bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of receptor activator of NFκB (RANK) signaling blockade on fracture healing
Authors: Flick Lisa M. , Weaver Jason M. , Ulrich‐Vinther Michael , Abuzzahab Faruk , Zhang Xinping , Dougall William C. , Anderson Dirk , O'Keefe Regis J. , Schwarz Edward M.
Published: March 2003

As dominant regulators of osteoclastogenesis and bone resorption, receptor activator of NFκB (RANK), receptor activator of NFκB ligand, and OPG have been identified as ideal drug targets for the treatment of metabolic bone disease. One concern regarding the therapeutic use of RANK signaling inhibitors is their effect on fracture healing. Therefore we tested if uncoupling and osteoclast depletion via RANK blockade affects callus formation, maturation and matrix remodeling, as well as union rates in a mouse tibia fracture model. Low dose (1 mg/kg i.p.) RANK:Fc therapy had no effect on callus formation, matrix maturation and remodeling, and resulted in 100% bony union by day 28. High dose RANK:Fc treatment (10 mg/kg i.p.) effectively eliminated osteoclasts at the fracture site on day 14, with no significant effects on fracture healing. When therapy was discontinued, normal numbers of osteoclasts were observed at the fracture site by day 28. However, continuous therapy resulted in a large osteopetrotic callus consisting of both mineralized and unmineralized matrix that was void of osteoclasts, but bony union was unaffected at day 28. We also evaluated this process in the complete absence of RANK signaling using RANK ‐/‐ mice. These animals exhibited significant radiographic and histologic evidence of callus formation, indicating that RANK signaling is not required for fracture callus formation. However, only 33% of RANK ‐/‐ animals formed bony unions compared to 100% of the osteopetrotic control mice. This defect was most likely a result of decreased blood flow, as evidenced by fewer blood vessels in the RANK ‐/‐ animals. Together, these data imply that osteoclast depletion via inhibition of RANK signaling is a viable option for the treatment of pathological bone loss since no adverse effects on fracture healing are observed when therapy is discontinued. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
Vascular adaptation of intact joint stabilizing structures in the posterior cruciate ligament deficient rabbit knee
Authors: Bray Robert C. , Leonard Catherine A. , Salo Paul T.
Published: March 2003

Loss of the posterior cruciate ligament (PCL) of the knee has a significant impact on joint stability and biomechanical function. Changes in joint biomechanics may result in mal‐adaptive tissue degeneration and functional alteration of supporting ligaments. This study examines the effects of joint laxity on the vascular physiology of the intact anterior cruciate (ACL) and medial collateral (MCL) ligaments after PCL transection in rabbits.

One‐year‐old female New Zealand white rabbits were assigned to control (n = 12), sham‐operated (n = 12) or PCL transected (2, 6 or 16 weeks, n = 12 per time point) groups. Half of the animals (n = 6 per group) were used for ACL and MCL blood flow determination using coloured microsphere infusion (ml/min/100 g), and half were used for vascular volume determination (given as vascular index, μl/g).

In the MCL, PCL transection induced large, significant (4–5‐fold) increases in blood flow (peak at 2 weeks) and vascular index (peak at 6 weeks) compared to sham‐operated animals that returned towards control values by 16 weeks. In contrast, the ACL showed no increase in blood flow in lax joints, and a relatively small (2‐fold) increase in vascular index at 6 weeks only. The wet weight and water content of both the MCL and ACL were significantly increased in PCL‐deficient joints.

We conclude that joint laxity (instability) subsequent to loss of the PCL in rabbits impacts the vascular physiology of intact supporting ligaments, inducing both vasomotor and angiogenic responses in the MCL. Changes in wet weight and water content of both the MCL and ACL demonstrate prolonged physiological adaptation of intact structures in lax joints. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
Leukemia inhibitory factor is augmented in the heart in experimental heart failure
Authors: Jougasaki Michihisa , Leskinen Hanna , Larsen Amy M. , Cataliotti Alessandro , Chen Horng H. , Burnett John C.
Published: March 2003

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that induces cardiac myocyte hypertrophy through the signal transducing molecule, glycoprotein 130. To date, localization of LIF in the heart and regulation of cardiac LIF expression in congestive heart failure (CHF) remain undefined. The present study investigates the potential activation of LIF expression in the failing canine heart that was produced by progressive rapid ventricular pacing. Immunohistochemistry for LIF revealed that LIF immunoreactivity was present in the atrial and ventricular myocytes of the normal heart and was markedly increased in the failing heart as compared to the normal heart. Northern blot analysis demonstrated that cardiac LIF mRNA was increased in both atrium and ventricle in CHF as compared to the normal heart (P<0.01). Linear regression analysis revealed a positive correlation between atrial LIF mRNA and atrial pressure (r=0.87, P<0.001 in right atrium and r=0.86, P<0.001 in left atrium). Positive correlations between left ventricular LIF mRNA and left ventricular dimensions (r=0.91, P<0.0001 in end‐systolic diameter; r=0.86, P<0.001 in end‐diastolic diameter), and an inverse correlation between left ventricular LIF mRNA and left ventricular ejection fraction (EF) were observed (r=−0.93, P<0.0001). There was a positive correlation between left ventricular LIF mRNA and left ventricular mass index (LVMI) (r=0.85, P<0.001). The present study demonstrates that cardiac LIF immunoreactivity and its gene expression are increased in a canine model of experimental CHF and suggests a potential role for LIF in the pathophysiology of CHF.
Regional myocardial perfusion during chronic biventricular pacing and after acute change of the pacing mode in patients with congestive heart failure and bundle branch block treated with an atrioventricular sequential biventricular pacemaker
Authors: Nielsen Jens Cosedis , Bøttcher Morten , Jensen Henrik Kjærulf , Nielsen Torsten Toftegaard , Pedersen Anders Kirstein , Mortensen Peter Thomas
Published: March 2003

Background:

Biventricular (BiV) pacing has been found to improve systolic function and exercise tolerance in patients with severe congestive heart failure and bundle branch block. The mechanisms behind this beneficial effect is still not sufficiently clarified.

Aim:

To evaluate the regional myocardial perfusion (MP) during BiV pacing and after acute change of the pacing mode to conventional dual chamber (DDD) pacing, and single chamber atrial (AAI) pacing in patients with severe congestive heart failure and prolonged QRS width treated with chronic BiV pacing.

Methods and Results:

Fourteen patients (age 63±7 years, 13 male) were evaluated 13±7 months after implantation of a triple‐chamber biventricular pacemaker. MP was quantified with 13N‐labeled ammonia positron emission tomography during BiV pacing, DDD pacing, and AAI pacing. MP was assessed in the anterior, lateral, inferior, and septal regions, and the global mean MP was calculated. Clinical assessment was performed before pacemaker implantation and after at least 3 months of BiV pacing including a 6‐min walk test (WT), New York Heart Association (NYHA) class functional score and echocardiography. Global mean MP (BiV: 0.65±0.20 vs. DDD: 0.65±0.21 vs. AAI: 0.65±0.18 mlg−1min−1) and MP in each of the four regions did not differ between the three pacing modes. The patients improved clinically during BiV pacing; 6 min WT increased (338±59 vs. 415±73 m, P<0.001), NYHA class score improved (class I/II/III/IV: 0/0/11/3 vs. 1/9/2/0, P<0.001), and left ventricular ejection fraction increased (21±5 vs. 29±8%, P=0.004).

Conclusion:

No differences in regional MP are detectable after chronic BiV pacing when the pacing mode is changed acutely in patients with severe congestive heart failure and bundle branch block. This finding indicates, that the clinical improvement caused by BiV pacing is not associated with any increase in the MP and thereby oxygen demand.
Transport of (Glyco)Sphingolipids in and Between Cellular Membranes; Multidrug Transporters and Lateral Domains
Authors: van Meer Gerrit , Sillence Dan , Sprong Hein , Kälin Nanette , Raggers René
Published: March 2003

Sphingolipids are highly enriched in the outer leaflet of the plasma membrane lipid bilayer. However, the first glycolipid, glucosylceramide, is synthesized in the opposite, cytosolic leaflet of the Golgi membrane. This has led us to experiments which suggest that the level of glucosylceramide in the cytosolic surface is carefully regulated both by the balance between synthesis and hydrolysis and by transport away from this surface through translocators, multidrug transporters, the same molecules that make cancer cells resistant to chemotherapy. Our data suggest a role for newly synthesized glucosylceramide not only in the formation of domains in the luminal leaflet of the Golgi but also on the cytosolic surface of this organelle.
Female Gametophyte Development in Higher Plants ‐ Meiosis and Mitosis Break the Cellular Barrier
Authors: Ranganath R. M.
Published: March 2003

Abstract: Meiotic products in higher plants should undergo a determined number of mitotic cycles before differentiating gametes. This creates a unique meiosis‐mitosis interface, traverse of which is an absolute requirement for gametophyte development. In the absence of cytokinesis during megasporogenesis ‐ as seen in the bisporic and tetrasporic types ‐ the haploid nuclei produced by meiosis are driven to undergo mitotic cycles within the same cell. Similarly, the last of the mitotic cycles leads to a unique type of cell wall formation resulting in cellularization of the coenocytic female gametophyte, creating a mitosis‐cellularization interface. Cell cycle regulation in terms of the molecules that interface with these two key spatio‐temporal developmental settings should be of interest to both cell and developmental biologists. High throughput techniques of functional genomics are required for both interpretation of female gametophyte evolution and success of the biotechnological initiatives of transferring apomixis‐related genes to crop plants.
Cladogram of Panamanian Clusia Based on Nuclear DNA: Implications for the Origins of Crassulacean Acid Metabolism
Authors: Gehrig H. H. , Aranda J. , Cushman M. A. , Virgo A. , Cushman J. C. , Hammel B. E. , Winter K.
Published: March 2003

Abstract: The internal transcribed spacer (ITS) region of 18‐26S nuclear ribosomal DNA repeat was sequenced for 31 of the approximately 40 species of Clusia known to occur in Panama. Several species from other genera of the Clusiaceae were used as outgroups in the phylogenetic calculation. High sequence alignment and minimal length variation among ITS‐1, 5.8S and ITS‐2 sequences facilitated determination of positional homology of nucleotide sizes. Sequence alignment was evaluated with character state (Maximum Parsimony) and distance methods (Neighbour Joining). Phylogenetic trees obtained with the two methods were largely concordant and revealed three main groups that roughly correspond to previous arrangements of species into three large morphological groups, the C. flava group, the C. minor group and the C. multiflora group. Because species of Clusia are either regular C3 plants or exhibit crassulacean acid metabolism (CAM) involving varying proportions of CO2 fixation in the dark versus the light, we mapped photosynthetic pathways onto the cladograms. Photosynthetic pathway classification was based on measurements of 13C/12C ratios of plant carbon and also on information available from the literature. Both the C. flava and C. minor group contained species exhibiting CAM, distributed on distinct branches of the cladograms, whereas the third group (C. multiflora group) was composed of species which are not known to use CAM.
Regional Planning Tensions: Planning for Economic Growth and Sustainable Development in Two Contrasting English Regions
Authors: Counsell David , Haughton Graham
Published: March 2003

The new regional governance arrangements for England are raising profound challenges for the integration of planning, sustainable-development, and economic-development strategies. The authors examine how tensions are emerging in respect of efforts to provide employment sites for large-scale inward investments, using the contrasting experiences of the South East and North East of England during the period 1997–2001. Some major ideological faultlines between national control over plan making and regional aspirations to devise distinctive approaches to planning for regional development are revealed.
Local Development Companies and the Regeneration of Britain's Cities
Authors: Raco Mike , Turok Ivan , Kintrea Keith
Published: March 2003

Efforts to decentralise the pursuit of economic and social development have increased in recent years. The authors examine the rationale for establishing local development companies in areas of high unemployment and deprivation. The broad purpose is to establish a new style of organisation that combines attributes of the public and private sectors-to adapt and integrate economic and social services to meet local needs, to champion local interests in external arenas, and to act as enabling agents to promote local investment and development. These arguments are elaborated and illustrated with reference to one of Britain's most successful local development companies, Govan Initiative. The analysis reveals important strengths of the Initiative, including its action orientation, commitment to quality, and a local leadership role, but also certain weaknesses including its limited leverage over wider policies and resource flows. Local development companies need meaningful commitment from regional and national public organisations to fulfil their potential.
Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cellsinvivo
Authors: Murdoch Barbara , Chadwick Kristin , Martin Matthew , Shojaei Farbod , Shah Kavita V. , Gallacher Lisa , Moon Randall T. , Bhatia Mickie
Published: March 2003

Human hematopoietic stem cells are defined by their ability to repopulate multiple hematopoietic lineages in the bone marrow of transplanted recipients and therefore are functionally distinct from hematopoietic progenitors detectedin vitro. Although factors capable of regulating progenitors are well established,in vivoregulators of hematopoietic repopulating function are unknown. By using a member of the vertebrate Wnt family, Wnt-5A, the proliferation and differentiation of progenitors cocultured on stromal cells transduced with Wnt-5A or treated with Wnt-5A conditioned medium (CM) was unaffected. However, i.p. injection of Wnt-5A CM into mice engrafted with human repopulating cells increased multilineage reconstitution by >3-fold compared with controls. Furthermore,in vivotreatment of human repopulating cells with Wnt-5A CM produced a greater proportion of phenotypically primitive hematopoietic progeny that could be isolated and shown to possess enhanced progenitor function independent of continued Wnt-5A treatment. Our study demonstrates that Wnt-5A augments primitive hematopoietic developmentin vivoand represents anin vivoregulator of hematopoietic stem cell function in the human. Based on these findings, we suggest a potential role for activation of Wnt signaling in managing patients exhibiting poor hematopoietic recovery shortly after stem cell transplantation.
Heat shock protein coinducers with no effect on protein denaturation specifically modulate the membrane lipid phase
Authors: Török Zsolt , Tsvetkova Nelly M. , Balogh Gábor , Horváth Ibolya , Nagy Enikő , Pénzes Zoltán , Hargitai Judit , Bensaude Olivier , Csermely Péter , Crowe John H. , Maresca Bruno , Vígh László
Published: March 2003

The hydroxylamine derivative bimoclomol (BM) has been shown to activate natural cytoprotective homeostatic responses by enhancing the capability of cells to cope with various pathophysiological conditions. It exerts its effect in synergy with low levels of stress to induce the synthesis of members of major stress protein families. We show here that the presence of BM does not influence protein denaturation in the cells. BM and its derivatives selectively interact with acidic lipids and modulate their thermal and dynamic properties. BM acts as a membrane fluidizer at normal temperature, but it is a highly efficient membrane stabilizer, inhibiting the bilayer–nonbilayer phase transitions during severe heat shock. We suggest that BM and the related compounds modify those domains of membrane lipids where the thermally or chemically induced perturbation of lipid phase is sensed and transduced into a cellular signal, leading to enhanced activation of heat shock genes. BM may be a prototype for clinically safe membrane-interacting drug candidates that rebalance the level and composition of heat shock proteins.
Therapeutic photobiomodulation for methanol-induced retinal toxicity
Authors: Eells J. T. , Henry M. M. , Summerfelt P. , Wong-Riley M. T. T. , Buchmann E. V. , Kane M. , Whelan N. T. , Whelan H. T.
Published: March 2003

Methanol intoxication produces toxic injury to the retina and optic nerve, resulting in blindness. The toxic metabolite in methanol intoxication is formic acid, a mitochondrial toxin known to inhibit the essential mitochondrial enzyme, cytochrome oxidase. Photobiomodulation by red to near-IR radiation has been demonstrated to enhance mitochondrial activity and promote cell survival
in vitro
by stimulation of cytochrome oxidase activity. The present studies were undertaken to test the hypothesis that exposure to monochromatic red radiation from light-emitting diode (LED) arrays would protect the retina against the toxic actions of methanol-derived formic acid in a rodent model of methanol toxicity. Using the electroretinogram as a sensitive indicator of retinal function, we demonstrated that three brief (2 min, 24 s) 670-nm LED treatments (4 J/cm
2
), delivered at 5, 25, and 50 h of methanol intoxication, attenuated the retinotoxic effects of methanol-derived formate. Our studies document a significant recovery of rod- and cone-mediated function in LED-treated, methanol-intoxicated rats. We further show that LED treatment protected the retina from the histopathologic changes induced by methanol-derived formate. These findings provide a link between the actions of monochromatic red to near-IR light on mitochondrial oxidative metabolism
in vitro
and retinoprotection
in vivo
. They also suggest that photobiomodulation may enhance recovery from retinal injury and other ocular diseases in which mitochondrial dysfunction is postulated to play a role.
Type I polyketide synthase requiring a discrete acyltransferase for polyketide biosynthesis
Authors: Cheng Yi-Qiang , Tang Gong-Li , Shen Ben
Published: March 2003

Type I polyketide synthases (PKSs) are multifunctional enzymes that are organized into modules, each of which minimally contains a β-ketoacyl synthase, an acyltransferase (AT), and an acyl carrier protein. Here we report that the leinamycin (LNM) biosynthetic gene cluster from
Streptomyces atroolivaceus
S-140 consists of two PKS genes,
lnmI
and
lnmJ
, that encode six PKS modules, none of which contain the cognate AT domain. The only AT activity identified within the
lnm
gene cluster is a discrete AT protein encoded by
lnmG
. Inactivation of
lnmG
,
lnmI
, or
lnmJ in vivo
abolished LNM biosynthesis. Biochemical characterization of LnmG
in vitro
showed that it efficiently and specifically loaded malonyl CoA to all six PKS modules. These findings unveiled a previously unknown PKS architecture that is characterized by a discrete, iteratively acting AT protein that loads the extender units in trans to “AT-less” multifunctional type I PKS proteins for polyketide biosynthesis. This PKS structure provides opportunities for PKS engineering as exemplified by overexpressing
lnmG
to improve LNM production.
Proteasome-dependent, ubiquitin-independent degradation of the Rb family of tumor suppressors by the human cytomegalovirus pp71 protein
Authors: Kalejta Robert F. , Shenk Thomas
Published: March 2003

Most of the substrates degraded by the proteasome are marked with polyubiquitin chains. However, there are a limited number of examples of nonubiquitinated proteins that are degraded by the proteasome. Here, we describe the degradation of the retinoblastoma family of tumor suppressor proteins by the proteasome in the absence of polyubiquitination. The retinoblastoma protein (p105), p107, and p130 are each targeted for degradation by the pp71 protein, which is encoded by the UL82 gene of human cytomegalovirus. It functions to direct their degradation in the absence of other viral proteins. While the pp71-mediated degradation of the retinoblastoma family of proteins requires proteasome function, it occurs without the attachment of ubiquitin to the substrates and in the absence of a functioning ubiquitin-conjugation system.
Gelsolin is a dorsalizing factor in zebrafish
Authors: Kanungo Jyotshnabala , Kozmik Zbynek , Swamynathan Shivalingappa K. , Piatigorsky Joram
Published: March 2003

The gene for gelsolin (an actin-binding, cytoskeletal regulatory protein) was shown earlier to be specialized for high corneal expression in adult zebrafish. We show here that zebrafish gelsolin is required for proper dorsalization during embryogenesis. Inhibition of gelsolin expression by injecting fertilized eggs with a specific morpholino oligonucleotide resulted in a range of concentration-dependent ventralized phenotypes, including those lacking a brain and eyes. These were rescued by coinjection of zebrafish gelsolin or chordin (a known dorsalizing agent) mRNAs, or human gelsolin protein. Moreover, injection of gelsolin mRNA or human gelsolin protein by itself dorsalized the developing embryos, often resulting in axis duplication. Injection of the gelsolin-specific morpholino oligonucleotide enhanced the expression of Vent mRNA, a ventral marker downstream of bone morphogenetic proteins, whereas injection of gelsolin mRNA enhanced the expression of chordin and goosecoid mRNAs, both dorsal markers. Our results indicate that gelsolin also modulates embryonic dorsal/ventral pattern formation in zebrafish.
Relaxed selective pressure on an essential component of pheromone transduction in primate evolution
Authors: Liman Emily R. , Innan Hideki
Published: March 2003

The vomeronasal organ (VNO) detects pheromones in many vertebrate species but is likely to be vestigial in humans.
TRPC2(TRP2)
, a gene that is essential for VNO function in the mouse, is a pseudogene in humans. Because
TRPC2
is expressed only in the VNO, the loss of selective pressure on this gene can serve as a molecular marker for the time at which the VNO became vestigial. By analyzing sequence data from the
TRPC2
gene of 15 extant primate species, we provide evidence that the VNO was most likely functional in the common ancestor of New World monkeys and Old World monkeys and apes, but then became vestigial in the common ancestor of Old World monkeys and apes. We propose that, at this point in evolution, other modalities, notably the development of color vision, may have largely replaced signaling by pheromones.
Cost minimization by helpers in cooperative vertebrates
Authors: Russell A. F. , Sharpe L. L. , Brotherton P. N. M. , Clutton-Brock T. H.
Published: March 2003

When parents invest heavily in reproduction they commonly suffer significant energetic costs. Parents reduce the long-term fitness implications of these costs through increased foraging and reduced reproductive investment in the future. Similar behavioral modifications might be expected among helpers in societies of cooperative vertebrates, in which helping is associated with energetic costs. By using multivariate analyses and experiments, we show that in cooperative meerkats,
Suricata suricatta
, helping is associated with substantial short-term growth costs but limited long-term fitness costs. This association forms because individual contributions to cooperation are initially condition dependent, and, because when helpers invest heavily in cooperation, they increase their foraging rate during the subsequent nonbreeding period and reduce their level of cooperative investment in the subsequent reproductive period. These results provide a unique demonstration that despite significant short-term costs, helpers, like breeders, are able to reduce the fitness consequences of these costs through behavioral modifications.
Pituitary tumor transforming gene-null male mice exhibit impaired pancreatic beta cell proliferation and diabetes
Authors: Wang Zhiyong , Moro Enrico , Kovacs Kalman , Yu Run , Melmed Shlomo
Published: March 2003

The mammalian securin, pituitary tumor transforming gene (PTTG), regulates sister chromatid separation during mitosis. Mice or cell lines deficient in PTTG expression, however, are surprisingly viable. Here we show that PTTG disruption in mice (PTTG−/−) severely impairs glucose homeostasis leading to diabetes during late adulthood, especially in males associated with nonautoimmune insulinopenia and reversed alpha/beta cell ratio. Islet beta cell mass in PTTG−/− mice was already diminished before development of frank diabetes and only increased minimally during growth. BrdUrd incorporation of islet cells in PTTG-null mice was ≈65% lower (
P
< 0.005) than in the WT pancreas, whereas apoptosis rates were similar. PTTG−/− beta cells had pleiotropic nuclei, suggesting defects in cell division. The results indicated that securin is indispensable for normal pancreatic beta cell proliferation.
Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci
Authors: Zhang Hong , Pan Kuang-Hung , Cohen Stanley N.
Published: March 2003

Replicative senescence is the state of irreversible proliferative arrest that occurs as a concomitant of progressive telomere shortening. By using cDNA microarrays and the
gabriel
system of computer programs to apply domain-specific and procedural knowledge for data analysis, we investigated global changes in gene transcription occurring during replicative senescence in human fibroblasts and mammary epithelial cells (HMECs). Here we report the identification of transcriptional “fingerprints” unique to senescence, the finding that gene expression perturbations during senescence differ greatly in fibroblasts and HMECs, and the discovery that despite the disparate nature of the chromosomal loci affected by senescence in fibroblasts and HMECs, the up-regulated loci in both types of cells show physical clustering. This clustering, which contrasts with the random distribution of genes down-regulated during senescence or up-regulated during reversible proliferative arrest (i.e., quiescence), supports the view that replicative senescence is associated with alteration of chromatin structure.
New AI and service robots
Authors: Gomi Takashi
Published: March 2003

A new breed of robotics more suitable for service applications than manufacturing is appearing. It focuses on autonomous operation rather than control, and is characterized by the flexible, robust, and agile nature of robots' motions. Some such robots, namely the ones called Behavior‐based robots and those robots that operate under the New AI paradigm, share principles of operation with biological systems such as animals and insects. They excel in their mobility and adaptability when allowed to operate “untethered” in the dynamic and highly non‐linear environment of the real world. Processes similar to evolution of living systems are sometimes applied to evolve the software (and occasionally hardware) of these bio‐robots to further increase their adaptability in the operational environment. Some early applications are presented.
The right to health of disaster victims
Authors: Gunn S. William A.
Published: March 2003

Health is a human right and remains so under all circumstances. It becomes, however, particularly vulnerable in emergency and disaster situations, and even in efficient and well‐meaning relief operations the health rights of victims usually get overlooked, if not downtrodden. Five international conventions or instruments that underpin this right and guide the disaster responder to respect it are put forward for more efficient and more humanitarian disaster management.
COMPLEX PATTERNS ON THE PLANE: DIFFERENT TYPES OF BASIN FRACTALIZATION IN A TWO-DIMENSIONAL MAPPING
Authors: LÓPEZ-RUIZ RICARDO , FOURNIER-PRUNARET DANIÈLE
Published: March 2003

Basins generated by a noninvertible mapping formed by two symmetrically coupled logistic maps are studied when the only parameter λ of the system is modified. Complex patterns on the plane are visualized as a consequence of the basins' bifurcations. According to the already established nomenclature in the literature, we present the relevant phenomenology organized in different scenarios: fractal islands disaggregation, finite disaggregation, infinitely disconnected basin, infinitely many converging sequences of lakes, countable self-similar disaggregation and sharp fractal boundary. By use of critical curves, we determine the influence of zones with different number of first rank preimages in the mechanisms of basin fractalization.
NUMERICAL OBSERVATIONS ON SEPARATRIX CROSSINGS
Authors: FRANCIS RUSSELL , YOUNG TODD
Published: March 2003

We investigate one degree of freedom Hamiltonian systems when trajectories cross a separatrix. We study such systems numerically using high precision computations and compare our results with first order, analytical predictions. In all our experiments we find oscillatory behavior which is not predicted by the first order analysis.
TWO-DIMENSIONAL BIFURCATION DIAGRAMS: BACKGROUND PATTERN OF FUNDAMENTAL DC–DC CONVERTERS WITH PWM CONTROL
Authors: BENADERO L. , EL AROUDI A. , OLIVAR G. , TORIBIO E. , GÓMEZ E.
Published: March 2003

One of the usual ways to build up mathematical models corresponding to a wide class of DC–DC converters is by means of piecewise linear differential equations. These models belong to a class of dynamical systems called Variable Structure Systems (VSS). From a classical design point of view, it is of interest to know the dynamical behavior of the system when some parameters are varied. Usually, Pulse Width Modulation (PWM) is adopted to control a DC–DC converter. When this kind of control is used, the resulting mathematical model is nonautonomous and periodic. In this case, the global Poincaré map (stroboscopic map) gives all the information about the system.

The classical design in these electronic circuits is based on a stable periodic orbit which has some desired characteristics. In this paper, the main bifurcations which may undergo this orbit, when the parameters of the circuit change, are described. Moreover, it will be shown that in the three basic power electronic converters Buck, Boost and Buck–Boost, very similar scenarios are obtained. Also, some kinds of secondary bifurcations which are of interest for the global dynamical behavior are presented. From a dynamical systems point of view, VSS analyzed in this work present some kinds of bifurcations which are typical in nonsmooth systems and it is impossible to find them in smooth systems.
PARALLEL SUBSPACE PROJECTION BEAMFORMING FOR AUTONOMOUS, PASSIVE SONAR SIGNAL PROCESSING
Authors: KIM KEONWOOK , GEORGE ALAN D.
Published: March 2003

Adaptive techniques can be applied to improve performance of a beamformer in a cluttered environment. The sequential implementation of an adaptive beamformer, for many sensors and over a wide band of frequencies, presents a serious computational challenge. By coupling each transducer node with a microprocessor, in-situ parallel processing applied to an adaptive beamformer on a distributed system can glean advantages in execution speed, fault tolerance, scalability, and cost. In this paper, parallel algorithms for Subspace Projection Beamforming (SPB), using QR decomposition on distributed systems, are introduced for in-situ signal processing. Performance results from parallel and sequential algorithms are presented using a distributed system testbed comprised of a cluster of computers connected by a network. The execution times, parallel efficiencies, and memory requirements of each parallel algorithm are presented and analyzed. The results of these analyses demonstrate that parallel in-situ processing holds the potential to meet the needs of future advanced beamforming algorithms in a scalable fashion.
FRACTAL CHANGES IN HEART RATE DYNAMICS WITH AGING AND HEART FAILURE
Authors: GUZMAN-VARGAS L. , CALLEJA-QUEVEDO E. , ANGULO-BROWN F.
Published: March 2003

In this work we analyze interbeat cardiac time series arising of three groups: healthy young and healthy elderly subjects and patients with congestive heart failure. We use the fractal dimension method proposed by Higuchi. We find that fractal organization is different for each group. In the case of healthy young subjects only one value of the fractal dimension is necessary to fit the interbeat data, whereas in the cases of healthy elderly and patients with congestive heart failure a crossover behavior in the fractal dimension is present but in opposite directions. By means of a "zoom" on the hinges of the crossover point interesting effects of aging are presented. Finally, we discuss our results in the context of heart interbeat dynamics.
Effects of Antiarrhythmic Drugs on Fibrillation in the Remodeled Atrium
Authors: Shinagawa Kaori , Shiroshita-Takeshita Akiko , Schram Gernot , Nattel Stanley
Published: March 2003

Background—

The basis of the unique effectiveness of amiodarone for atrial fibrillation (AF) is poorly understood. The present study tested the hypothesis that amiodarone blocks electrical remodeling induced by atrial tachycardia.

Methods and Results—

Mongrel dogs were subjected to atrial tachycardia (400 bpm for 7 days) in the absence and presence of therapy with amiodarone, the class III cardiac antiarrhythmic drug dofetilide, or the class I agent flecainide begun 3 days before the onset of tachypacing and maintained until a final electrophysiological study. AF vulnerability (percentage of sites with AF induction by single premature extrastimuli), mean AF duration, atrial effective refractory period (ERP), and conduction velocity were compared among these dogs and in unpaced dogs in the absence or presence of treatment with the same agents. Only amiodarone prevented promotion of AF duration and vulnerability by atrial tachycardia. Furthermore, only amiodarone eliminated tachycardia-induced ERP abbreviation and loss of ERP rate adaptation while obviating L-type Ca
2+
-current α
1c
-subunit downregulation as determined by Western blot. In an additional series of dogs monitored with repeated electrophysiological studies, amiodarone administered after the induction of atrial tachycardia remodeling reversed remodeling within several days, despite continued atrial tachypacing during amiodarone therapy.

Conclusions—

Amiodarone is uniquely effective against AF promotion by atrial tachycardia remodeling in this experimental model and prevents electrophysiological and biochemical consequences of remodeling. Amiodarone also reversed remodeling established by 4 days of atrial tachycardia. The inhibition of atrial tachycardia remodeling may therefore contribute to the superior efficacy of amiodarone in AF.
Cyclooxygenase-2 Expression and Role of Vasoconstrictor Prostanoids in Small Mesenteric Arteries From Patients With Crohn’s Disease
Authors: Tabernero Antonia , Reimund Jean-Marie , Chasserot Sylvette , Muller Christian Dominique , Andriantsitohaina Ramaroson
Published: March 2003

Background—

The present study investigates the vascular reactivity and the involvement of nitric oxide and prostanoids in regulating vasoconstriction of small mesenteric arteries from patients with Crohn’s disease (CD) to understand the vascular component of this pathology.

Methods and Results—

An increased production of proinflammatory cytokines (tumor necrosis factor-α and interleukins 1β, 6, and 8) has been observed in biopsy specimens of inflammatory intestinal mucosa. However, contractile responses of small mesenteric arteries from CD patients in response to norepinephrine were not changed ex vivo when compared with controls. Exposure to either the nitric oxide synthase inhibitor N
G
-nitro-
l
-arginine or the cyclooxygenase (COX) inhibitor indomethacin did not modify contractions induced by norepinephrine in either control or CD patients. However, in the latter, the specific COX-2 inhibitor N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide significantly attenuated norepinephrine-induced vasoconstriction. Furthermore, immunohistochemical analysis showed marked COX-2 expression in the whole arterial wall of vessels from CD patients. Vessels from control patients exhibited weak COX-2 staining in the adventitial and endothelial layers only.

Conclusions—

The above results provide direct evidence for COX-2 expression in small mesenteric arteries from CD patients. They also shed new light on the involvement of vasoconstrictor metabolites of COX in regulating contraction of these arteries. Of particular interest is the balance between vasoconstrictor products from COX-2 and unidentified vasodilatory products that maintained vascular reactivity in a physiological range despite an increase of circulatory cytokines in patients with CD.
Angiogenic Property of Hepatocyte Growth Factor Is Dependent on Upregulation of Essential Transcription Factor for Angiogenesis, ets-1
Authors: Tomita Naruya , Morishita Ryuichi , Taniyama Yoshiaki , Koike Hiromi , Aoki Motokuni , Shimizu Hideo , Matsumoto Kunio , Nakamura Toshikazu , Kaneda Yasufumi , Ogihara Toshio
Published: March 2003

Background—

Although hepatocyte growth factor (HGF) is an angiogenic growth factor, it is still unclear how it exerts its angiogenic effects. Thus, we focused on the role of an essential transcription factor for angiogenesis, ets-1. In this study, we addressed the following specific questions: (1) what genes responsible for angiogenesis can be regulated by HGF and (2) whether upregulation of gene expression for angiogenesis is dependent on ets-1.

Methods and Results—

In human endothelial cells, HGF significantly stimulated the matrix-degrading pathway, such as the production of matrix metalloprotease-1 (MMP-1) through its specific receptor, c-met. In addition, HGF also significantly increased HGF itself and its specific receptor, c-met. Moreover, HGF significantly increased the transcription activity and mRNA expression of ets-1 in a time-dependent manner. Importantly, transfection of antisense ets-1 oligodeoxynucleotides (ODN) resulted in a significant reduction in MMP-1, HGF and c-met. Interestingly, HGF also stimulated ets-1 mRNA in vascular smooth muscle cells, similar to endothelial cells. Of importance, transfection of antisense ets-1 ODN resulted in a significant decrease in vascular endothelial growth factor (VEGF) and HGF expression, whereas HGF stimulated both HGF and VEGF expression. Moreover, in vivo transfection of ets-1 antisense ODN resulted in an inhibition of angiogenesis induced by the HGF gene in a rat ischemic hindlimb model.

Conclusions—

Here, we demonstrated that HGF stimulated the expression of MMP-1, VEGF, HGF itself, and c-met in human endothelial cells and vascular smooth muscle cells. Upregulation of angiogenesis-related genes was largely dependent on the induction of ets, especially ets-1. These data provide new information about the mechanisms of angiogenesis.
The Naturally Occurring Variant of Estrogen Receptor (ER) ERΔE7 Suppresses Estrogen-Dependent Transcriptional Activation by Both Wild-Type ERα and ERβ
Authors: García Pedrero Juana M. , Zuazua Pedro , Martínez-Campa Carlos , Lazo Pedro S. , Ramos Sofía
Published: March 2003

We have isolated and functionally characterized the exon 7-skipped variant (ERΔE7) of estrogen receptor (ER)α, which has emerged as the predominant variant expressed in multiple normal and tumoral tissues. However, to date no function has been established for this variant in mammalian cells. ERΔE7 exhibits a negligible ability to bind ligands, insensitivity to allosteric modulation by estrogen and antiestrogens, and loss of estrogen-dependent interaction with p160 coactivators such as SRC-1 and AIB1. ERΔE7 is able to form heterodimers with both ERα and ERβ in a ligand-independent manner. Transient expression experiments in HeLa cells show that increasing amounts of ERΔE7 result in a progressive inhibition of the estrogen-dependent transcriptional activation by both wild-type ERα and ERβ on estrogen response element-driven promoters. The inhibitory effect of ERΔE7 is due to the inhibition of binding of wild-type receptors to their responsive elements. Surprisingly, the activation function (AF)-1-dependent transactivation triggered by epithelial growth factor and phorbol-12-myristate-13-acetate is also abolished in ERΔE7 despite AF1 integrity, suggesting a cross-talk between AF1 and AF2 regions of the receptor. These results indicate that the naturally occurring variant ERΔE7 is a dominant negative receptor that, when expressed at high levels relative to wild-type ERs, might have profound effects on several estrogen-dependent functions.
Coenzyme Q Induces Nigral Mitochondrial Uncoupling and Prevents Dopamine Cell Loss in a Primate Model of Parkinson’s Disease
Authors: Horvath Tamas L. , Diano Sabrina , Leranth Csaba , Garcia-Segura Luis Miguel , Cowley Michael A. , Shanabrough Marya , Elsworth John D. , Sotonyi Peter , Roth Robert H. , Dietrich Edwin H. , Matthews Russel T. , Barnstable Colin J. , Redmond D. Eugene
Published: March 2003

Parkinson’s disease is characterized by dopamine cell loss of the substantia nigra. Parkinson’s disease and the neurotoxin 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine may destroy dopamine neurons through oxidative stress. Coenzyme Q is a cofactor of mitochondrial uncoupling proteins that enhances state-4 respiration and eliminate superoxides. Here we report that short-term oral administration of coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine administration in monkeys.
The bHLH protein Dimmed controls neuroendocrine cell differentiation inDrosophila
Authors: Hewes Randall S. , Park Dongkook , Gauthier Sebastien A. , Schaefer Anneliese M. , Taghert Paul H.
Published: March 2003

Neuroendocrine cells are specialized to produce, maintain and release large stores of secretory peptides. We show that the Drosophila dimmed/Mist1 bHLH gene confers such a pro-secretory phenotype on neuroendocrine cells. dimmed is expressed selectively in central and peripheral neuroendocrine cells. In dimmed mutants, these cells survive, and adopt normal cell fates and morphology. However, they display greatly diminished levels of secretory peptide mRNAs, and of diverse peptides and proteins destined for regulated secretion. Secretory peptide levels are lowered even in the presence of artificially high secretory peptide mRNA levels. In addition, overexpression of dimmed in a wild-type background produces a complimentary phenotype: an increase in secretory peptide levels by neuroendocrine cells, and an increase in the number of cells displaying a neuroendocrine phenotype. We propose that dimmed encodes an integral component of a novel mechanism by which diverse neuroendocrine lineages differentiate and maintain the pro-secretory state.
Xbrafunctions as a switch between cell migration and convergent extension in theXenopusgastrula
Authors: Kwan Kristen M. , Kirschner Marc W.
Published: March 2003

During Xenopus gastrulation, the dorsal mesoderm exhibits two different cell behaviors in two different regions: active cell migration of prechordal mesoderm and convergent extension of chordamesoderm. Although many genes involved in specification and differentiation of the dorsal mesoderm have been studied, the role of these genes in controlling cell behaviors is poorly understood. To understand better the link between the development and cell behaviors of the dorsal mesoderm, we have examined these behaviors in dissociated cells and explants, where activin protein can induce both active cell migration and convergent extension. We find that Xbra, a transcription factor necessary for convergent extension, actively inhibits cell migration, both in animal cap explant assays and in the endogenous dorsal mesoderm. In addition, Xbra appears to inhibit cell migration by inhibiting adhesion to fibronectin. We propose that Xbra functions as a switch to keep cell migration and convergent extension as mutually exclusive behaviors during gastrulation.
Bazooka is a permissive factor for the invasive behavior ofdiscs largetumor cells inDrosophilaovarian follicular epithelia
Authors: Abdelilah-Seyfried Salim , Cox Daniel N. , Jan Yuh Nung
Published: March 2003

Drosophila Bazooka and atypical protein kinase C are essential for epithelial polarity and adhesion. We show here that wild-type bazookafunction is required during cell invasion of epithelial follicle cells mutant for the tumor suppressor discs large. Clonal studies indicate that follicle cell Bazooka acts as a permissive factor during cell invasion,possibly by stabilizing adhesion between the invading somatic cells and their substratum, the germline cells. Genetic epistasis experiments demonstrate thatbazooka acts downstream of discs large in tumor cell invasion. In contrast, during the migration of border cells, Bazooka function is dispensable for cell invasion and motility, but rather is required cell-autonomously in mediating cell adhesion within the migrating border cell cluster. Taken together, these studies reveal Bazooka functions distinctly in different types of invasive behaviors of epithelial follicle cells,potentially by regulating adhesion between follicle cells or between follicle cells and their germline substratum.
The effect of clamping a tensioned wire: Implications for the Ilizarov external fixation system
Authors: Watson M A , Mathias K J , Maffulli N , Hukins D W L
Published: March 2003

This study demonstrates that clamping a tensioned wire can cause a reduction in wire tension. Tension (about 1275 N) was applied to a wire that was subsequently clamped, using cannulated bolts, to the steel half-ring of an Ilizarov external fixator. The tension in the wire was monitored before, during and after clamping. The apparatus was disassembled and the deformations in the wire caused by the clamps were measured. This experiment was repeated 15 times. When the wire was clamped to the frame, the wire tension was reduced by 22 ± 7 per cent (mean ± standard deviation, SD). The drop in wire tension was linearly correlated ( r = 0.96; p < 0.001) with the deformation caused by the bolts. A finite element (FE) model of the wire was also constructed. The model was pre-stressed (tensioned), and the clamping effect replicated. This analysis showed that clamping the wire could be considered to squeeze the wire outwards (like toothpaste from a tube) and so reduce its tension during fixator assembly. To assess the magnitude of this effect in the clinical situation, the FE model analysis was repeated to replicate clamping a 1.8-mm-diameter wire to a 180-mm-diameter steel Ilizarov ring component. The analysis showed that for these conditions the tension reduced by 8–29 per cent. The results of this study highlight a general engineering problem: how can a tensioned wire be secured to a structure without an appreciable loss of tension? If the performance of the structure depends on the wire tension, this performance will change when the wire is secured.