bluuebunny/crossref_metadata_2025 huggingface dataset:
Influences of Increased Expression of the Ca2+ ATPase of the Sarcoplasmic Reticulum by a Transgenic Approach on Cardiac Contractility
Authors: DILLMANN WOLFGANG H.
Published: February 2006

ABSTRACT: Congestive heart failure is a significant clinical problem and leads to abnormalities in Ca2+ transients and to decreases in the level of the Ca2+ ATPase of the sarcoplasmic reticulum according to reports to some investigators. The Ca2+ ATPase of the sarcoplasmic reticulum (SERCA2) contributes in an important manner to diastolic Ca2+ lowering and relaxation of the heart. To determine the contractile alterations resulting from increased SERCA2 expression, we generated transgenic mice overexpressing a rat SERCA2 transgene. In these mice, SERCA2 mRNA was increased 2.6‐fold, the relative synthesis rate of SERCA2 protein 1.8‐fold, and SERCA2 protein levels 1.2‐fold. Functional analysis of Ca2+ handling and contractile parameters in isolated cardiac myocytes indicated that the intracellular Ca2+ decline and myocyte relengthening were each accelerated by 22‐23%. In addition, studies in isolated papillary muscles showed that the time to half‐maximal post‐rest potentiation was significantly shorter, hinting at an increased Ca2+ loading of the sarcoplasmic reticulum. Furthermore, in vivo cardiac functional studies demonstrated a significant accelerated contraction and relaxation in SERCA2 transgenic mice. We also cloned a SERCA2 transgene and mutants of the phospholamban gene into E1 deleted replication‐deficient human adenovirus 5 viral vectors and infected cardiac myocytes. In the cardiac myocytes, endogenous SERCA2 levels were decreased by PMA treatment. Infection of such myocytes with a SERCA2 expressing adenovirus could reconstitute the Ca2+ transient, and augmented oxalate facilitated SERCA2 Ca2+ uptake. In addition, phospholamban mutants with changes of basic to acidic amino acids in the cytoplasmic domain increased SERCA2 activity by 30‐35%. These findings, therefore, suggest that increased SERCA2 activity can be achieved by increasing SERCA2 levels or by expressing phospholamban mutants. Increased SERCA2 activity can lead to significant enhancements of Ca2+ transients and myocardial contractility.
Phospholamban Ablation and Compensatory Responses in the Mammalian Heart a
Authors: CHU GUOXIANG , FERGUSON DONALD G. , EDES ISTVAN , KISS EVA , SATO YOJI , KRANIAS EVANGELIA G.
Published: February 2006

ABSTRACT: Phospholamban is a low molecular weight phosphoprotein in cardiac sarcoplasmic reticulum. The regulatory role of phospholamban in vivo has recently been elucidated by targeting the gene of this protein in embryonic stem cells and generating phospholamban‐deficient mice. The phospholamban knockout hearts exhibited significantly enhanced contractile parameters and attenuated responses to β‐agonists. The hyperdynamic cardiac function of the phospholamban knockout mice was not accompanied by any cytoarchitectural abnormalities or alterations in the expression levels of the cardiac sarcoplasmic reticulum Ca2+‐ATPase, calsequestrin, Na+‐Ca2+ exchanger, or the contractile proteins. Furthermore, the attenuation of the cardiac responses to β‐agonists was not due to alterations in the phosphorylation levels of the other key cardiac phosphoproteins in the phospholamban knockout hearts. However, ablation of phospholamban was associated with down‐regulation of the ryanodine receptor, which suggests that a cross‐talk between cardiac sarcoplasmic reticulum Ca2+ uptake and Ca2+ release occurred in an attempt to maintain Ca2+ homeostasis in these hyperdynamic phospholamban knockout hearts.
Molecular Regulation of Phospholamban Function and Gene Expressiona
Authors: TADA MICHIHIKO , YABUKI MASANORI , TOYOFUKU TOSHIHIKO
Published: February 2006

ABSTRACT: Ca‐ATPase regulates intracellular Ca levels by pumping Ca into sarcoplasmic reticulum. Phospholamban (PLN) functions as an inhibitory cofactor for cardiac Ca‐ATPase (SERCA2). To define the molecular mode of interaction between two proteins, interaction sites have been identified. Studies using photoactivated cross‐linker and chimeric Ca‐ATPase between SERCA2 and nonmuscle Ca‐ATPase (SERCA3) indicated that potential binding residues are located just downstream of the active ATPase site (Asp351) of SERCA2. Site‐directed mutagenesis study of this region showed that six residues, Lys‐Asp‐Asp‐Lys‐Pro‐Val402, of SERCA2 are functionally important for the interaction. Further, mutagenesis study of PLN showed that the cytoplasmic region of PLN contains a potential binding site with SERCA2. The unique expression of PLN in cardiac cells has been analyzed by the transcriptional level of its gene using luciferase activity and Gel shift assays. CCAAT‐box in the 5′‐upstream region was found to be essential for its expression by associating with Y‐box binding transcriptional factors.
Models for the Transmembrane Region of the Phospholamban Pentamer: Which Is Correct?a
Authors: ADAMS PAUL D. , LEE ALBERT S. , BRÜNGER AXEL T. , ENGELMAN DONALD M.
Published: February 2006

ABSTRACT: Phospholamban is a 52‐amino acid protein that assembles into a pentamer in the membranes of the sarcoplasmic reticulum. Pentamer formation is driven in large part by interactions of the transmembrane regions of the protein, which are thought to be arranged as interacting α‐helices. The structural properties of phospholamban have been studied by mutagenesis and optical spectroscopy, resulting in a large database. In this discussion, we present advances in computational modeling, which identifies two probable structures for the transmembrane pentamer. A new approach to mutagenesis is described, which should lead to a clear distinction between the two possible models.
Direct Spectroscopic Detection of Molecular Dynamics and Interactions of the Calcium Pump and Phospholamban a
Authors: THOMAS DAVID D. , REDDY LAXMA G. , KARIM CHRISTINE B. , LI MING , CORNEA RAZVAN , AUTRY JOSEPH M. , JONES LARRY R. , STAMM JOHN
Published: February 2006

ABSTRACT: In order to test molecular models of cardiac calcium transport regulation, we have used spectroscopy to probe the structures, dynamics, and interactions of the Ca pump (Ca‐ATPase) and phospholamban (PLB) in cardiac sarcoplasmic reticulum (SR) and in reconstituted membranes. Electron paramagnetic resonance (EPR) and phosphorescence of probes bound to the Ca pump show that the activity of the pump is quite sensitive to its oligomeric interactions. In cardiac SR, PLB aggregates and inhibits the pump, and both effects are reversed by PLB phosphorylation. Previous analyses of PLB's oligomeric state were only in detergent solutions, so we used EPR and fluorescence to determine the oligomeric structure of PLB in its native state in lipid bilayers. Wild‐type PLB is primarily oligomeric in the membrane, while the mutant L37A‐PLB is monomeric. For both proteins, phosphorylation shifts the dynamic monomer‐oligomer equilibrium toward oligomers, and induces a similar structural change, as indicated by tyrosine fluorescence; yet L37A‐PLB is more effective than wild‐type PLB in inhibiting and aggregating the pump. Fluorescence energy transfer shows that the Ca pump increases the fraction of monomeric PLB, indicating that the pump preferentially binds monomeric PLB. These results support a reciprocal aggregation model for Ca pump regulation, in which the Ca pump is aggregated and inhibited by association with PLB monomers, and phosphorylation of PLB reverses these effects while decreasing the concentration of PLB monomers. To investigate the structure of the PLB pentamer in more detail, we measured the reactivities of cysteine residues in the transmembrane domain of PLB, and recorded EPR spectra of spin labels attached to these sites. These results support an atomic structural model, based on molecular dynamics simulations and mutagenesis studies, in which the PLB pentamer is stabilized by a leucine‐isoleucine zipper within the transmembrane domain.
The Sarcoplasmic Reticulum Ca2+ Pump: Inhibition by Thapsigargin and Enhancement by Adenovirus‐Mediated Gene Transfera
Authors: INESI GIUSEPPE , WADE ROBERT , ROGERS TERRY
Published: February 2006

ABSTRACT: The role of the sarcoplasmic reticulum Ca2+ pump in the excitation‐contraction coupling of cardiac muscle fibers was evaluated in experiments on SR ATPase inhibition with thapsigargin or, alternatively, on Ca2+ pump enhancement by SR ATPase transgenic expression. We found that thapsigargin, a highly specific and potent inhibitor of the SR ATPase, produces a strong reduction of cytosolic Ca2+ transient and contractile activation in neonatal rat myocytes, in the absence of any other functional effect. On the other hand, Ca2+ pump enhancement by ATPase transgenic expression affects dramatically Ca2+ transient and twitches, resulting in shorter duration and more rapid decay rates. Of particular interest is gene transfer mediated by recombinant adenovirus vectors under control of a cell‐specific promoter, resulting in transgenic expression of all myocytes in culture, and no expression in fibroblasts.
Sarcoplasmic Reticulum Proteins in Heart Failure
Authors: LEHNART STEPHAN E. , SCHILLINGER WOLFGANG , PIESKE BURKERT , PRESTLE JÜRGEN , JUST HANJÖRG , HASENFUSS GERD
Published: February 2006

ABSTRACT: Altered calcium homeostasis may play a key role in the pathophysiology of human heart failure. Levels of sarcoplasmic reticulum (SR) proteins and sarcolemmal Na+‐Ca2+ exchanger were analyzed by Western blot in failing and nonfailing human myocardium and related to myocardial function. Levels of the SR calcium release channel and of calcium storage proteins (calsequestrin and calreticulin) were not different in nonfailing and failing hearts. However, proteins involved in calcium removal were significantly altered in the failing human heart: (1) SR‐Ca2+‐ATPase levels and the ratio of SR‐Ca2+‐ATPase to its inhibitory protein phospholamban were significantly decreased, and (2) Na+‐Ca2+ exchanger levels and the ratio of Na+‐Ca2+ exchanger to SR‐Ca2+‐ATPase were significantly increased. SR‐Ca2+‐ATPase levels were closely correlated to systolic function as evaluated by frequency potentiation of contractile force. The frequency‐dependent rise of diastolic force was inversely correlated with protein levels of Na+‐Ca2+ exchanger. These findings indicate that altered expression of SR‐Ca2+‐ATPase and Na+‐Ca2+ exchanger is relevant for altered systolic and diastolic function in human heart failure.
cAMP‐Dependent Protein Kinase A‐Stimulated Sarcoplasmic Reticulum Function in Heart Failurea
Authors: SCHWINGER ROBERT H. G. , BÖLCK BIRGIT , MÜNCH GÖTZ , BRIXIUS KLARA , MÜLLER‐EHMSEN JOCHEN , ERDMANN ERLAND
Published: February 2006

ABSTRACT:It is unclear whether decreased protein expression of SERCA2 (sr‐Ca2+‐ATPase) and phospholamban (PLB), or alterations in the phosphorylation state of PLB leading to increased inhibition of SERCA2 are responsible for the reduced SERCA2 function in failing human myocardium. In crude membrane preparations from patients with terminal heart failure due to idiopathic dilated cardiomyopathy (DCM) and control hearts (NF), SERCA2 activity was measured with a NADH coupled assay. Protein expression of SERCA2 and PLB and the phosphorylation state at the two phosphorylation sites, serine‐16‐PLB and threonine‐17‐PLB, were investigated with specific (phosphorylation) antibodies and Western blot technique. In NF, the Vmaxand the Ca2+sensitivity of SERCA2 activity were significantly higher compared to DCM. Protein expression of SERCA2 and PLB were unchanged, whereas the phosphorylation status at both serine‐16‐PLB and threonine‐17‐PLB were significantly reduced in DCM. The native phosphorylation status of PLB measured by the back‐phosphorylation technique was reduced in DCM as well. After stimulation with protein kinase A only the Ca2+sensitivity, but not Vmax, increased. The reduced phosphorylation state of PLB may lead to decreased Ca2+sensitivity of SERCA2 in failing human myocardium. The altered regulation of the SR‐Ca2+‐ATPase in human heart failure may offer an opportunity for an improvement in the therapy of heart failure.
Sarco(endo)plasmic Reticulum Ca2+ ATPase Isoforms and Their Role in Muscle Physiology and Pathology
Authors: LOUKIANOV EVGENY , JI YONG , BAKER DEBRA L. , REED THOMAS , BABU JEGADEESH , LOUKIANOVA TANYA , GREENE ADAM , SHULL GARY , PERIASAMY MUTHU
Published: February 2006

ABSTRACT: Recent studies suggest that SR Ca2+ transport function is altered in hypertrophied and failing myocardium. To understand whether alterations in SR Ca2+ ATPase levels affect myocardial contractility, we generated transgenic mice that specifically overexpress SERCA2a or SERCA1 pump in the mouse heart, using the cardiac α‐MHC promoter. Analysis of SERCA2a transgenic mice show both an increase in mRNA and protein levels (120‐150% of the wild type). Isolated work performing heart preparations revealed that SERCA2a mice have improved myocardial performance. On the other hand, SERCA1 overexpression in the heart resulted in isoform replacement without any change in total SERCA protein. Interestingly, SERCA1 transgenic hearts exhibited super contractility with a significant increase in rates of muscle contraction (+dp/dt) and relaxation (−dp/dT). The time to peak pressure and half‐time to relaxation were significantly shorter.
IL‐6 and IL‐1β in Fever: Studies Using Cytokine‐Deficient (Knockout) Micea
Authors: KOZAK WIESLAW , KLUGER MATTHEW J. , SOSZYNSKI DARIUSZ , CONN CAROLE A. , RUDOLPH KARIN , LEON LISA R. , ZHENG HUI
Published: February 2006

ABSTRACT: Previous data support the hypothesis that during inflammation, interleukin (IL)‐1β and IL‐6 are involved in fever, in activation of the hypothalamic‐pituitary‐adrenal (HPA) axis, and in the induction of eicosanoids. Most of the pathophysiologic effects of IL‐1β and IL‐6 are mediated by prostaglandins (PGs), modulated by other cytokines, and antagonized by glucocorticoids (GC), a final product of the HPA axis. To further test these relationships, we measured changes in body temperature using biotelemetry in mice deficient in genes for IL‐1β and/or IL‐6 (IL‐1β knockout [KO] and IL‐6 KO) following injection with lipopolysaccharide (LPS) to induce systemic inflammation or turpentine to induce local abscess. Circulating IL‐6, tumor necrosis factor a (TNF‐α), GC, and PGE2 were measured in these mice after treatment. IL‐1β KO mice responded with reduced fever and IL‐6 KO mice with normal fever to a high dose of LPS. In contrast, neither type of KO mice produced fever to turpentine. PGE2 levels (measured in the circulation) were suppressed in both types of KO mice injected with turpentine. IL‐1β KO mice showed deficiency in IL‐6 following turpentine, but not LPS, injection. LPS‐induced increases in TNF‐α did not differ between IL‐1β KO mice and their wild‐type counterparts, whereas IL‐6 KO mice showed exacerbated LPS‐induced circulating TNF‐α. No differences were noted in plasma elevations of GC between KO and wild‐type mice following injection of LPS or turpentine, indicating that IL‐1β and IL‐6 are not required for activation of the HPA axis during inflammation. Our data demonstrate that in the mouse, IL‐1β and IL‐6 are critical for the induction of fever during local inflammation, whereas in systemic inflammation they appear only to contribute to fever.
Vasopressin‐Induced Antipyresis: Sex‐ and Experience‐Dependent Febrile Responsesa
Authors: PITTMAN QUENTIN J. , CHEN XIHUA , MOUIHATE ABDESLAM , MARTIN SHEILAGH
Published: February 2006

Abstract: There is now good evidence that vasopressin (AVP) acts, in the male rat, as a neurotransmitter in the ventral septal area to reduce fever. In light of the well known sexual dimorphism in the AVP innervation of the brain, we asked if female rats would (a) display fevers different from those seen in male rats, (b) respond to AVP with antipyresis, (c) display evidence of endogenous AVP‐induced antipyresis during fever, and (d) display altered fevers and AVP involvement as a function of hormonal status. Our experiments indicate that female rats display larger fevers to intracranial prostaglandin E2 (PGE2) but not to systemic lipopolysaccharide or interleukin‐1β than do male rats. The larger fevers may be due, in part, to a lack of AVP‐induced antipyresis, as an AVP antagonist elevates PGE2 fever in male but not in female rats and dialysates of the ventral septal area show increased AVP levels only in male rats during defervescence. Nonetheless, females respond to exogenous AVP with antipyresis. Throughout late pregnancy, parturition, and lactation, PGE2 fevers are reduced, but this appears to be due to a general suppression of autonomic output not involving enhanced AVP antipyresis. Fevers due to lipopolysaccharide and interleukin‐1β are also suppressed at this time, and in some animals, fevers are dramatically suppressed at about the time of parturition. Our results indicate that female rats may utilize different strategies for antipyresis than do male rats and that hormonal status may influence both peripherally generated and centrally activated fevers.
Peptide Modulation of Fever and Inflammation within the Braina
Authors: CATINIA ANNA , LIPTON JAMES M.
Published: February 2006

ABSTRACT:The importance of melanocortin peptides to host responses was recognized with the observation of the antipyretic effect of centrally administered α‐melanocyte stimulating hormone (α‐MSH). It is now clear that this neuropeptide also exerts remarkable antiinflammatory activity via direct actions on peripheral host cells, descending neurogenic antiinflammatory pathways stemming from CNS melanocortin receptors, and local actions on receptors that control inflammation within the brain. Recent studies of the latter influence indicate that α‐MSH inhibits brain tumor necrosis factor‐α (TNF‐α), previously linked to human neurodegenerative diseases, induced by local injection of lipopolysaccharide. Ischemia/reperfusion of the brain, a model of stroke, induces inflammation marked by disturbance of CNS function. α‐MSH given systemically modulates disturbances of auditory evoked potentials induced by ischemia/reperfusion in the posterior circulation. Such influences of the peptide may occur through inhibition of inflammatory agents produced by glia: α‐MSH 1‐13 and 11‐13 modulate TNF‐α and nitric oxide produced by activated murine microglia, and TNF‐α produced by human astrocytes. Because glia can secrete α‐MSH and express melanocortin receptors, they may, like peripheral macrophages, contain autocrine regulatory circuits based on the peptide. α‐MSH thus modulates both fever and inflammation in the brain by acting on local melanocortin receptors.
Role of IL‐10 in Inflammation: Studies Using Cytokine Knockout Micea
Authors: LEON LISA R. , KOZAK WIESLAW , KLUGER MATTHEW J.
Published: February 2006

ABSTRACT: Interleukin‐10 (IL‐10) inhibits the synthesis of proinflammatory cytokines known to be involved in fever, including IL‐1, IL‐6, and tumor necrosis factor‐α. We hypothesized that IL‐10 modulates lipopolysaccharide (LPS)‐induced fever in mice. Body temperature was measured by biotelemetry. Swiss Webster mice injected with recombinant murine IL‐10 (rmuIL‐10) were resistant to fever induced by a low dose of LPS (100 μg/kg, ip) and to the hypothermic and febrile effects of a high (septic‐like) dose of LPS (2.5 mg/kg, ip). Injection of rmuIL‐10 alone had no effect on afebrile body temperature of Swiss Webster mice. IL‐10 knockout mice showed an exacerbated and prolonged fever in response to a low dose of LPS (50 μg/kg, ip) compared to their wild‐type counterparts. These data support the hypothesis that IL‐10 acts as an endogenous cryogen during LPS‐induced fever in mice.
Neurobiological Basis of Fever
Authors: SAPER CLIFFORD B.
Published: February 2006

ABSTRACT: Fever is a coordinated endocrine, autonomic, and behavioral response organized by the brain in response to inflammatory stimuli. We examined the mechanism of the febrile response to intravenous lipopolysaccharide (LPS) in the rat. LPS caused activation of microglia and tissue macrophages in the meninges and along penetrating blood vessels. The microglia produce cytokines, such as tumor necrosis factor‐α, and cyclooxygenase type 2. The latter produces prostaglandins, which may cross the blood‐brain barrier. We found that inhibition of COX at the preoptic area prevented fever, whereas injection of PGE2 at this site produced fever. Either iv LPS or PGE2 into the preoptic area activated a specific set of pathways, including the ventromedial preoptic area, which we believe to be a key regulatory site, and the paraventricular nucleus, which we believe produces autonomic and endocrine responses that cause elevation of body temperature. We hypothesize that the pathway connecting these two sites involves a double inhibitory relay through temperature‐sensitive GABAergic neurons in the hypothalamus. This pathway would essentially “turn up the thermostat” during a fever, causing an increase in body temperature via normal thermoregulatory pathways.
Molecular Basis of Sickness Behaviora
Authors: DANTZER ROBERT , BLUTHÉ ROSE‐MARIE , GHEUSI GILLES , CREMONA SANDRINE , LAYÉ SOPHIE , PARNET PATRICIA , KELLEY KEITH W.
Published: February 2006

ABSTRACT: Peripheral and central injections of lipopolysaccharide (LPS), a cytokine inducer, and recombinant proinflammatory cytokines such as interleukin‐1β (IL‐1β) induce sickness behavior in the form of reduced food intake and decreased social activities. Mechanisms of the behavioral effects of cytokines have been the subject of much investigation during the last 3 years. At the behavioral level, the profound depressing effects of cytokines on behavior are the expression of a highly organized motivational state. At the molecular level, sickness behavior is mediated by an inducible brain cytokine compartment that is activated by peripheral cytokines via neural afferent pathways. Centrally produced cytokines act on brain cytokine receptors that are similar to those characterized on peripheral immune and nonimmune cells, as demonstrated by pharmacologic experiments using cytokine receptor antagonists, neutralizing antibodies to specific subtypes of cytokine receptors, and gene targeting techniques. Evidence exists that different components of sickness behavior are mediated by different cytokines and that the relative importance of these cytokines is not the same in the peripheral and central cytokine compartments.
Individual Variation in Hypothalamus‐Pituitary‐Adrenal Responsiveness of Rats to Endotoxin and Interleukin‐1β
Authors: LENCZOWSKI M.J. P. , SCHMIDT E. D. , VAN DAM A.‐M. , GAYKEMA R.P. A. , TILDERS F.J. H.
Published: February 2006

ABSTRACT: Intraperitoneal (ip) administration of lipopolysaccharide (LPS) or interleukin (IL)‐1β induces activation of the hypothalamus‐pituitary‐adrenal (HPA) axis. In some experiments, a marked individual variation has been observed in HPA responses to these stimuli. We reasoned that only parameters that correlate with this variability may reflect signals involved in HPA activation. Although IL‐1β is found in the peritoneal cavity and has been implicated in the HPA response to ip LPS, IL‐1β levels in peritoneal lavage fluid did not correlate with the variation in HPA responsiveness and neither did IL‐1β concentrations in plasma. In contrast, IL‐6 concentrations in plasma, but not in peritoneal lavage fluid, correlated with this variation to ip LPS or IL‐1β. We conclude that IL‐6 in the plasma represents a major determinant of the individual variation in HPA responses to ip LPS or IL‐1β. Because of its positive correlation with Fos expression in various brain‐stem nuclei, we suggest that circulating IL‐6 may facilitate the generation of signals in vagal afferents or potentiate vagal information transfer to lower brain‐stem nuclei.
Cytokine‐Induced Anorexia: Behavioral, Cellular, and Molecular Mechanismsa
Authors: PLATA‐SALAMÁN CARLOS R.
Published: February 2006

ABSTRACT: Cytokines induce anorexia. Recent issues concerning mechanistic aspects are: (1) Cytokines induce anorexia through different modes of behavioral action, that is, by affecting meal size, meal duration, and meal frequency differentially. Profiles also depend on the concentration or dosage. (2) The interface between the periphery and brain. Specific cytokines may be transported from the periphery to the brain. Cytokines generate mediators that can act on peripheral and/or brain target sites. Cerebrovasculature endothelium can also generate signals to modulate neural activities. Evidence indicates that the proposed vagal afferent signaling requires reassessment. Because of paracrine and autocrine actions, local cytokine production within the brain can induce anorexia. (3) Cytokines act directly on hypothalamic neurons proposed to participate in feeding. (4) Cytokine ←→ cytokine and cytokine ←→ peptide/neurotransmitter interactions are critical; for example, cytokines interact to induce anorexia synergistically, neuropeptide Y ←→ cytokine interactions are antagonist, and cytokine ←→ neurotransmitter and cytokine ←→ leptin ←→ neuropeptide Y ←→ CRH‐glucocorticoid and other endocrine interactions are important. A leptin receptor is related to gp 130, a signal transducer among interleukin (IL)‐6 subfamily receptors; gp 130 and related molecules may be an interface for feeding control in health and disease. Various cytokines upregulate leptin and gp 130. An integrative approach combining computerized meal pattern analyses with cellular and molecular approaches is being used to characterize mechanisms (ligands, receptors, transducing molecules, and intracellular mediators) involved in cytokine‐induced anorexia.
Brown Adipose Tissue: More Than an Effector of Thermogenesis?a
Authors: CANNON BARBARA , HOUSTEK JOSEF , NEDERGAARD JAN
Published: February 2006

ABSTRACT: Brown adipose tissue (BAT) produces heat by oxidation of fatty acids. This takes place when the tissue is stimulated by norepinephrine; the molecular background for the ability of BAT to produce heat is the tissue‐specific mitochondrial protein UCP1. In the classic view of BAT with respect to fever, BAT is an effector organ, producing heat especially during the onset phase of the fever. There is good evidence that BAT thermogenesis is stimulated via a lipopolysaccharide (LPS), interleukin (IL)‐1β, IL‐6, prostaglandin E cascade. Under physiologic conditions of constantly stimulated activity, BAT is expected to be recruited, but in fevers this is only evident in thyroxine fever. However, BAT may be more than merely an effector. There are indications of a correlation between the amount of BAT and the intensity of fevers, and brown adipocytes can indeed produce IL‐1α and IL‐6. Furthermore, brown adipocytes are directly sensitive to LPS; this LPS sensitivity is augmented in brown adipocytes from IL‐1β‐deficient mice. Thus, BAT may also have a controlling role in thermoregulation. The existence of transgenic mice with ablations of proteins central in fever and in BAT thermogenesis opens up possibilities for identification and elucidation of this putative new role for brown adipose tissue as an endocrine organ involved in the control of fever.
Fetal Anomalies and the Pediatrician
Authors: BIARENT DOMINIQUE
Published: February 2006

Abstract: The role of the pediatrician begins when the antenatal diagnosis of a congenital anomaly has been confirmed in a high‐risk perinatal center. The pediatrician contributes in establishing the prognosis and to discuss the best therapeutic possibilities based upon his own experience and the literature. The pediatrician plays an important role in the informing of the parents, particularly when the malformation is correctable. He will provide them with a complete explanation about the care of the baby, possible complications, and the prognosis. The parents meet the medical staff, see the place where their child will be treated after birth, gain confidence, and prepare the best possible mother‐infant and father‐infant links. The delivery should be planned in a high‐risk perinatal center to avoid the postnatal transportation of a sick newborn infant as well as the separation of the infant from the mother. A planned delivery is essential to permit the pediatrician to prepare and execute an early adapted‐to‐the‐malformation resuscitation and prompt surgery in the hope of reducing mortality and morbidity. After birth, the pediatrician plays a role not only in the pre‐ and postoperative care, but also in supporting the parents and facilitating their investment in the sick baby. The antenatal diagnosis permits the pediatrician and the surgeon to prepare and optimize the care of the newborn and allows the parents to anticipate the mourning of the imagined infant, providing them time to accept the diagnosis and the sick baby before the birth.
Anomalies and the Mental Health Professional
Authors: McNEIL THOMAS F. , NIMBY GUN TORSTENSSON
Published: February 2006

Abstract: Parental attitudes and reactions to the identification of fetal anomalies generally represent well‐documented, normally occurring phenomena. The appropriate clinical management of such emotional reactions is an important responsibility of the medical units delivering care and services to the parents. Medical policy decisions about whether and when to screen for offspring anomalies is a considerably more complex and controversial topic. Attitudes, feelings, and reactions both of parents and professionals to the identification of fetal abnormality and fetal normality have come to play an increasingly important role in such policy decisions. Adequate evaluation of the topic requires scientifically based knowledge of the psychological and psychosocial effects of screening of normal‐risk and high‐risk cases, as well as the short‐term and long‐term consequences of true positive, true negative, false negative, and false positive identifications of offspring abnormality. Only partial answers to these questions are available to date, and further empirical work is needed.
Central Nervous System Anomalies
Authors: CSABAY LÁSZLÓ , SZABÓ ISTVÁN , PAPP CSABA , TÓTH‐PÁL ERNÔ , PAPP ZOLTÁN
Published: February 2006

Abstract: The authors review the most common congenital anomalies of the central nervous system (CNS): neural tube defects (NTDs), ventriculomegaly/holoprosencephaly, hydranencephaly, holoprosencephaly sequence, iniencephaly, and microcephaly. They emphasize the importance of the diagnostic tools (biochemical markers of the maternal serum, ultrasound screening, invasive techniques), methods which are complementary to each other.
Prenatal Diagnosis of Gastrointestinal Anomalies with Ultrasound: What Have We Learned?
Authors: SKUPSKI DANIEL W.
Published: February 2006

Abstract: The use of routine obstetric ultrasound has been shown to accurately diagnose fetal gastrointestinal anomalies, both during and after the midtrimester. These are among the most accurately diagnosed of all anomalies, comprising 5‐7% of all fetal anomalies. From a review of the literature it is clear that the use of routine ultrasound allows: (1) the detection of multiple anomalies that are often present and affect outcome significantly, (2) preparation for delivery at a tertiary center where neonatal surgical experience will allow optimal outcome, and (3) decisions about mode and timing of delivery in cases where this is important, i.e., cases of omphalocele and gastroschisis.
Does the Prenatal Diagnosis of Fetal Urinary Tract Anomalies Affect Perinatal Outcome?
Authors: VALENTIN LIL , MARŠÁL KAREL
Published: February 2006

Abstract: A review of the literature is presented. Congenital renal and urinary tract anomalies are described, and the possible consequences of detecting them in utero are discussed. Prenatal detection of lethal anomalies affords the parents the option of terminating the pregnancy. If termination of pregnancy is not an acceptable option for the parents, the antenatal knowledge of lethal fetal anomaly helps the clinician to avoid unnecessary obstetric intervention, e.g., cesarean delivery for fetal distress. In certain cases of nonlethal renal and urinary tract anomalies, antenatal detection may influence both obstetric and postnatal management. It seems reasonable to anticipate that this might improve the prognosis of some children in terms of better preservation of kidney function. However, no scientific evidence is available to support such a statement. There are no randomized trials evaluating the outcome of congenital renal and urinary tract anomalies using different prenatal and postnatal diagnostic and therapeutic approaches. It is hoped that further research will lead to more rational antenatal and postnatal management protocols.
Surgical Treatment for Fetal Disease: The State of the Art
Authors: ALBANESE CRAIG T. , HARRISON MICHAEL R.
Published: February 2006

Abstract: Sophisticated imaging and fetal sampling techniques have defined the natural history and pathophysiologic characteristics of many previously mysterious conditions of newborn. Although most prenatally diagnosed malformations are best managed by appropriate medical and surgical therapy after delivery, an increasing number of simple anatomic abnormalities with predictably devastating developmental consequences have been successfully corrected before birth. Many of the technical intricacies of open fetal surgery have been solved, but preterm labor remains an omnipresent risk to the mother and fetus. The recent development of minimally invasive techniques to treat the fetus prenatally has significantly lessened preterm labor. Minimally invasive surgical techniques, in combination with new tocolytic strategies, promise to extend the indications for fetal surgical intervention.
Routine Ultrasound Screening of Congenital Anomalies: An Overview of the European Experience
Authors: LEVI SALVATOR
Published: February 2006

Abstract: Results from ultrasound in low‐risk pregnant women are significant when routine screening is performed on a large population because the anomalies are rare. Professionals expect from routine ultrasound objective information that cannot usually be obtained by clinical procedures. Parents seek reassurance about the absence of fetal congenital anomalies and overall fetal health. Therefore, Europeans view routine ultrasound as a part of obstetrical care, capable of filling important gaps by delivering much key information for improving obstetrical practice. Fetal anomalies screening (FAS) requires higher education and qualifications than obstetrical ultrasound. The health insurance systems support ultrasound screening and allow its spread in most European countries; approximately 98% of pregnant women are examined by ultrasound and, frequently, two to three times (usually once per trimester). Detection rate of congenital anomalies is about 28% in geographical areas (private practice and hospitals), 60 to 80% in Ob/Gyn's ultrasound labs. Routine ultrasound screening policy has not proved to result in an immoderate use of ultrasound; on the contrary, chaotic use of routine ultrasound can lead to an unproductive and excessive number of scans. New trends in FAS, such as the early detection of fetal defects and chromosomal anomalies, bring more arguments for routine screening. Effectiveness should increase by enhancing education and training and the systematic referral for FAS to accredited laboratories.
Quality Assurance in Obstetric and Gynecologic Ultrasound: The Hungarian Model
Authors: SZABÓ ISTVÁN , CSABAY LÁSZLÓE , TÓTH ZOLTÁN , TÖRÖK OLGA , PAPP ZOLTÁN
Published: February 2006

Abstract: The majority of physicians performing obstetric scans are radiologists and obstetricians. The radiologist is well trained in imaging but lacks the obstetric background required to interpret information obtained from the scan. The obstetrician is qualified in obstetric knowledge but often lacks the formal imaging training necessary to optimize the pictures. In Hungary, nearly 100% of the physicians who perform obstetric and gynecologic scans are obstetricians. In order to create a standard and to hold together the practitioners in obstetrics and gynecology, as well as to eliminate the serious consequences of clinical malpractice, we organized the Hungarian Society of Ultrasound in Obstetrics and Gynecology in 1992. The Society was established according to the standards of the most skilled obstetricians and gynecologists. In addition to working out the conditions and the standards, the Society provides for its members continuous education, postgraduate training, and monitors the knowledge and level of practitioners.

We have established three levels of qualification. Each level requires a medical undergraduate degree. The levels range from basic (A), intermediate (B), to specialist (C). To receive the certificate every user and ultrasound laboratory have to fulfill requirements based on skill as well as equipment and circumstances. The certificates are valid for one year. Every year the practitioner must pass a special examination at the appropriate level. By doing so, the Society provides its members with not only professional support, but ethical and legal security as well.
Sensitivity of Routine Ultrasound Screening of Pregnancies in the Eurofetus Database
Authors: GRANDJEAN HÉLÈNE , LARROQUE DANIÈLE , LEVI SALVATOR ,   THE EUROFETUS TEAM
Published: February 2006

Abstract: In this prospective study, we recorded details on 3,685 fetuses with congenital structural abnormalities from an unselected population of women who underwent routine ultrasound examination during their pregnancies. Overall, 2,262 fetuses were diagnosed as being abnormal before birth (sensitivity = 61.4%). The total number of abnormalities was 4,615, of which 1,733 (37.5%) were major abnormalities. The overall number of detected abnormalities was 2,593 (sensitivity = 56.2%). If only major abnormalities were considered, the sensitivity rose to 73.7%, compared to only 45.7% for the minor abnormalities. Within each severity group, the accuracy of detection varied across systems. For the major abnormalities, it was higher for the central nervous system (88.3%) and urinary tract (84.8%), but lower for heart and great vessels (38.8%). Detection of minor abnormalities was also effective for the urinary tract (89.1%), but not for the heart and great vessels (20.8%) and the musculoskeletal system (18%).
Managed Care and Ultrasound for the Diagnosis of Fetal Anomalies
Authors: BUECHLER ELIZABETH J.
Published: February 2006

Abstract: Managed care organizations and their affiliated group practices approach technology evaluation in a methodical way. This paper reviews the factors used in analysis of ultrasound for the diagnosis of fetal anomalies. It includes one group practice's strategies for ultrasound management while supporting the use of the second trimester fetal survey.
Detection of Anomalies: Alternatives to Ultrasound
Authors: EVANS MARK I. , O'BRIEN JOSEPH E. , CRITCHFIELD GREGORY
Published: February 2006

Abstract: Ultrasound and biochemical screening are complementary screening tests that each have limitations and advantages. The next several years will see variable progress in the evolution of these techniques, which, it is hoped, will result in an appropriate role for each to achieve a cost‐effective, highly sensitive and specific screening approach that will allow couples the most comfort in detecting problems during pregnancy, as well as a high degree of confidence that normal results are accurate.
Comparison of First and Second Trimester Screening for Fetal Anomalies
Authors: D'OTTAVIO GIUSEPPINA , MANDRUZZATO GIAMPAOLO , MEIR YORAM J. , RUSTICO MARIA ANGELA , FISCHER‐TAMARO LEO , CONOSCENTI GIANCARLO , NATALE ROBERTA
Published: February 2006

Abstract: Four thousand fifty unselected pregnant women bearing a total of 4,078 fetuses were examined by transvaginal sonography (TVS) at 14 weeks of gestational age and rescreened via transabdominal sonography (TAS) at 21 weeks. Fifty‐four of 88 anomalies were correctly identified at first scan whereas 34 were not; of these, 24 were discovered at second trimester rescreening, and the remaining 10 were observed later in pregnancy or after birth. The sensitivity of TVS screening with respect to final outcome was 61.4% (54 of 88 malformations in total) and 69.2% in comparison to TAS screening results (54 malformations detected among 78 recognized within 21 weeks). The association between fetal malformation and chromosomal aberrations was also investigated: in our study population there were 21 aneuploides, 14 of which were recognized because of abnormal findings at the 14 weeks' TVS, 5 at the TAS rescreening, and 2 after birth in neonates free of structural abnormalities.
Ultrasound Screening for Fetal Anomalies in Developing Countries: Wish or Reality?
Authors: KURJAK ASIM , KOS MILAN
Published: February 2006

Abstract: The main problems related to the screening of fetal anomalies in developing countries do include general ones of limited resources for health care and specific ones related to ultrasonographic practice, education, and instrumentation. The strategy to improve the detection of fetal anomalies is reliable, but has to be targeted to the following cornerstones: maintenance of obligate minimum of quality in perinatal care, establishment of three ultrasonographic examinations as a basic prerequisite of antenatal care, enhanced importance of first trimester screening, and a uniform program of education of sonographers, emphasizing the standardization of basic examination. Because of limited resources for perinatal care, we have to be highly responsible in selection of echographic instrumentation and appropriate education, subject to rigorous cost‐benefit analysis.
Self‐Consistent Gravitational Chaosa
Authors: MERRITT DAVID , VALLURI MONICA
Published: February 2006

Abstract: The motion of stars in the gravitational potential of a triaxial galaxy is generically chaotic. However, the timescale over which the chaos manifests itself in the orbital motion is a strong function of the degree of central concentration of the galaxy. Here, chaotic diffusion rates are presented for orbits in triaxial models with a range of central density slopes and nuclear black‐hole masses. Typical diffusion times are found to be less than a galaxy lifetime in triaxial models where the density increases more rapidly than ∼r−1 at the center, or which contain black holes with masses that exceed ∼0.1% of the galaxy mass. When the mass of a central black hole exceeds roughly 0.02 Mgal, there is a transition to global stochasticity and the galaxy evolves to an axisymmetric shape in little more than a crossing time. This rapid evolution may provide a negative feedback mechanism that limits the mass of nuclear black holes to a few percent of the stellar mass of a galaxy.
Nonlinear Cosmological Structure Formation aa
Authors: MA CHUNG‐PEI
Published: February 2006

Abstract: A general discussion of the evolution and model‐dependence of both the linear and nonlinear power spectrum of density fluctuations is presented. The features of the linear power spectrum in cosmological models with cold dark matter (CDM) and cold + hot dark matter (C + HDM) are reviewed, and useful analytical approximations are summarized. Cosmological numerical simulation results are then used to illustrate the process of nonlinear gravitational clustering and to compute the nonlinear power spectrum. A new analytical approximation relating the linear and nonlinear power spectrum in C + HDM models is presented.
On the Large‐Scale Structure of Hickson Compact Groups of Galaxies
Authors: DUPKE RENATO A. , WU WENTAO
Published: February 2006

Abstract: We present a study on the integral two‐point correlation functions of Hickson compact groups of galaxies. The results show no evidence that these objects form large‐scale structures beyond 10h−1 Mpc. Their clustering is much weaker than that expected from the universal dimensionless correlation function for galaxy associations, but is overall more similar to that of galaxies. The results suggest that either Compact Groups are not real physical systems or their “seeding” is very different from that of other galaxy associations.
Coupled Oscillators for Fun and Profit
Authors: WIESENFELD KURT
Published: February 2006

Abstract: A prime example of long‐range cooperative behavior is when populations of nonlinear oscillators spontaneously synchronize. This phenomenon crops up in many places in biology and applied physics. Some twenty years ago, Yoshiki Kuramoto introduced a simple tractable model which captures key elements of the phenomenon. It also provides new answers to old questions about certain superconducting circuits having applications for fast electronics.
Vertebrate Locomotion‐A Lamprey Perspectivea
Authors: GRILLNER STEN , PARKER DAVID , EL MANIRA ABDEL˙JABBAR
Published: February 2006

Abstract: The forebrain, brain stem, and spinal cord contribution to the control of locomotion is reviewed in this chapter. The lamprey is used as an experimental model because it allows a detailed cellular analysis of the neuronal network underlying locomotion. The focus is on cellular mechanisms that are important for the pattern generation, as well as different types of pre‐ and postsynaptic modulation. Neuropeptides target different cellular and synaptic mechanisms and cause long‐lasting changes (>24 h) in network function.
Central Circuits Controlling Locomotion in Young Frog Tadpoles
Authors: ROBERTS ALAN , SOFFE S. R. , WOLF E. S. , YOSHIDA M. , ZHAO F.‐Y.
Published: February 2006

Abstract: The young Xenopus tadpole is a very simple vertebrate that can swim. We have examined its behavior and neuroanatomy, and used immobilized tadpoles to study the initiation, production, coordination, and termination of the swimming motor pattern. We will outline the sensory pathways that control swimming behavior and the mainly spinal circuits that produce the underlying motor output. Our recent work has analyzed the glycinergic, glutamatergic, cholinergic, and electrotonic synaptic input to spinal neurons during swimming. This has led us to study the nonlinear summation of excitatory synaptic inputs to small neurons. We then analyzed the different components of excitation during swimming to ask which components control frequency, and to map the longitudinal distribution of the components along the spinal cord. The central axonal projection patterns of spinal interneurons and motoneurons have been defined in order to try to account for the longitudinal distribution of synaptic drive during swimming.
Basic Principles for Generating Motor Output in the Stomatogastric Ganglion
Authors: SELVERSTON A. , ELSON R. , RABINOVICH M. , HUERTA R. , ABARBANEL H.
Published: February 2006

Abstract: The lobster stomatogastric ganglion contains 30 neurons and when modulated can produce two distinct rhythmic motor patterns‐the gastric mill and the pyloric. The complete neural circuitry underlying both patterns is well known. Without modulatory input no patterns are produced, and the neurons fire tonically or are silent. When neuromodulators are released into the ganglion from specific neurons or are delivered as hormones, the properties of the neurons and synapses change dramatically and modulator‐specific gastric mill and pyloric patterns are produced. In general the rhythmicity derives from the induced burstiness of the neurons, and the pattern from the strengths of the electrical and chemical synapses. The organized activity can be traced to a marked reduction of chaotic activity in individual neurons when they shift from the unmodulated to the modulated state.