bluuebunny/crossref_metadata_2025 huggingface dataset:
Trial to Evaluate the Management of Paroxysmal Supraventricular Tachycardia During an Electrophysiology Study With Tecadenoson
Authors: Ellenbogen Kenneth A. , O’Neill Gearoid , Prystowsky Eric N. , Camm John A. , Meng Lixin , Lieu Hsiao Dee , Jerling Markus , Shreeniwas Revati , Belardinelli Luiz , Wolff Andrew A.
Published: June 2005

Background—

Tecadenoson is a potent selective A
1
-adenosine receptor agonist with a dose-dependent negative dromotropic effect on the AV node. Tecadenoson terminates induced paroxysmal supraventricular tachycardia (PSVT) without the clinically significant side effects caused by stimulation of other adenosine receptors. This trial was designed to determine a safe and effective tecadenoson bolus for termination of electrophysiologically induced PSVT.

Methods and Results—

Patients with a history of symptomatic PSVT and inducible PSVT at the time of a clinically indicated electrophysiology study were randomized into a multicenter, double-blind, placebo-controlled trial. Five 2-dose tecadenoson bolus regimens were evaluated versus placebo (75/150, 150/300, 300/600, 450/900, 900 μg/900 μg). The second bolus was administered only if PSVT persisted for 1 minute after the first bolus. Each tecadenoson regimen resulted in a significant therapeutic conversion rate compared with placebo (range, 50.0% to 90.3%, analysis of all patients dosed; n=181;
P
<0.0005). Conversion by the first bolus was dose related (range: placebo, 3.3% to 86.7% for 900 μg/900 μg). Time to conversion was dose dependent, with a median time of <1 minute for the 3 highest dose regimens. Postconversion arrhythmias were transient, requiring no additional treatment in 4 regimens (including placebo). Transient second- and third-degree heart block occurred at higher doses (300/600, 450/900, 900 μg/900 μg) and was supported with backup pacing when needed. No effect on blood pressure was observed. Ten patients with a history of asthma or chronic obstructive pulmonary disease tolerated tecadenoson without bronchospasm.

Conclusions—

We identified an optimal tecadenoson regimen (300 μg/600 μg) that effectively and rapidly converted 90% (28 of 31) of PSVT patients to normal sinus rhythm with no significant adverse effects.
Effects of Exercise and Ischemia on Mobilization and Functional Activation of Blood-Derived Progenitor Cells in Patients With Ischemic Syndromes
Authors: Sandri Marcus , Adams Volker , Gielen Stephan , Linke Axel , Lenk Karsten , Kränkel Nicolle , Lenz Dominik , Erbs Sandra , Scheinert Dierk , Mohr Friedrich Wilhelm , Schuler Gerhard , Hambrecht Rainer
Published: June 2005

Background—

Exercise training (ET) has been shown to improve regional perfusion in ischemic syndromes. This might be partially related to a regeneration of diseased endothelium by circulating progenitor cells (CPCs) or CPC-derived vasculogenesis. The aim of the present study was to determine whether ischemic stimuli during ET are required to promote CPC mobilization in patients with cardiovascular diseases.

Methods and Results—

Patients with peripheral arterial occlusive disease (PAOD) were randomized to 4 weeks of daily ischemic ET or control (group A). Successfully revascularized patients with PAOD were randomized to 4 weeks of daily nonischemic ET or control (group B). Patients with stable coronary artery disease were subjected to 4 weeks of subischemic ET or control (group C). At baseline and after 4 weeks, the number of KDR
+
/CD34
+
CPCs was determined by fluorescence-activated cell sorting analysis. Levels of vascular endothelial growth factor (VEGF) were measured by ELISA. A Matrigel assay was used to quantify CPC integration into vascular structures. Expression of the homing factor CXCR4 was determined by reverse transcription-polymerase chain reaction. In group A only, ischemic ET increased VEGF levels by 310% (
P
<0.05 versus control) associated with an increase in CPCs by 440% (
P
<0.05 versus control), increased CXCR4 expression, and enhanced integration of CPCs into endothelial networks. In contrast, subischemic ET in groups B and C increased CXCR4 expression and CPC integration.

Conclusions—

In training programs, symptomatic tissue ischemia seems to be a prerequisite for CPC mobilization. However, ischemic and subischemic ET programs affect CXCR4 expression of CPCs, which might lead to an improved CPC integration into endothelial networks.
Impaired Elastic Properties of the Ascending Aorta in Newborns Before and Early After Successful Coarctation Repair
Authors: Vogt Manfred , Kühn Andreas , Baumgartner Daniela , Baumgartner Christian , Busch Raymonde , Kostolny Martin , Hess John
Published: June 2005

Background—

Despite successful surgical correction, morbidity of patients with coarctation of the aorta is increased. It is well known that these patients have impaired elastic properties of the prestenotic arteries. To find out whether these abnormalities are primarily present or develop later, we studied 17 newborns before and early after surgical repair.

Methods and Results—

Aortic wall stiffness index and distensibility were calculated using ascending and abdominal aortic diameters determined by M-mode echocardiography and noninvasive estimation of aortic pulse pressure in the right arm and leg. Seventeen patients with aortic coarctation (mean age, 20±26 days) were compared with 17 normal neonates (mean age, 13±7 days) preoperatively and postoperatively (10±6 days after surgery). Ascending aortic distensibility in patients was significantly reduced preoperatively (79±58 versus 105±36;
P
=0.03) and postoperatively (65±24 versus 105±36;
P
<0.005). Preoperative and postoperative ascending aortic stiffness index was higher in patients (preoperative, 5.2±4.4 versus 2.7±0.9;
P
=0.04; postoperative, 4.0±1.6 versus 2.7±0.9;
P
<0.005). Elastic properties of the descending aorta did not differ preoperatively or postoperatively compared with those in normal subjects.

Conclusions—

Elastic properties of the prestenotic aorta of patients with coarctation seem to be impaired primarily, even in neonates, and remain unchanged early after successful operation. Surgical correction does not resolve inborn pathology of the prestenotic aortic vascular bed.
Reconsidering sustainability: some implications for community-based crime prevention
Authors: Kelly Katharine D. , Caputo Tullio , Jamieson Wanda
Published: June 2005

This paper examines the experiences of a community that has successfully sustained its crime prevention through social development activities for over a decade. It explores how a broad philosophical approach to sustainability can be applied to community-based initiatives such as crime prevention. In this regard, traditional situational crime prevention strategies are compared with crime prevention through social development. The evidence from the case study community illustrates the importance for sustainability of such factors as bottom-up decision-making, flexibility, inclusion and integration. The findings suggest that crime prevention through social development provides a framework for developing sustainable community-based crime prevention activities. The implications of these findings are considered with respect to the sustainability of other community-based initiatives.
The deportation machine: Europe, asylum and human rights
Authors: Fekete Liz
Published: June 2005

Issues of immigration, asylum and refugee rights have become targets for politicians of all persuasions across Europe, from social democrats to the far Right. Ever-increasing pressure, spear-headed by populist media and electioneering politicians, to reduce the numbers of those seeking asylum, to raise the bar for successful claims and return those whose claims have ‘failed’ has resulted in sustained abuse of human rights. Europe’s deportation programme serves to undermine not only the Geneva Convention, but also international conventions on human rights and children’s rights. Yet, despite the shocking nature of the practices exposed here, little heed is paid to them or to the traumas suffered by their victims - a blindness that is only explicable in terms of the xeno-racism meted out to the desperate and the dispossessed.
From Affliction to Affirmation: Narrative Transformation and the Therapeutics of Candomblé Mediumship
Authors: Seligman Rebecca
Published: June 2005

Through the presentation and analysis of a prototypical mediumship narrative, this article shows how individuals initiated into the Candomblé religion of north-eastern Brazil come to alter their own self-narratives by learning and internalizing the cultural model for an established social/religious role: that of the medium. As individuals come to identify with this ‘role model,’ they are able to reinterpret their own life histories in terms of the model’s structure and its symbolic content. This article also demonstrates how the social articulation and cognitive internalization of this new self-narrative act therapeutically, to foster a positive transformation in self-understanding that facilitates positive behavior.
The TUBB1 Q43P functional polymorphism reduces the risk of cardiovascular disease in men by modulating platelet function and structure
Authors: Freson Kathleen , De Vos Rita , Wittevrongel Christine , Thys Chantal , Defoor Johan , Vanhees Luc , Vermylen Jos , Peerlinck Kathelijne , Van Geet Chris
Published: June 2005

The discoid form of platelets is maintained by a marginal band of tightly coiled microtubules. β1-tubulin is the major isoform within platelet and megakaryocyte microtubules. In 24.2% of 33 unrelated inherited macrothrombocytopenia patients and in 10.6% of 272 subjects of a healthy population a P for Q substitution in β1-tubulin was found in the highly conserved residue 43. Heterozygous carriers of the Q43P variant showed a reduced platelet protein β1-tubulin expression. Transfection of green fluorescent protein (GFP)-tagged Q43P β1-tubulin in megakaryocytic MEG01 cells resulted in a disturbed tubulin organization. Electron microscopy revealed enlarged spherocytic platelets with a disturbed marginal band and organelle-free zones. In addition, platelets with the Q43P β1-tubulin variant had reduced adenosine triphosphate (ATP) secretion, thrombin receptor activating peptide (TRAP)-induced aggregation and collagen adhesion. The prevalence of the Q43P β1-tubulin variant was also 2 times higher (odds ratio, [OR] = 2.1;95% confidence interval [CI], 1.22-3.59) among control subjects than among patients with cardiovascular disease (10.4% versus 5.2%, P < .001). By analyzing this protective factor in men and women separately, this association was only found in men. This study thus presents the functional consequences of the platelet Q43P β1-tubulin substitution that is frequent in the healthy population and may protect men against arterial thrombosis.
Pregnancy-induced obsessive compulsive disorder: a case report
Authors: Kalra Harish , Tandon Rajul , Trivedi Jitendra kumar , Janca Aleksandar
Published: June 2005

Pregnancy is a well-recognised risk factor in precipitating obsessive-compulsive disorder. We present and discuss a case with the onset of obsessive-compulsive disorder in the fourth month of gestation, which fully recovered two weeks after delivery. The phenomenology of the observed disorder was similar to earlier reports of obsessive-compulsive disorder in pregnancy, i.e. the obsessions and compulsions were predominantly related to the concern of contaminating the foetus resulting in washing compulsions. Despite the initial success with anti-obsessional drugs, the patient stopped the medication in the last month of gestation. Nevertheless, she fully recovered two weeks after the delivery without any psychiatric intervention. There were no obsessive-compulsive symptoms at one-year follow up. The possible mechanisms involved in the aetiology of this case, and future research directions in understanding the role of pregnancy in OCD are discussed.
Relaxin Research in the Postgenomic Era
Authors: KAWAMURA KAZUHIRO , SUDO SATOKO , KUMAGAI JIN , PISARSKA MARGARETA , HSU SHEAU YU TEDDY , BATHGATE ROSS , WADE JOHN , HSUEH AARON J. W.
Published: June 2005

Abstract: Because of the coevolution of ligands and their cognate receptors, analysis of human genomic sequences allows prediction of the pairing of these elements. Initially, we identified a group of five human leucine‐rich repeat‐containing G‐protein‐coupled receptor (LGR) genes homologous to LH, FSH, and TSH receptors. Based on common phenotypes of INSL3 null mice and transgenic mice with LGR8 gene deletion, we hypothesized that INSL3, relaxin, and related genes are likely ligands for the paralogous LGR7 and LGR8 genes. Matching the relaxin family peptides with these two orphan LGRs led to the finding that relaxin is capable of activating LGR7 and LGR8 through the Gs pathway. In addition, INSL3 and relaxin 3 were found to be specific ligands for LGR8 and LGR7, respectively. Based on the known production of INLS3 by testicular Leydig cells and ovarian theca cells, we demonstrated the expression of the INSL3 receptor LGR8 in oocytes in ovary and in male germ cells in the testis. Furthermore, we found that LH stimulates INSL3 transcripts in ovarian theca and testicular Leydig cells. INSL3, in turn, binds LGR8 expressed in germ cells to initiate the meiotic progression of arrested oocytes in preovulatory follicles in vitro and in vivo and to suppress male germ cell apoptosis in vivo. INSL3 interacts with germ cells to activate the inhibitory G protein, thus leading to decreases in cAMP production. Our data demonstrate the importance of the INSL3‐LGR8 paracrine system in mediating gonadotropic actions in both ovary and testis.
The Human LGR7 Low‐Density Lipoprotein Class A Module Requires Calcium for Structure
Authors: HOPKINS EMMA J. , BATHGATE ROSS A. , GOOLEY PAUL R.
Published: June 2005

Abstract: The relaxin and INSL3 receptors, LGR7 and LGR8, are the only human G‐protein‐coupled receptors to contain a low‐density lipoprotein class‐A (LDL‐A) module. LDL‐A modules are well characterized in a variety of diverse biological functions that involve ligand binding to elicit a response. Common features of the LDL‐A modules characterized to date are the conservation of three disulfide bonds and the structural arrangement around a bound calcium ion. In this study we recombinantly produce the human LGR7 LDL‐A module for NMR studies and demonstrate that calicum is required for the module to form a stable and correctly folded structure.
The Chemistry and Biology of Human Relaxin‐3
Authors: TREGEAR GEOFFREY W. , BATHGATE ROSS A. , LAYFIELD SHARON , FERRARO TANIA , GUNDLACH ANDREW , MA SHERIE , LIN FENG , HANSON NICOLA F. , SUMMERS ROGER J. , ROSENGREN JOHAN , CRAIK DAVID J. , WADE JOHN D.
Published: June 2005

Abstract: A novel member of the human relaxin subclass of the insulin superfamily was recently discovered during a genomics database search and named relaxin‐3. Like human relaxin‐1 and relaxin‐2, relaxin‐3 is predicted to consist of a two‐chain structure and three disulfide bonds in a disposition identical to that of insulin. To undertake detailed biophysical and biological characterization of the peptide, its chemical synthesis was undertaken. In contrast to human relaxin‐1 and relaxin‐2, however, relaxin‐3 could not be successfully prepared by simple combination of the individual chains, thus necessitating recourse to the use of a regioselective disulfide bond formation strategy. Solid phase synthesis of the separate, selectively S‐protected A and B chains followed by their purification and the subsequent stepwise formation of each of the three disulfides led to the successful acquisition of human relaxin‐3. Comprehensive chemical characterization confirmed both the correct chain orientation and the integrity of the synthetic product. Relaxin‐3 was found to bind to and activate native relaxin receptors in vitro and stimulate water drinking through central relaxin receptors in vivo. Recent studies have demonstrated that relaxin‐3 will bind to and activate human LGR7, but not LGR8, in vitro. Secondary structural analysis showed it to adopt a less ordered confirmation than either relaxin‐1 or relaxin‐2, reflecting the presence in the former of a greater percentage of nonhelical forming amino acids. NMR spectroscopy and simulated annealing calculations were used to determine the three‐dimensional structure of relaxin‐3 and to identify key structural differences between the human relaxins.
Mechanisms of Relaxin Action in the Reproductive Tract: Studies in the Relaxin‐Deficient (Rlx−/−) Mouse
Authors: PARRY LAURA J. , McGUANE JONATHAN T. , GEHRING HELEN M. , KOSTIC IRNA GRACE T. , SIEBEL ANDREW L.
Published: June 2005

Abstract: The major functions of relaxin (RLX) are associated with female reproductive tract physiology, namely, the regulation of biochemical processes involved in remodeling of extracellular matrix components in the cervix and vagina at term. Studies in RLX‐deficient mice (Rlx−/−) demonstrate that although females give birth to live young without apparent dystocia, the pubic symphysis is not elongated, and they have abnormal cervical and vaginal morphology. The current study examined phenotypic differences in collagen, matrix metalloproteinases (MMP), and estrogen receptors (ERs) in the cervix and vagina of pregnant Rlx+/+ and Rlx−/− mice. Neither collagen nor TGFβ1 mRNA levels in the cervix and vagina differed significantly between Rlx+/+ and Rlx−/− at any stage of gestation, except on gestation day 18.5, with an increase in α1‐I collagen and TGFβ1 expression in Rlx−/− mice. MMP gene expression was also increased in Rlx−/− mice, especially at term. Administration of recombinant H2 RLX (0.05 μg/μL/h) to Rlx−/− mice for 6 d from gestation day 12.5 caused a significant decrease in α1‐I collagen and MMP‐13 gene expression in the cervix and vagina, but it had no effect on TGFβ1. There was also a significant reduction in ERβ expression in RLX‐treated Rlx−/− mice. Interestingly, RLX treatment caused a significant decrease in LGR7 expression in these reproductive tissues. In summary, these data show increases in MMP gene expression in Rlx−/− mice that are not correlated with changes in collagen expression. Furthermore, we report a novel ER phenotype in the cervix and vagina of Rlx−/− mice.
Relaxin Regulates Endometrial Structure and Function in the Rhesus Monkey
Authors: GOLDSMITH LAURA T. , WEISS GERSON
Published: June 2005

Abstract: The actions of relaxin are highly species specific. The role of relaxin in human endometrial function has not been well understood because of the paucity of in vivo studies in women or in suitable primate models. A model of early human pregnancy was established in ovariectomized, steroid‐primed rhesus monkeys. Relaxin exerts dramatic uterine effects in this model, including a pronounced increase in uterine weight and stimulation of endometrial angiogenesis. In addition, relaxin negatively regulates expression of endometrial matrix metalloproteinases (MMP), causing decreased endometrial levels of MMP‐1 and MMP‐3 proteins and increased protein levels of their endogenous inhibitor, tissue inhibitor of metalloproteinase 1. This results in maintenance of endometrial collagen content. The negative effects of relaxin on MMP expression in the endometrium are in distinct contrast to the positive regulation of MMPs previously shown in fibroblasts from other tissues including the cervix. Relaxin also significantly inhibits endometrial levels of estrogen receptor alpha and significantly inhibits levels of progesterone isoforms B and A. The findings that relaxin stimulates new blood vessel formation while maintaining endometrial connective tissue integrity are consistent with a significant role of relaxin in the establishment and/or maintenance of early pregnancy.
Effects of the Sucking Stimulus on Relaxin Receptor (LGR7) Expression in the Mammary Apparatus of the Tammar Wallaby (Macropus eugenii)
Authors: GWYTHER JANEY , GEHRING HELEN M. , PARRY LAURA J.
Published: June 2005

Abstract: Macropodid marsupials suckle young of different ages simultaneously, a phenomenon known as asynchronous lactation. The growth of the mammary glands supporting young of different ages varies considerably. This study investigates relaxin receptor (LGR7) expression in different mammary glands and nipples during early lactation in the wallaby. LGR7s were upregulated in the nipple and mammary gland supporting the neonate 5‐11 d postpartum. LGR7 mRNA concentrations were also significantly higher in the gland supporting the newborn young than the older young. These data suggest that a local stimulus, that is, continuous sucking by the neonate, may influence LGR7 expression in the mammary apparatus.
Increased Expression of the Relaxin Receptor (LGR7) in Human Endometrium during the Secretory Phase of the Menstrual Cycle
Authors: BOND COURTNEY P. , PARRY LAURA J. , SAMUEL CHRISHAN S. , GEHRING HELEN M. , LEDERMAN FIONA L. , ROGERS PETER A. W. , SUMMERS ROGER J.
Published: June 2005

Abstract: This study investigated localization and expression of relaxin and its receptor, LGR7, in the human endometrium during the proliferative and secretory phases of the menstrual cycle. H2 relaxin binding was identified in endometrium, but not myometrium, and particularly in the epithelium of the endometrial glands and uterine lumen. Binding sites increased in the early secretory phase of the menstrual cycle and were paralleled by similar increases in LGR7 mRNA measured by Q‐PCR. The increase in LGR7 expression and H2 relaxin binding in the secretory phase of the menstrual cycle suggests a specific role for relaxin after ovulation in the human uterus.
Relaxin‐Induced Angiogenesis in Ovary Contributes to Follicle Development
Authors: SHIROTA KYOKO , TATEISHI KAYOKO , EMOTO MAKOTO , HACHISUGA TORU , KUROKI MASAHIDE , KAWARABAYASHI TATSUHIKO
Published: June 2005

Abstract: CD31‐positive blood vessels increased in human ovarian cortical tissues cultured with relaxin than in tissues cultured without relaxin. The number of vWF‐positive vessels counted in rat ovaries after relaxin injection (40.5 ± 4.3) significantly increased compared to that in saline‐injected rats (24.3 ± 3.0). The proportion of primordial follicles was significantly decreased, that of primary follicles was significantly increased at 16 h, and that of early antral follicles was significantly increased at 24 h in rats after relaxin injection. These results suggest that relaxin may contribute to follicle development through the mechanism of angiogenesis in the ovary.
Recombinant Human Relaxin (rhRLX) Modifies Systemic Arterial Properties in Conscious Rats Irrespective of Gender, but in a Biphasic Fashion
Authors: DEBRAH DAN O. , CONRAD KIRK P. , NOVAK JACKIE , DANIELSON LEE A. , SHROFF SANJEEV G.
Published: June 2005

Abstract: Chronic administration of recombinant human relaxin (rhRLX) to conscious female nonpregnant rats that reaches serum concentrations of 10‐30 ng/mL increases cardiac output and reduces systemic arterial load comparable to levels observed in midterm pregnancy. Chronic administration of the hormone to male rats increases cardiac output and reduces systemic arterial load to a similar extent. Short‐term or chronic administration of rhRLX to conscious female rats that reaches serum concentrations of ∼80 ng/mL results in minimal and insignificant changes. We conclude that: (1) rhRLX increases cardiac output and reduces arterial load irrespective of gender, and (2)the rhRLX dose response is biphasic.
Renal Hemodynamic Effects of Relaxin in Humans
Authors: SMITH MARIE , DAVISON JOHN , CONRAD KIRK , DANIELSON LEE
Published: June 2005

Abstract: Rat studies have convincingly demonstrated the essential role of the ovarian hormone relaxin in mediating gestational renal hemodynamic and osmoregulatory changes in that species. We describe a model in nonpregnant volunteers using exogenous hCG to stimulate the production and release of ovarian relaxin in order to assess renal hemodynamic responses. Women (n= .0) were serially studied ± hCG stimulation during menstrual cycles with measurement of inulin, PAH, and neutral dextran clearances (to determine glomerular filtration rate [GFR], renal plasma flow [RPF], and glomerular porosity, respectively). Controls were women without ovarian function (n= 6) and men (n= .0). GFR and RPF were increased in the luteal phase compared to the follicular phase (15.3% increase in GFR, P <0.005; 17.8% increase in RPF, P <0.05). In controls, GFR and RPF were not significantly different between study occasions. Although exogenous hCG did not stimulate relaxin secretion in women without ovarian function or in men, it did so in normal women, but not into the pregnancy range. In no group were renal hemodynamics augmented by administered hCG. In naturally occurring cycles, increased serum relaxin is associated with augmented renal hemodynamics. As luteal stimulation with hCG failed to yield pregnancy relaxin levels, the use of exogenous relaxin for human administration is needed to further elucidate the renal vasodilatory properties of relaxin.
Relaxin Receptor Expression in Hepatic Stellate Cells and in Cirrhotic Rat Liver Tissue
Authors: BENNETT ROBERT G. , MAHAN KATRINA J. , GENTRY‐NIELSEN MARTHA J. , TUMA DEAN J.
Published: June 2005

Abstract: Relaxin has antifibrotic effects on the hepatic stellate cells (HSCs) responsible for collagen deposition in cirrhosis. The expression of relaxin receptors LGR7 and LGR8 in HSCs and liver disease was examined. Activated and quiescent HSCs expressed LGR7, whereas only activated HSCs expressed LGR8. Relaxin, relaxin‐3, or InsL3 treatment increased cAMP, suggesting activation of both receptors. LGR8 and LGR7 were present in cirrhotic rat liver, but were undetectable in normal liver. In conclusion, both LGR7 and LGR8 are expressed in activated HSCs and cirrhotic liver, suggesting that relaxin, InsL3, or relaxin‐3 may be useful in the treatment of hepatic fibrosis.
Investigating the Role of Relaxin in the Regulation of Airway Fibrosis in Animal Models of Acute and Chronic Allergic Airway Disease
Authors: MOOKERJEE ISHANEE , TANG MIMI L.K. , SOLLY NATASHA , TREGEAR GEOFFREY W. , SAMUEL CHRISHAN S.
Published: June 2005

Abstract: Airway remodeling is a characteristic feature of asthma that leads to chronic irreversible airway obstruction. Fibrosis in the basement membrane region is a hallmark of remodeling in asthma that is not found in other diseases. In the outlined studies, we investigated the relationship between relaxin and airway fibrosis in asthma using acute and chronic models of allergic airway disease. These studies confirm a critical role for relaxin, in the regulation of collagen deposition in the airway/lung in animal models of allergic airway disease.
Insulin‐Relaxin Family Peptide Signaling and Receptors in Mouse Brain Membranes and Neuronal Cells
Authors: ORTINAU STEFANIE , LIN FENG , WADE JOHN D. , TREGEAR GEOFFREY W. , BATHGATE ROSS A.D. , GUNDLACH ANDREW L.
Published: June 2005

Abstract: Several orphan G‐protein‐coupled receptors (GPCRs), LGR7 and LGR8, GPCR135 and GPCR142, were recently identified as putative, native receptors for different relaxin‐family peptides, and their cell signaling mechanisms were elucidated in stably transfected cell lines. Anatomic studies have demonstrated that discrete populations of neurons in rat brain express relaxin and relaxin‐3 mRNA/peptide, relaxin and relaxin‐3 binding sites, and LGR7 and GPCR135 mRNAs. Thus, we began to assess the ability of relaxin‐family peptides to alter cAMP production in brain and the involvement of the different native receptors. In mouse cortical membranes, a fixed concentration of relaxin peptides (100 nM) inhibited forskolin‐induced cAMP production, but further studies in normal and receptor knockout mouse strains are required to assess the specificity of these effects. In addition, whole‐cell signaling mechanisms are being investigated in a mouse hypothalamic cell line, GT1‐7. Such studies will help to establish the actions of relaxin‐family peptides via their different GPCRs in different brain pathways.
Relaxin Pretreatment Decreases Infarct Size in Male Rats after Middle Cerebral Artery Occlusion
Authors: WILSON BRIAN C. , MILNE PETER , SALEH TAREK M.
Published: June 2005

Abstract: We studied the possible neuroprotective action of relaxin in a rat stroke model. Relaxin (10 ng in 200 nL saline) or saline was injected into the secondary somatosensory cortex of anesthetized rats. Thirty minutes after treatment, the right middle cerebral artery was occluded, causing ischemic conditions. Brains were removed 4 hours after stroke, and 1‐mm coronal sections were stained using 2‐3‐5‐triphenoltetrazolium chloride. Digital photographs were taken of the sections, and the ratio of infarct area to ipsilateral hemispheric area was calculated. Relaxin treatment significantly (P <.05) reduced this ratio compared with that of saline‐treated controls. Results suggest that relaxin may prevent ischemia‐induced cell death.
Relaxin Stimulates cAMP Production in MCF‐7 Cells upon Overexpression of Type V Adenylyl Cyclase
Authors: NGUYEN BAO T. , DESSAUER CARMEN W.
Published: June 2005

Abstract: Relaxin stimulates cAMP production and activation of ERK and PI3K in THP‐1 cells. Relaxin also stimulates protein kinase C zeta (PKCζ) translocation to the plasma membrane in a PI3K‐dependent manner in THP‐1 and MCF‐7 cells. However, relaxin did not increase cAMP production in MCF‐7 cells. We overexpressed different adenylyl cyclase (AC) isoforms in MCF‐7 cells to examine coupling of endogenous relaxin receptors to cAMP production. Overexpression of types II and IV AC had no effect on cAMP production by relaxin. However, overexpression of type V AC, which is activated by PKCζ, showed synergistic stimulation of cAMP by relaxin and forskolin.
A Novel, Adenylate Cyclase, Signaling Mechanism of Relaxin H2 Action
Authors: SHPAKOV ALEXANDER , PERTSEVA MARIANNA , KUZNETSOVA LUDMILA , PLESNEVA SVETLANA
Published: June 2005

Abstract: For the first time, the adenylate cyclase signaling mechanism (ACSM) of the action of relaxin H2 was revealed and deciphered in human and rat muscle tissues. The comparative study of signaling blocks forming the ACSM of relaxin and insulin (discovered earlier) showed that the postreceptor signaling chain of relaxin coincides with that of insulin. However, the type of relaxin receptor involved in ACSM remains obscure. Currently, the ACSM of relaxin may be represented as a signaling cascade: receptor ⇒ Gi protein (βγ‐dimer) ⇒ phosphatidylinositol 3‐kinase (PI3K) ⇒ protein kinase Cζ (PKCζ) ⇒ Gs protein ⇒ adenylate cyclase.
Clinical Use of Relaxin to Facilitate Birth: Reasons for Investigating the Premise
Authors: LEE HYUNG‐YUL , ZHAO SHUANGPING , FIELDS P A , SHERWOOD O.D
Published: June 2005

Abstract: In the United States, both medical and nonmedical factors have driven the cesarean section rate to over 26% of all deliveries. In addition to questions of increased cost associated with operative delivery, some have questioned the ethics of performing cesarean section for nonmedical reasons. Reduction of both the duration and the pain associated with vaginal delivery would likely bring about a decline in the rate of both medical and nonmedical cesarean sections. This chapter summarizes recent findings that support the premise that through its growth‐promoting and softening effects on the cervix, short‐term subcutaneous administration of pharmacologic amounts of relaxin to women at term holds promise as a means of reducing the duration and discomfort associated with delivery. Two recent studies conducted in pregnant rats demonstrated that the cervix is highly responsive to relaxin during the antepartum period and that short‐term subcutaneous administration of the hormone to relaxin‐deficient animals not only promotes growth and softening of the cervix, but also reduces the duration of labor and delivery. Moreover, recent human clinical trials examining the influence of 24 weeks of continuous subcutaneous administration of recombinant human relaxin for the treatment of scleroderma provided evidence not only that the human reproductive tract is responsive to relaxin, but also that the administration of the hormone does not cause serious adverse side effects. It is concluded that recent findings provide an impetus for an investigation into relaxin's potential for cervical remodeling and facilitating birth in women.
Relaxin Concentrations in Serum and Urine of Endangered Species: Correlations with Physiologic Events and Use As a Marker of Pregnancy
Authors: STEINETZ BERNARD G. , BROWN JANINE L. , ROTH TERRI L. , CZEKALA NANCY
Published: June 2005

Abstract:Many mammalian species are facing extinction due to problems created by human encroachment, agriculture, pollution, and willful slaughter. Among those at risk are the Asian and African elephant, Sumatran rhinoceros, and giant panda. Conservation groups try to save species in the wild by preserving habitat and limiting animal‐human conflicts, often with limited success. Another alternative is to preserve the extant gene pool through captive breeding as a hedge against extinction. Measurement of circulating reproductive hormones is impractical for most wildlife species; determination of urinary or fecal hormone metabolites provides a more viable approach. To aid breeding management, one important tool is the ability to diagnose and monitor pregnancy, especially in species with long gestations (e.g., rhinos over 15 mo and elephants over 20 mo). Unfortunately, measuring progestins often is not useful diagnostically, because concentrations are similar during at least part of the pregnancy and the nonpregnant luteal phase in some species (e.g., elephants, rhinoceroses, and giant pandas). As serum relaxin reliably distinguishes between pregnancy and pseudopregnancy in bitches, relaxin measurement might also provide a method for detecting a successful pregnancy in endangered species. Appropriate immunoassay reagents have enabled the estimation of relaxin concentrations in the serum of elephants and rhinos and the determination of pregnancy establishment and the outcome. Relaxin was also detected in panda serum and urine. However, the extreme variability of the time between observed mating and parturition and the confounding factors of delayed implantation, pseudopregnancy, and frequent fetal resorptions made it impossible to use the panda relaxin data as a specific marker of pregnancy.
Basic Progress and Future Therapeutic Perspectives of Relaxin in Ischemic Heart Disease
Authors: BANI DANIELE , NISTRI SILVIA , SACCHI TATIANA BANI , BIGAZZI MARIO
Published: June 2005

Abstract: Relaxin has been validated as a cardiotropic hormone, being produced by the heart and acting on specific heart receptors. Evidence is accumulating that it could hamper the pathophysiologic mechanisms of ischemic heart disease. Time is ripe to study relaxin as a cardiotropic drug, as recombinant human relaxin (hrRLX) is now available and previous clinical trials have shown a virtual lack of toxicity and adverse side effects, even at high doses. Our recent observations suggest that relaxin, besides being a preventative agent, may also be effective in the treatment of acute myocardial infarction and may be an adjuvant for precursor cell grafting to repair postinfarct myocardium. In a swine model of myocardial infarction currently used to test cardiotropic drugs due to its similarities with human ischemic heart disease, hrRLX, given at reperfusion upon 30 min of ischemia, markedly reduced serum and tissue markers of myocardial injury, cardiomyocyte apoptosis and leukocyte recruitment, resulting in overall improvement in cardiac performance compared with the controls. In in vitro mixed cultures of mouse skeletal myoblasts and adult rat cardiomyocytes, relaxin increased gap junction formation and potentiated gap junction‐mediated intercellular exchanges and signaling between the coupled cells. In view of the therapeutic use of myoblast grafting for cardiac repair, relaxin could hence favor the electromechanical coupling of grafted myoblasts with the resident cardiomyocytes and facilitate their transdifferentiation towards a cardiac phenotype. Relaxin, therefore, shows promising therapeutic potential in cardiology and cardiac surgery.
Relaxin Favors the Morphofunctional Integration between Skeletal Myoblasts and Adult Cardiomyocytes in Coculture
Authors: FORMIGLI LUCIA , FRANCINI FABIO , CHIAPPINI LAURA , ZECCHI‐ORLANDINI SANDRA , BANI DANIELE
Published: June 2005

Abstract: We have investigated the interaction between mouse skeletal myoblasts and rat cardiomyocytes in coculture and the influence of relaxin. Connexin43 expression, Lucifer yellow microinjection, Ca2+ propagation, and electrophysiological analysis have shown that myoblasts and cardiomyocytes are coupled by functional gap junctions. Cardiomyocytes and relaxin upregulated connexin43 expression and gap junctional communication in myoblasts. Relaxin also increased transjunctional current between myoblasts and between myoblasts and cardiomyocytes. In conclusion, relaxin potentiates the intercellular coupling, upregulating the transcellular exchange of regulatory molecules between myoblasts and cardiomyocytes, including Ca2+. This could favor the transdifferentiation of myoblasts toward a cardiac phenotype.
Restricted Expression of LGR8 in Intralaminar Thalamic Nuclei of Rat Brain Suggests a Role in Sensorimotor Systems
Authors: SHEN PEI‐JUAN , FU PING , PHELAN KEVIN D. , SCOTT DANIEL J. , LAYFIELD SHARON , TREGEAR GEOFFREY W. , BATHGATE ROSS A.D. , GUNDLACH ANDREW L.
Published: June 2005

Abstract: LGR8 was recently identified as a cognate receptor for insulin‐like peptide‐3 (INSL3), and INSL3‐LGR8 signaling is best known for its role in testis descent during development. LGR8 mRNA has been detected in various human tissues including brain, but the regional and cellular distribution of LGR8 expression in the mammalian central nervous system is unknown. Therefore, in this study we investigated the presence and localization of LGR8 mRNA in rat brain using reverse transcription‐polymerase chain reaction and in situ hybridization histochemistry. Results revealed a distinct distribution of LGR8 in forebrain, with transcripts principally restricted to the posterior thalamus and highest densities detected in the parafascicular nucleus of both adult and developing rats. Unexpectedly, INSL3 mRNA was not detected in brain by similar methods, but preliminary electrophysiologic studies of parafascicular neurons revealed that INSL3 altered their activity. These findings suggest that LGR8 signaling may be involved in sensorimotor control in the rat and perhaps other species, particularly via actions on parafascicular neurons that project to basal ganglia and are depleted in Parkinson's disease.
Derivation of the Hematopoietic Stem Cell Compartment from Human Embryonic Stem Cell Lines
Authors: BHATIA MICKIE
Published: June 2005

Abstract: Since the derivation of human embryonic stem cell (hESC) lines, both experimental and clinical hematology have generated rising interest in differentiating functional hematopoietic progenitors from these pluripotent cell lines. Although the ability to generate primitive hematopoietic cells with in vivo reconstitution function has direct clinical application, success of this approach awaits a more in‐depth understanding of factor and mechanisms that govern specification of pluripotent hESCs to hematopoietic lineage specification. Here, we highlight some of our laboratory's recent efforts in this area, in the hopes of providing insights toward this complex yet important area of biomedical research.
Hematopoietic Stem Cell Transplantation across Major Genetic Barriers: Tolerance Induction by Megadose CD34 Cells and Other Veto Cells
Authors: REISNER YAIR , GUR HILIT , REICH‐ZELIGER SHLOMIT , MARTELLI MASSIMO F. , BACHAR‐LUSTIG ESTHER
Published: June 2005

Abstract: Studies in mice and humans demonstrate that transplantation of hematopoietic progenitors in numbers larger than commonly used overcomes major genetic barriers. In vitro studies suggest that veto cells, within the population of hematopoietic progenitors, facilitate this favorable outcome. Tolerance induction can be further enhanced by other veto cells. Perhaps the most potent veto cell is the CD8+ CTL. However, this cell is also associated with marked GVHD, which can be separated from the veto activity by generating anti‐third party CTLs under IL‐2 deprivation.
The Role of Sphingosine 1‐Phosphate Receptors in the Trafficking of Hematopoietic Progenitor Cells
Authors: SEITZ GABRIELE , BOEHMLER ANDREAS M. , KANZ LOTHAR , MÖHLE ROBERT
Published: June 2005

Abstract: Sphingosine 1‐phosphate (S1P) is an ubiquitously present extracellular lipid mediator that is released by several cell types, particularly by activated platelets. The effects of S1P are mediated by a specific family of G protein‐coupled sphingosine 1‐phosphate receptors (S1P1‐S1P5). We demonstrate that S1P acts on hematopoietic progenitor cells as a chemotactic factor, attracting peripheral blood CD34+ cells in vitro. Furthermore, constant activation of S1P receptors augments CXCR4‐mediated signal transduction induced by stromal cell‐derived factor 1 (SDF‐1). These effects are most likely mediated by the S1P1 receptor consistently expressed in both primitive and committed CD34+ hematopoietic progenitor cells (HPCs). In vivo, sustained activation of S1P1 by a receptor agonist during the homing process resulted in increased engraftment. Given the fact that activated platelets represent a major source of extracellular S1P, SDF‐1‐mediated stem cell homing may occur at sites of tissue injury in addition to the bone marrow. This could explain the previously observed contribution of primary hematopoietic stem cells to tissue repair in myocardial infarction and other diseases.
Role of GATA‐1 in Normal and Neoplastic Hemopoiesis
Authors: MIGLIACCIO ANNA RITA , RANA ROSA ALBA , VANNUCCHI ALESSANDRO M. , MANZOLI FRANCESCO A.
Published: June 2005

Abstract: GATA‐1 exerts a concentration‐dependent control on the differentiation of erythroid, megakaryocytic, mast, and eosinophilic cells. The concentration of GATA‐1 is, in turn, regulated by specific sequences within the GATA‐1 locus. On the basis of its levels of expression, the GATA‐1 protein becomes associated with suitable partners forming transcription complexes that, by binding to lineage‐specific enhancers, activate the expression of the corresponding target genes. Instrumental to our understanding of the role of GATA‐1 in hemopoietic differentiation has been the generation of genetically engineered mutant mice and the discovery of naturally occurring mutations associated with either inherited or acquired human pathologies. We review our current understanding of the role of GATA‐1 in normal and neoplastic hematopoiesis as emerging from these genetic approaches.
Lymphoid Potential of Primitive Bone Marrow Progenitors Evaluated In Vitro
Authors: WANG HONGFANG , PIERCE L JEANNE , SPANGRUDE GERALD J.
Published: June 2005

Abstract: Bone marrow contains a heterogeneous mixture of mature and maturing precursors of blood cells, progenitor cells for myeloid and lymphoid lineages, and hematopoietic and mesenchymal stem cells. The differentiation potential of these different stem, progenitor, and precursor populations can be evaluated by using transplantation and cell culture assays. In this study, we used a stromal cell co‐culture system to evaluate the B and T lineage potential of different subsets of mouse bone marrow. We enriched hematopoietic stem (Lin−Sca‐1+c‐kit+Thy1.1low [Thy1.1low]) cells and lymphoid progenitor (Lin−Sca‐1+c‐kit+Thy1.1− [Thy1.1−]) cells from mouse bone marrow and co‐cultured these populations with OP9 or OP9‐DL1 stromal cell lines. Development of the B and T lineages was evaluated over time. Both populations gave rise to B and T cells but with different kinetics. Thy1.1− lymphoid progenitors gave rise to B and T lineage cells earlier than did Thy1.1low stem cells; and at any given time, percentages of differentiating B and T cells were higher in Thy1.1− cultures than in Thy1.1low cultures. We also compared the lineage potential of Thy‐1.1− lymphoid progenitors with that of the recently described common lymphoid progenitor 2 (isolated as Lin−Sca‐1+c‐kit−Thy1.1−B220+ cells [B220+]). B220+ cells produced B lineage progeny in OP9 cultures more rapidly than did Thy1.1− cells and produced higher percentages of differentiating T cells in OP9‐DL1 cultures. These studies demonstrate the utility of the OP9 and OP9‐DL1 co‐culture systems for evaluation of lymphoid lineage potential and for determining the relative position of specific bone marrow populations within the hematopoietic hierarchy.
The Poisson-Voronoi tessellation: relationships for edges
Authors: Muche L.
Published: June 2005

In a unified approach, this paper presents distributional properties of a Voronoi tessellation generated by a homogeneous Poisson point process in the Euclidean space of arbitrary dimension. Probability density functions and moments are given for characteristics of the ‘typical’ edge in lower-dimensional section hyperplanes (edge lengths, adjacent angles). We investigate relationships between edges and their neighbours, called Poisson points or centres; namely angular distributions, distances, and positions of neighbours relative to the edge. The approach is analytical, and the results are given partly explicitly and partly as integral expressions, which are suitable for the numerical calculations also presented.
Profiles of random trees: correlation and width of random recursive trees and binary search trees
Authors: Drmota Michael , Hwang Hsien-Kuei
Published: June 2005

In a tree, a level consists of all those nodes that are the same distance from the root. We derive asymptotic approximations to the correlation coefficients of two level sizes in random recursive trees and binary search trees. These coefficients undergo sharp sign-changes when one level is fixed and the other is varying. We also propose a new means of deriving an asymptotic estimate for the expected width, which is the number of nodes at the most abundant level. Crucial to our methods of proof is the uniformity achieved by singularity analysis.
Fractional kinetic equations driven by Gaussian or infinitely divisible noise
Authors: Angulo J. M. , Anh V. V. , McVinish R. , Ruiz-Medina M. D.
Published: June 2005

In this paper, we consider a certain type of space- and time-fractional kinetic equation with Gaussian or infinitely divisible noise input. The solutions to the equation are provided in the cases of both bounded and unbounded domains, in conjunction with bounds for the variances of the increments. The role of each of the parameters in the equation is investigated with respect to second- and higher-order properties. In particular, it is shown that long-range dependence may arise in the temporal solution under certain conditions on the spatial operators.
Improving on bold play when the gambler is restricted
Authors: Schweinsberg Jason
Published: June 2005

Suppose that a gambler starts with a fortune in (0,1) and wishes to attain a fortune of 1 by making a sequence of bets. Assume that whenever the gambler stakes an amount s, the gambler's fortune increases by s with probability w and decreases by s with probability 1 − w, where w < ½. Dubins and Savage showed that the optimal strategy, which they called ‘bold play’, is always to bet min{f, 1 − f}, where f is the gambler's current fortune. Here we consider the problem in which the gambler may stake no more than ℓ at one time. We show that the bold strategy of always betting min{ℓ, f, 1 − f} is not optimal if ℓ is irrational, extending a result of Heath, Pruitt, and Sudderth.
Multitype branching processes observing particles of a given type
Authors: Ceci Claudia , Gerardi Anna
Published: June 2005

A multitype branching process is presented in the framework of marked trees and its structure is studied by applying the strong branching property. In particular, the Markov property and the expression for the generator are derived for the process whose components are the numbers of particles of each type. The filtering of the whole population, observing the number of particles of a given type, is discussed. Weak uniqueness for the filtering equation and a recursive structure for the linearized filtering equation are proved under a suitable assumption on the reproduction law.