bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular endothelial wound closure under shear stress: role of membrane fluidity and flow-sensitive ion channels
Authors: Gojova Andrea , Barakat Abdul I.
Published: February 2005

Sufficiently rapid healing of vascular endothelium following injury is essential for preventing further pathological complications. Recent work suggests that fluid dynamic shear stress regulates endothelial cell (EC) wound closure. Changes in membrane fluidity and activation of flow-sensitive ion channels are among the most rapid endothelial responses to flow and are thought to play an important role in EC responsiveness to shear stress. The goal of the present study was to probe the role of these responses in bovine aortic EC (BAEC) wound closure under shear stress. BAEC monolayers were mechanically wounded and subsequently subjected to either “high” (19 dyn/cm2) or “low” (3 dyn/cm2) levels of steady shear stress. Image analysis was used to quantify cell migration and spreading under both flow and static control conditions. Our results demonstrate that, under static conditions, BAECs along both wound edges migrate at similar velocities to cover the wounded area. Low shear stress leads to significantly lower BAEC migration velocities, whereas high shear stress results in cells along the upstream edge of the wound migrating significantly more rapidly than those downstream. The data also show that reducing BAEC membrane fluidity by enriching the cell membrane with exogenous cholesterol significantly slows down both cell spreading and migration under flow and hence retards wound closure. Blocking flow-sensitive K and Cl channels reduces cell spreading under flow but has no impact on cell migration. These findings provide evidence that membrane fluidity and flow-sensitive ion channels play distinct roles in regulating EC wound closure under flow.
Intravital microscopic observations of 15-μm microspheres lodging in the pulmonary microcirculation
Authors: Lamm Wayne J. E. , Bernard Susan L. , Wagner Wiltz W. , Glenny Robb W.
Published: February 2005

Vascular infusions of 15-μm-diameter microspheres are used to study pulmonary blood flow distribution. The sites of microsphere lodging and their effects on microvascular perfusion are debated but unknown. Using intravital microscopy of the subpleural surface of rat lungs, we directly observed deposition of fluorescent microspheres. In a pump-perfused lung model, ∼0.5 million microspheres were infused over 30 s into the pulmonary artery of seven rats. Microsphere lodging was analyzed for the location in the microvasculature and the effect on local flow after lodging. On average, we observed 3.2 microspheres per 160 alveolar facets. The microspheres always entered the arterioles as singlets and lodged at the inlets to capillaries, either in alveolar corner vessels or small arterioles. In all cases, blood flow continued either around the microspheres or into the capillaries via adjacent pathways. We conclude that 15-μm-diameter microspheres, in doses in excess of those used in typical studies, have no significant impact on pulmonary capillary blood flow distribution.
Observations on force enhancement in submaximal voluntary contractions of human adductor pollicis muscle
Authors: Oskouei Ali E. , Herzog Walter
Published: February 2005

It has been observed consistently and is well accepted that the steady-state isometric force after active muscle stretch is greater than the corresponding isometric force for electrically stimulated muscles and maximal voluntary contractions. However, this so-called force enhancement has not been studied for submaximal voluntary efforts; therefore, it is not known whether this property affects everyday movements. The purpose of this study was to determine whether there was force enhancement during submaximal voluntary contractions. Human adductor pollicis muscles ( n = 17) were studied using a custom-built dynamometer, and both force and activation were measured while muscle activation and force were controlled at a level of 30% of maximal voluntary contraction. The steady-state isometric force and activation after active stretch were compared with the corresponding values obtained during isometric reference contractions. There was consistent and reliable force enhancement in 8 of the 17 subjects, whereas there was no force enhancement in the remaining subjects. Subjects with force enhancement had greater postactivation potentiation and a smaller resistance to fatigue in the adductor pollicis. We conclude from these results that force enhancement exists during submaximal voluntary contractions in a subset of the populations and suggest that it may affect everyday voluntary movements in this subset. On the basis of follow-up testing, it appears that force enhancement during voluntary contractions is linked to potentiation and fatigue resistance and therefore possibly to the fiber-type distribution in the adductor pollicis muscle.
Influence of 90-day simulated microgravity on human tendon mechanical properties and the effect of resistive countermeasures
Authors: Reeves N. D. , Maganaris C. N. , Ferretti G. , Narici M. V.
Published: February 2005

While microgravity exposure is known to cause deterioration of skeletal muscle performance, little is known regarding its effect on tendon structure and function. Hence, the aims of this study were to investigate the effects of simulated microgravity on the mechanical properties of human tendon and to assess the effectiveness of resistive countermeasures in preventing any detrimental effects. Eighteen men (aged 25–45 yr) underwent 90 days of bed rest: nine performed resistive exercise during this period (BREx group), and nine underwent bed rest only (BR group). Calf-raise and leg-press exercises were performed every third day using a gravity-independent flywheel device. Isometric plantar flexion contractions were performed by using a custom-built dynamometer, and ultrasound imaging was used to determine the tensile deformation of the gastrocnemius tendon during contraction. In the BR group, tendon stiffness estimated from the gradient of the tendon force-deformation relation decreased by 58% (preintervention: 124 ± 67 N/mm; postintervention: 52 ± 28 N/mm; P < 0.01), and the tendon Young's modulus decreased by 57% postintervention ( P < 0.01). In the BREx group, tendon stiffness decreased by 37% (preintervention: 136 ± 66 N/mm; postintervention: 86 ± 47 N/mm; P < 0.01), and the tendon Young's modulus decreased by 38% postintervention ( P < 0.01). The relative decline in tendon stiffness and Young's modulus was significantly ( P < 0.01) greater in the BR group compared with the BREx group. Unloading decreased gastrocnemius tendon stiffness due to a change in tendon material properties, and, although the exercise countermeasures did attenuate these effects, they did not completely prevent them. It is suggested that the total loading volume was not sufficient to completely prevent alterations in tendon mechanical properties.
Determining central activation failure and peripheral fatigue in the course of sustained maximal voluntary contractions: a model-based approach
Authors: Schillings Maartje L. , Stegeman Dick F. , Zwarts Machiel J.
Published: February 2005

In the study of fatigue, several methods have been used to calculate the development of central activation failure (CAF) and peripheral fatigue (PF) in the course of a sustained maximal voluntary contraction (MVC). This paper presents a model that enables simultaneous determination of CAF and PF during sustained MVC by using only force registration and superimposed electrical stimulation. In the model, we explicitly use the assumption, which is virtually always made implicitly in earlier studies, that a constant relative fraction of maximal possible force is activated by the electrical stimulation. That fraction can be determined at the start and at the end of a sustained MVC. The model shows that in the course of a sustained MVC, CAF can be calculated by merely using 1) this fraction, 2) the amplitudes of the superimposed force responses to stimulation, and 3) the course of voluntary force. After CAF quantification, the development of PF during MVC becomes available as well. The present study first examines the model assumption with data of sustained MVCs of variable durations on six healthy subjects. Subsequently, it shows CAF values in a group of 27 healthy subjects determined with both the model and a method of linear interpolation for PF estimation. Model-based CAF values were significantly higher during, but not at the start and at the end of, a 2-min sustained MVC. Next to a well-justified CAF determination, the model has the advantage of simultaneously quantifying PF, which was not possible with the previous methods.
Interaction between fascicle and tendinous tissues in short-contact stretch-shortening cycle exercise with varying eccentric intensities
Authors: Ishikawa M. , Niemelä E. , Komi P. V.
Published: February 2005

The interaction between fascicle and tendinous tissues (TT) in short-contact drop jumps (DJ) with three different drop heights [low (Low), optimal (OP), and high (High)] was examined with 11 subjects. The ground reaction force (F z) and ankle and knee joint angles were measured together with real-time ultrasonography (fascicle length) and electromyographic activities of the medial gastrocnemius (MG) and vastus lateralis (VL) muscles during the movement. With increasing drop height, the braking force and flight time increased from Low to OP ( P < 0.05). In High, the braking force increased but the flight time decreased compared with OP ( P < 0.05). During contact of Low and OP conditions, the length of muscle-tendon unit and TT underwent lengthening before shortening in both MG and VL muscles. However, the two muscles differed in the fascicle behaviors. The MG fascicles behaved isometrically or shortened, and the VL fascicles underwent lengthening before shortening during contact. In High, the TT lengthening in both muscles decreased compared with OP ( P < 0.05). The rapid stretch occurred in the MG fascicles but not in VL fascicles during the braking phase. The elastic recoil ratio decreased in both muscles with increasing the intensity during DJ. These findings demonstrated that TT underwent lengthening before shortening during DJ. However, the efficacy of elastic recoil decreased with increasing the drop intensity. The effective catapult action in TT can be limited by the drop intensity. In addition, the measured muscles behaved differently during DJ, providing evidence that each muscle may have a specific means of fascicle-TT interaction.
Neural Stem Cells: Progenitors or Panacea?
Authors: Klein Corinna , Fishell Gord
Published: February 2005

Are neural stem cells (NSCs) maintained as totipotent precursors by the specialized environment within the stem cell niche or are they simply progenitors, which, while retaining their ability to proliferate, are parcellated and restricted along with their postmitotic brethren? In this review, we focus on what has been learned in recent years about endogenous populations of NSCs in the embryonic and adult brain. We compare the data garnered from in vitro analysis to what has been learned from the transplantation of NSCs into the developing, adult or lesioned brain.
Adult Neural Stem Cells: Attempting to Solve the Identity Crisis
Authors: Morshead Cindi M.
Published: February 2005

A prevailing view in the literature is that the central nervous system (CNS) develops from a population of self-renewing, multipotential stem cells that persist throughout life. The in vivo identification and isolation of this rare subpopulation of cells has been the focus of much attention. This review will discuss the in vivo characterization of neural stem cells in the embryonic and adult CNS and some recent discrepancies and limitations between in vivo and in vitro assays used to identify neural stem cells.
Neural Precursor Cells and Their Role in Neuro-Oncology
Authors: Shah Khalid , Hsich Gary , Breakefield Xandra O.
Published: February 2005

Neural precursor cells (NPCs) provide a new mode for delivery of genes and proteins to brain tumors. These cells exist both in the developing and the adult nervous systems of all mammalian organisms. They have the ability to self-renew, migrate to diseased areas of the brain and differentiate into neurons, astrocytes and oligodendrocytes. The migratory ability of NPCs and their capacity to differentiate into all neural phenotypes provides a powerful tool for the treatment of both diffuse and localized neurological disorders. NPCs have been used in transplantation to replace damaged cells and in cancer therapy to provide therapeutic proteins and vectors to eliminate malignant cells in the brain. This review focuses on the characteristics of NPCs and their experimental use in the therapy for brain tumors. Examples are provided of monitoring migration of NPCs by bioluminescence imaging in living animals and of using them to deliver the apoptotic protein, TRAIL, to kill tumor cells.
Characterization of Progenitor-Cell-Specific Genes Identified by Subtractive Suppression Hybridization
Authors: Cai Jingli , Xue Haipeng , Zhan Ming , Rao Mahendra S.
Published: February 2005

We have utilized subtractive suppression hybridization (SSH) to identify differentially expressed genes present in either neuroepithelial (NEP) cells or glial restricted precursor (GRP) cells. Eighteen clones enriched in GRP cells and 28 in NEP cells were identified. Five of the GRP-specific clones (tenascin C, cystatin C, GABA transporter 3, extracellular matrix molecule 2 and H2–4) were characterized further, and their glial specificity was confirmed by RT-PCR, in situ hybridization and immunocytochemistry. H2–4 (an expressed sequence tag) was shown to be part of chondroitin sulfate proteoglycan 3. Overall, our results show that SSH can be used to identify lineage- and stage-specific markers and that extracellular matrix molecules likely play important roles in the migration and differentiation of GRPs.
Molecular Signals Regulating Proliferation of Stem and Progenitor Cells in Mouse Olfactory Epithelium
Authors: Kawauchi Shimako , Beites Crestina L. , Crocker Candice E. , Wu Hsiao-Huei , Bonnin Alexandre , Murray Richard , Calof Anne L.
Published: February 2005

To understand how signaling molecules regulate the generation of neurons from proliferating stem cells and neuronal progenitors in the developing and regenerating nervous system, we have studied neurogenesis in a model neurogenic epithelium, the olfactory epithelium (OE) of the mouse. Our studies have employed a candidate approach to test signaling molecules of potential importance in regulating neurogenesis and have utilized methods that include tissue culture, in situ hybridization and mouse genetics. Using these approaches, we have identified three distinct stages of stem and transit amplifying progenitor cells in the differentiation pathway of olfactory receptor neurons (ORNs) and have identified mechanisms by which the development of each of these progenitor cell types is regulated by signals produced both within the OE itself and by its underlying stroma. Our results indicate that regulation of olfactory neurogenesis is critically dependent on multiple signaling molecules from two different polypeptide growth factor superfamilies, the fibroblast growth factors and the transforming growth factor β (TGF-β) group. In addition, they indicate that these signaling molecules interact in at least two important ways: first, opposing signals converge on cells at specific developmental stages in the ORN pathway to regulate proliferation and differentiation; and second, these signaling molecules – particularly the TGF-βs and their antagonists – play key roles in feedback loops that regulate the size of progenitor cell pools and thereby neuron number, during development and regeneration.
Altered Patterns of Neuron Production in the p27Kip1 Knockout Mouse
Authors: Goto Tomohide , Mitsuhashi Takayuki , Takahashi Takao
Published: February 2005

The number and distribution of neurons in the murine neocortex are altered by loss of function of p27Kip1, a cyclin-dependent kinase inhibitor that regulates cell cycle progression at the G1 phase. We show that a temporary decline in the production of non-GABAergic projection neurons occurs in the dorsomedial neopallium of the p27Kip1 knockout mouse during the mid-term of neuronogenesis. It is followed by an augmentation of neuron production later in neuronogenesis leading to an increased production of projection neurons for the upper layers of the neocortex (layers II–IV). p27Kip1 is likely to play a critical role in cell internal regulatory mechanisms of proliferation/differentiation behavior of neural progenitor cells and may be directly involved in the control of neuron number during the period when non-GABAergic projection neurons for layers II–IV are being produced.
Glutamate and Regulation of Proliferation in the Developing Mammalian Telencephalon
Authors: Luk Kelvin C. , Sadikot Abbas F.
Published: February 2005

Increasing evidence suggests that classical neurotransmitters play an important morphogenetic role during development of the mammalian central nervous system. Using in vitro and in vivo models, we have previously identified a role for the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors in the proliferation of striatal progenitors. Here, we compare the roles of ionotropic glutamate receptors in the proliferation of either striatal or cortical progenitors. In culture, glutamate receptor activation promoted proliferation of both striatal and cortical neuroblasts. However, cortical and striatal neuroblasts responded to distinct ionotropic receptors. Cortical cultures were sensitive to AMPA/KA receptor blockade, whereas striatal neuroblast proliferation was altered by NMDA antagonists. In vivo, BrdU uptake in the proliferative ventricular zone was reduced in embryos following acute administration of ionotropic glutamate receptor antagonists. In keeping with in vitro observations, proliferation in cortical and striatal ventricular regions was reduced, respectively, by either AMPA/KA or NMDA receptor blockade. We also determined whether forebrain-derived progenitors expanded as neurospheres in the presence of growth factors show similar ionotropic glutamatergic responses. Cells in neither dorsal nor ventral telencephalon-derived neurospheres showed altered proliferation following exposure to either class of ionotropic glutamate receptor antagonist. Together, these findings suggest that glutamate influences the proliferation of forebrain neuronal progenitors, but not more primitive populations represented in multipotential progenitors expanded in vitro. The effects on neuroblast proliferation in different forebrain domains are heterogeneous and are mediated by distinct subclasses of ionotropic glutamate receptors.
Influence of Dopamine on Precursor Cell Proliferation and Differentiation in the Embryonic Mouse Telencephalon
Authors: Popolo Margherita , McCarthy Deirdre M. , Bhide Pradeep G.
Published: February 2005

Dopamine and its receptor binding sites appear in the brain early in the embryonic period raising the possibility that dopamine may influence brain development. We show that one component of dopamine’s role in brain development is its ability to influence proliferation and differentiation of progenitor cells in the neostriatum and the dorsomedial prefrontal cortex on embryonic day 15 in mice. Dopamine and a D1-like receptor agonist reduce the relative proportion of progenitor cells incorporating the S phase marker bromodeoxyuridine. A D2-like agonist produces the opposite effect. Both the effects are evident in the lateral ganglionic eminence, neuroepithelial precursor of the neostriatum and in the neuroepithelium of the dorsomedial prefrontal cortex. Neostriatal progenitor cells are more responsive than cortical progenitor cells to the effects of dopamine receptor activation. Furthermore, progenitor cells in the ventricular zone are more responsive to D1-like agonists and progenitors in the subventricular zone more so to D2-like agonists. Thus, dopamine’s developmental effects show regional and progenitor cell type specificity, presumably due to heterogeneity in the distribution of its receptor binding sites.
Oligodendrocyte Progenitor Proliferation and Maturation Is Differentially Regulated by Male and Female Sex Steroid Hormones
Authors: Marin-Husstege Mireya , Muggironi Michela , Raban David , Skoff Robert P. , Casaccia-Bonnefil Patrizia
Published: February 2005

Using primary cultures of oligodendrocyte progenitors isolated from male and female neonatal rodent brains, we observed more oligodendrocytes in female-derived compared to male-derived cultures. To determine whether the observed differences were due to a differential effect of sex hormones on proliferation, we treated cultures with increasing doses of 17β-estradiol, testosterone or progesterone and labeled cells with bromodeoxyuridine to identify cells in S phase. Treatment with 17β-estradiol, but not progesterone or testosterone, delayed the exit of oligodendrocyte progenitor cells from the cell cycle. In addition, 17β-estradiol treatment enhanced membrane sheet formation, while progesterone increased cellular branching. Interestingly, the estrogen modulator tamoxifen mimicked the effect of 17β-estradiol on cell cycle exit, but not on membrane formation. Immunocytochemical localization of estrogen receptors (ERs) showed ERβ mainly localized to the cytoplasm of oligodendrocytes, suggesting that the effect of 17β-estradiol on membrane formation could be mediated by interaction with this receptor. We conclude that sex steroids differentially regulate oligodendrocyte progenitor number and myelin formation, possibly contributing to gender-specific differences in repair.
Concurrent Generation of Subplate and Cortical Plate Neurons in Developing Trisomy 16 Mouse Cortex
Authors: Cheng Aiwu , Haydar Tarik F. , Yarowsky Paul. J. , Krueger Bruce K.
Published: February 2005

During embryonic development of the mammalian cerebral cortex, the generation of the marginal zone (MZ) and subplate (SP) precedes that of the cortical plate (CP). MZ and SP neurons are believed to play a ‘pioneering’ role in directing the organization of the CP and the specificity of connections between the CP and other brain regions. Here we report that this sequential order of neurogenesis is disrupted in the trisomy 16 (Ts16) mouse, a potential animal model of Down syndrome. Bromodeoxyuridine labeling was used to establish the date of generation of postmitotic SP and CP neurons in the somatosensory cortex. As has been previously reported, most SP neurons in euploid (control) cortex were generated on embryonic day 12.5 (E12.5), and production of CP neurons began a day later. In contrast, in the Ts16 cortex, few SP neurons were born on E12.5 and most were generated on E13.5 and E14.5 when CP neurons were also being produced. Thus, in the Ts16 cortex, many CP neurons are born and arrive at their destinations before the normal complement of SP neurons is present. This disruption of the temporal sequence of SP and CP generation may, therefore, interfere with the pioneering functions of the SP during cortical neurogenesis and may alter the connectivity of the cortex. Indeed, using lipophilic membrane tracers to label axonal projections, we found very little thalamocortical innervation of the Ts16 SP at an age when there is extensive innervation of the euploid SP.
DNA Microarrays
Authors: Hofman Paul
Published: February 2005

Until recently, diagnostic and prognostic assessment of diseased tissues in a Pathology laboratory relied on histological and immunohistological studies. DNA microarray technology now allows the simultaneous analysis of up to thousands of different genes in histological or cytological specimens. Thus, the microarray techniques offer opportunities for the pathologist to obtain ‘molecular signatures’ of the state of activity of diseased cells in patient tissue samples, providing new information, such as the biological staging of tumors, a risk assessment of pre-malignant lesions, resistance to, and side effects of, treatment, molecular mechanisms in neurodegeneration and inflammation, and detection of micro-organisms. However, despite the great promise of this revolutionary technology, there are several issues that may undermine the power of the DNA microarray approach. After a short summary of the different forms of microarray and the contribution of this technology to understanding human disease, this short review focuses on the potential pitfalls and the important issues that must be considered when using a DNA microarray. Although this new approach shows great potential, the successful application of gene arrays to diagnostic and prognostic problems requires thoughtful interpretation and a strong correlation with other data, such as clinical, histopathological and immunohistochemical findings.
Parenteral Iron Therapy in Treatment of Anemia in End-Stage Renal Disease Patients: A Comparative Study between Iron Saccharate and Gluconate
Authors: Sheashaa Hussein , El-Husseini Amr , Sabry Alaa , Hassan Nabil , Salem Ayman , Khalil Abdalla , El-Agroudy Amgad , Sobh Mohamed
Published: February 2005

Background: Anemia in hemodialysis patients is a complex syndrome. The impetus of this study was to assess the safety and efficacy of iron saccharate complex (ISC) and sodium ferric gluconate complex (SFGC) in treating anemia in hemodialysis patients. Methods: Forty-eight adult anemic patients of both genders (33 males and 15 females) who had an adequate level of both hemodialysis and nutrition status and received neither EPO nor parenteral iron therapy during the preceding 6 months were randomized to 2 groups. The first group comprised 22 patients who were treated with parenteral ISC, 100 mg twice weekly for 2 months and once weekly thereafter. The second group included 26 patients who received SFGC, 62.5 mg twice weekly for 2 months and once weekly thereafter. The patients were followed up for 6 months. Results: This head-to-head study showed that iron stores were adequately repleted by the use of both drugs. Repletion of iron stores was associated with a significant rise in both hemoglobin and hematocrit in both groups at the end of the follow-up period in comparison to their initial values at the start of the study (p < 0.001). Both parenteral iron therapy preparations were tolerated without a statistical difference between both groups. Conclusion: This head-to-head study confirmed that both parenteral iron preparations are effective for adequate repletion of iron stores and constituted a step forward in the management of anemic hemodialysis patients without noticeable adverse effects related to the administration of both iron preparations.
Comparison of the Retinal Structure and Function in Four Bird Species as a Function of the Time They Start Singing in the Morning
Authors: McNeil R. , McSween A. , Lachapelle P.
Published: February 2005

We postulated that the retinas of bird species that are the earlier singers are more sensitive to low light conditions than species that sing closer to sunrise. The selected species were the American Robin (Turdus migratorius) and the Hermit Thrush (Catharus guttatus) as early singers, the Common Grackle (Quiscalus quiscula) and the Mourning Dove (Zenaida macroura) which join the dawn chorus near sunrise. Scotopic electroretinogram (ERGs) intensity-response functions were obtained from anesthetized birds, following which the animals were euthanized and their retinas processed for histological analysis. Based on k values, generally considered an adequate measurement of the scotopic (rod) retinal sensitivity, all species yielded comparable night vision capabilities. However, based on the maximal (mixed rod-cone response) amplitude of the scotopic b-wave, our results indicate that robins and thrushes yield larger scotopic ERGs compared with doves and grackles, but unexpectedly do not have higher rod:cone ratios. Increased thickness of the retinal inner nuclear layer and higher numbers of ganglion cells in robins and thrushes compared with doves and grackles suggest a greater number of synaptic connections maximizing vision under low light conditions, and might support their higher retinal responses under scotopic conditions. The higher ERG Vmax of robins and thrushes might also be explained, at least in part, by the optics (i.e., their lower minimum F-numbers), resulting in brighter retinal images, rather than from higher sensitivity of their retina. Our results suggest that an early onset of dawn singing might be correlated with the retinal ability to detect the first dim crepuscular lights.
Comparative Analysis of Caspase Activation and Apoptosis in Renal Tubular Epithelial Cells and Renal Cell Carcinomas
Authors: Davidson Keryn , Percy Christine , Rennick Alina J. , Pat Betty K. , Li Jun , Nicol David , Johnson David W. , Gobe Glenda C.
Published: February 2005

Background/Aims: Treatment of renal cell carcinoma (RCC) is limited by its resistance to conventional chemotherapies. This may occur, in part, from resistance to apoptosis. The role of caspase activation in apoptosis resistance in treated RCCs was investigated. Methods: Two human RCC cell lines (ACHN and SN12K1) and renal tubular epithelial cells (HK2) were treated with 5-fluorouracil (0.2–20 µg/ml) or cisplatin (1–100 µM). Activation of caspase-3 and -2 was analysed and compared with levels of apoptosis. Caspase function was analysed using pan-caspase inhibition (z-VAD-fmk) and caspase-2 inhibition (z-VDVAD-fmk). Results: RCC apoptosis was significantly lower (p < 0.05) than in HK2s after treatment, confirming their chemoresistance. Pro-caspase-3 (32 kDa) was detected in all cell lines. Cleaved caspase-3 (19 kDa) was not detected by Western immunoblots in treated RCCs and only minimal activated caspase-3 was detected in treated RCCs using immunohistochemistry. All cells had pro-caspase-2 (48 kDa) and the activated form (33 kDa) appeared in all treated cells. Caspase inhibition caused a reduction in, but not negation of, therapy-induced apoptosis in HK2s and RCCs (p < 0.05 for HK2s and ACHN cells), indicating that a caspase activation pathway must occur in RCC apoptosis but this pathway does not act via caspase-3 cleavage. Inhibition of caspase-2 reduced apoptosis only in HK2s, indicating that the activated caspase-2, identified in treated RCCs, was not responsible for their apoptosis induction. Conclusion: Specific differences in caspase-3 and -2 activation were identified in renal tubular epithelium and RCCs after chemotherapy. Identification of RCC-specific caspase inactivation or redundancy may explain, in part, the resistance of RCCs to cancer therapies and may be useful in targeting apoptotic pathways to overcome RCC resistance to treatment.
Filter Run Time in CVVH: Pre- versus Post-Dilution and Nadroparin versus Regional Heparin-Protamine Anticoagulation
Authors: van der Voort P.H.J. , Gerritsen R.T. , Kuiper M.A. , Egbers P.H.M. , Kingma W.P. , Boerma E.C.
Published: February 2005

Background/Aims: To study the effect of different modes of continuous veno-venous haemofiltration (CVVH) on filter run time (FRT). Methods: We studied, in two consecutive prospective, randomised and crossover studies, 16 and 15 patients with acute renal failure during critical illness. Study A compared pre- versus post-dilution, and study B compared regional anticoagulation with heparin (pre-filter) and protamine (post-filter) (HP) versus nadroparin (NP) pre-filter. All CVVH sessions were standardised. Analyses were by Wilcoxon rank sum tests. Results: Study A: During pre-dilution the median FRT was 45.7 vs. 16.1 h in post-dilution CVVH (p = 0.005). The median creatinine clearance during pre-dilution was 33 vs. 45 ml/min in post-dilution (p = 0.001). Study B: During NP, median FRT was 39.5 vs. 12.3 h during HP CVVH (p = 0.045). Conclusions: Pre-dilution CVVH results in the greatest FRT but a lower plasma creatinine clearance compared to post-dilution. Regional anticoagulation with heparin-protamine resulted in a significantly shorter FRT compared to systemic NP anticoagulation.
Detection of Fluorescently Labeled Microparticles in Blood
Authors: Brandl M. , Hartmann J. , Posnicek T. , Ausenegg F.R. , Leitner A. , Falkenhagen D.
Published: February 2005

Background: A microsphere-based detoxification system is an adsorption system, whereby microadsorbent particles having diameters of 1–20 µm circulate in an extracorporeal filtrate circle. A thin-wall hollow-fiber membrane filter separates the microparticle-plasma suspension from the bloodstream. For patient safety, it is necessary to have a means to detect membrane ruptures that could lead to a release of microparticles into the patient’s bloodstream. Methods: An optical detection system was developed to monitor the venous bloodstream for the presence of microparticles from the filtrate circuit. For detection purposes, cellulose microspheres, both ferromagnetic and fluorescence labeled, were included with the microsphere adsorbant particles. In the case of a membrane rupture, the labeled particles would also be released into the bloodstream. By illuminating a small volume of blood with an excitation wavelength (590 nm) of the fluorescence marker, the particles can be detected by their emission light at 620 nm. The detector sensitivity is increased by collecting the ferromagnetic and fluorescently labeled microparticles using a magnetic trap. The efficiency of magnetic trap arrangements was tested by adjusting the magnet placements. Results: In vitro experiments were performed by pumping whole blood and labeled microparticles through the fluorescence detector. The efficiency of a magnetic trap arrangement was determined. With an optimal trap setup, 5–10 µl of labeled microparticles can be clearly detected in streaming whole blood. Conclusion: An easy to handle microparticle detector was developed, ready for use in particle based blood detoxification systems. The microparticle detection system fulfills the medical and technical requirements to bring the MDS into clinical tests.
Endothelin-1 Levels and Conduit Artery Mechanical Properties in End-Stage Renal Disease
Authors: Dammers Ruben , Hoeks Arnold P.G. , Tordoir Jan H.M. , Welten Rob J.Th.J. , Hamulyák Karly , Kooman Jeroen P. , Kitslaar Peter J.E.H.M.
Published: February 2005

Background: Endothelial cell (EC) dysfunction markers are increased in end-stage renal disease (ESRD). The present study focused on the relationship between EC markers, conduit artery wall mechanics and hemodynamics in ESRD. Methods: In 29 ESRD patients and 16 controls, brachial artery diameter, distension, and wall thickness was measured and circumferential wall stress (CWS) calculated. Shear stress was determined with a shear rate-estimating system. Furthermore, von Willebrand factor antigen (vWF) and endothelin-1 (ET-1) levels were measured. Results: vWF (p = 0.002) and ET-1 (p < 0.001) were higher in ESRD patients and vWF was related to ET-1 (r = 0.70, p = 0.005). Peak (p = 0.001) and mean shear stress (p = 0.003) were significantly lower in ESRD patients, and ET-1 showed an inverse log linear relation with both (peak: r = –0.59, p = 0.016; mean: r = –0.64, p = 0.007). Also, ET-1 was log linearly related to CWS (r = 0.58, p = 0.014). Conclusion: These results indicate that, in ESRD, conduit artery shear stress is lower, which might be secondary to an increased peripheral vascular resistance caused by higher ET-1 levels.
LDL Receptor–Related Protein and the Vascular Wall
Authors: Llorente-Cortés Vicenta , Badimon Lina
Published: February 2005

LDL receptor–related protein 1 (LRP1) is highly expressed in the vascular wall and is mainly associated with macrophages and vascular smooth muscle cells (VSMCs). Overexpression of LRP1 in atherosclerotic lesions has been demonstrated in several animal models and human lesions. Clinical studies have suggested a relation between alterations in LRP1 expression and coronary heart disease. Indeed, it has been demonstrated that
LRP1
gene expression is increased in blood mononuclear cells from patients with coronary obstruction and that the LRP1 mRNA-protein expression ratio is altered in coronary patients. Taken together, these results seem to suggest that LRP1 may be a pivotal receptor in the etiology of atherosclerosis. Our group has contributed to the elucidation of the physiopathologic role of LRP1 in the vascular wall by demonstrating that LRP1-mediated, matrix-retained LDL internalization could be crucial for VSMC–foam cell formation, that LRP1 is upregulated by lipid during human atherosclerotic lesion progression, and that LRP1-mediated aggregated LDL uptake causes the prothrombotic transformation of the vascular wall. Therefore, LRP1 seems to play a pathologic function during atherosclerotic lesion progression; however, LRP1 also seems to be essential for embryonic development and for the maintenance of vascular integrity. The protective effect of LRP1 in the vessel wall seems to be mainly due to its role in controlling certain signaling pathways. In this review, we will focus on the description of the main physiopathologic functions of LRP1 in the vascular wall.
Effect of P-Selectin on Phosphatidylserine Exposure and Surface-Dependent Thrombin Generation on Monocytes
Authors: del Conde Ian , Nabi Faisal , Tonda Raúl , Thiagarajan Perumal , López José A. , Kleiman Neal S.
Published: February 2005

Objective—Stimulation of monocytes with P-selectin induces the synthesis of an array of mediators of inflammation, as well as the expression of tissue factor (TF), the main initiator of coagulation. Because the membrane-bound reactions of coagulation are profoundly influenced by the presence of phosphatidylserine on the membranes of cells, factors that increase its expression may have an impact on coagulation.

Methods and Results—Using flow cytometry, we studied the effect of P-selectin on phosphatidylserine expression in blood monocytes and in the monocytic cells, THP-1. Soluble P-selectin at biologically relevant concentrations (0.31 to 2.5 μg/mL) induced a time-dependent increase in phosphatidylserine expression, an effect that could be inhibited with an anti–PSGL-1 blocking antibody, and by genistein, a tyrosine kinase inhibitor. Binding of activated platelets to THP-1 cells also resulted in a significant increase in phosphatidylserine expression that was dependent on PSGL-1. Consistent with the role of phosphatidylserine on surface-dependent reactions of coagulation, treatment of monocytic cells with soluble P-selectin led to increased thrombin generation. We excluded P-selectin induced apoptosis of monocyte as a mechanism for the increased phosphatidylserine exposure.

Conclusion—In summary, we show that P-selectin, either soluble or in its membrane-bound form, induces phosphatidylserine exposure in monocytes through a mechanism dependent on PSGL-1.
Epigenetic Histone Modification and Cardiovascular Lineage Programming in Mouse Embryonic Stem Cells Exposed to Laminar Shear Stress
Authors: Illi Barbara , Scopece Alessandro , Nanni Simona , Farsetti Antonella , Morgante Liliana , Biglioli Paolo , Capogrossi Maurizio C. , Gaetano Carlo
Published: February 2005

Experimental evidence indicates that shear stress (SS) exerts a morphogenetic function during cardiac development of mouse and zebrafish embryos. However, the molecular basis for this effect is still elusive. Our previous work described that in adult endothelial cells, SS regulates gene expression by inducing epigenetic modification of histones and activation of transcription complexes bearing acetyltransferase activity. In this study, we evaluated whether SS treatment could epigenetically modify histones and influence cell differentiation in mouse embryonic stem (ES) cells. Cells were exposed to a laminar SS of 10 dyne per cm
2
/s
−1
, or kept in static conditions in the presence or absence of the histone deacetylase inhibitor trichostatin A (TSA). These experiments revealed that SS enhanced lysine acetylation of histone H3 at position 14 (K14), as well as serine phosphorylation at position 10 (S10) and lysine methylation at position 79 (K79), and cooperated with TSA, inducing acetylation of histone H4 and phosphoacetylation of S10 and K14 of histone H3. In addition, ES cells exposed to SS strongly activated transcription from the vascular endothelial growth factor (VEGF) receptor 2 promoter. This effect was paralleled by an early induction of cardiovascular markers, including smooth muscle actin, smooth muscle protein 22-α, platelet-endothelial cell adhesion molecule-1, VEGF receptor 2, myocyte enhancer factor-2C (MEF2C), and α-sarcomeric actin. In this condition, transcription factors MEF2C and Sma/MAD homolog protein 4 could be isolated from SS-treated ES cells complexed with the cAMP response element-binding protein acetyltransferase. These results provide molecular basis for the SS-dependent cardiovascular commitment of mouse ES cells and suggest that laminar flow may be successfully applied for the in vitro production of cardiovascular precursors.
Subjective Visual Vertical in Pitch and Roll in Right Hemispheric Stroke
Authors: Saj Arnaud , Honoré Jacques , Bernati Thérèse , Coello Yann , Rousseaux Marc
Published: February 2005

Background and Purpose—

Patients with right hemispheric stroke usually present an anticlockwise deviation of the subjective visual vertical (SVV) in the frontal (roll) plane. However, the occurrence of a similar disorder in the sagittal (pitch) plane has never been assessed. We investigated the subjective visual vertical in both planes in those patients.

Methods—

Eight patients, 4 with spatial neglect (N+) and 4 without neglect (N−), were compared with 4 healthy participants (C). They sat facing a luminous bar adjustable in rotation, either in the roll or in the pitch plane, and had to orient it in a vertical position, in the dark.

Results—

Compared with N− (−0.1°) and C (+1.1°) groups, N+ patients presented with a significant backward deviation (−4.5°) of the SVV in pitch. In accordance with other studies, they also showed a significant anticlockwise deviation (−8.8°) of the SVV in roll, as compared with N− (−1.9°) and C (+0.4°) subjects. This was associated with an opposite trunk deviation in both planes.

Conclusions—

While confirming the anticlockwise deviation already reported in the frontal plane, we showed for the first time to our knowledge a backward deviation of the SVV in neglect patients, which has to be put in relation with their balance disorders.
Cardiac Power During Exercise and the Risk of Stroke in Men
Authors: Kurl S. , Laukkanen J.A. , Niskanen L. , Rauramaa R. , Tuomainen T.P. , Sivenius J. , Salonen J.T.
Published: February 2005

Background and Purpose—

Low maximal oxygen uptake (VO
2max
) has been shown to predict the risk of stroke. However, VO
2max
does not take into account the differences in cardiac afterload between subjects. The aim of this study was to examine the relationship of exercise cardiac power (ECP), defined as a ratio of VO
2max
with peak systolic blood pressure (SBP) during exercise, with the risk for stroke.

Methods—

Population-based cohort study with an average follow-up of 12 years from eastern Finland. A total of 1761 men with no history of stroke or coronary heart disease at baseline participated. Among these men, 91 strokes occurred, of which 69 were attributable to ischemic causes.

Results—

The relative risk of any stroke in men with low ECP (<10.3 mL/mm Hg) was 2.7 (95% CI, 1.2 to 6.0;
P
=0.01;
P
=0.02 for the trend across the quartiles), and the relative risk for ischemic stroke was 2.7 (95% CI, 1.1 to 7.0;
P
=0.03;
P
=0.04 for trend across the quartiles) compared with men having high ECP (>14.3 mL/mm Hg) during exercise after adjusting for age, examination year, cigarette smoking, alcohol consumption, body mass index, diabetes, serum total cholesterol level, energy expenditure of physical activity, exercise-induced myocardial ischemia, and the use of antihypertensive medication. After further adjustment for resting SBP, results were statistically nonsignificant.

Conclusions—

Low ECP provides noninvasive and easily available measure for stroke risk. One of the most potential explanations for the association between ECP and the increased risk of stroke is an elevated afterload and peripheral resistance indicated by elevated SBP.
Leading by Biography: Towards a Life-story Approach to the Study of Leadership
Authors: Shamir Boas , Dayan-Horesh Hava , Adler Dalya
Published: February 2005

Most leadership theories view leaders’ influence as stemming from their traits or behaviors. We suggest that the field of leadership studies has overlooked another potentially important source of the leader’s influence, namely his or her life-story. We argue that the leader’s life-story is an important source of information from which followers and potential followers learn about the leader’s traits and behaviors, that the leader’s life story provides the leader with a self-concept from which he or she can lead, and that telling the life story or parts of it is an important leadership behavior. As an example of the life-story approach, we present a study of leadership development themes appearing in leaders’ life stories. We conclude by proposing that a biographical and narrative approach to leadership studies should complement the currently dominant emphasis on leadership styles, and by suggesting some research directions that stem from this approach.
Leadership and Organizing: Sensemaking in Action
Authors: Pye Annie
Published: February 2005

This article aims to challenge some of the assumptions which we make in our understanding of leadership, through empirical illustration from a large organization where a chief executive endeavours to ‘lead’ global change. The continuing search for the Holy Grail, which seems to characterize interest in leadership, implies that research efforts are perhaps being directed at ‘solving the wrong problem’. Leadership as a form of social influence is hard to distinguish from many other influences in relationships between people yet, it is argued, its emphasis on moving towards future action encourages a conception not dissimilar to organizing. The case analysis developed in this article goes on to reframe leadership as an example of sensemaking. It concludes that while sensemaking will never replace leadership as a focus or topic of interest, to understand leadership as a sensemaking process helps illustrate more clearly what happens in the daily doing of leading.
Leading from the Chalk-face: An Overview of School Leadership
Authors: Harris Alma
Published: February 2005

This article offers an overview of the school leadership literature by outlining the main theoretical perspectives that currently dominate much of the writing and research in this area. Its main purpose is to provide a commentary on the dominant theoretical positions that characterize the contemporary leadership field and to explore the empirical foundation of these different theoretical traditions. The article does not claim to be the definitive word on school leadership; instead it aims to provide an overview of the main theoretical perspectives on school leadership that, firstly, have a theoretical and empirical base and, secondly, offer some insight into the relationship between leadership practice and organizational change and improvement.