bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of thrombin inhibition with melagatran on renal hemodynamics and function and liver integrity during early endotoxemia
Authors: Nitescu Nicoletta , Grimberg Elisabeth , Ricksten Sven-Erik , Marcussen Niels , Nordlinder Hans , Guron Gregor
Published: October 2006

Sepsis is associated with an activation of the coagulation system and multiorgan failure. The aim of the study was to examine the effects of selective thrombin inhibition with melagatran on renal hemodynamics and function, and liver integrity, during early endotoxemia. Endotoxemia was induced in thiobutabarbital-anesthetized rats by an intravenous bolus dose of lipopolysaccharide (LPS; 6 mg/kg). Sham-Saline, LPS-Saline, and LPS-Melagatran study groups received isotonic saline or melagatran immediately before (0.75 μmol/kg iv) and continuously during (0.75 μmol·kg−1·h−1iv) 4.5 h of endotoxemia. Kidney function, renal blood flow (RBF), and intrarenal cortical and outer medullary perfusion (OMLDF) measured by laser-Doppler flowmetry were analyzed throughout. Markers of liver injury and tumor necrosis factor (TNF)-α were measured in plasma after 4.5 h of endotoxemia. In addition, liver histology and gene expression were examined. Melagatran treatment prevented the decline in OMLDF observed in the LPS-Saline group ( P < 0.05, LPS-Melagatran vs. LPS-Saline). However, melagatran did not ameliorate reductions in mean arterial pressure, RBF, renal cortical perfusion, and glomerular filtration rate or attenuate tubular dysfunctions during endotoxemia. Melagatran reduced the elevated plasma concentrations of aspartate aminotransferase (−34 ± 11%, P < 0.05), alanine aminotransferase (−21 ± 7%, P < 0.05), bilirubin (−44 ± 9%, P < 0.05), and TNF-α (−32 ± 14%, P < 0.05) in endotoxemia. Melagatran did not diminish histological abnormalities in the liver or the elevated hepatic gene expression of TNF-α, intercellular adhesion molecule-1, and inducible nitric oxide synthase in endotoxemic rats. In summary, thrombin inhibition with melagatran preserved renal OMLDF, attenuated liver dysfunction, and reduced plasma TNF-α levels during early endotoxemia.
Des-serine-proline brain natriuretic peptide 3–32 in cardiorenal regulation
Authors: Boerrigter Guido , Costello-Boerrigter Lisa C. , Harty Gail J. , Lapp Harald , Burnett John C.
Published: October 2006

Brain natriuretic peptide (BNP 1–32) plays an important physiologic role in cardiorenal homeostasis. Recently, it has been reported that BNP 1–32 is rapidly cleaved by the ubiquitous enzyme dipeptidyl peptidase IV to BNP 3–32, which lacks the two NH2-terminal amino acids of BNP 1–32. The bioactivity of BNP 3–32 in cardiorenal regulation is unknown. We hypothesized that BNP 3–32 has reduced vasodilating and natriuretic bioactivity compared with BNP 1–32 in vivo. Synthetic human BNP 3–32 and BNP 1–32 were administered to eight anesthetized normal canines. After baseline measurements, BNP 1–32 at 30 ng·kg−1·min−1was administered, followed by a washout, a postinfusion clearance, and a clearance with an equimolar dose of BNP 3–32. In four studies, the sequence of BNP 1–32 and BNP 3–32 infusion was reversed. Peptides were compared by analyzing the changes from the respective preinfusion clearance to the respective infusion clearance. * P < 0.05 between peptides. BNP 3–32, unlike BNP 1–32, did not decrease mean arterial pressure (0 ± 1 vs. −7 ± 2* mmHg, respectively) and did not increase renal blood flow (+12 ± 10 vs. +52 ± 10* ml/min). Effects on heart rate and cardiac output were similar. Urinary sodium excretion increased 128 ± 18 μeq/min with BNP 3–32 and 338 ± 40* μeq/min with BNP 1–32. Urine flow increased 1.1 ± 0.2 ml/min with BNP 3–32 and 2.8 ± 0.4* ml/min with BNP 1–32. Plasma BNP immunoreactivity was lower with BNP 3–32, suggesting accelerated degradation. In this study, BNP 3–32 showed reduced natriuresis and diuresis and a lack of vasodilating actions compared with BNP 1–32.
Maximal oxygen uptake is not limited by a central nervous system governor
Authors: Brink-Elfegoun T. , Kaijser L. , Gustafsson T. , Ekblom B.
Published: October 2006

We tested the hypothesis that the work of the heart was not a limiting factor in the attainment of maximal oxygen uptake (V̇o2 max). We measured cardiac output (Q̇) and blood pressures (BP) during exercise at two different rates of maximal work to estimate the work of the heart through calculation of the rate-pressure product, as a part of the ongoing discussion regarding factors limiting V̇o2 max. Eight well-trained men (age 24.4 ± 2.8 yr, weight 81.3 ± 7.8 kg, and V̇o2 max59.1 ± 2.0 ml·min−1·kg−1) performed two maximal combined arm and leg exercises, differing 10% in watts, with average duration of time to exhaustion of 4 min 50 s and 3 min 40 s, respectively. There were no differences between work rates in measured V̇o2 max, maximal Q̇, and peak heart rate between work rates (0.02 l/min, 0.3 l/min, and 0.8 beats/min, respectively), but the systolic, diastolic, and calculated mean BP were significantly higher (19, 5, and 10 mmHg, respectively) in the higher than in the lower maximal work rate. The products of heart rate times systolic or mean BP and Q̇ times systolic or mean BP were significantly higher (3,715, 1,780, 569, and 1,780, respectively) during the higher than the lower work rate. Differences in these four products indicate a higher mechanical work of the heart on higher than lower maximal work rate. Therefore, this study does not support the theory, which states that the work of the heart, and consequently V̇o2 max, during maximal exercise is hindered by a command from the central nervous system aiming at protecting the heart from being ischemic.
Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol
Authors: Kline William O. , Panaro Frank J. , Yang Hayung , Bodine Sue C.
Published: October 2006

Clenbuterol and other β2-adrenergic agonists are effective at inducing muscle growth and attenuating muscle atrophy through unknown mechanisms. This study tested the hypothesis that clenbuterol-induced growth and muscle sparing is mediated through the activation of Akt and mammalian target of rapamycin (mTOR) signaling pathways. Clenbuterol was administered to normal weight-bearing adult rats to examine the growth-inducing effects and to adult rats undergoing muscle atrophy as the result of hindlimb suspension or denervation to examine the muscle-sparing effects. The pharmacological inhibitor rapamycin was administered in combination with clenbuterol in vivo to determine whether activation of mTOR was involved in mediating the effects of clenbuterol. Clenbuterol administration increased the phosphorylation status of PKB/Akt, S6 kinase 1/p70s6k, and eukaryotic initiation factor 4E binding protein 1/PHAS-1. Clenbuterol treatment induced growth by 27–41% in normal rats and attenuated muscle loss during hindlimb suspension by 10–20%. Rapamycin treatment resulted in a 37–97% suppression of clenbuterol-induced growth and a 100% reduction of the muscle-sparing effect. In contrast, rapamycin was unable to block the muscle-sparing effects of clenbuterol after denervation. Clenbuterol was also shown to suppress the expression of the MuRF1 and MAFbx transcripts in muscles from normal, denervated, and hindlimb-suspended rats. These results demonstrate that the effects of clenbuterol are mediated, in part, through the activation of Akt and mTOR signaling pathways.
C5-blocking antibody reduces fluid requirements and improves responsiveness to fluid infusion in hemorrhagic shock managed with hypotensive resuscitation
Authors: Peckham Russell M. , Handrigan Michael T. , Bentley Timothy B. , Falabella Michael J , Chrovian Andrew D. , Stahl Gregory L. , Tsokos George C.
Published: October 2006

Hypotensive resuscitation strategies and inhibition of complement may both be of benefit in hemorrhagic shock. We asked if C5-blocking antibody (anti-C5) could diminish the amount of fluid required and improve responsiveness to resuscitation from hemorrhage. Awake, male Sprague-Dawley rats underwent controlled hemorrhage followed by prolonged (3 h) hypotensive resuscitation with lactated Ringer’s or Hextend, with or without anti-C5. Anti-C5 treatment led to an estimated 62.3 and 58.5% reduction in the volume of Hextend and lactated Ringer’s, respectively. In the subgroup of animals with a positive mean arterial pressure (MAP) response to fluid infusion following prolonged hypotension, anti-C5 treatment led to an estimated 4.7- and 4.1-fold increase in mean arterial pressure response per unit Hextend and lactated Ringer’s infused, respectively. We observed no significant postresuscitation metabolic differences between the anti-C5 groups and controls. Whether anti-C5 could serve as a volume-sparing adjunct that improves responsiveness to fluid administration in humans deserves further study.
Endocrine Receptors as Targets for New Drugs
Authors: Altman Jennifer
Published: October 2006

Increasingly detailed knowledge of cellular signalling pathways is providing a sound basis for the development of specific drugs aimed at selected components of the pathways. Many of these targets are receptors and the multitude of hormone receptors makes endocrine functions a rich proving ground for this research. This article reviews a recent meeting (Insights into Receptor Function and New Drug Development Targets; 5th Endocrinology Colloquium of the Fondation Ipsen, Paris, December 5, 2005) where progress in defining suitable targets for drug therapies in the endocrine system and in designing drugs for some of these targets was discussed. Although the family of G-protein-coupled receptors, ubiquitous in the endocrine system, was the central focus, comparisons with other receptor families were made. Many mutations affecting genes coding for receptors or other components of signalling pathways have been found in a wide range of endocrine disorders including obesity, parathyroid malfunction, disorders involving thyroid-stimulating hormone and follicle-stimulating hormone, and tumours in the anterior pituitary, as well as in many types of cancer. These are being used to dissect the normal control mechanisms as well as to provide information for the development of selective drugs. Recently identified mutations that affect the intracellular traffic in newly synthesised receptors open up possibilities of another dimension of cellular regulation of signalling. Both the discovery of hormones such as apelin and its pairing with an ‘orphan’ receptor, and the unexpected action of a drug against cannabinoid receptors point to further levels of complexity in cardiovascular regulation. Deeper understanding of the evolution of receptor families and of the molecular mechanisms of signal transduction is enabling the design of highly specific agonists and antagonists. Pharmacological intervention is not limited to the ligand-receptor interaction but can extend to inhibition of selected steps in the intracellular pathway, such as the regulation of G protein deactivation. The progress in this area is both leading to improved treatment for a range of endocrine disorders and serving as a model for the study of signalling in other physiological systems.
Hormonersatztherapie bei internistischen Risikopatientinnen
Authors: Mueck Alfred O.
Published: October 2006

Für eine Hormonersatztherapie (HRT) gelten absolute und relative Kontraindikationen, die in den Fachinformationen primär unter Annahme von Gruppeneffekten nach dem «Worst-case»-Prinzip gelistet sind, um forensischen Anforderungen zu genügen. Bei starkem Leidensdruck kann es aber sinnvoll erscheinen, eine HRT auch bei erhöhtem Risiko durchzuführen. Zur Risikominimierung ergibt sich neben einer allgemeinen Dosisreduktion eine differenzierte Wahl der Präparate vor allem bezüglich der Gestagenkomponente und Applikationsform. Für internistische Risikopatientinnen ist dabei häufig die Bevorzugung von transdermalem Östradiol in Form von Pflastern oder Gelen und neutralen Gestagenen wie Progesteron und Dydrogesteron bzw. Kombipflaster zur komplett transdermalen HRT zu empfehlen. In der Women’s Health Initiative, einer Studie mit einem kardiovaskulär stark belasteten Kollektiv, ergaben sich als wichtigste Risiken venöse Thrombosen und Hirninsulte, im hohen Alter auch Herzinfarkte. Im direkten Zusammenhang damit haben die Risikogruppen mit Diabetes, Hypertonie und Dyslipoproteinämie sowie allgemein Raucherinnen besondere Bedeutung. Weitere häufige internistische Risikogruppen sind Frauen mit Schilddrüsenerkrankungen und Leber-/Gallenwegserkrankungen; seltene, aber prognostisch wichtige Erkrankungen wie Porphyrien und Lupus erythematodes gelten als relative Kontraindikationen. Die Datenlage bei diesen Risikogruppen wird dargestellt und praktische Empfehlungen werden gegeben.
Hormonal Replacement Therapy after Gynaecological Cancer
Authors: Biglia Nicoletta , Mariani Luca , Marenco Davide , Robba Claudio , Peano Elisa , Kubatzki Franziska , Sismondi Piero
Published: October 2006

Thousands of women are treated each year for gynaecological cancers; many of these are already in menopause, while other younger patients will go into early menopause due to surgery, chemotherapy and/or radiotherapy to the pelvic region. The aim of this paper is to review the biological and clinical evidence in favour and against hormone replacement therapy (HRT) use after gynaecological cancers. With the exception of breast and endometrial cancer, there is no biological evidence that HRT may increase the recurrence risk. In women with previous endometrial cancer, HRT use is not supported by univocal and conclusive data to formulate specific recommendations, whereas most authors suggest that oestrogens may be used after adequate information about risks and benefits. The use of HRT in breast cancer patients is, at present, considered contra-indicated, even if results of clinical trials are not concordant. Therapeutic non-hormonal alternatives may be proposed to these patients.
Low Birth Weight for Gestational Age Associates with Reduced Glucose Concentrations at Birth, Infancy and Childhood
Authors: Ghirri Paolo , Ladaki Christini , Bartoli Ambra , Scirè Giuseppe , Vuerich Marco , Spadoni Gian Luigi , Maiorana Arianna , Geremia Caterina , Boldrini Antonio , Cianfarani Stefano
Published: October 2006

Background/Aims: Our aim was to investigate glucose homeostasis, insulin sensitivity and insulin-like growth factor (IGF) system status in children born small for gestational age (SGA). Methods: A case-control study was carried out at birth, infancy and childhood, comparing SGA with children appropriate for gestational age strictly matched for age, gender, pubertal status and body mass index. Ninety newborns, 52 infants, and 68 children were studied. Fasting insulin (IF), fasting glucose (GF) to IF ratio (GF/IF), the homeostasis model assessment of insulin sensitivity, the quantitative insulin sensitivity check index, insulinogenic index and the triglyceride/high-density lipoprotein-cholesterol ratio were measured. IGF-I, IGF-binding protein-3 and the IGF-I/IGF-binding protein-3 molar ratio were assessed. Results: Glucose concentrations were lower in SGA newborns (p < 0.0001), infants (p = 0.01), and children (p = 0.001). Birth weight correlated with glucose levels at birth (r = 0.59, p < 0.0001), 12 months (r = 0.29, p = 0.04) and childhood (r = 0.44, p < 0.0001). Conclusion: Our results provide evidence for a developmental adaptation of glucose metabolism in SGA children leading to reduced glucose concentrations.
Evaluation of Patients’ Opinion and Metabolic Control after Transfer of Young Adults with Type 1 Diabetes from a Pediatric Diabetes Clinic to Adult Care
Authors: Busse F.P. , Hiermann P. , Galler A. , Stumvoll M. , Wiessner T. , Kiess W. , Kapellen T.M.
Published: October 2006

Background: Transferring adolescents with diabetes from pediatric to adult care remains a challenge and the outcome is often unknown. The aims of this study were to determine the patients’ perception of transfer arrangements and to analyze health care use and metabolic control. Methods: A telephone questionnaire was conducted for patients who had been transferred from the pediatric clinic to adult care between 1995 and 2003. Of 161 identified patients, 101 (58 females, 43 males, mean age 22.1 ± 2.4 years) were interviewed. Pediatric case notes and, if available (n = 44), current notes were analyzed to validate answers from the interview. Results: After transfer, 52.5% of patients changed their health care provider at least once. The mean frequency of changes was 1.47. There was a significant decrease in clinic attendance rate after transition (8.5 ± 2.3/years vs. 6.7 ± 3.2/years). Patients criticized the lack of arrangements, poor information about transfer and the specific age for transition (18 years) set by legislation. The transfer was considered a negative experience by 58 patients. The patients assumed their metabolic control (HbA1c) was better than it really was (7.5 ± 1.3% vs. 8.3 ± 1.6%, p < 0.05). Actual HbA1c from case notes pre- and post-transfer did not change significantly (8.5 ± 1.5% vs. 8.4 ± 1.7%, n = 44, p = 0.441). Conclusion: The establishment of transition clinics and closer cooperation between specialists in pediatric and adult medicine is mandatory. Such changes are demanded by patients and would ensure better uptake of health care services after transfer.
Novel Late Response Genes of PTHrP in Chondrocytes
Authors: Hoogendam Jakomijn , Farih-Sips Hetty , van Beek Ermond , Löwik Clemens W.G.M. , Wit Jan M. , Karperien Marcel
Published: October 2006

To gain more insight into the downstream effectors of parathyroid hormone (PTH) related peptide (PTHrP) signaling in chondrocytes, we performed microarray analysis to identify late PTHrP response genes using the chondrogenic ATDC5 cell line and studied their response in the osteoblastic KS483 cell line and explanted metatarsals. At day 8 of micromass culture, ATDC5 cells have pre-hypertrophic-like characteristics and at this time point the cells were stimulated with PTHrP for 24 and 72 h and RNA was isolated. PTHrP treatment inhibited outgrowth of cartilage matrix and decreased the expression of Col10a1 mRNA, which is in line with the inhibitory effects of PTHrP on chondrocyte differentiation. Using cDNA microarray analysis, a list of 9 genes (p< 10–3) was generated, including 3 upregulated (IGFBP4, Csrp2, and Ecm1) and 6 downregulated (Col9a1, Col2a1, Agc, Hmgn2, Calm1, and Mxd4) response genes. Four out of 9 genes are novel PTHrP response genes and 2 out of 9 have not yet been identified in cartilage. Four out of 9 genes are components of the extra-cellular matrix and the remaining genes are involved in signal transduction and transcription regulation. The response to PTHrP was validated by quantitative PCR, using the same RNA samples as labeled in the microarray experiments and RNA samples isolated from a new experiment. In addition, we examined whether these genes also reacted to PTHrP in other PTHrP responsive models, like KS483 osteoblasts and explanted metatarsals. The expression of late PTHrP response genes varied between ATDC5 chondrocytes, KS483 osteoblasts and metatarsals, suggesting that the expression of late response genes is dependent on the cellular context of the PTHrP responsive cells.
Rapid Endocytosis of Copper-Zinc Superoxide Dismutase into Human Endothelial Cells: Role for Its Vascular Activity
Authors: Waelti Ernst R. , Barton Matthias
Published: October 2006

Cytosolic CuZn-SOD (SOD1) is a dimeric, carbohydrate-free enzyme with a molecular weight of about 32 kDa and also circulates in human blood plasma. Due to its molecular mass it has been believed that the enzyme cannot penetrate the cell membrane. Here we report that rapid endocytosis of FITC-CuZn-SOD into human endothelial cells occurs within 5 min. Moreover, relaxation of rat aortic rings in response to CuZn-SOD is associated with a lag time of 45–60 s and only observed in the presence of intact endothelial cells. The results indicate acute and rapid endothelial cell endocytosis of CuZn-SOD, possibly via activation of a receptor-mediated pathway. Intracellular uptake via endocytosis may contribute to the vascular effects of CuZn-SOD, including vasodilation, and is likely to play a role in regulation of vascular tone and diseases such as atherosclerosis.
Activation of PPARβ/δ Induces Endothelial Cell Proliferation and Angiogenesis
Authors: Piqueras Laura , Reynolds Andrew R. , Hodivala-Dilke Kairbaan M. , Alfranca Arántzazu , Redondo Juan M. , Hatae Toshihisa , Tanabe Tadashi , Warner Timothy D. , Bishop-Bailey David
Published: October 2006

Objective—

The role of the nuclear receptor peroxisome-proliferator activated receptor (PPAR)-β/δ in endothelial cells remains unclear. Interestingly, the selective PPARβ/δ ligand GW501516 is in phase II clinical trials for dyslipidemia. Here, using GW501516, we have assessed the involvement of PPARβ/δ in endothelial cell proliferation and angiogenesis.

Methods and Results—

Western blot analysis indicated PPARβ/δ was expressed in primary human umbilical and aortic endothelial cells, and in the endothelial cell line, EAHy926. Treatment with GW501516 increased human endothelial cell proliferation and morphogenesis in cultures in vitro, endothelial cell outgrowth from murine aortic vessels in vitro, and angiogenesis in a murine matrigel plug assay in vivo. GW501516 induced vascular endothelial cell growth factor mRNA and peptide release, as well as adipose differentiation-related protein (ADRP), a PPARβ/δ target gene. GW501516-induced proliferation, morphogenesis, vascular endothelial growth factor (VEGF), and ADRP were absent in endothelial cells transfected with dominant-negative PPARβ/δ. Furthermore, treatment of cells with cyclo-VEGFI, a VEGF receptor1/2 antagonist, abolished GW501516-induced endothelial cell proliferation and tube formation.

Conclusions—

PPARβ/δ is a novel regulator of endothelial cell proliferation and angiogenesis through VEGF. The use of GW501516 to treat dyslipidemia may need to be carefully monitored in patients susceptible to angiogenic disorders.
Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice
Authors: van Wanrooij Eva J.A , van Puijvelde Gijs H.M , de Vos Paula , Yagita Hideo , van Berkel Theo J.C. , Kuiper Johan
Published: October 2006

Objective—Atherosclerosis is a chronic (auto-)inflammatory disease and T cell activation is an important factor in this process. Tnfrsf4 (OX40) and Tnfsf4 (OX40 ligand) are members of the tumor necrosis factor (TNF) and TNF receptor family and OX40/OX40L mediated signaling is important in co-activation of T cells and facilitates B-T cell interaction. In this study we assessed the role of the OX40/OX40L pathway in atherosclerosis and the effect of interruption of the OX40/OX40L pathway on lesion development.

Methods and Results—We treated low-density lipoprotein receptor-deficient (LDLr−/−) mice with an anti-OX40L antibody which lead to a 53% decrease in atherosclerotic lesion formation. Treatment resulted in inhibition of Th2 mediated isotype switching by decreasing interleukin (IL)-4 secretion and subsequent low IgG1 serum levels against oxLDL, whereas protective anti-oxLDL specific IgM titers were increased in treated mice compared with control.

Conclusions—We conclude that blocking the OX-40/OX40L interaction reduced atherogenesis by inhibition of IL-4 mediated Th2 induced isotype switching and subsequent increased levels of anti-oxLDL IgM.
Pioglitazone Inhibits In-Stent Restenosis in Atherosclerotic Rabbits by Targeting Transforming Growth Factor-β and MCP-1
Authors: Joner Michael , Farb Andrew , Cheng Qi , Finn Aloke V. , Acampado Eduardo , Burke Allen P. , Skorija Kristi , Creighton Wendy , Kolodgie Frank D. , Gold Herman K. , Virmani Renu
Published: October 2006

Objective—

Although emerging data from preclinical and clinical studies suggests a reduction of in-stent restenosis with peroxisome proliferator-activated receptor (PPAR)-γ agonists, the reduction of neointimal growth via anti-inflammatory mechanisms has not been explored.

Methods and Results—

Hypercholesterolemic New Zealand White rabbits (n=45) received bilateral balloon-expandable stents implanted into atherosclerotic iliac arteries. Animals were randomized to oral pioglitazone 3 (low dose) or 10 mg/kg per day (high dose) started on the day of stent implantation; control rabbits received placebo. Tissue harvest was performed 28 days after stenting, and stented segments underwent histology, morphometry, immunostaining for macrophages, and scanning electron microscopy. In selected animals, stented arterial segments were placed in organoid culture for 48 hours, and the conditioned media was assayed for 23 different cytokines. There was a 21% reduction in neointimal area for high-dose pioglitazone treated versus placebo rabbits (
P
<0.005), which was associated with a significant reduction of neointimal macrophages. Analysis of conditioned media revealed an 82% and 74% reduction in the release of monocyte chemoattractant protein-1 (MCP-1) (
P
<0.007) and transforming growth factor (TGF)-β1 (
P
<0.01), respectively, in stented segments from animals treated with 10 mg/kg per day pioglitazone versus placebo.

Conclusions—

Oral pioglitazone suppresses in-stent neointimal growth by limiting local inflammatory pathways and may be useful as an adjunctive therapy in patients undergoing percutaneous interventions.
Effects on Coagulation and Fibrinolysis Induced by Influenza in Mice With a Reduced Capacity to Generate Activated Protein C and a Deficiency in Plasminogen Activator Inhibitor Type 1
Authors: Keller Tymen T. , van der Sluijs Koen F. , de Kruif Martijn D. , Gerdes Victor E. A. , Meijers Joost C. M. , Florquin Sandrine , van der Poll Tom , van Gorp Eric C. M. , Brandjes Dees P. M. , Büller Harry R. , Levi Marcel
Published: October 2006

Influenza infections increase the risk of diseases associated with a prothrombotic state, such as venous thrombosis and atherothrombotic diseases. However, it is unclear whether influenza leads to a prothrombotic state in vivo. To determine whether influenza activates coagulation, we measured coagulation and fibrinolysis in influenza-infected C57BL/6 mice. We found that influenza increased thrombin generation, fibrin deposition, and fibrinolysis. In addition, we used various anti- and prothrombotic models to study pathways involved in the influenza-induced prothrombotic state. A reduced capacity to generate activated protein C in TM
pro/pro
mice increased thrombin generation and fibrinolysis, whereas treatment with heparin decreased thrombin generation in influenza-infected C57Bl/6 mice. Thrombin generation was not changed in hyperfibrinolytic mice, deficient in plasminogen activator inhibitor type-1 (PAI-1
−/−
); however, increased fibrin degradation was seen. Treatment with tranexamic acid reduced fibrinolysis, but thrombin generation was unchanged. We conclude that influenza infection generates thrombin, increased by reduced levels of protein C and decreased by heparin. The fibrinolytic system appears not to be important for thrombin generation. These findings suggest that influenza leads to a prothrombotic state by coagulation activation. Heparin treatment reduces the influenza induced prothrombotic state.
M1 Muscarinic Acetylcholine Receptor Agonism Alters Sleep without Affecting Memory Consolidation
Authors: Nissen Christoph , Power Ann E. , Nofzinger Eric A. , Feige Bernd , Voderholzer Ulrich , Kloepfer Corinna , Waldheim Bernhard , Radosa Marc-Philipp , Berger Mathias , Riemann Dieter
Published: October 2006

Preclinical studies have implicated cholinergic neurotransmission, specifically M1 muscarinic acetylcholine receptor (mAChR) activation, in sleep-associated memory consolidation. In the present study, we investigated the effects of administering the direct M1 mAChR agonist RS-86 on pre-post sleep memory consolidation. Twenty healthy human participants were tested in a declarative word-list task and a procedural mirror-tracing task. RS-86 significantly reduced rapid eye movement (REM) sleep latency and slow wave sleep (SWS) duration in comparison with placebo. Presleep acquisition and postsleep recall rates were within the expected ranges. However, recall rates in both tasks were almost identical for the RS-86 and placebo conditions. These results indicate that selective M1 mAChR activation in healthy humans has no clinically relevant effect on pre-post sleep consolidation of declarative or procedural memories at a dose that reduces REM sleep latency and SWS duration.
A Single System Explains Human Speed Perception
Authors: van Boxtel Jeroen J. A. , van Ee Raymond , Erkelens Casper J.
Published: October 2006

Motion is fully described by a direction and a speed. The processing of direction information by the visual system has been extensively studied; much less is known, however, about the processing of speed. Although it is generally accepted that the direction of motion is processed by a single motion system, no such consensus exists for speed. Psychophysical data from humans suggest two separate systems processing luminance-based fast and slow speeds, whereas neurophysiological recordings in monkeys generally show continuous speed representation, hinting at a single system. Although the neurophysiological findings hint at a single system, they remain inconclusive as only a limited amount of cells can be measured per study and, possibly, the putative different motion systems are anatomically separate. In three psychophysical motion adaptation experiments, we show that predictions on the basis of the two-motion system hypothesis are not met. Instead, concurrent modeling showed that both here-presented and previous data are consistent with a single system subserving human speed perception. These findings have important implications for computational models of motion processing and the low-level organization of the process.
Inhibitory Control is Slowed in Patients with Right Superior Medial Frontal Damage
Authors: Floden Darlene , Stuss Donald T.
Published: October 2006

Inhibitory control is an essential part of behavior. Comprehensive knowledge of the neural underpinnings will shed light on complex behavior, its breakdown in neurological and psychological disorders, and current and future techniques for the pharmacological or structural remediation of disinhibition. This study investigated the neural mechanisms involved in rapid response inhibition. The stop signal task was used to estimate inhibitory speed in a group of neurologically normal control subjects and patients with discrete frontal lobe lesions. Task procedures were controlled to rule out probable confounds related to strategic changes in task effort. The findings indicate that the frontal lobes are necessary for inhibitory control and, furthermore, that the integrity of the right superior medial frontal region is key for rapid inhibitory control under conditions controlling for strategically slow responses, forcing reliance more on a rapid, “kill-switch” inhibitory system. These results are interpreted within an anatomical framework of corticospinal motor control.
Cerebrocerebellar Circuits for the Perceptual Cancellation of Eye-movement-induced Retinal Image Motion
Authors: Lindner Axel , Haarmeier Thomas , Erb Michael , Grodd Wolfgang , Thier Peter
Published: October 2006

Despite smooth pursuit eye movements, we are unaware of resultant retinal image motion. This example of perceptual invariance is achieved by comparing retinal image slip with an internal reference signal predicting the sensory consequences of the eye movement. This prediction can be manipulated experimentally, allowing one to vary the amount of self-induced image motion for which the reference signal compensates and, accordingly, the resulting percept of motion. Here we were able to map regions in CRUS I within the lateral cerebellar hemispheres that exhibited a significant correlation between functional magnetic resonance imaging signal amplitudes and the amount of motion predicted by the reference signal. The fact that these cerebellar regions were found to be functionally coupled with the left parieto-insular cortex and the supplementary eye fields points to these cortical areas as the sites of interaction between predicted and experienced sensory events, ultimately giving rise to the perception of a stable world despite self-induced retinal motion.
When and How Does Depersonalization Increase Conformity to Group Norms in Computer-Mediated Communication?
Authors: Lee Eun-Ju
Published: October 2006

The experiment reported herein examined how depersonalization, operationalized as the lack of individuating information, affects conformity to a group norm in anonymous computer-mediated communication. Participants made a decision about choice dilemmas and exchanged their decisions and supporting arguments with three ostensible partners via computer, who unanimously endorsed the position opposite of the participant’s. As predicted, depersonalization led to a more extreme perception of the group norm, better recall of the interactants’ arguments, and more positive evaluations of the interactants’ arguments through group identification, albeit only for women. Moreover, depersonalization was more likely to facilitate conformity to group norms among those with higher need for public individuation and among women. A test of indirect effects showed that group identification and extremity of the perceived group norm mediated the effects of depersonalization on conformity.
Learning Versus Knowing
Authors: Maurer Marcus , Reinemann Carsten
Published: October 2006

Many studies have shown that voters do learn about political issues from televised debates. Because debaters may not be interested in educating voters but in gaining votes, this does not necessarily mean that debate viewers improve their knowledge (i.e., learning something that is correct). Instead, they may become misinformed by watching a debate. Taking the second debate in the 2002 German general election as an example, we first compare people’s knowledge about economic facts before and after the debate with the actual situation as represented by official statistics. In a second step, we trace back the change or stability of their assessments of the state of the economy to candidates’ statements on that issue during the debate by using continuous-response measurement (CRM) measurement. Our analysis shows substantial learning effects among debate viewers. However, most of them did not improve their knowledge. They were rather misled by candidates’ selective presentation of facts.
Acidity compensation of electrochemical measurements for on-site monitoring of heavy metals
Authors: Christidis Konstantinos , Robertson Peter K. J. , Gow Ken S. , Pollard Pat M.
Published: October 2006

This paper presents an electrochemical instrumentation system capable of real-time in situ detection of heavy metals. A practical approach to introduce acidity compensation against changes in amplitude of the peak currents is also presented. The compensated amplitudes can then be used to predict the concentration level of heavy metals. The system uses differential pulse anodic stripping voltammetry, which is a precise and sensitive analytical method with excellent limits of detection. The instrument is capable of detecting lead, cadmium, zinc, nickel and copper with good sensitivity and precision. The system avoids expensive and time-consuming procedures and may be used in a variety of situations to help environmental assessment and control.
Fuzzy control of flexible cable overhead cranes with load hoisting
Authors: Moustafa Kamal A. F. , Ismail Mohamed I. S. , Gad Emil H. , El-Moneer Ahmed M. A.
Published: October 2006

This work considers the control problem of overhead cranes with flexible cable and load hoisting or lowering during crane travel. The objective is to drive the overhead crane to its final desired position while suppressing the payload swing. The proposed control strategy is based on three fuzzy logic controllers where the control action is based on expert knowledge. These controllers are a trolley motion controller, payload hoist controller and payload anti-swing controller. Numerical simulations are provided to show the effectiveness of the proposed fuzzy control scheme.
The Linear Model of Innovation
Authors: Godin Benoît
Published: October 2006

One of the first (conceptual) frameworks developed for understanding the relation of science and technology to the economy has been the linear model of innovation. The model postulated that innovation starts with basic research, is followed by applied research and development, and ends with production and diffusion. The precise source of the model remains nebulous, having never been documented. Several authors who have used, improved, or criticized the model in the past fifty years rarely acknowledged or cited any original source. The model usually was taken for granted. According to others, however, it comes directly from V. Bush’s Science: The Endless Frontier ([1945] 1995). This article traces the history of the linear model, suggesting that it developed in three steps corresponding to three scientific communities looking at science analytically. The article argues that statistics is a main reason the model is still alive despite criticisms, alternatives, and having been proclaimed dead.
“Stretching the Friendship”
Authors: Shepherd Chris J. , Gibbs Martin R.
Published: October 2006

In this article, we address the problem of how technoscience knowledge and practices are translated when they are relocated during the highly organized, international encounters between cultures, often called “development.” We examine efforts to build a “model” Australian dairy and instantiate Australian dairy practices in East Timor following East Timor’s recent emergence as a nation-state. Through this ethnography of development’s construction of a heterogeneous sociotechnical assemblage, we show how knowledge and power inform the practices that enable Western models of production and exchange to be reassembled in postcolonial spaces. In aiming to conduct a symmetrical anthropology of development based in the actor-network approach, we follow development’s actors and actants as well as its epistemic divisions—nature and culture, human and nonhuman, us and them—into East Timor, arguing that the politics and agency of technology transfer is distributed among discourse, epistemology, and human and nonhuman actors.
Lost in translation? International migration, learning and knowledge
Authors: Williams Allan M.
Published: October 2006

There are changing but increasingly important ways in which international migration contributes to knowledge creation and transfer. The paper focuses on four main issues. First, the different ways in which knowledge is conceptualized, and the significance of corporeal mobility in effecting knowledge creation and transfer in relation to each of these types. Second, the significance of international migration in knowledge creation and transfer, and how this is mediated by whether migration is constituted within bounded (by company structures) or boundaryless careers, and as free agent labour migration. Third, the situating of migrants within firms, and the particular obstacles to their engagement in co-learning and knowledge translation: especially positionality, intercultural communication and social identities. Fourth, a focus on the importance of place, which is explored through theories of learning regions and creativity, and notions of the transferability of social learning across different public and private spheres. The need to view migrant learning and knowledge creation/transfer as widely dispersed, rather than as elite practices in privileged regions, is a recurrent theme.
Primitive accumulation, accumulation by dispossession, accumulation by ‘extra-economic’ means
Authors: Glassman Jim
Published: October 2006

David Harvey's adaptation and redeployment of Marx's notion of ‘primitive accumulation’–under the heading of ‘accumulation by dispossession’–has reignited interest in the concept among geographers. This adaptation of the concept of primitive accumulation to different contexts than those Marx analyzed raises a variety of theoretical and practical issues. In this paper, I review recent uses and transformations of the notion of primitive accumulation that focus on its persistence within the Global North, addressing especially the political implications that attend different readings of primitive accumulation in the era of neoliberal globalization.
British Intelligence and the July Bomb Plot of 1944: A Reappraisal
Authors: Winter P. R.J.
Published: October 2006

During the summer of 1949 Winston Churchill invited a surviving member of the German opposition to his home in Chartwell, Kent. He informed his guest that ‘during the war he had been misled by his assistants about the considerable strength and size of the German anti-Hitler resistance’. In the light of recent archival research, we now know this statement to be not entirely truthful. Using previously unpublished material from the Guy Liddell diaries, the memoirs of the late Hugh Trevor-Roper, and a selection of Foreign Office (FO) minutes and wartime interrogation reports, this article will aim to overturn the prevailing view that the July bomb plot and its antecedents represented a British ‘intelligence failure’ as opposed to a failure of political judgement and imagination on the part of Churchill, Eden, and the FO. It will be asserted that, because of a mixture of political indifference and ‘group think’, crucial intelligence concerning the existence of a determined anti-Hitler resistance was ignored. Documentary evidence confirms that when von Stauffenberg’s bomb exploded the officially held view that no such element existed in Germany, senior figures in Whitehall were ‘naked’ in the face of events. These officials were victims not only of their own political misjudgement, but ultimately of the Churchillian policy of ‘absolute silence’ which ensured that the intelligence cupboard was bare at the very moment they, as ‘consumers’ of intelligence, were most hungry for information.
The Dialectic Tension Between ‘Being’ and ‘Not Being’ a Good Nurse
Authors: Fagerström Lisbeth
Published: October 2006

The aim of this hermeneutic study was to gain a broader understanding of nurses’ workload and what characterizes a nurse’s experience in terms of the various levels of intensity of nursing care. Twenty-nine nurses participated in seven focus groups. The interpretation process took place in six different phases and the three laws of dialectics were used as interpretation rules. An optimal nursing care intensity level can be understood as a situation characterized by the balance between the intensity of care needed by patients and the external and internal factors of the current nursing care situation. The nurses’ work situation can be understood as a dialectic struggle between ‘being’ and ‘not being’ a good nurse; this can be said to be the underlying root metaphor. Nursing care can be understood as consisting of ‘complex and meaningful caring situations’. Dialectics can be used as a fruitful method of revealing the complexity of clinical reality.
Re-evaluation of the cost effectiveness of temozolomide for malignant gliomas in British Columbia
Authors: Mabasa Vincent H , Taylor Suzanne CM
Published: October 2006

Study objectives. To re-evaluate the cost effectiveness and median overall survival (OS) achieved in patients with recurrent malignant gliomas treated with temozolomide in British Columbia, as compared to previous lomustine use in the same patient population based on updated outcomes data. Results were also compared to temozolomide literature reports.

Methods. A retrospective medical record review was performed to identify patients who received single agent temozolomide or lomustine during successive, prespecified time periods. Data were collected on survival, duration of therapy, drug cost, labour and supplies, and successive or prior chemotherapy.

Results. Forty-one patients in the temozolomide group and 25 patients in the lomustine group were analysed. The median OS was 33.3 weeks (95% CI 28.4, 42.1 weeks) and 37.7 weeks (95% CI 25.0, 88.4 weeks) respectively ( P=0.783). Temozolomide patients received a mean of 5.1 cycles of drug treatment, with a mean cost per patient of $10 746 (CAD). In contrast, lomustine patients received a mean of 3.3 cycles of therapy, with a mean cost per patient of $129 (CAD). The cost-effectiveness analysis showed that temozolomide was generally not a cost-effective strategy and that lomustine was the dominant strategy. In the sensitivity analysis, in scenarios where median OS was prolonged with temozolomide as compared to lomustine, the incremental cost-effectiveness ratio for each life year gained ranged from $32,247 to $162,186.

Conclusion. No difference in survival was observed between patients treated with single agent lomustine and temozolomide. Based on the higher cost and lack of additional clinical benefit of temozolomide, lomustine is a more cost-effective treatment strategy.
An evaluation of pharmacist contribution to an oncology ward in a Swedish hospital
Authors: Bremberg Eva Rämme , Hising Christina , Nylén Urban , Ehrsson Hans , Eksborg Staffan
Published: October 2006

Aim. The aim of this project was to establish the importance of a pharmacist in the health-care team in improving drug use in an oncology ward in the Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.

Methods and patients. The pharmacist participated in the medical round in the mornings and worked as a member of the health-care team. Drug-related problems (DRPs) were identified by drug chart reviews based on data from medical files, laboratory tests and interviews with patients and/or relatives. A questionnaire to physicians and nurses was used to evaluate their experiences of the pharmacist’s contribution to the oncology ward.

Results. In total, 114 DRPs were identified in 58 patients. For each DRP, the pharmacist gave proposals for solutions. Sixty-eight suggestions out of 114 (59.6%) were implemented by the physician. Two suggestions (1.8%) were partly followed. For 32 suggestions (28.0%) it was unclear if they had caused any change in medication. Twelve suggestions (10.5%) were not followed. Most of the physicians and nurses acknowledged the pharmacist’s contribution to improved drug use in the ward.

Conclusion. A pharmacist can improve drug use in an oncology ward as a member of the health-care team. The pharmacist contributes with a systematic focus on the patient from a drug perspective.
Recent advances in targeted therapies for colorectal cancer
Authors: Milano M , Guerin O
Published: October 2006

Background. Recent advances in the molecular biology and genetics of colorectal cancer have led to the identification of potential therapeutic targets such as epidermal growth factor receptor, vascular endothelial growth factor and endothelial receptors.

Objective. This review will examine the major therapeutic advances along with the preclinical basis justifying their combination with conventional therapeutic tools. This review will also critically consider current possibilities offered to identify responding patients.

Data sources. Preclinical and primary clinical trial results published in peer-review journals. The authors examined the relevance and subsequent inclusion of the data.

Conclusions. Cetuximab and bevacizumab provide new benefits in terms of the response rate and survival. There remain, however, important questions concerning, for instance, optimal combinations between conventional cytotoxic agents and targeted therapies and also between targeted drugs themselves. These new targeted treatments are costly and in this context the question of the identification of the right drug for the right patient is particularly relevant. Adequate tools in predicting the efficacy of targeted treatments are still needed.