bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Fever in Disease
Authors: KLUGER MATTHEW J. , KOZAK WIESLAW , CONN CAROLE A. , LEON LISA R. , SOSZYNSKI DARIUSZ
Published: February 2006

ABSTRACT: Infection, trauma, and injury result in a stereotypical response that includes loss of food appetite, increased sleepiness, muscle aches, and fever. For thousands of years fever was considered a protective response, and fevers were induced by physicians to combat certain infections. But with the advent of antipyretic drugs, physicians started to reduce fevers, and fever therapy was virtually abandoned. As a result of (1) studies on the evolution of fever, (2) further understanding of just how tightly the process of fever is regulated, and (3) detailed studies on how fever affects host morbidity and mortality, the view of fever as a host defense response has reemerged. However, data indicate that not all fevers are protective and that high fevers are maladaptive. These issues are discussed in the context of the evolution of host defense responses versus modern medical technology. In short, we speculate that patients who would not have survived severe sepsis in the past are now being kept alive and that the occasionally high fevers seen in these patients may be maladaptive.
Adaptive Interactions between Cytokines and the Hypothalamic‐Pituitary‐Gonadal Axis
Authors: CANNON JOSEPH G.
Published: February 2006

ABSTRACT: Circulating and tissue concentrations of pyrogenic cytokines, especially interleukin (IL)‐1β, vary temporally through the menstrual cycle and pregnancy. The secretion of these cytokines in vitro by isolated human mononuclear cells is significantly influenced by exogenous gonadal steroids and gonadotropins. Reciprocally, cytokines influence gonadotropin secretion by the pituitary and steroidogenesis by the ovaries and testes. Several hypotheses have been advanced regarding the adaptive value of these interrelationships. Cytokine‐induced synthesis of proteolytic enzymes and extracellular matrix proteins may be important for the tissue remodeling necessary for ovulation, implantation, and delivery. Tolerance of the fetal allograft may require downregulation of cytotoxic effector cells and reciprocal upregulation of humoral and nonspecific host defenses. The inhibitory influence of IL‐1β on the luteinizing hormone surge may prevent inopportune conception, and the abortive influences of tumor necrosis factor‐α and gamma interferon may terminate pregnancy during periods of infection.
Proinflammatory Cytokines and Treatment of Disease
Authors: VAN DER MEER JOS W.M. , VOGELS MARIA T.E. , NETEA MIHAI G. , KULLBERG BART JAN
Published: February 2006

ABSTRACT: Bacterial infections in the immunocompromised host cause considerable mortality, and even recently developed antimicrobial strategies often fail to cure these infections, especially in granulocytopenic patients. Cytokines and hematopoietic growth factors have been shown to stimulate host defense mechanisms in vitro and in vivo. The possible role of the proinflammatory cytokines interleukin (IL)‐1, tumor necrosis factor‐α, IL‐6, and IL‐8 as modulators of host resistance to bacterial infections is discussed. Interleukin‐1 has been effective in various animal models of potentially lethal bacterial infection, even during severe granulocytopenia. The protective mechanism of IL‐1 may be mediated by downregulation of cytokine receptors and cytokine production and induction of acute phase proteins. Moreover, in subacute and chronic infections IL‐1 interferes with microbial outgrowth via mechanisms that have only been partly elucidated.
Influence of Prenatal Diagnosis on Congenital Heart Defects
Authors: DeVORE GREGGORY R.
Published: February 2006

Abstract: The impact of prenatal detection of congenital heart defects (CHD) using the four‐chamber screening examination cannot be accurately ascertained because of the wide range of detection rates that affect the cost associated with it. Assuming a screening ultrasound cost of $200 per examination, recent studies in which examiners not trained in fetal echocardiography obtained and interpreted the four‐chamber view only identified 5.3% of CHD, for a cost of $476,190 per malformation. When the four‐chamber screening examination was performed by an individual trained in fetal echocardiography, the detection rate increased to 55%, for a cost of $45,454 per malformation. This resulted in a savings of 90%, or $430,736. Because individuals trained in fetal echocardiography are not available to perform and interpret all of the heart screening examinations, another approach is for the fetal echocardiographer to review one to two minute video clips of the four‐chamber and outflow tracts screening examination obtained by the individual performing the fetal screening examination. It is estimated that at a charge of $30 per video clip review, the cost to detect 50% of CHD would be $7,500 per defect. This would result in a reduction of 98% for the detection of CHD using current screening methods. This approach would increase the detection rate of CHD by 10‐fold, remove the liability of missing CHD from the untrained individual performing the screening examination, and provide revenue to tertiary centers in which individuals skilled in fetal echocardiography could maximize their diagnostic skills.
Eurofetus: An Evaluation of Routine Ultrasound Screening for the Detection of Fetal Defectsa: Aims and Method
Authors: LEVI SALVATOR , MONTENEGRO NUNO AIRES
Published: February 2006

Abstract: The aims of this study are (1) to evaluate the efficiency of ultrasound in detecting CA in low‐risk populations of pregnant women by routine screening performed in hospital ultrasound labs (level II); (2) to highlight the areas where improvement could be obtained; (3) to determine efficient timing and number of examinations; (4) to evaluate the psychological returns of detection and nondetection of CA; and (5) to evaluate the cost‐effectiveness ratio of antenatal screening of CA. A European collaboration was supposed to help in meeting these objectives because results concerning the analysis of individual CAs or groups of CAs can only be statistically significant when their number is sufficiently large. It was estimated that it was necessary to collect nearly 5,000 CA; this corresponds to about 200,000 pregnant women, the prevalence of malformations at birth being estimated at 2.5%. These conditions yield worthy conclusions, given the following circumstances: a large variety of CA, the extremely low incidence of each CA, the multiple approaches for diagnosis and management, the manifold classes of defects, the differences in gestational age when anomalies are detectable and detected. We study prospectively (1) the reliability of ultrasound in detecting antenatal malformations by recording all CA, ultrasonically suspected and not; (2) the gestational age of anomaly recognition; (3) the response to antenatal diagnosis of CA; (4) the individual outcome of pregnancies; (5) the financial cost of the screening program; and (6) the psychological consequences for the parents.
Sensitivity of Fetal Anomaly Detection as a Function of Timea
Authors: DERVAUX B. , LELEU H. , LEBRUN TH. , LEVI S. , GRANDJEAN H.
Published: February 2006

Abstract: In this paper, we show that the ratio of the number of fetal anomalies detected by ultrasounds (US) to the total number of cases is not a consistent estimator of the US sensitivity. As Eddy 1 pointed out, when the disease evolves over time, the sensitivity of a test also varies over time according to the development of the disease. To assess correctly the detection capability of a test, it is therefore necessary to estimate a time continuous function (sensitivity function) instead of a single parameter. From a methodological point of view, by considering the “detectability” time of a fetal anomaly as a random variable and parametrizing its distribution function, we estimate the probability that an anomaly is detected conditional upon the precise timing of actually performed US during pregnancy. We fit this model with Eurofetus data (about 7,300 abnormal fetuses), and we compare estimations for different kinds of anomalies (classification based on the system involved and/or severity of the handicap). To allow for heterogeneity of anomalies regarding the detectability time, we generally adopt mixture models. For instance, we select a bi‐gamma distribution for major malformations and estimate that 63% of such anomalies are detectable quite early in pregnancy (conditional mean: 15.2 weeks of amenorrhea (WA) ± 4.2 WA), the others becoming detectable later (30.3 WA ± 6.4 WA). Such results are then integrated in a cost‐effectiveness analysis.
Detection of Chromosomal Abnormalities, an Outcome of Ultrasound Screening
Authors: GRANDJEAN HÉLÈNE , LARROQUE DANIÈLE , LEVI SALVATOR ,   THE EUROFETUS TEAM
Published: February 2006

Abstract: Chromosomal abnormalities were recorded from all the fetuses of women who benefited from sonographic examinations in the Eurofetus centers, excluding those for whom karyotyping was motivated by age or personal history. Among the 378 chromosomal abnormalities recorded, 210 were detected before birth (sensitivity = 55.6%). Down syndrome (trisomy 21) represented 197 cases, of which 68 were detected before birth (sensitivity = 34.5%). Eighty‐two of the cases of Down syndrome had associated structural abnormalities; the sensitivity in these cases increased to 57%. Among the 115 cases of Down syndrome without structural abnormalities, 21 (18.3%) had associated abnormal ultrasound findings that led to prenatal detection. Sensitivity of prenatal detection was 58.1% for trisomy 13 and 79% for trisomy 18. For the abnormalities detected before birth, spontaneous fetal death occurred in 27% of cases, and an early termination of pregnancy was decided in 53% of cases.
Reduced Costs of Congenital Anomalies from Fetal Ultrasound: Are They Sufficient to Justify Routine Screening in the United States?
Authors: WAITZMAN NORMAN J. , ROMANO PATRICK S.
Published: February 2006

Abstract: No comprehensive benefit‐to‐cost analysis has been performed to date on a policy of routine ultrasound screening for fetal anomalies in the United States. We performed a preliminary benefit‐to‐cost analysis drawing upon our previous research on the cost of birth defects in the United States and upon the literature regarding (1) the sensitivity of ultrasound in detecting congenital anomalies, (2) the rate at which pregnancies are terminated upon detection of fetal anomalies, (3) the number of ultrasounds performed per pregnancy under a routine screening policy, and (4) the average cost of an ultrasound. We assumed a 100% subsequent replacement rate of terminated pregnancies with a normal child, an assumption most favorable to routine screening. The benefit‐to‐cost ratio ranged from .33 to 3, suggesting that a routine screening policy for fetal anomalies is of uncertain net societal benefit. Routine screening may be justified, however, based on standards that elude the methods for establishing societal benefits adopted in this analysis.
Can Decision Analysis Help Us Decide Whether Ultrasound Screening for Fetal Anomalies Is Worth It?
Authors: ROMANO PATRICK S. , WAITZMAN NORMAN J.
Published: February 2006

Abstract: Decision analysis is a widely used tool to improve clinical decision making when randomized controlled trials are infeasible, underpowered, or lack generalizability. We performed an exploratory decision analysis of routine second trimester ultrasound to detect fetal anomalies, focusing on the assumptions that would have the greatest impact. Six outcome categories were considered: (1) abnormal ultrasound, anomalous child, (2) abnormal ultrasound, elective abortion of anomalous fetus, (3) abnormal ultrasound, healthy child, (4) abnormal ultrasound, elective abortion of healthy fetus, (5) normal ultrasound, healthy child, and (6) normal ultrasound, anomalous child. Live birth and fetal death rates for nine sonographically detectable anomalies were obtained from the California Birth Defects Monitoring Program. The sensitivity and specificity of ultrasound were estimated through meta‐analysis of recent series. Plausible ranges for the probabilities of cesarean delivery and elective abortion, by anomaly, were determined through review of the literature. Standard gamble, willingness‐to‐pay, and human capital estimates of utility were rescaled for comparability. We found that routine ultrasound appears to be the preferred strategy for most women. This choice is sensitive primarily to the specificity of ultrasound and women's willingness‐to‐pay for the reassurance of a normal ultrasound.
Routine Ultrasound Scanning for Congenital Abnormalities
Authors: WALD NICHOLAS J. , KENNARD ANNE
Published: February 2006

Abstract: Screening has been defined as “the systematic application of a test or enquiry, to identify individuals at sufficient risk of a specific disorder to benefit from further investigation or direct preventive action, among persons who have not sought medical attention on account of symptoms of that disorder” (Wald, N.J. 1994. J. Med. Screen. 1: 76). The purpose of screening is to benefit the individuals being screened. The early detection of abnormalities should not be an end in itself, and the value of a screening approach needs to be determined before it is introduced into practice. Ultrasound as a means of screening for fetal abnormalities has not been adequately assessed even though it is widely used in this way. To assess its value it is helpful to classify abnormalities that can be detected on the basis of the clinical usefulness of doing so. To this end we propose four categories similar to those independently suggested by the Royal College of Obstetricians and Gynaecologists Working Party on Ultrasound Screening for Fetal Abnormalities. Four groups were specified: (A) major abnormalities‐death inevitable, (B) abnormalities associated with long‐term handicap, (C) abnormalities potentially amenable to intrauterine treatment, and (D) fetal conditions that require immediate postnatal investigation and/or treatment. For each abnormality, the screening detection and false‐positives need to be estimated together with the medical and financial costs of screening, particularly those arising from findings of uncertain or little medical consequence that may lead to worry and further unnecessary obstetric intervention.
Ethical Dimensions of Ultrasound Screening for Fetal Anomalies
Authors: CHERVENAK FRANK A. , McCULLOUGH LAURENCE B.
Published: February 2006

Abstract: The ethical dimensions of the debate on routine ultrasound are analyzed. The central role of the informed consent process, based on a respect for the autonomy of the pregnant woman, is presented. Failure to offer quality ultrasound in clinical settings where it is available restricts access to pregnant women to the diagnosis of fetal anomalies and therefore restricts access to the options of abortion and fetal therapy. We show that beneficence‐ and justice‐based considerations do not supersede respect for autonomy.
Psychological Impact of the Announcement of a Fetal Abnormality on Pregnant Women and on Professionals
Authors: DETRAUX J.‐J. , GILLOT‐DE VRIES FR. , EYNDE S. VANDEN , COURTOIS A. , DESMET A.
Published: February 2006

Abstract: The psychological impact of the announcement of a fetal abnormality after ultrasound examinations is examined in relation to the building up of the mother‐child attachment. It represents the “psychological cost” of such techniques. Understanding the subjective experience of the patients could increase the effectiveness of clinical practice. We have assumed that the relationship between parents and professionals is a critical element that contributes to the establishment of an emotional link between the mother and her child. Pregnant women, mothers, and professionals were approached for interviews and by questionnaires including anamnestic data, opinions, and projective methods. The results showed that the women with fetopathy were less centered on themselves during the pregnancy. Long‐term effects were found to be important. In pregnant women, ultrasound examination was experienced with satisfaction even if some ambivalence remained. In mothers with an impaired child, ultrasound examination was viewed as a technique with low reliability. Professionals reported not having preparation in making such an announcement. We concluded that a need exists for better management of the modalities of ultrasound examinations. Many parents have expressed their need for psychological support.
Legal Problems Related to Obstetrical Ultrasound
Authors: SANDERS ROGER C.
Published: February 2006

Abstract: Malpractice suits related to fetal anomalies are now the most common type of litigation involving ultrasound, surpassing ectopic pregnancy. Missing an anomaly on a sonogram performed for a standard indication, such as dating, is the most frequent type of litigation. Other causes of litigation include invented anomalies and unrecognized anomalies that are visible in retrospect on the ultrasonic images. Rarer causes of malpractice problems relate to failure to communicate the results of a sonogram in a timely fashion, failure to inform the patient of the findings about the sonogram at the time the patient is seen, and failure to perform ultrasound studies for anomalies when there is clinical indication to do so, such as elevated alpha‐fetoprotein or polyhydramnios. The level of protection given by the obstetrical guidelines are discussed. Particular areas of concern relate to litigation involving missed fetal heart malformations, spina bifida, absent distal limbs, and twins.
Long‐Range Correlations in Nonequilibrium Fluidsa
Authors: DUFTY JAMES W.
Published: February 2006

Abstract: Simple fluids with short‐range atomic forces at equilibrium exhibit long‐range correlations only at thermodynamic critical points. In contrast, the same fluids have long‐range correlations for a wide class of nonequilibrium states. The mechanism behind such nonequilibrium correlations is described here briefly, both from linear response methods and from kinetic theory.
Renormalization of Self‐Organized Critical Models
Authors: HASTY JEFF , WIESENFELD KURT
Published: February 2006

Abstract: Self‐organized criticality refers to a mechanism whereby complex dissipative dynamical systems naturally evolve to a self‐sustaining critical point, exhibiting correlations on all length scales and time scales. A recent theory based on a real space renormalization group approach sheds light on fundamental aspects of the phenomenon.
Two‐Dimensional Vortex Crystalsa
Authors: JIN D. Z. , DUBIN D.H. E.
Published: February 2006

Abstract: Magnetically confined pure electron columns evolve as nearly inviscid, incompressible two‐dimensional (2‐D) fluids. Experiments on these columns have found that the decay of 2‐D turbulence leads to spontaneous formation of “vortex crystals,” which are symmetric arrays of strong vortices within a background of lower vorticity. These vortex crystals can be described as maximum fluid entropy states for a system with an ergodically mixed background and a conserved number of strong vortices.
Collisionless Relaxation in Galactic Dynamics and the Evolution of Long‐Range Order
Authors: KANDRUP HENRY E.
Published: February 2006

Abstract: This paper presents a critical assessment of certain aspects of collisionless galactic dynamics, focusing on the interpretation and limitations of the collisionless Boltzmann equation and the physical mechanisms associated with collisionless, or near‐collisionless, relaxation. Numerical and theoretical arguments are presented to motivate the idea that the evolution of a system far from equilibrium should be interpreted as involving nonlinear gravitational landau damping, a picture which implies a greater overall coherence and remembrance of initial conditions than is implicit in the conventional paradigm of violent relaxation.
Gravity and Large‐Scale Structure: Observational Evidencea
Authors: FRY J. N.
Published: February 2006

Abstract: In our present understanding, cosmological structure on large scales is formed by the action of gravity amplifying small initial fluctuations. On large scales, where fluctuations are weak and perturbation theory applies, that presumption can be tested against observations. In particular, the anisotropic shapes of structures formed by gravity predicts a characteristic behavior of the bispectrum, or third moment of density in Fourier space, that can be used as a signature to separate effects of gravity from more local, nongravitational forces that may play a role in galaxy formation.
Magnetohydrodynamic Origin of Jets from Accretion Disksa
Authors: LOVELACE R.V. E. , ROMANOVA M. M.
Published: February 2006

Abstract: A review is made of recent magnetohydrodynamic simulations of outflows from accretion disks for different distributions of magnetic field threading the disk. The problem of the opening of a closed field line configuration linking a magnetized star and an accretion disk is also discussed.
Buoyancy‐Driven Rotating Boundary Currentsa
Authors: YECKO P. A. , MEACHAM S. P.
Published: February 2006

Abstract: The structure of boundary currents formed from intermediately dense water introduced into a rotating, stably stratified, two‐layer environment is investigated in a series of laboratory experiments, performed for Froude numbers ranging from 0.01 to 1. The thickness and streamwise velocity profiles in quasi‐steady currents are measured and found to agree with analytic solutions and numerical models. A sloping boundary in a stratified background results in robust stability at all experimental Froude numbers. Such stability is in sharp contrast to the rapid breakup into eddies of such a current flowing against a vertical boundary, or of a current flowing along a slope in a uniform background. The possibility of wave radiation supported by a variety of wave mechanisms found in the ambient fluid might account for the observed stability.
Coherent Structures in Convection and Parametrically Driven Surface Wavesa
Authors: VIÑALS JORGE
Published: February 2006

Abstract: A system maintained outside of thermodynamic equilibrium often develops complex spatial structures and, in some cases, persistent dynamics. The amplitude equation formalism has been widely used to study pattern formation in the weakly nonlinear regime (slightly beyond onset of instability from some stationary reference state.) Application of the formalism is briefly discussed for Rayleigh‐Benard convection, and at some length for parametrically driven surface waves (Faraday waves).
Analysis of the Central Pattern Generator for Swimming in the Mollusk Clionea
Authors: ARSHAVSKY Y. I. , DELIAGINA T. G. , ORLOVSKY G. N. , PANCHIN Y. V. , POPOVA L. B. , SADREYEV R. I.
Published: February 2006

Abstract: The pteropod mollusk Clione limacina swims by rhythmic movements of two wings. The central pattern generator (CPG) for swimming, located in the pedal ganglia, is formed by three groups of interneurons. The interneurons of the groups 7 and 8 are of crucial importance for rhythm generation. They are endogenous oscillators capable of generating rhythmic activity with a range of frequencies typical of swimming after extraction from the ganglia. This endogenous rhythmic activity is enhanced by serotonin. The interneurons 7 and 8 produce one prolonged action potential (about 100 ms in duration) per cycle. Prolonged action potentials contribute to determining the duration of the cycle phases. The interneurons of two groups inhibit one another determining their reciprocal activity. The putative transmitters of groups 7 and 8 interneurons are glutamate and acetylcholine, respectively. Transition from one phase to the other is facilitated by the plateau interneurons of group 12 that contribute to termination of one phase and to initiation of the next phase. Maintaining the rhythm generation and transition from one phase to the other is also promoted by postinhibitory rebound. The redundant organization of the swimming generator guarantees the high reliability of its operation. Generation of the swimming output persisted after the inhibitory input from interneurons 8 to 7 had been blocked by atropine. Activity of the swimming generator is controlled by a set of command neurons that activate, inhibit or modulate the operation of the swimming CPG in relation to a behaviorally relevant context.
Distribution of Central Pattern Generators for Rhythmic Motor Outputs in the Spinal Cord of Limbed Vertebratesa
Authors: KIEHN OLE , KJAERULFF OLE
Published: February 2006

Abstract: Neuronal networks in the spinal cord are capable of producing rhythmic movements, such as walking and swimming, when the spinal cord itself is isolated from the brain and sensory inputs. These spinal networks, also called central pattern generators or CPGs, serve as relatively simple model systems for our understanding of brain functions. In this paper we concentrate on spinal CPGs in limbed vertebrates and in particular address the question: Where in the spinal cord, in the longitudinal and transverse planes, are they located? We will review the use of lesions to isolate the rhythm and pattern‐generating parts of the CPG network, indirect methods like activity‐dependent labeling with [14C]‐2‐deoxyglucose, c‐fos, sulforhodamine 101, and WGA‐HRP, which label presumed rhythmically active neurons en bloc, and direct methods such as calcium‐imaging, extracellular and intracellular recordings, which identify rhythmically active cells directly. With this review we hope to highlight the scientific disagreements and the consensus, which have emerged from these studies with regard to the distribution of the CPG networks in the spinal cord.
Neuromodulation Intrinsic to the Central Pattern Generator for Escape Swimming in Tritoniaa
Authors: KATZ PAUL S.
Published: February 2006

Abstract: Extrinsic neuromodulatory inputs to central pattern generators (CPGs) can alter the properties and synaptic interactions of neurons in those circuits and thereby modify the output of the CPG. Recent work in a number of systems has now demonstrated that neurons intrinsic to CPG can also evoke neuromodulatory actions on other members of the CPG. Such “intrinsic neuromodulation” plays a role in controlling the CPG underlying the escape swim response of the nudibrach mollusc, Tritonia diomedea. The dorsal swim interneurons (DSIs) are a bilaterally represented set of three serotonergic neurons that participate in the generation of the rhythmic swim motor program. Serotonin released from these CPG neurons functions both as a fast neurotransmitter and as a slower neuromodulator. In its modulatory role, serotonin enhances the release of neurotransmitter from another CPG neuron, C2, and also increases C2 excitability by decreasing spike frequency adaptation. These neuromodulatory actions intrinsic to the CPG may be important for the initial self‐configuration of the system into a function CPG and for experience‐dependent changes in the output such as behavioral sensitization and habituation.
Neuronal Basis of Afferent‐evoked Enhancement of Locomotor Activitya
Authors: McCREA DAVID A.
Published: February 2006

Abstract:Activation of ankle extensor group Ia muscle spindle or Ib tendon organ afferents during locomotion can prolong and enhance hindlimb extensor motoneuron activity. A growing body of evidence suggests that these group I evoked reflexes not only compensate for a changing environment but also help shape extensor activity during normal, unperturbed locomotion. In this paper we review four mechanisms that underlie the group I evoked enhancement of ipsilateral extensor activity during locomotion. The first three are pre‐motoneuronal mechanisms that are part of group I reflex pathway reorganization during locomotion. They are (1) a suppression of group I evoked nonreciprocal inhibition, (2) a release from inhibition of excitatory interneurons in disynaptic pathways from group I afferents to extensor motoneurons, and (3) longer latency excitation evoked through extensor portions of the locomotor circuitry. The fourth factor contributing to group I evoked increases in motoneuron activity during locomotion is the increase in motoneuron excitability produced by postsynaptic changes in motoneuron membrane conductances. Most results to be discussed were obtained during locomotion in decerebrate cats in which fictive locomotion was evoked by stimulation of the midbrain following neuromuscular blockade.
Intersegmental Coordination of Swimmeret Movements: Mathematical Models and Neural Circuitsa
Authors: MULLONEY BRIAN , SKINNER FRANCES K. , NAMBA HISAAKI , HALL WENDY M.
Published: February 2006

Abstract: Swimmerets move periodically through a cycle of power‐strokes and return‐strokes. Swimmerets on neighboring segments differ in phase by ~25%, and maintain this difference even when the period of the cycle changes from < 1 to >4 Hz. We constructed a minimal cellular model of the segmental pattern‐generating circuit which incorporated its essential components, and whose dynamics were like those of the local circuit. Three different intersegmental coordinating units were known to link neighboring ganglia, but their targets are unknown. We constructed different intersegmental circuits which these units might form between neighboring cellular models, and compared their dynamics with the real system. One intersegmental circuit could maintain an ~25% phase difference through a range of periods.

In physiological experiments, we identified three types of intersegmental interneurons that originate in each ganglion and project to its neighbors. These neurons fire bursts at certain parts of the swimmeret cycle in their home ganglion. These three neurons are necessary and sufficient to maintain normal coordination between neighboring segments. Their properties conform to the predictions of the cellular model.
Differential Expression and Targeting of K+ Channel Genes in the Lobster Pyloric Central Pattern Generatora
Authors: BARO DEBORAH J. , HARROS‐WARRICK RONALD M.
Published: February 2006

Abstract: A molecular analysis of motor pattern generation is an essential complement to electrophysiological and computational investigations. In arthropods, A‐channels are posttranslationally modified multimeric proteins containing Shaker family α‐subunits that may interact with β‐subunits, γ‐subunits, and other auxiliary proteins. One consequence of A‐channel structure is that several mechanisms could underlie the cell‐specific differences in pyloric IAs including differential gene expression, alternate splicing, and posttranslational modifications. Oocyte expression studies, single‐cell RT‐PCR, and immunocytochemistry suggest that differential α‐subunit gene expression is not a mechanism for creating pyloric IA heterogeneity, and that the same gene, shal, encodes the a‐subnuits for the entire family of somatic IAs in the pyloric network. Changes in the level of shal gene expression alter A‐channel density between cells, but cannot account for the differences in the biophysical properties of the six pyloric IAs. Preliminary data suggest that the shal gene also encodes the A‐channel α‐subunits for the coarse and fine neuropil but not for most axons. A second gene, shaker, encodes the A‐channel α‐subunits in the majority of axons and at the neuromuscular junction. The distinct properties of the two types of A‐channels are consistent with the different roles of IA at the different locations. Both the shaker and shal genes are alternately spliced, and investigations are under way to determine whether alternate splicing is a mechanism for generating pyloric IA heterogeneity.
Behavioral and Electrophysiological Analysis of Ca‐activated K‐channel Transgenes in Drosophilaa
Authors: ATKINSON NIGEL S. , BRENNER ROBERT , BOHM RUDI A. , YU JOYCE Y. , WILBUR JENNETTE L.
Published: February 2006

Abstract: The slowpoke gene of Drosophila melanogaster encodes a Ca‐activated K channel. This gene is expressed in neurons, muscles, tracheal cells, and the copper and iron cells of the midgut. The gene produces a large number of alternative products using tissue‐specific transcriptional promoters and alternative mRNA splicing. We have described in great depth how transcription is regulated and are now cataloging the tissue‐specificity of different splice variants. It is believed that the diversity of products serves to tailor channel attributes to the needs of specific tissues. Electrophysiological and behavioral assays indicate that at least some of these products produce channels with distinct properties.
Reorganization of Locomotor Activity during Development in the Prenatal Rata
Authors: KUDO NORIO , NISHIMARU HIROSHI
Published: February 2006

Abstract: Development of neuronal circuits generating locomotor activity was studied using an isolated lumbar spinal cord preparation from fetal and neonatal rats. Bath application of N‐methyl‐d‐aspartate (NMDA) or 5‐HT evoked patterned motor activity resembling that seen during normal fictive locomotion on embryonic day (E) 20.5. Glycine‐mediated inhibition was essential to the formation of this coordinated motor activity. In preparations from fetuses at the earlier stages (E14.5‐E16.5), we observed spontaneous motoneuronal activity and chemically induced rhythmic bursts, which were synchronized on the two sides in the corresponding ventral roots. The spontaneous activity was not blocked by kynurenate, the glutamate receptor blocker, although it was completely abolished by strychnine, the glycine receptor antagonist. A brief application of glycine evoked excitatory responses resembling the spontaneous bursts in both time course and amplitude. It is concluded that glycine functions transiently as excitatory transmitters at these stages. These results suggest that functional change in glycine‐induced responses during development plays an important role in differentiation of the neuronal circuits generating locomotion.
Development and Aminergic Neuromodulation of a Spinal Locomotor Network Controlling Swimming in Xenopus Larvaea
Authors: SILLAR KEITH T. , REITH CAROLYN A. , McDEARMID JOE R.
Published: February 2006

Abstract: In this article we review our research on the development and intrinsic neuromodulation of a spinal network controlling locomotion in a simple ventral roovertebrate. Swimming in hatchling Xenopus embryos is generated by a restricted network of well‐characterized spinal neurons. This network produces a stereotyped motor pattern which, like real swimming, involves rhythmic activity that alternates across the body and progresses rostrocaudally with a brief delay between muscle segments. The stereotypy results from motoneurons discharging a single impulse in each cycle; because all motoneurons appear to behave similarly there is little scope for altering the output to the myotomes from one cycle to the next. Just one day later, however, Xenopus larvae generate a more complex and flexible motor pattern in which motoneurons can discharge a variable number of impulses which contribute to ventral root bursts in each cycle.

This maturation of swimming is due, in part, to the influence of serotonin released from brain‐stem raphespinal interneurons whose axonal projections innervate the cord early in larval life. Larval swimming is differentially modulated by both serotonin and by noradrenaline: serotonin leads to relatively fast, intense swimming whereas noradrenaline favors slower, weaker activity. Thus, these two biogenic amines select opposite extremes from the spectrum of possible output patterns that the swimming network can produce. Our studies on the cellular and synaptic effects of the amines indicate that they can control the strength of reciprocal glycinergic inhibition in the spinal cord. Serotonin and noradrenaline act presynaptically on the terminals of glycinergic commissural interneurons to weaken and strengthen, respectively, crossed glycinergic inhibition during swimming. As a result, serotonin reduces and noradrenaline increases interburst intervals. The membrane properties of spinal neurons are also affected by the amines. In particular, serotonin can induce intrinsic oscillatory membrane properties in the presence of NMDA. These depolarizations are slow compared to the cycle periods during swimming and so may contribute to enhancement of swimming over several consecutive cycles of activity.
Pharmacological Activation and Modulation of the Central Pattern Generator for Locomotion in the Cata
Authors: ROSSIGNOL S. , CHAU C. , BRUSTEIN E. , GIROUX N. , BOUYER L. , BARBEAU H. , READER T. A.
Published: February 2006

Abstract:Pharmacological agents have been shown to be capable of inducing a pattern of rhythmic activity recorded in muscle nerves or motoneurons of paralyzed spinal cats that closely resembles the locomotor pattern seen in intact cats. Further work, using intraperitoneal or intrathecal injections, suggests that different neurotransmitters may be involved in various aspects of locomotor control, e.g., initiation and modulation of the pattern. Although precursors, agonists or the neurotransmitters themselves of several systems have been investigated (noradrenergic, dopaminergic, serotonergic, glutamatergic), the noradrenergic system seems the most efficient in triggering locomotion in complete spinal cats, with the α‐2 agonists (clonidine, tizanidine, oxymetazoline) being more potent than the α‐1 agonist, methoxamine. Moreover, the potency of the drugs may depend on the time of application after the spinal lesion. In chronic spinal cats capable of spontaneous walking on hindlimbs on the treadmill, all neurotransmitters appear to exert distinct recognizable effects on the locomotor pattern. More recent work also suggests that the effects of drugs may differ significantly depending on the type of spinal lesion. For instance, clonidine further reduces the level of weight support during quadrupedal locomotion of cats with lesions of the ventral‐ventrolateral funiculi, possibly due to an interference of clonidine with essential compensatory mechanisms used by these animals to walk. Such considerations as the type of drugs, type of lesions, and the time after the lesion will be important for future studies in spinal cord injured patients.
Evidence for a Spinal Central Pattern Generator in Humansa
Authors: DIMITRIJEVIC MILAN R. , GERASIMENKO YURI , PINTER MICHAELA M.
Published: February 2006

Abstract: Non‐patterned electrical stimulation of the posterior structures of the lumbar spinal cord in subjects with complete, long‐standing spinal cord injury, can induce patterned, locomotor‐like activity. We show that epidural spinal cord stimulation can elicit step‐like EMG activity and locomotor synergies in paraplegic subjects. An electrical train of stimuli applied over the second lumbar segment with a frequency of 25 to 60 Hz and an amplitude of 5‐9 V was effective in inducing rhythmic, alternating stance and swing phases of the lower limbs. This finding suggests that spinal circuitry in humans has the capability of generating locomotor‐like activity even when isolated from brain control, and that externally controlled sustained electrical stimulation of the spinal cord can replace the tonic drive generated by the brain.
Does Neurorehabilitation Play a Role in the Recovery of Walking in Neurological Populations?a
Authors: BARBEAU H. , NORMAN K. , FUNG J. , VISINTIN M. , LADOUCEUR M.
Published: February 2006

Abstract:This review demonstrates that neurorehabilitation approaches, based on recent neuroscience findings, can enhance locomotor recovery after a spinal cord injury or stroke. Findings are presented from more than 20 clinical studies conducted by numerous research groups on the effect of locomotor training using either body weight support (BWS), functional electrical stimulation (FES), pharmacological approaches or a combination of them. Among the approaches, only BWS‐assisted locomotor training has been demonstrated to have a greater effect than conventional or locomotor training alone. However, when study results were combined and weighted for the number of subjects, the results indicated that there is a gradient of effects from small changes with the immediate application of FES or BWS to larger changes when locomotor training is combined with FES or BWS or pharmacological approaches. The findings of these studies suggest that these neurorehabilitation approaches do play a role in the recovery of walking in subjects with spinal cord injury or stroke. Several factors contribute to the potential for recovery including the site, etiology, and chronicity of the injury, as well as the type, duration, and specificity of the intervention and whether interventions are combined. Furthermore, how these neurorehabilitation approaches may take advantage of the plasticity process following neurological lesion is also discussed.
Recovery of Locomotion following Transplantation of Monoaminergic Neurons in the Spinal Cord of Paraplegic Ratsa
Authors: RIBOTTA MINERVA GIMÉNEZ Y , ORSAL DIDIER , FERABOLI‐LOHNHERR DELPHINE , PRIVAT ALAIN
Published: February 2006

Abstract:Severe traumatic lesions of the spinal cord yield a permanent deficit of motricity in adult mammals and specifically a loss of locomotor activity of hindlimbs when the lesion is located at the lower thoracic level. To restore this function, we have developed a paradigm of transplantation in rats based on a transection model of the spinal cord and the subsequent injection at the sublesional level of a suspension of embryonic brainstem monoaminergic neurons which play a key role in the modulation of locomotion. A genuine locomotion was characterized in transplanted animals by electromyographic and electroneurographic recordings. This correlated with a specific reinnervation pattern of targets, where typical synapses were found, and with the normalization of biochemical parameters.
The Future Promises of Xenotransplantation a,b
Authors: PLATT JEFFREY L. , LIN SHU S.
Published: February 2006

ABSTRACT: The use of animals as a source of organs and tissues for humans has been an enduring goal of transplantation. Xenotransplantation, as such, would overcome a shortage of human donors and allow for biochemical or genetic approaches to modification of transplants. The use of animal organs and tissues, however, is hindered by an intense immune response of the recipient against the graft. The molecular basis for this immune response has recently been elucidated, at least in part, and specific approaches to therapy, including the genetic engineering of source animals, have been developed. Other hurdles, including the physiologic limitations of the transplant and the possibility of transferring infectious agents from the transplant into the host, may also be important. The development of specific therapies and the application of genetic engineering to overcome these problems can now be envisioned. As the immunologic, physiologic, and infectious hurdles to xenotransplantation are addressed, new efforts will focus on the use of the transplant to impart novel functions to answer the therapeutic needs of the transplant recipient.
Physiological Obstacles after Xenotransplantation
Authors: HAMMER CLAUS
Published: February 2006

ABSTRACT: The incompatibility of allografts is restricted to immunologic factors such as the MHC class I and class II antigens. Anatomic, physiological, and biochemical characteristics are identical. This is completely different in xenografts. The upright position of man is unique in nature. Gravity therefore exerts a different impact on the anatomic situation of organs such as lung, heart, liver, and kidney. More pronounced are differences on the humoral and enzymatic basis. Complex interactions existing in allografts are totally disturbed in xenogeneic situations. Up‐ and downregulation controlled by releasing factors on the one hand and inhibitors on the other must be species‐specific. These actions of mainly proteases are both fast and in most cases depend on species‐specific receptors. Examples are growth hormones which could stimulate the xenografts to unrestricted growth, as in pig hearts in the human patient. Enzymes not metabolized by the liver would constantly stimulate mechanisms to a level that is not compatible with life, and other reactions could be more expressed in the donor species than in man and thus disturb these interactions. Products like albumin are carriers for other molecules and need to be compatible for binding sites. Pig and human albumin have an amino acid identity of less than 65% erythropoetin (EPO) of less than 82%, and complement of less than 70%. All factors are obviously without specific function in the future recipient, the human patient. In contrast, pig complement would, as a foreign molecule, induce the alternative complement pathway in the human recipient, leading to unknown side effects. It is not sufficiently investigated whether under such physiological and anatomic differences a long‐term survival of xenograft or recipient is possible‐a chain is as strong as its weakest link.
Genetic Engineering in the Pig: Gene Knockout and Alternative Techniques
Authors: VANHOVE BERNARD , RENARD JEAN‐PAUL , SOULILLOU JEAN‐PAUL
Published: February 2006

ABSTRACT: Since endothelial cells (EC) are the major target cells during hyperacute rejection and are likely in delayed graft rejection, most of the genetic engineering of the xenotransplant donor is aimed at modifying their properties. Among the various strategies that are reviewed are the genotypic or phenotypic knockout of the αl,3Gal antigen, which is a major target of xenoantibodies and is also probably involved in innate cellular response. In addition, the success of the transgeny of complement regulatory proteins is well established. In vitro data from analyses of the mechanisms of endothelial cell activation also suggest that other molecules could be used to regulate apoptosis or thrombotic microenvironment or to minimize recipient T‐cell activation by inhibiting costimulatory proteins such as CD40 or B7. Alternative to usual knockout techniques (thus far not available in pigs, where no ES cells have been derived) will be presented.
Induction of Bilateral Transplantation Tolerance to Cellular and Perfused Allografts and Xenografts with Donor Hematopoietic Cells a
Authors: SLAVIN SHIMON , GUREVITCH OLGA , PRIGHOZINA TATIANA
Published: February 2006

ABSTRACT: We have recently introduced a new approach for induction of transplantation tolerance to donor alloantigens using well‐tolerated non‐myeloablative conditioning across MHC and xenogeneic barriers in mice. Our regimen consists of no or very low doses of total lymphoid irradiation (TLI), previously shown to be tolerogenic because of profound yet non‐myeloablative immunosuppression, followed by deletion of donor‐reactive host lymphocytes activated in vivo with donor hematopoietic cells with a single dose of cyclophosphamide. Recipients of immunosuppressive regimen with lower intensity (e.g., no or one single dose of TLI) required a larger inoculum of donor bone marrow cells; the reverse was also true, both regimens resulting in stable mixed chimerism. A combination of low‐dose TLI followed by depletion of donor‐reactive host cells with cyclophosphamide resulted in consistent engraftment of even low numbers of T‐cell‐depleted donor‐derived hematopoietic cells, known to be much more difficult to engraft, with consistent induction of permanent and donor‐specific transplantation tolerance to donor skin allografts with signs of similar success across xenogeneic barriers.