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Omega-3 fatty acids inhibit the up-regulation of endothelial chemokines in maintenance hemodialysis patients.
Hung AM, Booker C, Ellis CD, Siew ED, Graves AJ, Shintani A, Abumrad NN, Himmelfarb J, Ikizler TA
(2015) Nephrol Dial Transplant 30: 266-74
MeSH Terms: Adult, Aged, Biomarkers, C-Reactive Protein, Calcitonin, Calcitonin Gene-Related Peptide, Chemokines, Docosahexaenoic Acids, Double-Blind Method, Eicosapentaenoic Acid, Endothelium, Vascular, Fatty Acids, Omega-3, Feasibility Studies, Female, Humans, Inflammation Mediators, Interleukin-6, Male, Middle Aged, Pilot Projects, Protein Precursors, Renal Dialysis, Renal Insufficiency, Chronic, Risk Factors, Up-Regulation
Show Abstract · Added September 29, 2014
BACKGROUND - Chronic systemic inflammation is common in patients with chronic kidney disease on dialysis (CKD5D) and has been considered a key mediator of the increased cardiovascular risk in this patient population. In this study, we tested the hypothesis that supplementation of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) will attenuate the systemic inflammatory process in CKD5D patients.
METHODS - The design was a randomized, double-blinded, placebo controlled pilot trial (NCT00655525). Thirty-eight patients were randomly assigned in a 1 : 1 fashion to receive 2.9 g of eicosapentaenoic acid (C20:5, n-3) plus docosahexaenoic acid (C22:6, n-3) versus placebo for 12 weeks. The primary outcome was change in pro-inflammatory chemokines measured by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs). Secondary outcomes were changes in systemic inflammatory markers. Analysis of covariance was used to compare percent change from baseline to 12 weeks.
RESULTS - Thirty-one patients completed 12 weeks and three patients completed 6 weeks of the study. Median age was 52 (interquartile range 45, 60) years, 74% were African-American and 79% were male. Supplementation of ω-3 PUFAs effectively decreased the LPS-induced PBMC expression of RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) and MCP-1 (Monocyte Chemotactic Protein-1; unadjusted P = 0.04 and 0.06; adjusted for demographics P = 0.02 and 0.05, respectively). There was no significant effect of the intervention on serum inflammatory markers (C-reactive protein, interleukin-6 and procalcitonin).
CONCLUSIONS - The results of this pilot study suggest that supplementation of ω-3 PUFAs is beneficial in decreasing the levels of endothelial chemokines, RANTES and MCP-1. Studies of larger sample size and longer duration are required to further evaluate effects of ω-3 PUFAs on systemic markers of inflammation, other metabolic parameters and clinical outcomes, particularly cardiovascular outcomes in CKD5D patients.
© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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25 MeSH Terms
Procalcitonin and C-reactive protein levels at admission as predictors of duration of acute brain dysfunction in critically ill patients.
McGrane S, Girard TD, Thompson JL, Shintani AK, Woodworth A, Ely EW, Pandharipande PP
(2011) Crit Care 15: R78
MeSH Terms: Aged, Biomarkers, C-Reactive Protein, Calcitonin, Calcitonin Gene-Related Peptide, Critical Illness, Delirium, Female, Humans, Male, Middle Aged, Patient Admission, Pilot Projects, Predictive Value of Tests, Prospective Studies, Protein Precursors, Respiration, Artificial, Time Factors
Show Abstract · Added September 23, 2015
INTRODUCTION - Non-intensive care unit (ICU) cohorts have shown an association between inflammatory disturbances and delirium, though these relationships have not been studied in critically ill patients. This study sought to investigate the relationship between two inflammatory biomarkers, procalcitonin and C-reactive protein (CRP), and duration of acute brain dysfunction in ventilated patients.
METHODS - Patients enrolled in the Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial were assessed daily for delirium using the Confusion Assessment Method-ICU. Plasma levels of procalcitonin and CRP were obtained within 24 hours of enrollment. Proportional odds logistic regression was used to examine the association between procalcitonin and CRP separately with delirium/coma-free days, adjusting for age, acute physiology score (APS) of the Acute Physiology And Chronic Health Evaluation (APACHE) II, sedation group (dexmedetomidine vs. lorazepam), and sepsis. Secondary analyses examined the association of these markers with other organ dysfunctions and 28-day survival.
RESULTS - Eighty-seven patients were included in this analysis. The median age of the patients was 60 years with APACHE II scores of 28; 68% had sepsis within 48 hours of admission. Higher levels of procalcitonin were associated with fewer delirium/coma-free days [odds ratio (OR), 0.5; 95% confidence interval (CI), 0.3 to 1.0; P = 0.04], whereas higher CRP levels showed trends towards fewer delirium/coma-free days (OR, 0.6; 95% CI, 0.3 to 1.1; P = 0.08). Similar relationships were found regardless of the presence of sepsis. No associations were found between procalcitonin or CRP with 28-day survival (P = 0.40 and 0.16, respectively).
CONCLUSIONS - In our pilot study, high baseline inflammatory biomarkers predicted prolonged periods of acute brain dysfunction, implicating inflammation as an important mechanism in the pathophysiology of delirium and coma during critical illness, irrespective of whether patients had sepsis or not.
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18 MeSH Terms
Procalcitonin as a marker of severe bacterial infection in children in the emergency department.
Deis JN, Creech CB, Estrada CM, Abramo TJ
(2010) Pediatr Emerg Care 26: 51-60; quiz 61-3
MeSH Terms: Bacterial Infections, Biomarkers, Bronchitis, Calcitonin, Calcitonin Gene-Related Peptide, Emergency Service, Hospital, Glycoproteins, Hospitals, Pediatric, Humans, Protein Precursors, Severity of Illness Index
Show Abstract · Added February 3, 2014
Procalcitonin, the prohormone of calcitonin, is a relatively new and innovative marker of bacterial infection that has multiple potential applications in the pediatric emergency department. In healthy individuals, circulating levels of procalcitonin are generally very low (<0.05 ng/mL), but in the setting of severe bacterial infection and sepsis, levels can increase by hundreds to thousands of fold within 4 to 6 hours. Although the exact physiologic function of procalcitonin has not been determined, the consistent response and rapid rise of this protein in the setting of severe bacterial infection make procalcitonin a very useful biomarker for invasive bacterial disease. In Europe, serum procalcitonin measurements are frequently used in the diagnosis and the management of patients in a variety of clinical settings. To date, the use of procalcitonin has been limited in the United States, but this valuable biomarker has many potential applications in both the pediatric emergency department and the intensive care unit. The intent of this article is to review the history of procalcitonin, describe the kinetics of the molecule in response to bacterial infection, describe the laboratory methods available for measuring procalcitonin, examine the main causes of procalcitonin elevation, and evaluate the potential applications of procalcitonin measurements in pediatric patients.
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11 MeSH Terms
The role of calcitonin and alpha-calcitonin gene-related peptide in bone formation.
Huebner AK, Keller J, Catala-Lehnen P, Perkovic S, Streichert T, Emeson RB, Amling M, Schinke T
(2008) Arch Biochem Biophys 473: 210-7
MeSH Terms: Alternative Splicing, Animals, Calcitonin, Calcitonin Gene-Related Peptide, Mice, Mice, Knockout, Mutation, Osteogenesis
Show Abstract · Added July 12, 2010
The Calca gene encodes two polypeptides, calcitonin (CT) and alpha-calcitonin gene-related peptide (alpha-CGRP), generated through alternative splicing. While CT, a hormone mainly produced by thyroidal C cells, has been described as a major regulator of bone resorption, alpha-CGRP, a neuropeptide expressed in the cells of the central and peripheral nervous system, is mostly known as a regulator of vascular tone. Surprisingly, the generation and skeletal analyses of two mouse deficiency models has recently uncovered a physiological function for both peptides in the regulation of bone formation. In the first model, where the replacement of exons 2-5 of the Calca gene resulted in the combined deficiency of CT and alpha-CGRP, an increased bone formation rate (BFR) was observed, whereas decreased BFR was found in the second model, where the introduction of a translational termination codon into exon 5 of the Calca gene resulted in the specific absence of alpha-CGRP.
1 Communities
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8 MeSH Terms
Protective roles of alpha-calcitonin and beta-calcitonin gene-related peptide in spontaneous and experimentally induced colitis.
Thompson BJ, Washington MK, Kurre U, Singh M, Rula EY, Emeson RB
(2008) Dig Dis Sci 53: 229-41
MeSH Terms: Animals, Calcitonin Gene-Related Peptide, Colitis, Dextran Sulfate, Disease Models, Animal, Disease Progression, Gene Expression, Immunohistochemistry, Mice, Mice, Mutant Strains, Polymerase Chain Reaction, RNA, Severity of Illness Index
Show Abstract · Added August 13, 2010
Calcitonin gene-related peptide (CGRP) is thought to be involved in the regulation of gastric and mesenteric blood flow, in the control of gastric acid secretion and in the modulation of intestinal motility, yet the precise physiological roles of CGRP remain to be elucidated. To further examine the role(s) of CGRP in gastrointestinal function, we examined mutant mice lacking alphaCGRP or betaCGRP expression. Mutant mice did not demonstrate any overt phenotypic changes, yet exhibited a spontaneous, adult-onset colitis and increased colonic damage using a dextran sulfate sodium model of experimental colitis. Surprisingly, mice lacking betaCGRP show no obvious alterations in CGRP immunoreactivity in the gut, accompanied by an increase in alphaCGRP messenger RNA expression, suggesting an adaptive mechanism to compensate for the lack of betaCGRP. These data demonstrate that both alphaCGRP and betaCGRP play a protective role in the generation of spontaneous colitis, supporting a role for both extrinsic and intrinsic CGRP-containing neurons.
2 Communities
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13 MeSH Terms
Calcitonin deficiency in mice progressively results in high bone turnover.
Huebner AK, Schinke T, Priemel M, Schilling S, Schilling AF, Emeson RB, Rueger JM, Amling M
(2006) J Bone Miner Res 21: 1924-34
MeSH Terms: Aging, Animals, Bone Density, Bone Diseases, Metabolic, Bone Remodeling, Calcitonin, Calcitonin Gene-Related Peptide, Humans, Mice, Mice, Knockout
Show Abstract · Added July 12, 2010
UNLABELLED - Although the pharmacological action of calcitonin (CT) as an inhibitor of bone resorption is well established, there is still some controversy regarding its physiological function. Unexpectedly, Calca-deficient mice lacking CT and alpha-calcitonin gene-related peptide (alphaCGRP) were described to have a high bone mass phenotype caused by increased bone formation with normal bone resorption. Here we show that these mice develop a phenotype of high bone turnover with age, suggesting that CT is a physiological inhibitor of bone remodeling.
INTRODUCTION - The absence of significant changes in bone mineral density caused by decline or overproduction of CT in humans has raised the question, whether the pharmacological action of CT as an inhibitor of bone resorption is also of physiological relevance. To study the physiological role of mammalian CT, we have analyzed the age-dependent bone phenotype of two mouse models, one lacking CT and alphaCGRP (Calca-/-), the other one lacking only alphaCGRP (alphaCGRP-/-).
MATERIALS AND METHODS - Bones from wildtype, Calca-/- -mice and alphaCGRP-/- -mice were analyzed at the ages of 6, 12 and 18 months using undecalcified histology. Differences of bone remodeling were quantified by static and dynamic histomorphometry as well as by measuring the urinary collagen degradation products. To rule out secondary mechanisms underlying the observed phenotype, we determined serum concentrations of relevant hormones using commercially available antibody-based detection kits.
RESULTS - Whereas alphaCGRP-/- -mice display an osteopenia at all ages analyzed, the Calca-/- -mice develop a phenotype of high bone turnover with age. Histomorphometric analysis performed at the age of 12 months revealed significant increases of bone formation and bone resorption specifically in the Calca-/- -mice. This severe phenotype that can result in hyperostotic lesions, can not be explained by obvious endocrine abnormalities other than the absence of CT.
CONCLUSIONS - In addition to the previously described increase of bone formation in the Calca-deficient mice, we have observed that there is also an increase of bone resorption with age. This suggests that CT has a dual action as an inhibitor of bone remodeling, which may explain why alterations of CT serum levels in humans do not result in major changes of bone mineral density.
1 Communities
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10 MeSH Terms
Decreased bone formation and osteopenia in mice lacking alpha-calcitonin gene-related peptide.
Schinke T, Liese S, Priemel M, Haberland M, Schilling AF, Catala-Lehnen P, Blicharski D, Rueger JM, Gagel RF, Emeson RB, Amling M
(2004) J Bone Miner Res 19: 2049-56
MeSH Terms: Alternative Splicing, Animals, Bone Diseases, Metabolic, Bone and Bones, Calcitonin, Calcitonin Gene-Related Peptide, Gene Deletion, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mice, Transgenic, Osteoblasts, Osteogenesis, Peptides, Phenotype, Radioimmunoassay, Reverse Transcriptase Polymerase Chain Reaction, Tomography, X-Ray Computed
Show Abstract · Added July 12, 2010
UNLABELLED - We recently described an unexpected high bone mass phenotype in mice lacking the Calca gene that encodes CT and alphaCGRP. Here we show that mice specifically lacking alphaCGRP expression display an osteopenia caused by a decreased bone formation. These results show that alphaCGRP is a physiological activator of bone formation and that the high bone mass phenotype of the Calca-deficient mice is caused by the absence of CT.
INTRODUCTION - Calcitonin (CT) and alpha-calcitonin gene-related peptide (alphaCGRP) are two polypeptides without completely defined physiologic functions that are both derived from the Calca gene by alternative splicing. We have recently described an unexpected high bone mass phenotype in mice carrying a targeted deletion of the Calca gene. To uncover whether this phenotype is caused by the absence of CT or by the absence of alphaCGRP, we analyzed a mouse model, where the production of alphaCGRP is selectively abolished.
MATERIALS AND METHODS - Bones from Calca(-/-) mice, alphaCGRP(-/-) mice, and their corresponding wildtype controls were analyzed using radiography, muCT imaging, and undecalcified histology. Cellular activities were assessed using dynamic histomorphometry and by measuring the urinary collagen degradation products. CT expression was determined using radioimmunoassay and RT-PCR. Immunohistochemistry was performed using an anti-CGRP antibody on decalcified bone sections.
RESULTS - Unlike the Calca-deficient mice, the alphaCGRP-deficient mice do not display a high bone mass phenotype. In contrast, they develop an osteopenia that is caused by a reduced bone formation rate. Serum levels and thyroid expression of CT are not elevated in alphaCGRP-deficient mice. While CGRP expression is detectable in neuronal cell close to trabecular bone structures, the components of the CGRP receptor are expressed in differentiated osteoblast cultures.
CONCLUSION - The discrepancy between the bone phenotypes of Calca(-/-) mice and alphaCGRP(-/-) mice show that the high bone mass phenotype of the Calca(-/-) mice is caused by the absence of CT. The osteopenia observed in the alphaCGRP(-/-) mice that have normal levels of CT further show that alphaCGRP is a physiologic activator of bone formation.
1 Communities
1 Members
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18 MeSH Terms
Loss of alpha CGRP reduces sound-evoked activity in the cochlear nerve.
Maison SF, Emeson RB, Adams JC, Luebke AE, Liberman MC
(2003) J Neurophysiol 90: 2941-9
MeSH Terms: Acoustic Stimulation, Amino Acid Sequence, Animals, Auditory Threshold, Calcitonin Gene-Related Peptide, Cochlear Nerve, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data
Show Abstract · Added July 12, 2010
alpha-Calcitonin gene-related peptide (alphaCGRP) is one of several neurotransmitters immunolocalized in the unmyelinated component of the cochlear efferent innervation, the lateral olivocochlear (OC) system, which makes axo-dendritic synapses with cochlear sensory neurons. In rodents, CGRP is also immunocolocalized in the myelinated medial OC system, which contacts cochlear outer hair cells (OHCs). To understand the role(s) of this neuropeptide in the OC system, we characterized the auditory phenotype of alphaCGRP-null mice. Cochlear threshold sensitivity was normal in mutant mice, both via a neural metric, the auditory brain stem response (ABR), and an OHC-based metric, distortion product otoacoustic emissions (DPOAEs). Medial OC function and resistance to acoustic injury were also unaffected by alphaCGRP deletion: the former was assessed by measuring cochlear response suppression with electrical stimulation of the OC bundle, the latter by measuring temporary threshold shifts after exposure to high level sound. However, significant abnormality in alphaCGRP-null mice was seen in the growth of cochlear neural responses with increasing stimulus level. This observation, contrasted with normal amplitude-versus-level functions for DPOAEs, is consistent with a selective, postsynaptic effect on cochlear neurons via alphaCGRP release from lateral OC terminals. This constitutes the most direct evidence to date for a functional role of the lateral OC system in the auditory periphery.
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10 MeSH Terms
Mice lacking alpha-calcitonin gene-related peptide exhibit normal cardiovascular regulation and neuromuscular development.
Lu JT, Son YJ, Lee J, Jetton TL, Shiota M, Moscoso L, Niswender KD, Loewy AD, Magnuson MA, Sanes JR, Emeson RB
(1999) Mol Cell Neurosci 14: 99-120
MeSH Terms: Aging, Amino Acid Sequence, Animals, Aorta, Base Sequence, Blood Pressure, Calcitonin Gene-Related Peptide, Heart, Heart Rate, Mice, Mice, Knockout, Molecular Sequence Data, Neuromuscular Junction, Phenotype, Physical Exertion, Receptors, Nicotinic, Restriction Mapping, Stem Cells
Show Abstract · Added December 10, 2013
alpha-Calcitonin gene-related peptide (alphaCGRP) is a pleiotropic peptide neuromodulator that is widely expressed throughout the Central and peripheral nervous systems. CGRP has been implicated in a variety of physiological processes including peripheral vasodilation, cardiac acceleration nicotinic acetylcholine receptor (AChR) synthesis and function, testicular descent, nociception, carbohydrate metabolism, gastrointestinal motility, neurogenic inflammation, and gastric acid secretion. To provide a better understanding of the physiological role(s) mediated by this peptide neurotransmitter, we have generated alphaCGRP-null mice by targeted modification in embryonic stem cells. Mice lacking alpha CGRP expression demonstrate no obvious phenotypic differences from their wild-type littermates. Detailed analysis of systemic cardiovascular function revealed no differences between control and mutant mice regarding heart rate and blood pressure under basal or exercise-induced conditions and subsequent to pharmacological manipulation. Characterization of neuromuscular junction in morphology including nicotinic receptor localization, terminal sprouting in response to denervation, developmental regulation of AChR subunit expression, and synapse elimination also revealed no differences in alphaCGRP-deficient animals. These results suggest that alphaCGRP is not required for the systemic regulation of cardiovascular hemodynamics or development of the neuromuscular junction.
3 Communities
5 Members
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18 MeSH Terms
The site of origin of calcitonin gene-related peptide-like immunoreactive afferents to the inferior olivary complex of the mouse.
Peltier AC, Bishop GA
(1999) Neurosci Res 34: 177-86
MeSH Terms: Animals, Brain Stem, Calcitonin Gene-Related Peptide, Fluorescent Dyes, Immunohistochemistry, Injections, Intraperitoneal, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Microspheres, Neurons, Afferent, Olivary Nucleus
Show Abstract · Added December 10, 2013
The intent of the present study is to define the brainstem nuclei which give rise to CGRP-immunolabeled afferents to the inferior olivary complex of the mouse. A technique which combines retrograde transport of fluorescent microspheres with immunohistochemistry was used to address this question. In the present study, intensely labeled CGRP neurons were localized within several cranial nerve nuclei including the hypoglossal, facial, oculomotor, motor nucleus of the trigeminal nerve and nucleus ambiguus, as well as in the parabrachial nucleus, locus coeruleus and medullary and pontine reticular formation. In addition, lightly labeled CGRP neurons were identified within the deep cerebellar nuclei, the inferior olivary complex, lateral reticular nucleus, medial and lateral vestibular nuclei, nucleus Darkschewitsch, interstitial nucleus of Cajal, the central gray area adjacent to the third ventricle, and the zona incerta. The origin of the projection to the inferior olivary complex primarily arises from the deep cerebellar nuclei, the locus coeruleus, and the central gray matter of the mesodiencephalic area. In addition, a small CGRP input is derived from the superior and lateral vestibular nuclei as well as the zona incerta. In conclusion, we have identified several extrinsic sources of CGRP to the inferior olivary complex and have localized it within afferents that have been shown to have either excitatory (mesodiencephalic nuclei) or inhibitory (cerebellar nuclei) effects on olivary circuits. The presence of CGRP in these functionally diverse brainstem and cerebellar afferents suggests that the peptide may act as a co-transmitter to modulate the activity of olivary neurons.
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12 MeSH Terms