84-year-old white woman with no history of cardiac disease was treated for an exacerbation of chronic obstructive pulmonary disease with albuterol 5 mg and ipratropium bromide 500 μg nebulized with oxygen; the albuterol was given in the same dose every 2 hours. Her respiratory condition improved, but soon after the sixth dose of albuterol, she developed increasing chest tightness. The electrocardiogram (ECG) showed ST segment elevation in the chest leads (V2,3) and, subsequently, the troponin I concentration and creatine kinase rose. Urgent coronary angiography showed smooth coronary arteries with no obstructive coronary artery disease or thrombosis. Left ventriculography showed anterior hypokinesia consistent with anterior myocardial injury. A subsequent echocardiogram also revealed normal left ventricular size but anterior, anteroseptal, and apical hypokinesia. An objective causality assessment revealed that albuterol had a probable likelihood of causing the AMI in this patient.

DISCUSSION

A MEDLINE search (1966–February 2004) revealed 6 other case reports of AMI associated with albuterol treatment. The possible pathogenesis of albuterol-induced myocardial necrosis includes activation of cardiac and peripheral β2-adrenoceptors, inducing positive chronotropic and inotropic effects and vasodilation with coronary blood flow redistribution. Albuterol can also cause hypokalemia and other metabolic and electrical changes, including prolonged QT interval. These effects may be especially detrimental in patients with hypoxia, hypercapnea, and preexisting heart diseases.

CONCLUSIONS

Although myocardial injury is a rare complication following albuterol therapy, clinicians should use high-dose β2 agonists with caution. Close monitoring of ECG and metabolic changes is recommended before early repeated high doses are administered.
Acute Colchicine Intoxication During Clarithromycin Administration
Authors: Rollot Florence , Pajot Olivier , Chauvelot-Moachon Laurence , Nazal Eve M , Kélaïdi Charikleia , Blanche Philippe
Published: October 2004

OBJECTIVE

To report a case of colchicine intoxication occurring with institution of clarithromycin.

CASE SUMMARY

A 76-year-old man with familial Mediterranean fever (FMF) had received colchicine 1.5 mg daily for 6 years. The patient underwent 7 days of clarithromycin, amoxicillin, and omeprazole treatment for Helicobacter pylori–associated gastritis. Fever, abdominal pain, and diarrhea occurred 3 days after treatment initiation. On day 8, dehydration, pancytopenia, metabolic acidosis, and increased lipase level necessitated hospitalization. Alopecia was observed 2 weeks later. The patient recovered fully after the colchicine dosage was reduced to 0.5 mg/day and rehydration was performed. The previous dosage was then reinstituted without adverse reaction. An objective causality assessment revealed that the adverse event was probable.

DISCUSSION

Continuous colchicine administration is used in treatment of microcrystalline arthritis, Behçet's disease, and FMF. Colchicine is primarily eliminated through biliary excretion. Renal elimination and cytochrome P450 metabolism play a less significant role. Colchicine is also a substrate of P-glycoprotein, a transporter involved in cellular efflux and elimination of numerous drugs. Three cases of intoxication have been reported when colchicine was combined with erythromycin, josamycin, or clarithromycin. Macrolides are inhibitors of P-glycoprotein and cytochrome P450–dependent enzymes and may decrease colchicine's biliary excretion through P-glycoprotein inhibition.

CONCLUSIONS

Coadministration of colchicine and macrolides may impair colchicine elimination, resulting in excess drug exposure and toxicity. To this end, colchicine should be used with extreme caution in patients receiving P-glycoprotein inhibitors, particularly if they are elderly and/or renally compromised.
Probable Sulbactam/Ampicillin–Associated Prolonged Cholestasis
Authors: Köklü Seyfettin , Köksal Aydın Ş , Asıl Mehmet , Kıyıcı Halil , Çoban Şahin , Arhan Mehmet
Published: October 2004

OBJECTIVE

To present a single case of sulbactam/ampicillin–induced chronic cholestasis and a literature review of antibiotic-associated chronic cholestasis.

CASE SUMMARY

A 74-year-old man with Hodgkin's disease in remission developed severe and prolonged cholestasis after treatment with sulbactam/ampicillin 750 mg twice daily for 7 days. All other etiologies, including Hodgkin's disease, were appropriately ruled out and the cholestasis was ascribed to sulbactam/ampicillin treatment. The patient improved gradually and became asymptomatic 7 months after the last dose of sulbactam/ampicillin. According to the Naranjo probability scale, sulbactam/ampicillin was the probable cause of the cholestasis.

DISCUSSION

Ampicillin, a semisynthetic penicillin, has rarely been associated with hepatic injury when used alone. Hepatocellular and acute cholestatic injury due to ampicillin have been described. Cholestasis secondary to sulbactam/ampicillin use has not been previously reported.

CONCLUSIONS

Sulbactam/ampicillin, one of the most widely used antibiotics, may cause chronic cholestatic hepatitis. Clinicians should be aware of this adverse affect and consider it during diagnostic workup of liver injury.
Stability of Cefepime in Icodextrin Peritoneal Dialysis Solution
Authors: Elwell Rowland J , Volino Lucio R , Frye Reginald F
Published: October 2004

BACKGROUND

Icodextrin is a glucose polymer used as an alternative osmotic agent in peritoneal dialysis (PD) solutions. Cefepime may be a suitable antibiotic for the treatment of PD-related peritonitis. The stability of cefepime in icodextrin PD solution has not been examined.

OBJECTIVE

To determine the chemical stability of cefepime in icodextrin PD solution over a 7-day period.

METHODS

Samples were prepared by adding cefepime HCl 1000 mg to commercially available 2.0-L bags of icodextrin 7.5% PD solution. Nine bags were prepared and stored in the following conditions: 3 under refrigeration (4 °C), 3 at room temperature (20 °C), and 3 at body temperature (37 °C). Study samples were drawn from each bag immediately after preparation and at predetermined intervals over the subsequent 7 days. Solutions were visually inspected for precipitation, cloudiness, or discoloration at each sampling interval. Total concentration of cefepime in dialysate fluid was determined by liquid chromatography-tandem mass spectrometry.

RESULTS

Under refrigeration, a mean ± SD of 95.7 ± 4.2% of the initial cefepime concentration remained at 168 hours (7 days). At room temperature, 92.0 ± 17.9% remained at 48 hours. At body temperature, 92.2 ± 4.7% remained at 4 hours. Beyond these respective time points, <90% of the initial cefepime concentrations remained.

CONCLUSIONS

Pre-mixed cefepime–icodextrin PD solutions stored at room temperature were stable for up to 48 hours. However, it is recommended that these be kept refrigerated whenever possible. When refrigerated, cefepime–icodextrin solutions were found to be stable for up to 7 days. Solutions stored at body temperature were stable up to 4 hours, permitting the practice of pre-warming solutions prior to administration.