Publications by authors named "Steven W Sutton"

32 Publications

Evolution of membrane oxygenator technology for utilization during pediatric cardiopulmonary bypass.

Pediatric Health Med Ther 2016 28;7:45-56. Epub 2016 Jun 28.

Alaskan Native Tribal Health Consortium, Anchorage, AK.

The development of the membrane oxygenator for pediatric cardiopulmonary bypass has been an incorporation of ideology and technological advancements with contributions by many investigators throughout the past two centuries. With the pursuit of this technological achievement, the ability to care for mankind in the areas of cardiac surgery has been made possible. Heart disease can affect anyone within the general population, but one such segment that it can affect from inception includes children. Currently, congenital heart defects are the most common birth defects nationally and worldwide. A large meta-analysis study from 1930 to 2010 was conducted in review of published medical literature totaling 114 papers with a study population of 24,091,867 live births, and divulged a staggering incidence of congenital heart disease involving 164,396 subjects with diverse cardiac illnesses. The prevalence of these diseases increased from 0.6 per 1,000 live births from 1930-1934 to 9.1 per 1,000 live births after 1995. These data reveal an emphasis on a growing public health issue regarding congenital heart disease. This discovery displays a need for heightened awareness in the scientific and medical industrial community to accelerate investigative research on emerging cardiovascular devices in an effort to confront congenital anomalies. One such device that has evolved over the past several decades is the pediatric membrane oxygenator. The pediatric membrane oxygenator, in conjunction with the heart lung machine, assists in the repair of most congenital cardiac defects. Numerous children born with congenital heart disease with or without congestive heart failure have experienced improved clinical outcomes in quality of life, survival, and mortality as a result of the inclusion of this technology during their cardiac surgical procedure. The purpose of this review is to report a summary of the published medical and scientific literature related to development of the pediatric membrane oxygenator from its conceptual evolutionary stages to artificially supporting whole body perfusion in the modern pediatric cardiac surgical setting.
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http://dx.doi.org/10.2147/PHMT.S35070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683297PMC
June 2016

Brain α7 Nicotinic Acetylcholine Receptor Assembly Requires NACHO.

Neuron 2016 Mar 11;89(5):948-55. Epub 2016 Feb 11.

Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA. Electronic address:

Nicotine exerts its behavioral and additive actions through a family of brain nicotinic acetylcholine receptors (nAChRs). Enhancing α7-type nAChR signaling improves symptoms in Alzheimer's disease and schizophrenia. The pharmaceutical study of α7 receptors is hampered because these receptors do not form their functional pentameric structure in cell lines, and mechanisms that underlie α7 receptor assembly in neurons are not understood. Here, a genomic screening strategy solves this long-standing puzzle and identifies NACHO, a transmembrane protein of neuronal endoplasmic reticulum that mediates assembly of α7 receptors. NACHO promotes α7 protein folding, maturation through the Golgi complex, and expression at the cell surface. Knockdown of NACHO in cultured hippocampal neurons or knockout of NACHO in mice selectively and completely disrupts α7 receptor assembly and abolishes α7 channel function. This work identifies NACHO as an essential, client-specific chaperone for nAChRs and has implications for physiology and disease associated with these widely distributed neurotransmitter receptors.
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http://dx.doi.org/10.1016/j.neuron.2016.01.018DOI Listing
March 2016

GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine.

Mol Pharmacol 2015 Nov 8;88(5):911-25. Epub 2015 Sep 8.

Janssen Research & Development LLC, San Diego, California.

GPR139 is an orphan G-protein-coupled receptor expressed in the central nervous system. To identify its physiologic ligand, we measured GPR139 receptor activity from recombinant cells after treatment with amino acids, orphan ligands, serum, and tissue extracts. GPR139 activity was measured using guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding, calcium mobilization, and extracellular signal-regulated kinases phosphorylation assays. Amino acids L-tryptophan (L-Trp) and L-phenylalanine (L-Phe) activated GPR139, with EC50 values in the 30- to 300-μM range, consistent with the physiologic concentrations of L-Trp and L-Phe in tissues. Chromatography of rat brain, rat serum, and human serum extracts revealed two peaks of GPR139 activity, which corresponded to the elution peaks of L-Trp and L-Phe. With the purpose of identifying novel tools to study GPR139 function, a high-throughput screening campaign led to the identification of a selective small-molecule agonist [JNJ-63533054, (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl) benzamide]. The tritium-labeled JNJ-63533054 bound to cell membranes expressing GPR139 and could be specifically displaced by L-Trp and L-Phe. Sequence alignment revealed that GPR139 is highly conserved across species, and RNA sequencing studies of rat and human tissues indicated its exclusive expression in the brain and pituitary gland. Immunohistochemical analysis showed specific expression of the receptor in circumventricular regions of the habenula and septum in mice. Together, these findings suggest that L-Trp and L-Phe are candidate physiologic ligands for GPR139, and we hypothesize that this receptor may act as a sensor to detect dynamic changes of L-Trp and L-Phe in the brain.
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http://dx.doi.org/10.1124/mol.115.100412DOI Listing
November 2015

Global deletion of MGL in mice delays lipid absorption and alters energy homeostasis and diet-induced obesity.

J Lipid Res 2015 06 4;56(6):1153-71. Epub 2015 Apr 4.

Department of Nutritional Sciences Rutgers University, New Brunswick, NJ 08901 Rutgers Center for Lipid Research, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ 08901.

Monoacylglycerol lipase (MGL) is a ubiquitously expressed enzyme that catalyzes the hydrolysis of monoacylglycerols (MGs) to yield FFAs and glycerol. MGL contributes to energy homeostasis through the mobilization of fat stores and also via the degradation of the endocannabinoid 2-arachidonoyl glycerol. To further examine the role of MG metabolism in energy homeostasis, MGL(-/-) mice were fed either a 10% (kilocalories) low-fat diet (LFD) or a 45% (kilocalories) high-fat diet (HFD) for 12 weeks. Profound increases of MG species in the MGL(-/-) mice compared with WT control mice were found. Weight gain over the 12 weeks was blunted in both diet groups. MGL(-/-) mice were leaner than WT mice at both baseline and after 12 weeks of LFD feeding. Circulating lipids were decreased in HFD-fed MGL(-/-) mice, as were the levels of several plasma peptides involved in glucose homeostasis and energy balance. Interestingly, MGL(-/-) mice had markedly reduced intestinal TG secretion following an oral fat challenge, suggesting delayed lipid absorption. Overall, the results indicate that global MGL deletion leads to systemic changes that produce a leaner phenotype and an improved serum metabolic profile.
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http://dx.doi.org/10.1194/jlr.M058586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442873PMC
June 2015

Relaxin-3 receptor (Rxfp3) gene knockout mice display reduced running wheel activity: implications for role of relaxin-3/RXFP3 signalling in sustained arousal.

Behav Brain Res 2015 Feb 22;278:167-75. Epub 2014 Sep 22.

The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Victoria, Australia. Electronic address:

Anatomical and pharmacological evidence suggests the neuropeptide, relaxin-3, is the preferred endogenous ligand for the relaxin family peptide-3 receptor (RXFP3) and suggests a number of putative stress- and arousal-related roles for RXFP3 signalling. However, in vitro and in vivo evidence demonstrates exogenous relaxin-3 can activate other relaxin peptide family receptors, and the role of relaxin-3/RXFP3 signalling in specific brain circuits and associated behaviours in mice is not well described. In this study, we characterised the behaviour of cohorts of male and female Rxfp3 gene knockout (KO) mice (C57/B6J(RXFP3TM1/DGen)), relative to wild-type (WT) littermates to determine if this receptor KO strain has a similar phenotype to its ligand KO equivalent. Rxfp3 KO mice displayed similar performance to WT littermates in several acute behavioural paradigms designed to gauge motor coordination (rotarod test), spatial memory (Y-maze), depressive-like behaviour (repeat forced-swim test) and sensorimotor gating (prepulse inhibition of acoustic startle). Notably however, male and female Rxfp3 KO mice displayed robust and consistent (dark phase) hypoactivity on voluntary home-cage running wheels (∼20-60% less activity/h), and a small but significant decrease in anxiety-like behavioural traits in the elevated plus maze and light/dark box paradigms. Importantly, this phenotype is near identical to that observed in two independent lines of relaxin-3 KO mice, suggesting these phenotypes are due to the elimination of ligand or receptor and RXFP3-linked signalling. Furthermore, this behavioural characterisation of Rxfp3 KO mice identifies them as a useful experimental model for studying RXFP3-linked signalling and assessing the selectivity and/or potential off-target actions of RXFP3 agonists and antagonists, which could lead to an improved understanding of dysfunctional arousal in mental health disorders, including depression, anxiety, insomnia and neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.bbr.2014.09.028DOI Listing
February 2015

Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation.

Proc Natl Acad Sci U S A 2014 Aug 4;111(33):12163-8. Epub 2014 Aug 4.

Janssen Research and Development, Spring House, PA 19002.

The RAR-related orphan receptor gamma t (RORγt) is a nuclear receptor required for generating IL-17-producing CD4(+) Th17 T cells, which are essential in host defense and may play key pathogenic roles in autoimmune diseases. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol and lipid metabolism. Here, we describe the identification of several naturally occurring oxysterols as RORγt agonists. The most potent and selective activator for RORγt is 7β, 27-dihydroxycholesterol (7β, 27-OHC). We show that these oxysterols reverse the inhibitory effect of an RORγt antagonist, ursolic acid, in RORγ- or RORγt-dependent cell-based reporter assays. These ligands bind directly to recombinant RORγ ligand binding domain (LBD), promote recruitment of a coactivator peptide, and reduce binding of a corepressor peptide to RORγ LBD. In primary cells, 7β, 27-OHC and 7α, 27-OHC enhance the differentiation of murine and human IL-17-producing Th17 cells in an RORγt-dependent manner. Importantly, we showed that Th17, but not Th1 cells, preferentially produce these two oxysterols. In vivo, administration of 7β, 27-OHC in mice enhanced IL-17 production. Mice deficient in CYP27A1, a key enzyme in generating these oxysterols, showed significant reduction of IL-17-producing cells, including CD4(+) and γδ(+) T cells, similar to the deficiency observed in RORγt knockout mice. Our results reveal a previously unknown mechanism for selected oxysterols as immune modulators and a direct role for CYP27A1 in generating these RORγt agonist ligands, which we propose as RORγt endogenous ligands, driving both innate and adaptive IL-17-dependent immune responses.
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http://dx.doi.org/10.1073/pnas.1322807111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143045PMC
August 2014

Involvement of β-arrestin-2 and clathrin in agonist-mediated internalization of the human cannabinoid CB2 receptor.

Curr Mol Pharmacol 2014 ;7(1):67-80

College of Life Sciences, Zhejiang University, Zijingang Campus, 388 Yuhang Tang Rd., Hangzhou, 310058, China.

The CB2 cannabinoid receptor is a promising therapeutic target for the treatment of inflammatory diseases, neuropathic pain, liver diseases, cancer and cardiovascular diseases. Obtaining detailed information on the internalization and trafficking of the human CB2 receptor in response to agonist will have a significant impact on drug discovery. Visualization and quantitative detection of EGFP-tagged CB2 receptor showed that, upon WIN55,212-2 stimulation, the CB2 receptor was rapidly internalized in a dose- and time-dependent manner from the cell membrane into the cytoplasm. Pretreatment with hypertonic sucrose, MDC clathrin inhibitor, or siRNA-mediated knock-down of clathrin heavy chain led to significant inhibition of agonist-induced CB2 internalization. Using the RNA interference method, we showed that knockdown of β-arrestin2 expression significantly impaired receptor internalisation. Further investigation demonstrated that the internalized CB2 receptors were co-localized with the early endosome probe and were recycled to the cell surface after the removal of agonist, but treatment with specific cell-permeable proteasome inhibitor MG132 a inhibited the recycling of internalized CB2 receptor, suggesting that the proteasome-mediated degradation pathway may be involved in CB2 internalization. Moreover, the single residue Ser(352) and residue cluster S(335)S(336)T(338)T(340) at the C-terminal tail are shown to be essential for receptor phosphorylation and β-arrestin2 association. These data provide new insights into the mechanisms regulating agonist-mediated internalization and trafficking of the human CB2 receptor.
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http://dx.doi.org/10.2174/1874467207666140714115824DOI Listing
September 2015

Analysis of the structural and molecular basis of voltage-sensitive sodium channel inhibition by the spider toxin huwentoxin-IV (μ-TRTX-Hh2a).

J Biol Chem 2013 Aug 12;288(31):22707-20. Epub 2013 Jun 12.

Department of Neuroscience Discovery, Janssen Research & Development, LLC, San Diego, California 92121, USA.

Voltage-gated sodium channels (VGSCs) are essential to the normal function of the vertebrate nervous system. Aberrant function of VGSCs underlies a variety of disorders, including epilepsy, arrhythmia, and pain. A large number of animal toxins target these ion channels and may have significant therapeutic potential. Most of these toxins, however, have not been characterized in detail. Here, by combining patch clamp electrophysiology and radioligand binding studies with peptide mutagenesis, NMR structure determination, and molecular modeling, we have revealed key molecular determinants of the interaction between the tarantula toxin huwentoxin-IV and two VGSC isoforms, Nav1.7 and Nav1.2. Nine huwentoxin-IV residues (F6A, P11A, D14A, L22A, S25A, W30A, K32A, Y33A, and I35A) were important for block of Nav1.7 and Nav1.2. Importantly, molecular dynamics simulations and NMR studies indicated that folding was normal for several key mutants, suggesting that these amino acids probably make specific interactions with sodium channel residues. Additionally, we identified several amino acids (F6A, K18A, R26A, and K27A) that are involved in isoform-specific VGSC interactions. Our structural and functional data were used to model the docking of huwentoxin-IV into the domain II voltage sensor of Nav1.7. The model predicts that a hydrophobic patch composed of Trp-30 and Phe-6, along with the basic Lys-32 residue, docks into a groove formed by the Nav1.7 S1-S2 and S3-S4 loops. These results provide new insight into the structural and molecular basis of sodium channel block by huwentoxin-IV and may provide a basis for the rational design of toxin-based peptides with improved VGSC potency and/or selectivity.
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http://dx.doi.org/10.1074/jbc.M113.461392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829356PMC
August 2013

Identification of Hydroxybenzoic Acids as Selective Lactate Receptor (GPR81) Agonists with Antilipolytic Effects.

ACS Med Chem Lett 2012 Aug 11;3(8):637-9. Epub 2012 Jun 11.

Janssen Research & Development, LLC , San Diego, California 92121, United States.

Following the characterization of the lactate receptor (GPR81), a focused screening effort afforded 3-hydroxybenzoic acid 1 as a weak agonist of both GPR81 and GPR109a (niacin receptor). An examination of structurally similar arylhydroxy acids led to the identification of 3-chloro-5-hydroxybenzoic acid 2, a selective GPR81 agonist that exhibited favorable in vivo effects on lipolysis in a mouse model of obesity.
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http://dx.doi.org/10.1021/ml3000676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025785PMC
August 2012

In vitro pharmacological characterization of RXFP3 allosterism: an example of probe dependency.

PLoS One 2012 7;7(2):e30792. Epub 2012 Feb 7.

Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, California, United States of America.

Recent findings suggest that the relaxin-3 neural network may represent a new ascending arousal pathway able to modulate a range of neural circuits including those affecting circadian rhythm and sleep/wake states, spatial and emotional memory, motivation and reward, the response to stress, and feeding and metabolism. Therefore, the relaxin-3 receptor (RXFP3) is a potential therapeutic target for the treatment of various CNS diseases. Here we describe a novel selective RXFP3 receptor positive allosteric modulator (PAM), 3-[3,5-Bis(trifluoromethyl)phenyl]-1-(3,4-dichlorobenzyl)-1-[2-(5-methoxy-1H-indol-3-yl)ethyl]urea (135PAM1). Calcium mobilization and cAMP accumulation assays in cell lines expressing the cloned human RXFP3 receptor show the compound does not directly activate RXFP3 receptor but increases functional responses to amidated relaxin-3 or R3/I5, a chimera of the INSL5 A chain and the Relaxin-3 B chain. 135PAM1 increases calcium mobilization in the presence of relaxin-3(NH2) and R3/I5(NH2) with pEC50 values of 6.54 (6.46 to 6.64) and 6.07 (5.94 to 6.20), respectively. In the cAMP accumulation assay, 135PAM1 inhibits the CRE response to forskolin with a pIC50 of 6.12 (5.98 to 6.27) in the presence of a probe (10 nM) concentration of relaxin-3(NH2). 135PAM1 does not compete for binding with the orthosteric radioligand, [(125)I] R3I5 (amide), in membranes prepared from cells expressing the cloned human RXFP3 receptor. 135PAM1 is selective for RXFP3 over RXFP4, which also responds to relaxin-3. However, when using the free acid (native) form of relaxin-3 or R3/I5, 135PAM1 doesn't activate RXFP3 indicating that the compound's effect is probe dependent. Thus one can exchange the entire A-chain of the probe peptide while retaining PAM activity, but the state of the probe's c-terminus is crucial to allosteric activity of the PAM. These data demonstrate the existence of an allosteric site for modulation of this GPCR as well as the subtlety of changes in probe molecules that can affect allosteric modulation of RXFP3.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030792PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3274524PMC
July 2012

A tribute to John Capehart, MD, "Sooner proud" and 1961 National Spelling Bee champion.

Proc (Bayl Univ Med Cent) 2011 Oct;24(4):343-5

Department of Thoracic and Cardiovascular Surgery, Baylor University Medical Center at Dallas.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205161PMC
http://dx.doi.org/10.1080/08998280.2011.11928753DOI Listing
October 2011

Oxysterols direct B-cell migration through EBI2.

Nature 2011 Jul 27;475(7357):519-23. Epub 2011 Jul 27.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

EBI2 (also called GPR183) is an orphan G-protein-coupled receptor that is highly expressed in spleen and upregulated upon Epstein-Barr-virus infection. Recent studies indicated that this receptor controls follicular B-cell migration and T-cell-dependent antibody production. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol metabolism. The biological effects of oxysterols have largely been credited to the activation of nuclear hormone receptors. Here we isolate oxysterols from porcine spleen extracts and show that they are endogenous ligands for EBI2. The most potent ligand and activator is 7α,25-dihydroxycholesterol (OHC), with a dissociation constant of 450 pM for EBI2. In vitro, 7α,25-OHC stimulated the migration of EBI2-expressing mouse B and T cells with half-maximum effective concentration values around 500 pM, but had no effect on EBI2-deficient cells. In vivo, EBI2-deficient B cells or normal B cells desensitized by 7α,25-OHC pre-treatment showed reduced homing to follicular areas of the spleen. Blocking the synthesis of 7α,25-OHC in vivo with clotrimazole, a CYP7B1 inhibitor, reduced the content of 7α,25-OHC in the mouse spleen and promoted the migration of adoptively transferred pre-activated B cells to the T/B boundary (the boundary between the T-zone and B-zone in the spleen follicle), mimicking the phenotype of pre-activated B cells from EBI2-deficient mice. Our results show an unexpected causal link between EBI2, an orphan G-protein-coupled receptor controlling B-cell migration, and the known immunological effects of certain oxysterols, thus uncovering a previously unknown role for this class of molecules.
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http://dx.doi.org/10.1038/nature10226DOI Listing
July 2011

Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists.

Eur J Pharmacol 2011 Sep 12;667(1-3):120-8. Epub 2011 Jun 12.

Neuroscience Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

Orexin receptor antagonists are being investigated as therapeutic agents for insomnia and addictive disorders. In this study the interactions between the orexin receptors (orexin 1 receptor and orexin 2 receptor), orexin peptides, and small molecule orexin antagonists were explored. To study these phenomena, a variety of mutant orexin receptors was made and tested using receptor binding and functional assays. Domains of the two orexin receptors were exchanged to show the critical ligand binding domains for orexin peptides and representative selective orexin receptor antagonists. Results from domain exchanges between the orexin receptors suggest that transmembrane domain 3 is crucially important for receptor interactions with small molecule antagonists. These data also suggest that the orexin peptides occupy a larger footprint, interacting with transmembrane domain 1, the amino terminus and transmembrane domain 5 as well as transmembrane domain 3. Transmembrane domain 3 has been shown to be an important part of the small molecule binding pocket common to rhodopsin and β2-adrenergic receptors. Additional orexin receptor 2 point mutations were made based on the common arrangement of receptor transmembrane domains shown in the G-protein coupled receptor crystal structure literature and the impact of orexin 2 receptor residue threonine 135 on the ligand selectivity of the 2 orexin receptors. These data support a model of the orexin receptor binding pocket in which transmembrane domains 3 and 5 are prominent contributors to ligand binding and functional activity. The data also illustrate key contact points for ligand interactions in the consensus small molecule pocket of these receptors.
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http://dx.doi.org/10.1016/j.ejphar.2011.05.074DOI Listing
September 2011

Distribution of relaxin-3 and RXFP3 within arousal, stress, affective, and cognitive circuits of mouse brain.

J Comp Neurol 2010 Oct;518(19):4016-45

Florey Neuroscience Institutes, The University of Melbourne, Victoria 3010, Australia.

Relaxin-3 (RLN3) and its native receptor, relaxin family peptide 3 receptor (RXFP3), constitute a newly identified neuropeptide system enriched in mammalian brain. The distribution of RLN3/RXFP3 networks in rat brain and recent experimental studies suggest a role for this system in modulation of arousal, stress, metabolism, and cognition. In order to facilitate exploration of the biology of RLN3/RXFP3 in complementary murine models, this study mapped the neuroanatomical distribution of the RLN3/RXFP3 system in mouse brain. Adult, male wildtype and RLN3 knock-out (KO)/LacZ knock-in (KI) mice were used to map the central distribution of RLN3 gene expression and RLN3-like immunoreactivity (-LI). The distribution of RXFP3 mRNA and protein was determined using [(35)S]-oligonucleotide probes and a radiolabeled RXFP3-selective agonist ([(125)I]-R3/I5), respectively. High densities of neurons expressing RLN3 mRNA, RLN3-associated beta-galactosidase activity and RLN3-LI were detected in the nucleus incertus (or nucleus O), while smaller populations of positive neurons were observed in the pontine raphé, the periaqueductal gray and a region adjacent to the lateral substantia nigra. RLN3-LI was observed in nerve fibers/terminals in nucleus incertus and broadly throughout the pons, midbrain, hypothalamus, thalamus, septum, hippocampus, and neocortex, but was absent in RLN3 KO/LacZ KI mice. This RLN3 neural network overlapped the regional distribution of RXFP3 mRNA and [(125)I]-R3/I5 binding sites in wildtype and RLN3 KO/LacZ KI mice. These findings provide further evidence for the conserved nature of RLN3/RXFP3 systems in mammalian brain and the ability of RLN3/RXFP3 signaling to modulate "behavioral state" and an array of circuits involved in arousal, stress responses, affective state, and cognition.
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http://dx.doi.org/10.1002/cne.22442DOI Listing
October 2010

Neuropeptide S stimulates dopaminergic neurotransmission in the medial prefrontal cortex.

J Neurochem 2010 Oct 30;115(2):475-82. Epub 2010 Aug 30.

Department of Pharmaceutical Sciences, University of California Irvine, Irvine, California 92697, USA.

Neuropeptide S (NPS) is known to produce anxiolytic-like effects and facilitate extinction of conditioned fear. Catecholaminergic neurotransmission in the medial prefrontal cortex (mPFC) has been suggested to be crucially involved in these brain functions. In the current study, we investigated the effect of NPS on the release of dopamine and serotonin in the mPFC by in vivo microdialysis in rats. Central administration of NPS dose-dependently enhanced extracellular levels of dopamine and its major metabolite 3,4-dihydroxyphenylacetic acid, with maximal effects lasting up to 120 min. In contrast, no effect on serotonergic neurotransmission was detected. Dopamine release in the mPFC has been previously linked to modulation of anxiety states and fear extinction. The present results may thus provide a physiological and anatomical basis for the reported effects of NPS on these behaviors.
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http://dx.doi.org/10.1111/j.1471-4159.2010.06947.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2970681PMC
October 2010

Modulation of hippocampal theta oscillations and spatial memory by relaxin-3 neurons of the nucleus incertus.

Learn Mem 2009 Nov 30;16(11):730-42. Epub 2009 Oct 30.

Howard Florey Institute, The University of Melbourne, Victoria 3010, Australia.

Hippocampal theta rhythm is thought to underlie learning and memory, and it is well established that "pacemaker" neurons in medial septum (MS) modulate theta activity. Recent studies in the rat demonstrated that brainstem-generated theta rhythm occurs through a multisynaptic pathway via the nucleus incertus (NI), which is the primary source of the neuropeptide relaxin-3 (RLN3). Therefore, this study examined the possible contribution of RLN3 to MS activity, and associated hippocampal theta activity and spatial memory. In anesthetized and conscious rats, we identified the ability of intraseptal RLN3 signaling to modulate neuronal activity in the MS and hippocampus and promote hippocampal theta rhythm. Behavioral studies in a spontaneous alternation task indicated that endogenous RLN3 signaling within MS promoted spatial memory and exploratory activity significantly increased c-Fos immunoreactivity in RLN3-producing NI neurons. Anatomical studies demonstrated axons/terminals from NI/RLN3 neurons make close contact with septal GABAergic (and cholinergic) neurons, including those that project to the hippocampus. In summary, RLN3 neurons of the NI can modulate spatial memory and underlying hippocampal theta activity through axonal projections to pacemaker neurons of the MS. NI/RLN3 neurons are highly responsive to stress and express corticotropin-releasing factor type-1 receptors, suggesting that the effects observed could be an important component of memory processing associated with stress responses.
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http://dx.doi.org/10.1101/lm.1438109DOI Listing
November 2009

Metabolic and neuroendocrine responses to RXFP3 modulation in the central nervous system.

Ann N Y Acad Sci 2009 Apr;1160:242-9

Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121, USA.

Neuroanatomical studies have shown relaxin-3 neurons, primarily found in the rodent nucleus incertus (NI), project widely into a large number of areas expressing the relaxin-3 receptor (RXFP3), and these data suggest relaxin-3/RXFP3 signaling modulates sensory, emotional, and neuroendocrine processing. The similar distribution of this receptor-ligand pair in the rat, mouse, and monkey brain suggests that experimental findings obtained in lower species will translate to higher species. A role for relaxin-3 and RXFP3 in modulating stress responses is strongly suggested by the expression of corticotropin-releasing factor R1 (CRF-R1) by NI cells, increased relaxin-3 expression in the NI after stress or CRF injection, and hormonal responses to intracerebroventricular (i.c.v.) relaxin-3 injection. Recent data are consistent with a further role for this ligand-receptor pair in modulating memory. In addition, relaxin-3 has been reported to modulate feeding and body weight control. Acute or chronic central (i.c.v. or intraparaventricular) injections of relaxin-3 have shown a consistent stimulatory effect on food consumption while relaxin was inactive, suggesting the phagic effect of relaxin-3 is mediated by RXFP3. We have confirmed the role of RXFP3 in modulating feeding and body weight by using a selective RXFP3 agonist (R3/I5) and antagonist [R3(Delta23-27)R/I5], collecting feeding, body weight, hormone, and body composition data. In addition, we have preliminary body weight and magnetic resonance imaging data from relaxin-3 knockout mice, which on a 129S5:B6 background are smaller and leaner than congenic controls. These data suggest relaxin-3, acting through RXFP3, is involved in coordinating stress, learning and memory, and feeding responses as predicted on the basis of neuroanatomy.
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http://dx.doi.org/10.1111/j.1749-6632.2008.03812.xDOI Listing
April 2009

Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat.

J Pharmacol Exp Ther 2009 Jul 10;330(1):142-51. Epub 2009 Apr 10.

Neuroscience, Johnson & Johnson PRD, 3210 Merryfield Row, San Diego, CA 92121, USA.

Orexins are peptides produced by lateral hypothalamic neurons that exert a prominent role in the maintenance of wakefulness by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptor located in wake-active structures. Pharmacological blockade of both receptors by the dual OX1/2R antagonist (2R)-2-[(1S)-6,7-dimethoxy-1-{2-[4-(trifluoromethyl)phenyl]ethyl}-3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylethanamide (almorexant) has been shown to promote sleep in animals and humans during their active period. However, the selective distribution of OX1R and OX2R in distinct neuronal circuits may result in a differential impact of these receptors in sleep-wake modulation. The respective role of OX1R and OX2R on sleep in correlation with monoamine release was evaluated in rats treated with selective antagonists alone or in combination. When administered in either phase of the light/dark cycle, the OX2R antagonist 1-(2,4-dibromophenyl)-3-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea (JNJ-10397049) decreased the latency for persistent sleep and increased nonrapid eye movement and rapid eye movement sleep time. Almorexant produced less hypnotic activity, whereas the OX1R antagonist 1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea (SB-408124) had no effect. Microdialysis studies showed that either OX2R or OX1/2R antagonism decreased extracellular histamine concentration in the lateral hypothalamus, whereas both OX1R and OX1/2R antagonists increased dopamine release in the prefrontal cortex. Finally, coadministration of the OX1R with the OX2R antagonist greatly attenuated the sleep-promoting effects of the OX2R antagonist. These results indicate that blockade of OX2R is sufficient to initiate and prolong sleep, consistent with the hypothesis of a deactivation of the histaminergic system. In addition, it is suggested that simultaneous inhibition of OX1R attenuates the sleep-promoting effects mediated by selective OX2R blockade, possibly correlated with dopaminergic neurotransmission.
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http://dx.doi.org/10.1124/jpet.109.152009DOI Listing
July 2009

Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81.

J Biol Chem 2009 Jan 1;284(5):2811-2822. Epub 2008 Dec 1.

Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121.

Lactic acid is a well known metabolic by-product of intense exercise, particularly under anaerobic conditions. Lactate is also a key source of energy and an important metabolic substrate, and it has also been hypothesized to be a signaling molecule directing metabolic activity. Here we show that GPR81, an orphan G-protein-coupled receptor highly expressed in fat, is in fact a sensor for lactate. Lactate activates GPR81 in its physiological concentration range of 1-20 mM and suppresses lipolysis in mouse, rat, and human adipocytes as well as in differentiated 3T3-L1 cells. Adipocytes from GPR81-deficient mice lack an antilipolytic response to lactate but are responsive to other antilipolytic agents. Lactate specifically induces internalization of GPR81 after receptor activation. Site-directed mutagenesis of GPR81 coupled with homology modeling demonstrates that classically conserved key residues in the transmembrane binding domains are responsible for interacting with lactate. Our results indicate that lactate suppresses lipolysis in adipose tissue through a direct activation of GPR81. GPR81 may thus be an attractive target for the treatment of dyslipidemia and other metabolic disorders.
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http://dx.doi.org/10.1074/jbc.M806409200DOI Listing
January 2009

2-Aryloxymethylmorpholine histamine H(3) antagonists.

Bioorg Med Chem Lett 2008 Nov 24;18(21):5796-9. Epub 2008 Sep 24.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., San Diego, CA 92121-1126, USA.

The synthesis and biological activity of a new series of 2-aryloxymethylmorpholine histamine H(3) antagonists is described. The new compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain.
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http://dx.doi.org/10.1016/j.bmcl.2008.09.077DOI Listing
November 2008

Relaxin family peptide receptors--from orphans to therapeutic targets.

Drug Discov Today 2008 Aug 6;13(15-16):640-51. Epub 2008 Jun 6.

Department of Pharmacology, Monash University, Clayton, 3800 Vic, Australia.

The relaxin family peptides have distinct expression profiles and physiological functions. Several of them are the cognate ligands for 4 G-protein-coupled relaxin family peptide receptors (RXFPs; formerly LGR7, LGR8, GPCR135, GPCR142). The relaxin/RXFP1 system has roles in reproductive physiology but is also involved in fibrosis, wound healing and responses to infarction. Relaxin has a potential use in congestive heart failure where fibrosis plays an important role in organ failure. The INSL3/RXFP2 system has biological roles in reproductive biology that may have limited therapeutic potential. However, the recently characterized relaxin-3/RXFP3 system is important in stress/anxiety and body composition. RXFP3 receptor antagonists are potentially novel anti-anxiety and anti-obesity drugs.
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http://dx.doi.org/10.1016/j.drudis.2008.04.002DOI Listing
August 2008

G-protein-coupled receptor (GPCR)-142 does not contribute to relaxin-3 binding in the mouse brain: further support that relaxin-3 is the physiological ligand for GPCR135.

Neuroendocrinology 2005 13;82(3-4):139-50. Epub 2006 Jan 13.

Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, CA 92121, USA.

Relaxin-3 is a recently discovered member of the insulin/relaxin superfamily that has been shown to be the endogenous ligand for G-protein-coupled receptor (GPCR)135 (SALPR). In addition, relaxin-3 has demonstrated affinity and functional agonism for GPCR142 (GPR100) and LGR7 receptors in vitro. Recent evidence suggests GPCR142 is the insulin-like peptide 5 (INSL5) receptor and LGR7 is the actual relaxin receptor. We have recently described a chimeric R3/I5 peptide that selectively activates GPCR135 and GPCR142, but lacks affinity for LGR7. GPCR142 is a pseudogene in the rat, which allowed the use of [(125)I]-R3/I5 to show GPCR135-like binding sites in the rat central nervous system by autoradiography. However, mouse GPCR142 is a viable gene. In the present study we explore whether GPCR142 is expressed in the mouse brain and whether it is likely to contribute to or interfere with the pharmacological evaluation of relaxin-3 ligands. Competition binding studies confirmed mINSL5 and [(125)I]-mINSL5 bind to mGPCR142 with high affinity. However, no detectable specific [(125)I]-mINSL5 binding sites were detected throughout the mouse brain and unlabelled INSL5 did not displace [(125)I]-R3/I5 binding sites, indicating an absence of detectable GPCR142 binding sites. Consistent with these findings, neither GPCR142 nor INSL5 mRNA were detectable in mouse brain by in situ hybridization. Overall, the distribution of GPCR135 mRNA overlapped with the distribution of GPCR135 binding sites shown by autoradiography using [(125)I]-R3/I5. GPCR135 mRNA and GPCR135 receptor binding sites are most prominent in the mouse amygdala and hypothalamus. These data suggest that relaxin-3/GPCR135 is the receptor ligand pair with physiological relevance in mouse brain.
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http://dx.doi.org/10.1159/000091267DOI Listing
June 2006

Cardiopulmonary bypass and mitral valve replacement during pregnancy.

Perfusion 2005 Oct;20(6):359-68

Baylor University Medical Center, Dallas, USA.

Gravid patient cardiopulmonary bypass remains a high-risk procedure with regard to fetal preservation. Maternal mortality is similar to that of the nonpregnant female at 1.5-5%. However, fetal mortality remains high at 16-33%, with an average of 19% over the past 25 years, with no correlation to gestational age. Teratogenesis is a major consideration in the first trimester. Variations in the timing of surgical intervention, gestational age, maternal health status, type of procedure, pre- or postorganogenesis, perfusion protocol, and pharmaceutical therapy are all factors that can influence fetomaternal outcome. In this report, we present a literature review along with our experience of a 26-year-old female who developed complications with her pregnancy at approximately 17 weeks gestation, with adverse neurological sequelae. The patient was 152 cm in height and weighed 48 kg, with a calculated body surface area of 1.40 M2. She had no prior history of cardiac disease and, upon admission to our institution, presented with a declining health status in pulmonary edema and was treated medically, with an ultimate requirement for mitral valve replacement. The total cardiopulmonary bypass time was 99 min with an aortic crossclamp time of 83 min. The literature, as expected, is limited to case reports and reviews since a controlled clinical trial during pregnancy is nonexistent, using extracorporeal circulation. This greatly challenges the medical staff in managing such difficult cases, with an incidence of heart disease during pregnancy of 1.2-3.7%.
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http://dx.doi.org/10.1191/0267659105pf832oaDOI Listing
October 2005

Intraperitoneal hyperthermic chemotherapy: experience at Baylor University Medical Center.

Proc (Bayl Univ Med Cent) 2002 Oct;15(4):359-62

Department of Surgery, Baylor University Medical Center, Dallas, Texas, USA.

Context: Patients with peritoneal carcinomatosis have a dismal prognosis despite systemic chemotherapy or palliative surgery. A novel strategy of complete tumor debulking with intraoperative hyperthermia with chemotherapy has been proposed to provide prolonged survival.

Objective: To retrospectively analyze the preliminary experience with this technique at Baylor University Medical Center.

Methods: All patients underwent attempted tumor debulking followed by intraperitoneal hyperthermia with 40 mg mitomycin-C over 2 hours.

Results: Patient diagnoses included nonmucinous colorectal carcinomatosis (n = 9), diffuse peritoneal adenomucinosis (n = 1), peritoneal mucinous carcinomatosis (n = 2), and gastric carcinomatosis (n = 3). Tumors in most patients (13/15) were resected to < or = 5 mm, and those in 10 of 15 were resected to no gross disease. Complications included ileus (n = 9), bowel leak (n = 2), infection (n = 1), and fistula (n = 1). One patient died of progressive gastric cancer at 1 month. Within a median follow-up of 4 months, 8 patients had no tumor by radiologic or tumor marker analysis.

Conclusion: Intraoperative hyperthermia with chemotherapy is a viable treatment for patients with isolated peritoneal carcinomatosis from colorectal or gastric origin.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1276636PMC
http://dx.doi.org/10.1080/08998280.2002.11927864DOI Listing
October 2002

Recent progress in relaxin-3-related research.

Ann N Y Acad Sci 2005 May;1041:47-60

Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121.

Relaxin-3 (R3) is the latest member of the insulin (INSL) superfamily, which is composed of peptides with diverse sequences held together by characteristic disulfide links connecting A and B peptide chains. R3 has nearly exclusive expression in the brainstem and was demonstrated to be an additional ligand for LGR7. We recently identified R3 as a ligand for two orphan G-protein coupled receptors, GPCR135 and GPCR142. The predominant brain expression for both R3 and GPCR135, coupled with their high affinity interaction, strongly suggests that R3 is the endogenous ligand for GPCR135. Both R3 and GPCR135 from different species are highly conserved from genetic sequences to in vitro pharmacology. By contrast, GPCR142 is a pseudogene in the rat, and the mouse gene is less conserved with human GPCR142, suggesting that GPCR142 may have a diminished role as a receptor for R3 in the rodent. In addition, the tissue expression pattern of GPCR142, which is primarily in peripheral tissue, is drastically different from that of R3, suggesting that GPCR142 may have an endogenous ligand other than R3. Sequence analysis among INSL/relaxin family members shows that INSL5 is the closest member of R3. We were able to demonstrate that INSL-5 is an agonist for GPCR142 but not for GPCR135. We also showed that the mRNA expression pattern of INSL-5 overlaps with that of GPCR142. By substituting the A chain of R3 with the A chain of INSL-5, we devised a chimeric peptide (R3/I5) that is about 1000-fold selective for GPCR135 and GPCR142 over LGR7. Autoradiographic distribution of GPCR135 binding sites using [125I]R3/I5 in rat brain shows that GPCR135 receptor is most prominent in areas known for the processing of sensory signals.
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http://dx.doi.org/10.1196/annals.1282.009DOI Listing
May 2005

Distribution of G-protein-coupled receptor (GPCR)135 binding sites and receptor mRNA in the rat brain suggests a role for relaxin-3 in neuroendocrine and sensory processing.

Neuroendocrinology 2004 26;80(5):298-307. Epub 2005 Jan 26.

Neuroscience Group, Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

G-protein-coupled receptor 135 (GPCR135), a former orphan GPCR also known as SALPR, has recently been shown to be modulated by relaxin-3 (R3). In addition to GPCR135, R3 has been shown to be an agonist for GPCR142 (which is a pseudogene in the rat) and to activate LGR7, which is primarily the receptor for relaxin-1/2. The interaction of R3 with LGR7 has confounded the autoradiographic study of the GPCR135 distribution in the rat CNS due to significant expression of LGR7 in the brain. R3/I5, a chimera of the B-chain of R3 bonded to the A-chain of INSL-5, is a specific GPCR135 agonist which is highly selective for GPCR135 over LGR7. [(125)I]R3/I5 specifically binds to sites on rat brain sections with a pharmacology matching results from membrane preparations of recombinant GPCR135 receptors. Autoradiographic studies show the GPCR135 receptor density is most prominent in areas such as the olfactory bulb, sensory cortex, amygdala, thalamus, paraventricular nucleus, supraoptic nucleus, inferior and superior colliculus. The GPCR135 mRNA distribution generally overlaps the pattern of GPCR135 binding sites shown by autoradiography using [(125)I]R3/I5. The nucleus incertus, which has been implicated in the extrapituitary actions of corticotropin-releasing hormone, is the primary source of R3 in the rat central nervous system and expresses GPCR135 receptors. These binding autoradiography and in situ hybridization data suggest that GPCR135 plays an important role in the central processing of sensory signals in rats, are consistent with a putative role for R3/GPCR135 as modulators of stress responses, and confirm the identity of R3 as the central nervous system ligand for GPCR135.
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http://dx.doi.org/10.1159/000083656DOI Listing
April 2005

Leukocyte filtration and miniature perfusion during arrested heart CABG on a Jehovah's Witness patient.

Perfusion 2004 Nov;19(6):375-9

Baylor University Medical Center, Dallas, TX, USA.

Bloodless surgery and a reduction in the use of allogeneic blood products has long been the standard of care in medicine. Many individuals in our communities have demanded this form of surgical treatment for personal and religious reasons. On 6 December 2002, a 72-year-old male patient was admitted to our institution as a critical air flight transfer. The patient's height was 190.5 cm and weight was 59.3 kg (body surface area 1.83 m2). His preliminary diagnosis was chest pain with myocardial infarction as evidenced by elevated blood cardiac isoenzymes. His principle diagnosis was subendocardial infarction with paroxysmal ventricular tachycardia. Cardiac catheterization was performed and demonstrated severe triple vessel disease with an ejection fraction of 30%. He was evaluated and accepted as a candidate for coronary artery bypass grafting. Multidisciplinary consultation concluded that a safe and effective method of perioperative treatment would involve the use of arrested heart support with cold blood cardioplegia using a low prime miniature perfusion circuit as no blood products would be considered for use. Additionally, the combined modalities of perfusion interventions to minimize hemodilution consisted of intraoperative autologous blood collection totaling 500 mL and rapid autologous priming of the miniature perfusion circuit. The miniature perfusion system was a low prime Cardiovention (Santa Clara, CA) CORx device which includes a hollow-fiber oxygenator and integral centrifugal pump with a surface area of 1.2 m2. This system also incorporates an air sensing solenoid which triggers rapid air evacuation in a bolus range of 1 mL or greater. Kinetic venous drainage is another feature of this device as the centrifugal pump is integrated into the oxygenator. We believed that a miniature extracorporeal circuit would enhance the desired clinical outcome as opposed to the risk of: (1) off-pump coronary artery bypass (OPCAB) approach and the concern of emergent transition to an on-pump procedure and (2) use of larger surface area with conventional systems that impose a greater hemodilutional effect. Leukocyte filtration was employed as the patient had a significant past medical history of chronic obstructive pulmonary disease. We herein report our clinical experience with this method of treatment on a patient who refused the use of blood products in his surgical treatment. It is our belief that the multiple modalities utilized in combination during this procedure resulted in positive clinical outcomes as demonstrated by an intubation time of 8 hours 35 min with a discharge on the fifth postoperative day.
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http://dx.doi.org/10.1191/0267659104pf773crDOI Listing
November 2004

Perfusion-assisted beating heart support with a miniature extracorporeal circuit and leukocyte filtration: a 58-year-old patient with severe COPD.

Perfusion 2004 Nov;19(6):369-73

Baylor University Medical Center, Dallas, Texas, USA.

Patients with severe chronic obstructive pulmonary disease (COPD) impose a significant risk for postoperative morbidity and mortality requiring cardiovascular surgical intervention and the use of extracorporeal circulation. Recently, we treated a 58-year-old male with acute coronary syndrome complicated with recurrent ventricular arrhythmia, hypoxemia secondary to severe COPD and resolving pneumonia, who required urgent coronary revascularization. A novel operative strategy was used that included beating heart bypass grafting with cardiac decompression and support with a miniature perfusion circuit, kinetic-assisted venous return, rapid autologous priming and leukocyte filtration. The combination of multiple modalities was chosen because the patient was in a pre-existing inflammatory condition and had severe COPD. We herein report our perioperative clinical experience with this patient and the use of multiple modalities for extracorporeal perfusion therapy in managing this challenging case. We believe that, based upon his clinical course of ventilation time (17.4 hours) and postoperative length of hospital stay (5 days), this high risk patient demonstrated a positive clinical outcome as a result of these techniques.
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http://dx.doi.org/10.1191/0267659104pf772crDOI Listing
November 2004

Pharmacological characterization of relaxin-3/INSL7 receptors GPCR135 and GPCR142 from different mammalian species.

J Pharmacol Exp Ther 2005 Jan 14;312(1):83-95. Epub 2004 Sep 14.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Relaxin-3 has recently been identified as a ligand for two structurally related G-protein-coupled receptors, human GPCR135 and GPCR142. This current study reports the characterization of mouse and rat GPCR135 as well as GPCR142 from mouse, monkey, cow, and pig at the molecular and pharmacological levels. Mouse and rat GPCR135 exhibit high homology (>85%) to the human GPCR135 and have very similar pharmacological properties to that of the human GPCR135. Human and mouse/rat relaxin-3 both bind to and activate mouse, rat, and human GPCR135 at high affinity with IC(50) or EC(50) values close to 0.5 nM. In contrast, the mouse GPCR142 is less well conserved (74% homology) with human GPCR142. The rat GPCR142 gene was found to be a pseudogene. We further cloned GPCR142 genes from monkey, cow, and pig and found that they are highly homologous (>84%) to human GPCR142. Pharmacological characterization of GPCR142 from different species demonstrated that relaxin-3 binds to GPCR142 from different species at high affinity (IC(50) < 5 nM). However, relaxin-3 does not stimulate a Ca(2+) response in cells coexpressing Galpha(16) and mouse GPCR142, whereas it does for cells expressing GPCR142 from other species tested. Our results suggest that GPCR142 may have a diminished role as a receptor for relaxin-3 in rodents, or perhaps GPCR142 functions as a receptor for another ligand in nonrodents. Boels and Schaller recently reported bradykinin as a ligand for GPCR142 (also known as GPR100). In this report, we demonstrate that bradykinin activates neither GPCR135 nor GPCR142, whereas relaxin-3 does.
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http://dx.doi.org/10.1124/jpet.104.073486DOI Listing
January 2005