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Sample records for asialoglycoprotein receptor deficiency

  1. Asialoglycoprotein receptor targeted imaging using Tc-99m galactosylated chitosan

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    Kim, E. M.; Jeong, H. J.; Kim, B. C.; Kim, C. K [Wonkang University College of Medicine, Iksan (Korea, Republic of)

    2004-07-01

    The asialoglycoprotein receptor (ASGP-R) is expressed on liver hepatocytes. Chitosan conjugates of galactose have shown to be specifically taken up by liver parenchymal cells via ASGP-R. In this study, Tc-99m hydrazino nicotinamide (HYNIC)-galactosylated chitosan (HYNIC-GC) was synthesized and evaluated as a targeted agent for the imaging of hepatocytes. GC was obtained after coupling of lactobionic acid as the galactose moiety and coupled with HYNIC. HYNIC-GC was radiolabeled with Tc-99m using stannous chloride and tricine as reducing agent and coligand respectively. Hepatic uptake property of Tc-99m HYNIC-GC was studied in female Balb/C mouse. Tc-99m HYNIC--GC and Tc-99m HYNIC-Chitosan as a control were intravenously injected into mice. Receptor binding was identified by coinjection with 50 mM and 80mM free galactose respectively. Biodistribution was determined at three different time points. The level of galactose substitution was 7.6%. Labeling efficiency was >90% both in vitro and serum up to 24 h. Tc-99m HYNIC-GC injected via tail vein of mice showed high selectivity of liver. On the other hands, Tc-99m HC without galactose group showed low uptake (Fig. 1A, 1B). Hepatic uptake of Tc-99m HYNIC-GC was dramatically blocked by 50 mM and 80 mM free galactose coinjection (Fig. 1C, 1D). The liver accumulated about 14 percent injected dose per gram (%ID/g) up to 120 min after injection. Tc-99m HYNIC-GC showed specific and rapid targeting to liver. It is a promising specific radiopharmaceutical with potential applications in the imaging of liver parenchymal cells.

  2. Characterization of the interaction between urinary urokinase and the asialoglycoprotein receptor of liver cells

    NARCIS (Netherlands)

    Rijken, D.C.; Kaaden, M.E. van der; Groeneveld, E.; Barrett-Bergshoeff, M.M.; Thjc, B. van; Kuiper, J.

    1996-01-01

    Urokinase-type plasminogen activator (u-PA) is rapidly cleared from the circulation with a half-life of a few minutes. We have previously shown that non-glycosylated recombinant u-PA is recognized by LRP, whereas urinary u-PA is recognized by the asialoglycoprotein receptor (ASGPr) on liver

  3. Effects of chronic ethanol administration on total asialoglycoprotein receptor content in isolated rat hepatocytes

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    Casey, C.A.; Kragskow, S.L.; Sorrell, M.F.; Tuma, D.J.

    1987-05-01

    The authors have previously shown that chronic ethanol administration impairs receptor-mediated endocytosis of asialoorosomucoid (ASOR) in hepatocytes. Decreased surface binding, degradation, and internalization of /sup 125/I-ASOR, along with decreased receptor recycling, was shown in hepatocytes isolated from rats fed a liquid ethanol diet for 5-7 weeks as compared to values obtained from hepatocytes isolated from chow-fed and pair-fed control rats. The present study was undertaken to determine the effect of chronic ethanol feeding on total asialoglycoprotein receptor number and on the distribution of intracellular versus surface membrane receptor content of the hepatocytes. Chronic ethanol administration produced a significant decrease (30-50%, p<.01) in the total number of binding sites/10/sup 6/ cells, as determined by /sup 125/I-ASOR binding to cells which has been permeabilized with .055% digitonin, when compared to controls. The distribution of surface membrane/intracellular binding site number was, however, unchanged by chronic ethanol feeding. The decrease in both total and surface binding of /sup 125/I-ASOR to cells from ethanol-fed rats was confirmed using anti-rat antibody binding to intact and permeabilized cells. These results indicate that both surface and total asialoglycoprotein receptor content is decreased by chronic ethanol feeding.

  4. ASGR1 and ASGR2, the Genes that Encode the Asialoglycoprotein Receptor (Ashwell Receptor, Are Expressed in Peripheral Blood Monocytes and Show Interindividual Differences in Transcript Profile

    Directory of Open Access Journals (Sweden)

    Rebecca Louise Harris

    2012-01-01

    Full Text Available Background. The asialoglycoprotein receptor (ASGPR is a hepatic receptor that mediates removal of potentially hazardous glycoconjugates from blood in health and disease. The receptor comprises two proteins, asialoglycoprotein receptor 1 and 2 (ASGR1 and ASGR2, encoded by the genes ASGR1 and ASGR2. Design and Methods. Using reverse transcription amplification (RT-PCR, expression of ASGR1 and ASGR2 was investigated in human peripheral blood monocytes. Results. Monocytes were found to express ASGR1 and ASGR2 transcripts. Correctly spliced transcript variants encoding different isoforms of ASGR1 and ASGR2 were present in monocytes. The profile of transcript variants from both ASGR1 and ASGR2 differed among individuals. Transcript expression levels were compared with the hepatocyte cell line HepG2 which produces high levels of ASGPR. Monocyte transcripts were 4 to 6 orders of magnitude less than in HepG2 but nonetheless readily detectable using standard RT-PCR. The monocyte cell line THP1 gave similar results to monocytes harvested from peripheral blood, indicating it may provide a suitable model system for studying ASGPR function in this cell type. Conclusions. Monocytes transcribe and correctly process transcripts encoding the constituent proteins of the ASGPR. Monocytes may therefore represent a mobile pool of the receptor, capable of reaching sites remote from the liver.

  5. Understanding the Selectivity Mechanism of the Human Asialoglycoprotein Receptor (ASGP-R) toward Gal- and Man- type Ligands for Predicting Interactions with Exogenous Sugars

    OpenAIRE

    Emo Chiellini; Federica Chiellini; Anna Maria Bianucci; Laura Murgia; Ilaria Massarelli

    2007-01-01

    A practical approach for addressing the computer simulation of protein-carbohydrate interactions is described here. An articulated computational protocol was set up and validated by checking its ability to predict experimental data, available in the literature, and concerning the selectivity shown by the Carbohydrate Recognition Domain (CRD) of the human asialoglycoprotein receptor (ASGP-R) toward Gal-type ligands. Some required features responsible for the interactions were identified. Subse...

  6. Electrochemical evidence for asialoglycoprotein receptor – mediated hepatocyte adhesion and proliferation in three dimensional tissue engineering scaffolds

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    Vasanthan, Kirthanashri S.; Sethuraman, Swaminathan; Parthasarathy, Meera, E-mail: meera_p@scbt.sastra.edu

    2015-08-26

    Asialoglycoprotein receptor (ASGPR) is one of the recognition motifs on the surface of hepatocytes, which promote their adhesion to extracellular matrix in liver tissue and appropriate artificial surfaces. ASGPR-mediated adhesion is expected to minimize trans-differentiation of hepatocytes in vitro that is generally observed in integrin-mediated adhesion. The aim of the present study is to verify the role of ASGPR in hepatocyte adhesion and proliferation in scaffolds for hepatic tissue engineering. Scanning Electrochemical Microscopy (SECM) is emerging as a suitable non-invasive analytical tool due to its high sensitivity and capability to correlate the morphology and activity of live cells. HepG2 cells and rat primary hepatocytes cultured in Polyvinyl alcohol (PVA)/Gelatin hydrogel scaffolds with and without galactose (a ligand for ASGPR) modification are studied using SECM. Systematic investigation of live cells cultured for different durations in scaffolds of different compositions (9:1 and 8:2 PVA:Gelatin with and without galactose) reveals significant improvement in cell–cell communication and proliferation on galactose incorporated scaffolds, thereby demonstrating the positive influence of ASGPR-mediated adhesion. In this work, we have also developed a methodology to quantify the respiratory activity and intracellular redox activity of live cells cultured in porous tissue engineering scaffolds. Using this methodology, SECM results are compared with routine cell culture assays viz., MTS ((1-Oxyl-2,2,5,5,-tetramethyl-Δ3-pyrroline-3-methyl) Methanethiosulfonate) and Albumin assays to demonstrate the better sensitivity of SECM. In addition, the present study demonstrates SECM as a reliable and sensitive tool to monitor the activity of live cells cultured in scaffolds for tissue engineering, which could be used on a routine basis. - Highlights: • A methodology for electrochemical imaging of polymer scaffolds is proposed. • The new methodology allows

  7. Human IgA as a heterovalent ligand: switching from the asialoglycoprotein receptor to secretory component during transport across the rat hepatocyte.

    Science.gov (United States)

    Schiff, J M; Fisher, M M; Jones, A L; Underdown, B J

    1986-03-01

    Asialoglycoproteins are taken up by the rat liver for degradation; rat polymeric IgA is taken up via a separate receptor, secretory component (SC), for quantitative delivery to bile. There is negligible uptake of these ligands by the converse receptor, and only a low level of missorting of ligands to opposite destinations. The two pathways are not cross-inhibitable and operate independently (Schiff, J.M., M. M. Fisher, and B. J. Underdown, 1984, J. Cell Biol., 98:79-89). We report here that when human IgA is presented as a ligand in the rat, it is processed using elements of both pathways. To study this in detail, different IgA fractions were prepared using two radiolabeling methods that provide separate probes for degradation or re-secretion. Behavior of intravenously injected human polymeric IgA in the rat depended on its binding properties. If deprived of SC binding activity by affinity adsorption or by reduction and alkylation, greater than 80% of human IgA was degraded in hepatic lysosomes; radioactive catabolites were released into bile by a leupeptin-inhibitable process. If prevented from binding to the asialoglycoprotein receptor by competition or by treatment with galactose oxidase, human IgA was cleared and transported to bile directly via SC, but its uptake was about fivefold slower than rat IgA. Untreated human IgA was taken up rapidly by the asialoglycoprotein receptor, but depended on SC binding to get to bile: the proportion secreted correlated 1:1 with SC binding activity determined in vitro, and the IgA was released into bile with SC still attached. These results demonstrate that human IgA is normally heterovalent: it is first captured from blood by the asialoglycoprotein receptor, but escapes the usual fate of asialoglycoproteins by switching to SC during transport. Since the biliary transit times of native human and rat IgA are the same, it is probable that the receptor switching event occurs en route. This implies that the two receptors briefly

  8. Asialoglycoprotein receptor facilitates infection of PLC/PRF/5 cells by HEV through interaction with ORF2.

    Science.gov (United States)

    Zhang, Li; Tian, Yabin; Wen, Zhiheng; Zhang, Feng; Qi, Ying; Huang, Weijin; Zhang, Heqiu; Wang, Youchun

    2016-12-01

    Although the biological and epidemiological features of hepatitis E virus (HEV) have been studied extensively in recent years, the mechanism by which HEV infects cells is still poorly understood. In this study, coimmunoprecipitation, pull-down, and ELISA were used to show that the HEV ORF2 protein interacts directly with the ectodomain of both ASGR1 and ASGR2. Susceptibility to HEV correlated positively with the expression level of surface asialoglycoprotein receptor (ASGPR) in cell lines. ASGPR-directed small interfering RNA (siRNA) in HEV-infected PLC/PRF/5 cells had no significant effect on HEV release, suggesting that ASGPR mainly regulates the viral binding and entry steps. Both the purified ASGPR ectodomain and anti-ASGPR antibodies disturbed the binding of HEV to PLC/PRF/5 cells. The classic ASGPR ligands asialofetuin, asialoganglioside, and fibronectin competitively inhibited the binding of HEV to hepatocytes in the presence of calcium. HeLa cell lines stably expressing ASGPR displayed increased HEV-binding capacity, whereas ASGPR-knockout PLC/PRF/5 cell lines had lower HEV-binding capacity. Thus, our study demonstrates that ASGPR is involved in and facilitates HEV infection by binding to ORF2. J. Med. Virol. 88:2186-2195, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. Evaluation of asialoglycoprotein receptor imaging agent as a marker of hepatic ischemia-reperfusion injury and recovery

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    Toyama, Hiroshi; Suzuki, Kazuo; Naito, Aiko [Fujita Health Univ., Toyoake, Aichi (Japan)] [and others

    1999-06-01

    Protection of hepatocytes from ischemia-reperfusion injury is a clinically important issue. The purpose of this study was to evaluate changes in acute liver damage and recovery after ischemia-reperfusion in rats with asialoglycoprotein receptor (ASGP-R) ligand. Ischemia was induced by clamping the hepatoduodenal ligament for 90 min. At 1, 3, 24, 48 hr, 1 and 2 wk after reperfusion, I-125-GSA was injected. Five min after injection, blood samples were obtained and the liver was removed. Several regions from each lobe were dissected, weighed and counted. Mean uptakes (% dose/g) in the liver and blood samples were calculated. Histologic sections stained with hematoxylin-eosin (H-E) stain showed ischemic damage at 1 and 3 hr, and focal hepatocyte necrosis at 24 hr. Predominant massive necrosis was not seen. The mitotic index with H-E stain and proliferating cell nuclear antigen (PCNA) labeling index were highest at 1 wk, indicating liver regeneration. At 1 and 3 hr, liver uptake was significantly decreased, and blood uptake was significantly increased, indicating decreased tissue blood flow and ischemic damage. Liver uptake showed significant increases at 48 hr and 1 wk, and was the highest at 1 wk, indicating liver regeneration during the convalescence stage. ASGP-R binding may provide valuable information on ischemia-reperfusion injury and recovery. (author)

  10. Radiolabelled {sup 153}Sm-chelates of glycoconjugates: multivalence and topology effects on the targeting of the asialoglycoprotein receptor

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    Torres, S. [Centro de Quimica, Campus de Gualtar, Univ. do Minho, Braga (Portugal); Martins, J.A.; Andre, J.P.; Neves, M. [Inst. Tecnologico e Nuclear, Sacavem (Portugal); Santos, A.C.; Prata, M.I.M. [Servico de Biofisica, IBILI, Univ. de Coimbra (Portugal); Geraldes, C.F.G.C. [Dept. de Bioquimica, Centro de Espectroscopia RMN e Centro de Neurociencias e Biologia Celular, Univ. de Coimbra (Portugal)

    2007-07-01

    In this paper we report and discuss the biodistribution studies with Wistar rats of a series of {sup 153}Sm(III)-glycoconjugates, based on DO3A and DO2A(cis) scaffolds (DO3A = 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane; DO2A(cis) = 1,4-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane). The effects of changing the sugar type (galactose, lactose and glucose), valency (mono and divalent) and topology on the targeting ability of the liver asialoglycoprotein receptor (ASGPR) are evaluated. Divalent glycoconjugates with different topologies were generated by a pendant glycodendrimeric (generation 1) architecture on a DO3A scaffold and by a linear DO2A(cis)-bis derivative. The results show that the galactose conjugates are more target efficient than the lactose analogues, while the glucose conjugates have no liver targeting ability. Divalent galactose conjugates are more efficiently targeted to the liver than the monovalent ones, while the dendrimeric topology of DO3A-Gal{sub 2} has higher targeting efficiency than that of the DO2A(cis)-Gal{sub 2}. (orig.)

  11. A new splice variant of the major subunit of human asialoglycoprotein receptor encodes a secreted form in hepatocytes.

    Directory of Open Access Journals (Sweden)

    Jia Liu

    Full Text Available BACKGROUND: The human asialoglycoprotein receptor (ASGPR is composed of two polypeptides, designated H1 and H2. While variants of H2 have been known for decades, the existence of H1 variants has never been reported. PRINCIPAL FINDINGS: We identified two splice variants of ASGPR H1 transcripts, designated H1a and H1b, in human liver tissues and hepatoma cells. Molecular cloning of ASGPR H1 variants revealed that they differ by a 117 nucleotide segment corresponding to exon 2 in the ASGPR genomic sequence. Thus, ASGPR variant H1b transcript encodes a protein lacking the transmembrane domain. Using an H1b-specific antibody, H1b protein and a functional soluble ASGPR (sASGPR composed of H1b and H2 in human sera and in hepatoma cell culture supernatant were identified. The expression of ASGPR H1a and H1b in Hela cells demonstrated the different cellular loctions of H1a and H1b proteins at cellular membranes and in intracellular compartments, respectively. In vitro binding assays using fluorescence-labeled sASGPR or the substract ASOR revealed that the presence of sASGPR reduced the binding of ASOR to cells. However, ASOR itself was able to enhance the binding of sASGPR to cells expressing membrane-bound ASGPR. Further, H1b expression is reduced in liver tissues from patients with viral hepatitis. CONCLUSIONS: We conclude that two naturally occurring ASGPR H1 splice variants are produced in human hepatocytes. A hetero-oligomeric complex sASGPR consists of the secreted form of H1 and H2 and may bind to free substrates in circulation and carry them to liver tissue for uptake by ASGPR-expressing hepatocytes.

  12. Asialoglycoprotein-receptor-targeted hepatocyte imaging using {sup 99m}Tc galactosylated chitosan

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    Kim, Eun-Mi [Department of Nuclear Medicine, Research Institute of Clinical Medicine, Chonbuk National University School of Medicine, Jeonju, Jeonbuk (Korea, Republic of); Jeong, Hwan-Jeong [Department of Nuclear Medicine, Research Institute of Clinical Medicine, Chonbuk National University School of Medicine, Jeonju, Jeonbuk (Korea, Republic of)]. E-mail: jayjeong@chonbuk.ac.kr; Kim, Se-Lim [Department of Nuclear Medicine, Research Institute of Clinical Medicine, Chonbuk National University School of Medicine, Jeonju, Jeonbuk (Korea, Republic of); Sohn, Myung-Hee [Department of Nuclear Medicine, Research Institute of Clinical Medicine, Chonbuk National University School of Medicine, Jeonju, Jeonbuk (Korea, Republic of); Nah, Jae-Woon [Division of Applied Materials Engineering, Department of Polymer Science and Engineering, Sunchon National University, Sunchon, Jeonnam (Korea, Republic of); Bom, Hee-Seung [Department of Nuclear Medicine, Chonnam National University School of Medicine, Gwangju (Korea, Republic of); Park, In-Kyu [School of Agricultural Biotechnology, Seoul National University, Seoul (Korea, Republic of); Cho, Chong-Su [School of Agricultural Biotechnology, Seoul National University, Seoul (Korea, Republic of)

    2006-05-15

    This study investigated the usefulness of {sup 99m}Tc hydrazinonicotinamide-galactosylated chitosan (HGC) in hepatocyte imaging. HGC was obtained by coupling the galactose moiety of both lactobionic acid and succinimidyl 6-hydrazinonicotinate hydrochloride (succinimidyl HYNIC). The coupled product was then radiolabeled with {sup 99m}Tc using stannous chloride and tricine as reducing agent and coligand, respectively. Labeling efficiency was >90% both in room temperature and in serum up to 24 h after injection. The hepatic uptake properties of {sup 99m}Tc HGC were studied in Balb/C mice. {sup 99m}Tc HGC and {sup 99m}Tc hydrazinonicotinamide chitosan (HC) were intravenously injected into mice, with receptor binding identified by coinjection with 9 and 14 mg of free galactose. Images were acquired with a {gamma}-camera. After injection via the tail vein of the mice, {sup 99m}Tc HGC showed high selectivity for the liver, while {sup 99m}Tc HC without a galactose group showed low liver uptake. In addition, the hepatic uptake of {sup 99m}Tc HGC was blocked by coinjection of free galactose. Tissue distribution was determined at three different times (10, 60 and 120 min). The liver accumulated 13.16{+-}2.72%, 16.11{+-}5.70% and 16.55{+-}2.28% of the injected dose per gram at 10, 60 and 120 min after injection, respectively. {sup 99m}Tc HGC showed specific and rapid targeting of hepatocytes. It is a promising receptor-specific radiopharmaceutical with potential applications in liver imaging for the evaluation of hepatocytic function.

  13. Epitope Structure of the Carbohydrate Recognition Domain of Asialoglycoprotein Receptor to a Monoclonal Antibody Revealed by High-Resolution Proteolytic Excision Mass Spectrometry

    Science.gov (United States)

    Stefanescu, Raluca; Born, Rita; Moise, Adrian; Ernst, Beat; Przybylski, Michael

    2011-01-01

    Recent studies suggest that the H1 subunit of the carbohydrate recognition domain (H1CRD) of the asialoglycoprotein receptor is used as an entry site into hepatocytes by hepatitis A and B viruses and Marburg virus. Thus, molecules binding specifically to the CRD might exert inhibition towards these diseases by blocking the virus entry site. We report here the identification of the epitope structure of H1CRD to a monoclonal antibody by proteolytic epitope excision of the immune complex and high-resolution MALDI-FTICR mass spectrometry. As a prerequisite of the epitope determination, the primary structure of the H1CRD antigen was characterised by ESI-FTICR-MS of the intact protein and by LC-MS/MS of tryptic digest mixtures. Molecular mass determination and proteolytic fragments provided the identification of two intramolecular disulfide bridges (seven Cys residues), and a Cys-mercaptoethanol adduct formed by treatment with β-mercaptoethanol during protein extraction. The H1CRD antigen binds to the monoclonal antibody in both native and Cys-alkylated form. For identification of the epitope, the antibody was immobilized on N-hydroxysuccinimide (NHS)-activated Sepharose. Epitope excision and epitope extraction with trypsin and FTICR-MS of affinity-bound peptides provided the identification of two specific epitope peptides (5-16) and (17-23) that showed high affinity to the antibody. Affinity studies of the synthetic epitope peptides revealed independent binding of each peptide to the antibody.

  14. Zonal differences in ethanol-induced impairments in receptor-mediated endocytosis of asialoglycoproteins in isolated rat hepatocytes

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    Casey, C.A.; Kragskow, S.L.; Sorrell, M.F.; Tuma, D.J. (Department of Veterans Affairs Medical Center, Omaha, NE (USA))

    1991-02-01

    We have shown previously that ethanol-induced defects in receptor-mediated endocytosis of asialoorosomucoid occurred as early as 1 wk after ethanol feeding. This study was undertaken as an initial attempt to establish a possible role of defective receptor-mediated endocytosis in liver injury by investigating whether differences exist in the effects of ethanol on receptor-mediated endocytosis in hepatocytes isolated from different regions of the liver. Perivenule cells, present in the distal half of the liver, are thought to be more susceptible to ethanol-induced liver injury than are the periportal cells located in the proximal half of the liver acini. For these studies, we fed male Sprague-Dawley rats for 7 days with liquid diets containing either ethanol (36% of calories) or isocaloric carbohydrate. Perivenule and periportal hepatocytes were then isolated using a digitonin-collagenase perfusion method. In control animals, cells isolated from the perivenule region bound significantly more ligand than did cells from the periportal region. Amounts of ligand internalized and degraded were also greater in perivenule than in periportal cells in these animals. After ethanol feeding, cells isolated from both the perivenule and periportal regions bound significantly less ligand than their respective controls. This impairment in surface and total binding was more pronounced in perivenule than in periportal cells. Internalization and degradation of the ligand were also more adversely affected in the centrilobular region as shown by decreases of greater than 60% in perivenule cells and by only 20% to 30% in periportal cells of ethanol-fed animals compared with controls.

  15. Design of cholesterol arabinogalactan anchored liposomes for asialoglycoprotein receptor mediated targeting to hepatocellular carcinoma: In silico modeling, in vitro and in vivo evaluation.

    Science.gov (United States)

    Pathak, Pankaj; Dhawan, Vivek; Magarkar, Aniket; Danne, Reinis; Govindarajan, Srinath; Ghosh, Sandipto; Steiniger, Frank; Chaudhari, Pradip; Gopal, Vijaya; Bunker, Alex; Róg, Tomasz; Fahr, Alfred; Nagarsenker, Mangal

    2016-07-25

    We have developed active targeting liposomes to deliver anticancer agents to ASGPR which will contribute to effective treatment of hepatocellular carcinoma. Active targeting is achieved through polymeric ligands on the liposome surface. The liposomes were prepared using reverse phase evaporation method and doxorubicin hydrocholoride, a model drug, was loaded using the ammonium sulphate gradient method. Liposomes loaded with DOX were found to have a particle size of 200nm with more than 90% entrapment efficiency. Systems were observed to release the drug in a sustained manner in acidic pH in vitro. Liposomes containing targeting ligands possessed greater and selective toxicity to ASGPR positive HepG2 cell lines due to specific ligand receptor interaction. Bio-distribution studies revealed that liposomes were concentrated in the liver even after 3h of administration, thus providing conclusive evidence of targeting potential for formulated nanosystems. Tumor regression studies indicated greater tumor suppression with targeted liposomes thereby establishing superiority of the liposomal system. In this work, we used a novel methodology to guide the determination of the optimal composition of the targeting liposomes: molecular dynamics (MD) simulation that aided our understanding of the behaviour of the ligand within the bilayer. This can be seen as a demonstration of the utility of this methodology as a rational design tool for active targeting liposome formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Role of sialic acid for platelet life span: exposure of beta-galactose results in the rapid clearance of platelets from the circulation by asialoglycoprotein receptor-expressing liver macrophages and hepatocytes

    DEFF Research Database (Denmark)

    Sørensen, Anne Louise; Rumjantseva, Viktoria; Nayeb-Hashemi, Sara

    2009-01-01

    Although surface sialic acid is considered a key determinant for the survival of circulating blood cells and glycoproteins, its role in platelet circulation lifetime is not fully clarified. We show that thrombocytopenia in mice deficient in the St3gal4 sialyltransferase gene (St3Gal-IV(-/-) mice)...

  17. DEFICIENCY OF INTERLEUKIN-1 RECEPTOR ANTAGONIST RESPONSIVE TO ANAKINRA

    Science.gov (United States)

    SCHNELLBACHER, CHARLOTTE; CIOCCA, GIOVANNA; MENENDEZ, ROXANNA; AKSENTIJEVICH, IVONA; GOLDBACH-MANSKY, RAPHAELA; DUARTE, ANAM.; RIVAS-CHACON, RAFAEL

    2012-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acutephase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy. PMID:22471702

  18. Growth hormone receptor deficiency (Laron syndrome) in black ...

    African Journals Online (AJOL)

    Non-Caucasians with growth honnone receptor (GHR) deficiency/Lamn syndrome among the approximately 180 recognised cases are rare, and include a Japanese and 3. African Americans. Black African siblings, a brother and a sister seen initially at 11 years 9 months and 5 years 6 months of age respectively were -7,4 ...

  19. Growth hormone receptor deficiency (Laron syndrome) in black ...

    African Journals Online (AJOL)

    Non-Caucasians with growth honnone receptor (GHR) deficiency/Lamn syndrome among the approximately 180 recognised cases are rare, and include a Japanese and 3 African Americans. Black African siblings, a brother and a sister seen initially at 11 years 9 months and 5 years 6 months of age respectively were -7,4 ...

  20. Soluble Transferrin Receptor - A Marker For Iron Deficiency; A Review

    African Journals Online (AJOL)

    The serum transferrin are shed into the blood and its level has been found to correlate with the level of iron stores and thereby the degree of erythropoietic activity. The aim of this literature review is to explore the physical properties of the serum transferrin receptor and its usefulness in the detection of iron deficiency.

  1. Serum transferrin receptors in detection of iron deficiency in pregnancy.

    Science.gov (United States)

    Rusia, U; Flowers, C; Madan, N; Agarwal, N; Sood, S K; Sikka, M

    1999-08-01

    A prospective hospital-based study was conducted to evaluate the efficacy of serum transferrin receptors in the detection of iron deficiency in pregnant women. The iron status of 100 pregnant women with single uncomplicated term pregnancies in the first stage of labor was established using standard laboratory measures. These included complete hemogram, red cell indices, serum iron, percent transferrin saturation, and serum ferritin. In addition, serum transferrin receptor (STFR) was estimated. The results of 81 women with complete laboratory profiles were analyzed. Thirty-five (43.2%) women were anemic (hemoglobin <11 g/dl). Hemoglobin (Hb) showed a significant correlation with MCH, MCHC, serum iron, and percent transferrin saturation, suggesting that the anemia was likely to be due to iron deficiency. The mean STFR level was 18.05+/-9.9 mg/l in the anemic women and was significantly raised (p<0.001) compared with that of the nonanemic women. STFR correlated significantly with Hb (p<0.001), MCH (p<0.05), MCHC (p<0.01), serum iron (p<0.01), and percent transferrin saturation (p<0.01) and also showed a highly significant correlation with the degree of anemia. Serum ferritin in these women did not correlate with Hb, and only 54.4% of the women had levels <12 ng/ml, which does not reflect the true prevalence of iron deficiency. Serum transferrin receptor estimation is thus a useful measure for detecting iron deficiency in pregnancy.

  2. CRF1 receptor-deficiency increases cocaine reward.

    Science.gov (United States)

    Contarino, Angelo; Kitchener, Pierre; Vallée, Monique; Papaleo, Francesco; Piazza, Pier-Vincenzo

    2017-05-01

    Stimulant drugs produce reward but also activate stress-responsive systems. The corticotropin-releasing factor (CRF) and the related hypothalamus-pituitary-adrenal (HPA) axis stress-responsive systems are activated by stimulant drugs. However, their role in stimulant drug-induced reward remains poorly understood. Herein, we report that CRF1 receptor-deficient (CRF1-/-), but not wild-type, mice show conditioned place preference (CPP) responses to a relatively low cocaine dose (5 mg/kg, i.p.). Conversely, wild-type, but not CRF1-/-, mice display CPP responses to a relatively high cocaine dose (20 mg/kg, i.p.), indicating that CRF1 receptor-deficiency alters the rewarding effects of cocaine. Acute pharmacological antagonism of the CRF1 receptor by antalarmin also eliminates cocaine reward. Nevertheless, CRF1-/- mice display higher stereotypy responses to cocaine than wild-type mice. Despite the very low plasma corticosterone concentration, CRF1-/- mice show higher nuclear glucocorticoid receptor (GR) levels in the brain region of the hippocampus than wild-type mice. Full rescue of wild-type-like corticosterone and GR circadian rhythm and level in CRF1-/- mice by exogenous corticosterone does not affect CRF1 receptor-dependent cocaine reward but induces stereotypy responses to cocaine. These results indicate a critical role for the CRF1 receptor in cocaine reward, independently of the closely related HPA axis activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Role of Leptin Deficiency, Inefficiency, and Leptin Receptors in Obesity.

    Science.gov (United States)

    Wasim, Muhammad; Awan, Fazli Rabbi; Najam, Syeda Sadia; Khan, Abdul Rehman; Khan, Haq Nawaz

    2016-10-01

    Leptin protein consists of 167 amino acids, which is mainly secreted from the white adipose tissue. This protein acts on the hypothalamic regions of the brain which control eating behavior, thus playing a significant role in maintaining body's metabolism. Leptin receptors belong to glycoprotein 130 (gp130) family of cytokine receptors and exist in six isoforms (LEPR a-f), and all the isoforms are encoded by LEPR gene; out of these isoforms, the LEPR-b receptor is the 'longest form,' and in most of the cases, mutations in this isoform cause severe obesity. Also, mutations in the leptin gene (LEP) or its receptors gene can lead to obesity. Some biochemical pathways affect the bioactivity of leptin and/or its receptors. To date, eleven pathogenic mutations have been reported in the LEP which are p.L72S, p.N103K, p.R105W, p.H118L, p.S141C, p.W121X c.104_106delTCA, c.135del3bp, c.398delG, c.481_482delCT, and c.163C>T. Different mutations in the LEPR have also been reported as c.2396-1 G>T, c.1675 G>A, p.P316T, etc. In some studies, where leptin was deficient, leptin replacement therapy has shown positive impact by preventing weight gain and obesity.

  4. Impact of AT2 receptor deficiency on postnatal cardiovascular development.

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    Daniel Biermann

    Full Text Available BACKGROUND: The angiotensin II receptor subtype 2 (AT2 receptor is ubiquitously and highly expressed in early postnatal life. However, its role in postnatal cardiac development remained unclear. METHODOLOGY/PRINCIPAL FINDINGS: Hearts from 1, 7, 14 and 56 days old wild-type (WT and AT2 receptor-deficient (KO mice were extracted for histomorphometrical analysis as well as analysis of cardiac signaling and gene expression. Furthermore, heart and body weights of examined animals were recorded and echocardiographic analysis of cardiac function as well as telemetric blood pressure measurements were performed. Moreover, gene expression, sarcomere shortening and calcium transients were examined in ventricular cardiomyocytes isolated from both genotypes. KO mice exhibited an accelerated body weight gain and a reduced heart to body weight ratio as compared to WT mice in the postnatal period. However, in adult KO mice the heart to body weight ratio was significantly increased most likely due to elevated systemic blood pressure. At postnatal day 7 ventricular capillarization index and the density of α-smooth muscle cell actin-positive blood vessels were higher in KO mice as compared to WT mice but normalized during adolescence. Echocardiographic assessment of cardiac systolic function at postnatal day 7 revealed decreased contractility of KO hearts in response to beta-adrenergic stimulation. Moreover, cardiomyocytes from KO mice showed a decreased sarcomere shortening and an increased peak Ca(2+ transient in response to isoprenaline when stimulated concomitantly with angiotensin II. CONCLUSION: The AT2 receptor affects postnatal cardiac growth possibly via reducing body weight gain and systemic blood pressure. Moreover, it moderately attenuates postnatal vascularization of the heart and modulates the beta adrenergic response of the neonatal heart. These AT2 receptor-mediated effects may be implicated in the physiological maturation process of the heart.

  5. Hematopoietic sphingosine 1-phosphate lyase deficiency decreases atherosclerotic lesion development in LDL-receptor deficient mice.

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    Martine Bot

    Full Text Available AIMS: Altered sphingosine 1-phosphate (S1P homeostasis and signaling is implicated in various inflammatory diseases including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we investigated the impact of hematopoietic S1P lyase (Sgpl1(-/- deficiency on leukocyte subsets relevant to atherosclerosis. METHODS AND RESULTS: LDL receptor deficient mice that were transplanted with Sgpl1(-/- bone marrow showed disrupted S1P gradients translating into lymphopenia and abrogated lymphocyte mitogenic and cytokine response as compared to controls. Remarkably however, Sgpl1(-/- chimeras displayed mild monocytosis, due to impeded stromal retention and myelopoiesis, and plasma cytokine and macrophage expression patterns, that were largely compatible with classical macrophage activation. Collectively these two phenotypic features of Sgpl1 deficiency culminated in diminished atherogenic response. CONCLUSIONS: Here we not only firmly establish the critical role of hematopoietic S1P lyase in controlling S1P levels and T cell trafficking in blood and lymphoid tissue, but also identify leukocyte Sgpl1 as critical factor in monocyte macrophage differentiation and function. Its, partly counterbalancing, pro- and anti-inflammatory activity spectrum imply that intervention in S1P lyase function in inflammatory disorders such as atherosclerosis should be considered with caution.

  6. Altered pupillary light reflex in PACAP receptor 1-deficient mice

    DEFF Research Database (Denmark)

    Engelund, Anna; Fahrenkrug, Jan; Harrison, Adrian Paul

    2012-01-01

    The pupillary light reflex (PLR) is regulated by the classical photoreceptors, rods and cones, and by intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin. IpRGCs receive input from rods and cones and project to the olivary pretectal nucleus (OPN......), which is the primary visual center involved in PLR. Mice lacking either the classical photoreceptors or melanopsin exhibit some changes in PLR, whereas the reflex is completely lost in mice deficient of all three photoreceptors. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP......) is co-stored with melanopsin in ipRGCs and mediates light signaling to the brain via the specific PACAP receptor 1 (PAC1R). Here, we examined the occurrence of PACAP and PAC1R in the mouse OPN, and studied if lack of PAC1R affected the PLR. PACAP-immunoreactive nerve fibers were shown in the mouse OPN...

  7. Insulin-degrading enzyme deficiency in bone marrow cells increases atherosclerosis in LDL receptor-deficient mice.

    Science.gov (United States)

    Caravaggio, Justin W; Hasu, Mirela; MacLaren, Robin; Thabet, Mohamed; Raizman, Joshua E; Veinot, John P; Marcel, Yves L; Milne, Ross W; Whitman, Stewart C

    2013-01-01

    Insulin-degrading enzyme (IDE), a protease implicated in several chronic diseases, associates with the cytoplasmic domain of the macrophage Type A scavenger receptor (SR-A). Our goal was to investigate the effect of IDE deficiency (Ide(-/-)) on diet-induced atherosclerosis in low density lipoprotein-deficient (Ldlr(-/-)) mice and on SR-A function. Irradiated Ldlr(-/-) or Ide(-/-)Ldlr(-/-) mice were reconstituted with wild-type or Ide(-/-) bone marrow and, 6 weeks later, were placed on a high-fat diet for 8 weeks. After 8 weeks on a high-fat diet, male Ldlr(-/-) recipients of Ide(-/-) bone marrow had more atherosclerosis, higher serum cholesterol and increased lesion-associated β-amyloid, an IDE substrate, and receptor for advanced glycation end products (RAGE), a proinflammatory receptor for β-amyloid, compared to male Ldlr(-/-) recipients of wild-type bone marrow. IDE deficiency in male Ldlr(-/-) recipient mice did not affect atherosclerosis or cholesterol levels and moderated the effects of IDE deficiency of bone marrow-derived cells. No differences were seen between Ldlr(-/-) and Ide(-/-)Ldlr(-/-) female mice reconstituted with Ide(-/-) or wild-type bone marrow. IDE deficiency in macrophages did not alter SR-A levels, cell surface SR-A, or foam cell formation. IDE deficiency in bone marrow-derived cells results in larger atherosclerotic lesions, increased lesion-associated Aβ and RAGE, and higher serum cholesterol in male, Ldlr(-/-) mice. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Toxicity of teriflunomide in aryl hydrocarbon receptor deficient mice.

    Science.gov (United States)

    Redaelli, Chiara; Gaffarogullari, Ece Cazibe; Brune, Maik; Pilz, Caroline; Becker, Simon; Sonner, Jana; Jäschke, Andres; Gröne, Hermann-Josef; Wick, Wolfgang; Platten, Michael; Lanz, Tobias Volker

    2015-12-01

    The intracellular transcription factor aryl hydrocarbon receptor (AHR) is bound and activated by xenobiotics, thereby promoting their catabolism by inducing expression of cytochrome P450 oxidase (CYP) genes through binding xenobiotic response elements (XRE) in their promoter region. In addition, it is involved in several cellular pathways like cell proliferation, differentiation, regeneration, tumor invasiveness and immune responses. Several pharmaceutical compounds like benzimidazoles activate the AHR and induce their own metabolic degradation. Using newly generated XRE-reporter mice, which allow in vivo bioluminescence imaging of AHR activation, we show here that the AHR is activated in vivo by teriflunomide (TER), which has recently been approved for the treatment of multiple sclerosis. While we did not find any evidence that the AHR mediates the immunomodulatory effects of TER, AHR activation led to metabolism and detoxification of teriflunomide, most likely via CYP. Mice deficient for the AHR show higher blood levels of teriflunomide, suffer from enhanced thrombo- and leukopenia and elevated liver enzymes as well as from severe gastrointestinal ulcers and bleeding which are lethal after 8-11 days of treatment. Leukopenia, acute liver damage and diarrhea have also been described as common side effects in human trials with TER. These data suggest that the AHR is relevant for detoxification not only of environmental toxins but also of drugs in clinical use, with potential implications for the application of AHR-modifying therapies in conjunction to TER in humans. The XRE-reporter mouse is a useful novel tool for monitoring AHR activation using in vivo imaging. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Increased vascular sympathetic modulation in mice with Mas receptor deficiency.

    Science.gov (United States)

    Rabello Casali, Karina; Ravizzoni Dartora, Daniela; Moura, Marina; Bertagnolli, Mariane; Bader, Michael; Haibara, Andrea; Alenina, Natalia; Irigoyen, Maria Claudia; Santos, Robson A

    2016-01-01

    The angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas axis could modulate the heart rate (HR) and blood pressure variabilities (BPV) which are important predictors of cardiovascular risk and provide information about the autonomic modulation of the cardiovascular system. Therefore we investigated the effect of Mas deficiency on autonomic modulation in wild type and Mas-knockout (KO) mice. Blood pressure was recorded at high sample rate (4000 Hz). Stationary sequences of 200-250 beats were randomly chosen. Frequency domain analysis of HR and BPV was performed with an autoregressive algorithm on the pulse interval sequences and on respective systolic sequences. The KO group presented an increase of systolic arterial pressure (SAP; 127.26±11.20 vs 135.07±6.98 mmHg), BPV (3.54±1.54 vs 5.87±2.12 mmHg(2)), and low-frequency component of systolic BPV (0.12±0.11 vs 0.47±0.34 mmHg(2)). The deletion of Mas receptor is associated with an increase of SAP and with an increased BPV, indicating alterations in autonomic control. Increase of sympathetic vascular modulation in absence of Mas evidences the important role of Ang-(1-7)/Mas on cardiovascular regulation. Moreover, the absence of significant changes in HR and HRV can indicate an adaptation of autonomic cardiac balance. Our results suggest that the Ang-(1-7)/Mas axis seems more important in autonomic modulation of arterial pressure than HR. © The Author(s) 2016.

  10. The significance of soluble transferrin receptors in diagnosing iron deficiency anemia

    Directory of Open Access Journals (Sweden)

    Tijanić Ivan

    2015-08-01

    Full Text Available Introduction. In recent years, determination of soluble transferrin receptor levels has been emerging as a test that can reliably indicate iron deficiency in various states, and that is non-invasive and easy to use. The aim of this study was: to determine reference values of soluble transferrin receptor concentrations in serums in our population, to examine the reliability of this method in the diagnosis of anemia due to iron deficiency and associated iron deficiency in anemia accompanying malignant hemopathies, and to identify possible limitations of the test in certain conditions.

  11. Serum transferrin receptor levels in the evaluation of iron deficiency in the neonate.

    Science.gov (United States)

    Rusia, U; Flowers, C; Madan, N; Agarwal, N; Sood, S K; Sikka, M

    1996-10-01

    Iron deficiency anemia (IDA) is a major global problem. Early onset of iron deficiency in developing countries makes it imperative to identify iron deficiency in neonates. Most conventional laboratory parameters of iron status fail to distinguish neonates with iron deficient erythropoiesis. Serum transferrin receptor (STFR) levels are a recent sensitive measure of iron deficiency and the present study was carried out to evaluate the usefulness of cord serum transferrin receptors in identifying iron deficient erythropoiesis in neonates. A complete hemogram, red cell indices, iron profile: serum iron (SI), percent transferrin saturation (TS%) and serum ferritin (SF) was carried out in 100 full-term neonates and their mothers at parturition. Cord and maternal STFR levels were estimated using a sensitive enzyme-linked immunosorbent assay (ELISA) technique. Anemic women had a significantly lower SI, their TS% and high STFR levels suggesting that iron deficiency was responsible for the anemia. In the neonates of iron deficient mothers, cord SI, TS% and cord ferritin were not significantly different from those of neonates born to non-anemic mothers. Cord STFR level correlated well with hemoglobin (Hb) and laboratory parameters of iron status, and its level was significantly higher in neonates born to anemic mothers than in those born to non-anemic mothers. It was the only laboratory parameter to differentiate between neonates born to anemic and non-anemic mothers. Therefore, STFR is a sensitive index of iron status in neonates and identifies neonates with iron deficient erythropoiesis.

  12. Toll-like receptor 2 or toll-like receptor 4 deficiency does not modify lupus in MRLlpr mice.

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    Simon J Freeley

    Full Text Available Systemic lupus erythematosus is an autoimmune disease with a high morbidity and nephritis is a common manifestation. Previous studies in murine lupus models have suggest a role for Toll-like receptor 2 and 4. We examined the role of these molecules in MRL lpr mice which is one of the most established and robust murine models. We compared disease parameters in Toll-like receptor 2 or Toll-like receptor 4 deficient mice with their littermate controls. We found no difference in the severity of glomerulonephritis as assessed by histology, serum creatinine and albuminuria when Toll-like receptor 2 or Toll-like receptor 4 deficient MRLlpr mice were compared with Toll-like receptor sufficient controls. We also found similar levels of anti-dsDNA and anti-ssDNA antibodies. These results show that Toll-like receptor 2 and Toll-like receptor 4 do not play a significant role in MRLlpr mice, and therefore they may not be important in human lupus.

  13. Methamphetamine increases locomotion and dopamine transporter activity in dopamine d5 receptor-deficient mice.

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    Seiji Hayashizaki

    Full Text Available Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behavioral response to methamphetamine. Interestingly, D5 dopamine receptor-deficient mice displayed increased ambulation in response to methamphetamine. Furthermore, dopamine transporter threonine phosphorylation levels, which regulate amphetamine-induced dopamine release, were elevated in D5 dopamine receptor-deficient mice. The increase in methamphetamine-induced locomotor activity was eliminated by pretreatment with the dopamine transporter blocker GBR12909. Taken together, these results suggest that dopamine transporter activity and threonine phosphorylation levels are regulated by D5 dopamine receptors.

  14. The assessment of frequency of iron deficiency in athletes from the transferrin receptor-ferritin index.

    Science.gov (United States)

    Malczewska, J; Szczepańska, B; Stupnicki, R; Sendecki, W

    2001-03-01

    The transferrin receptor-ferritin index (sTfR/logFerr) was determined in 131 male and 121 female athletes in order to assess the frequency of iron deficiency (threshold value of that index taken as 1.8). Blood was drawn for determining morphological indices as well as sTfR, ferritin, iron, total iron binding capacity (TIBC), and haptoglobin. A significantly (p iron deficiency was observed in women (26%) than in men (11%). The iron deficiency was latent, since no subject was found to be anemic. The plasma iron was significantly lower and TIBC higher (p iron-deficient subgroups than in the non-deficient ones. This confirmed the latent character of iron deficiency. Some hematological indices (Hb, MCH, MCHC, MCV) were significantly lower in iron-deficient female athletes than in male athletes, which suggested a more profound iron deficiency in the former. The sTfR/logFerr index might thus be useful in detecting iron deficiency in athletes, especially in those with erythropoiesis disorders, since physical loads may affect the widely used ferritin levels.

  15. Epithelial-microbial crosstalk in polymeric Ig receptor deficient mice

    NARCIS (Netherlands)

    Reikvam, D.H.; Derrien, M.M.N.; Islam, R.; Erofeev, A.; Grcic, V.; Sandvik, A.; Gaustad, P.; Meza-Zepeda, L.A.; Jahnsen, F.L.; Smidt, H.; Johansen, F.E.

    2012-01-01

    Innate and adaptive mucosal defense mechanisms ensure a homeostatic relationship with the large and complex mutualistic gut microbiota. Dimeric IgA and pentameric IgM are transported across the intestinal epithelium via the epithelial polymeric Ig receptor (pIgR) and provide a significant portion of

  16. Physiological roles revealed by ghrelin and ghrelin receptor deficient mice

    Science.gov (United States)

    Ghrelin is a hormone made in the stomach and known primarily for its growth hormone releasing and orexigenic properties. Nevertheless, ghrelin through its receptor, the GHS-R1a, has been shown to exert many roles including regulation of glucose homeostasis, memory & learning, food addiction and neur...

  17. A Milk-Free Diet Downregulates Folate Receptor Autoimmunity in Cerebral Folate Deficiency Syndrome

    Science.gov (United States)

    Ramaekers, Vincent T.; Sequeira, Jeffrey M.; Blau, Nenad; Quadros, Edward V.

    2008-01-01

    In cerebral folate deficiency syndrome, the presence of autoantibodies against the folate receptor (FR) explains decreased folate transport to the central nervous system and the clinical response to folinic acid. Autoantibody crossreactivity with milk FR from different species prompted us to test the effect of a milk-free diet. Intervention with a…

  18. Soluble transferrin receptor and immature reticulocytes are not useful for distinguishing iron-deficiency anemia from heterozygous beta-thalassemia

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    Gisélia Aparecida Freire Maia de Lima

    Full Text Available Iron deficiency and heterozygous beta-thalassemia are important causes of hypochromic-microcytic anemia. Two laboratory parameters are suggested for the differentiation of such anemia. High-fluorescence reticulocyte counts and soluble transferrin receptor levels were determined in iron-deficiency anemia patients (n = 49 and heterozygous beta-thalassemia patients (n = 43. There was no significant difference in high-fluorescence reticulocyte and soluble transferrin receptor values between the two groups, but a correlation was observed between high-fluorescence reticulocytes and soluble transferrin receptors in iron-deficiency anemia, probably due to increased receptor synthesis as a response to decreased iron content in erythrocytes.

  19. Deficiency of the GPR39 receptor is associated with obesity and altered adipocyte metabolism

    DEFF Research Database (Denmark)

    Petersen, Pia Steen; Jin, Chunyu; Madsen, Andreas Nygaard

    2011-01-01

    GPR39, a constitutively active 7TM receptor important for glucose-induced insulin secretion and maturation of pancreatic ß-cell function, is up-regulated in adipose tissue on abstinence from food and chemically induced diabetes. In the present study, we investigated the effect of GPR39 deficiency...... on body weight and adipocyte metabolism. GPR39-deficient mice were subjected to a high-fat diet and body composition, glucose tolerance, insulin secretion, food intake, and energy expenditure were evaluated. The cell biology of adipocyte metabolism was studied on both mRNA and protein levels....... A significant increase in body weight corresponding to a 2-fold selective increase in fat mass was observed in GPR39-deficient mice fed a high-fat diet as compared with wild-type littermate controls fed the same diet. The GPR39-deficient animals had similar food intake but displayed almost eliminated diet...

  20. Deficiencies

    Data.gov (United States)

    U.S. Department of Health & Human Services — A list of all deficiencies currently listed on Nursing Home Compare, including the nursing home that received the deficiency, the associated inspection date,...

  1. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis.

    Science.gov (United States)

    Zigmond, Ehud; Bernshtein, Biana; Friedlander, Gilgi; Walker, Catherine R; Yona, Simon; Kim, Ki-Wook; Brenner, Ori; Krauthgamer, Rita; Varol, Chen; Müller, Werner; Jung, Steffen

    2014-05-15

    Interleukin-10 (IL-10) is a pleiotropic anti-inflammatory cytokine produced and sensed by most hematopoietic cells. Genome-wide association studies and experimental animal models point at a central role of the IL-10 axis in inflammatory bowel diseases. Here we investigated the importance of intestinal macrophage production of IL-10 and their IL-10 exposure, as well as the existence of an IL-10-based autocrine regulatory loop in the gut. Specifically, we generated mice harboring IL-10 or IL-10 receptor (IL-10Rα) mutations in intestinal lamina propria-resident chemokine receptor CX3CR1-expressing macrophages. We found macrophage-derived IL-10 dispensable for gut homeostasis and maintenance of colonic T regulatory cells. In contrast, loss of IL-10 receptor expression impaired the critical conditioning of these monocyte-derived macrophages and resulted in spontaneous development of severe colitis. Collectively, our results highlight IL-10 as a critical homeostatic macrophage-conditioning agent in the colon and define intestinal CX3CR1(hi) macrophages as a decisive factor that determines gut health or inflammation. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Urethral dysfunction in female mice with estrogen receptor β deficiency.

    Directory of Open Access Journals (Sweden)

    Yung-Hsiang Chen

    Full Text Available Estrogen has various regulatory functions in the growth, development, and differentiation of the female urogenital system. This study investigated the roles of ERβ in stress urinary incontinence (SUI. Wild-type (ERβ(+/+ and knockout (ERβ(-/- female mice were generated (aged 6-8 weeks, n = 6 and urethral function and protein expression were measured. Leak point pressures (LPP and maximum urethral closure pressure (MUCP were assessed in mice under urethane anesthesia. After the measurements, the urethras were removed for proteomic analysis using label-free quantitative proteomics by nano-liquid chromatography-mass spectrometry (LC-MS/MS analysis. The interaction between these proteins was further analysed using MetaCore. Lastly, Western blot was used to confirm the candidate proteins. Compared with the ERβ(+/+ group, the LPP and MUCP values of the ERβ(-/- group were significantly decreased. Additionally, we identified 85 differentially expressed proteins in the urethra of ERβ(-/- female mice; 57 proteins were up-regulated and 28 were down-regulated. The majority of the ERβ knockout-modified proteins were involved in cell-matrix adhesion, metabolism, immune response, signal transduction, nuclear receptor translational regelation, and muscle contraction and development. Western blot confirmed the up-regulation of myosin and collagen in urethra. By contrast, elastin was down-regulated in the ERβ(-/- mice. This study is the first study to estimate protein expression changes in urethras from ERβ(-/- female mice. These changes could be related to the molecular mechanism of ERβ in SUI.

  3. Deficiencies in the CD40 and CD154 receptor-ligand system reduce experimental lung metastasis.

    Science.gov (United States)

    Ingersoll, Susan Blaydes; Langer, Florian; Walker, Jamie M; Meyer, Todd; Robson, Theresa; Amaya, Mildred; Desai, Hina; Francis, John L; Amirkhosravi, Ali

    2009-01-01

    It is established that experimental metastasis requires platelet activity. CD154 expressed on and released from activated platelets induces an inflammatory response in endothelial cells and monocytes, including tissue factor production. CD154 has also been shown to activate platelets in vitro and promote thrombus stability in vivo. These CD154 effects may be mediated, at least in part, by CD40 signaling on platelets and vascular endothelial cells. We have previously demonstrated prolonged bleeding and PFA-100 closure times in mice deficient for Cd154 or its receptor Cd40. In the present study, we hypothesized that Cd40 and Cd154 promote lung tumor formation in experimental metastasis in mice. We created mice doubly deficient in Cd40 and Cd154 (Dbl KO) and found them to be both fertile and viable. Injected tumor cells seeded poorly in mice deficient in Cd40 or Cd154, as well as Dbl KO, compared to wild-type mice. We sought to determine whether blood-borne Cd40 versus endothelial Cd40 contribute differentially to reduced experimental lung metastasis, as observed in Cd40 deficient mice. By bone marrow transplantation, we created mice deficient for Cd40 either in the blood compartment but not in the endothelium, or vice versa. We found that mice deficient in blood compartment Cd40 had fewer lung nodules compared to wild-type mice and mice deficient in endothelial Cd40. Our findings suggest an important contribution of the Cd40-Cd154 pathway to experimental lung metastasis. Furthermore, the data points to a selective role for peripheral blood cell Cd40 in this process.

  4. Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency.

    Science.gov (United States)

    Lam, Jameson R; Schneider, Jennifer L; Quesenberry, Charles P; Corley, Douglas A

    2017-03-01

    Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) suppress gastric acid production, which can inhibit iron absorption. However, few data exist regarding whether these medications increase the risk of clinical iron deficiency. A community-based case-control study evaluated the association between acid-suppressing medication use and the subsequent risk of iron deficiency. It contrasted 77,046 patients with new iron deficiency diagnoses (January 1999-December 2013), with 389,314 controls. Medication exposures, outcomes, and potential confounders used electronic databases. We excluded patients with pre-existing risk factors for iron deficiency. Associations were estimated using conditional logistic regression. Among cases, 2343 (3.0%) received a prior ≥2-year supply of PPIs and 1063 (1.4%) received H2RAs (without PPI use). Among controls, 3354 (0.9%) received a prior ≥2-year supply of PPIs and 2247 (0.6%) H2RAs. Both ≥2 years of PPIs (adjusted odds ratio, 2.49; 95% confidence interval, 2.35-2.64) and ≥2 years of H2RAs (odds ratio, 1.58; 95% CI, 1.46-1.71) were associated with an increased subsequent risk for iron deficiency. Among PPI users, the associations were stronger for higher daily doses (>1.5 vs 1.5 pills per day for at least 10 years (odds ratio, 4.27; 95% CI, 2.53-7.21). No similar strong associations were found for other commonly used prescription medications. Among patients without known risk factors for iron deficiency, gastric acid inhibitor use for ≥2 years was associated with an increased subsequent risk of iron deficiency. The risk increased with increasing potency of acid inhibition and decreased after medication discontinuation. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  5. [Learning and Memory Capacity and NMDA Receptor Expression in Shen Deficiency Constitution Rats].

    Science.gov (United States)

    Sun, Yu-ru; Sun, Yao-guang; Zhang, Qi; Wang, Xiao-di; Wang, Xing; Sun, Li-jun

    2016-05-01

    To explore material bases and neurobiological mechanisms of "Shen storing will" by observing learning and memory capacities and N-methyl-D-aspartic acid (NMDA) receptor expressions in Shen deficiency constitution (SDC) rats. Totally 40 SD rats were randomly divided into the model group, the Zuogui Pill (ZP) group, the Yougui Pill (YP) group, the blank control group (consisting of normal pregnant rats), 10 in each group. SDC young rat model (inherent deficiency and postnatal malnutrition) was prepared by the classic way of "cat scaring rat". Medication started when they were scared by cat. Rats in the ZP group and the YP group were administered by gastrogavage with ZP suspension 0.1875 g/mL and YP suspension 0.0938 g/mL respectively. Equal volume of normal saline was administered to rats in the blank control group and the model group by gastrogavage. All medication was given once per day, 5 days in a week for 2 consecutive months. Learning and memory capacities were detected by Morris water maze test. Expressions of NMDA receptor subunits NR2A and NR2B in hippocamus were detected by immunohistochemical method. Compared with the blank control group, the latency period, total distance in Morris water maze test were longer in the model group (P learning and memory capacities and lowered NMDA receptor expressions. ZP and YP could up-regulate learning and memory capacities and NMDA receptor expressions, thereby improving deterioration of brain functions in SDC rats.

  6. Resistance to diet-induced adiposity in cannabinoid receptor-1 deficient mice is not due to impaired adipocyte function

    NARCIS (Netherlands)

    Oosterveer, Maaike H.; Koolman, Anniek H.; de Boer, Pieter T.; Bos, Trijnie; Bleeker, Aycha; Bloks, Vincent W.; Kuipers, Folkert; Sauer, Pieter J. J.; van Dijk, Gertjan

    2011-01-01

    Background: Overactivity and/or dysregulation of the endocannabinoid system (ECS) contribute to development of obesity. In vitro studies indicate a regulatory role for the cannabinoid receptor 1 (CB1) in adipocyte function and CB1-receptor deficient (CB1-/-) mice are resistant to high fat

  7. Sweet taste receptor deficient mice have decreased adiposity and increased bone mass.

    Directory of Open Access Journals (Sweden)

    Becky R Simon

    Full Text Available Functional expression of sweet taste receptors (T1R2 and T1R3 has been reported in numerous metabolic tissues, including the gut, pancreas, and, more recently, in adipose tissue. It has been suggested that sweet taste receptors in these non-gustatory tissues may play a role in systemic energy balance and metabolism. Smaller adipose depots have been reported in T1R3 knockout mice on a high carbohydrate diet, and sweet taste receptors have been reported to regulate adipogenesis in vitro. To assess the potential contribution of sweet taste receptors to adipose tissue biology, we investigated the adipose tissue phenotypes of T1R2 and T1R3 knockout mice. Here we provide data to demonstrate that when fed an obesogenic diet, both T1R2 and T1R3 knockout mice have reduced adiposity and smaller adipocytes. Although a mild glucose intolerance was observed with T1R3 deficiency, other metabolic variables analyzed were similar between genotypes. In addition, food intake, respiratory quotient, oxygen consumption, and physical activity were unchanged in T1R2 knockout mice. Although T1R2 deficiency did not affect adipocyte number in peripheral adipose depots, the number of bone marrow adipocytes is significantly reduced in these knockout animals. Finally, we present data demonstrating that T1R2 and T1R3 knockout mice have increased cortical bone mass and trabecular remodeling. This report identifies novel functions for sweet taste receptors in the regulation of adipose and bone biology, and suggests that in these contexts, T1R2 and T1R3 are either dependent on each other for activity or have common independent effects in vivo.

  8. Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB₁ receptors: implications for schizophrenia.

    Science.gov (United States)

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-08-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB₁-dependent manner, whereas pharmacological blockade of CB₁ receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB₁ receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB₁-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB₁ receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

  9. Erythroblast transferrin receptors and transferrin kinetics in iron deficiency and various anemias

    Energy Technology Data Exchange (ETDEWEB)

    Muta, K.; Nishimura, J.; Ideguchi, H.; Umemura, T.; Ibayashi, H.

    1987-06-01

    To clarify the role of transferrin receptors in cases of altered iron metabolism in clinical pathological conditions, we studied: number of binding sites; affinity; and recycling kinetics of transferrin receptors on human erythroblasts. Since transferrin receptors are mainly present on erythroblasts, the number of surface transferrin receptors was determined by assay of binding of /sup 125/I-transferrin and the percentage of erythroblasts in bone marrow mononuclear cells. The number of binding sites on erythroblasts from patients with an iron deficiency anemia was significantly greater than in normal subjects. Among those with an aplastic anemia, hemolytic anemia, myelodysplastic syndrome, and polycythemia vera compared to normal subjects, there were no considerable differences in the numbers of binding sites. The dissociation constants (Kd) were measured using Scatchard analysis. The apparent Kd was unchanged (about 10 nmol/L) in patients and normal subjects. The kinetics of endocytosis and exocytosis of /sup 125/I-transferrin, examined by acid treatment, revealed no variations in recycling kinetics among the patients and normal subjects. These data suggest that iron uptake is regulated by modulation of the number of surface transferrin receptors, thereby reflecting the iron demand of the erythroblast.

  10. Abalation of Ghrelin receptor in leptin-deficient mice has paradoxical effects on glucose homeostasis compared to Ghrelin-abalated Leptin-deficient mice

    Science.gov (United States)

    Ghrelin is produced predominantly in stomach and is known to be the endogenous ligand of the growth hormone secretagogue receptor (GHSR). Ghrelin is a GH stimulator and an orexigenic hormone. In contrast, leptin is an anorexic hormone, and leptin-deficient ob/ob mice are obese and diabetic. To study...

  11. Obesity, diabetes and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency.

    Science.gov (United States)

    Guevara-Aguirre, Jaime; Rosenbloom, Arlan L

    2015-01-01

    Obesity with insulin-resistant diabetes and increased cancer risk is a global problem. We consider the alterations of metabolism attendant on the underlying pathogenic overnutrition and the role of the growth hormone (GH)-IGF-1 axis in this interaction. Obesity-induced insulin resistance is a determinant of diabetes. Excess glucose, and an elevated concentration of insulin acting through its own receptors along with complex interactions with the IGF-1 system, will add extra fuel and fuel signalling for malignant growth and induce anti-apoptotic activities, permitting proliferation of forbidden clones. In Ecuador there are ~100 living adults with lifelong IGF-1 deficiency caused by a GH receptor (GHR) mutation who, despite a high percentage of body fat, have markedly increased insulin sensitivity compared with age- and BMI-matched control relatives, and no instances of diabetes, which is present in 6% of unaffected relatives. Only 1 of 20 deceased individuals with GHR deficiency died of cancer vs 20% of ~1,500 relatives. Fewer DNA breaks and increased apoptosis occurred in cell cultures exposed to oxidant agents following addition of serum from GHR-deficient individuals vs serum from control relatives. These changes were reversible by adding IGF-1 to the serum from the GHR-deficient individuals. The reduction in central regulators of pro-ageing signalling thus appears to be the result of an absence of GHR function. The complex inter-relationship of obesity, diabetes and cancer risk is related to excess insulin and fuel supply, in the presence of heightened anti-apoptosis and uninhibited DNA damage when GHR function is normal.

  12. Mutations in Prokineticin 2 and Prokineticin receptor 2genes in Human Gonadotrophin-Releasing Hormone Deficiency: Molecular Genetics and Clinical Spectrum

    OpenAIRE

    Cole, Lindsay W.; Sidis, Yisrael; Zhang, Chengkang; Quinton, Richard; Plummer, Lacey; Pignatelli, Duarte; Hughes, Virginia A.; Dwyer, Andrew A.; Raivio, Taneli; Hayes, Frances J.; Seminara, Stephanie B.; Huot, Celine; Alos, Nathalie; Speiser, Phyllis; Takeshita, Akira

    2008-01-01

    Context: Mice deficient in prokineticin 2(PROK2) and prokineticin receptor2 (PROKR2) exhibit variable olfactory bulb dysgenesis and GnRH neuronal migration defects reminiscent of human GnRH deficiency.

  13. Accumulation of glycated proteins suggesting premature ageing in lamin B receptor deficient mice.

    Science.gov (United States)

    Hause, Frank; Schlote, Dietmar; Simm, Andreas; Hoffmann, Katrin; Santos, Alexander Navarrete

    2017-10-28

    Accumulation of advanced glycation end products (AGEs) is accompanied by increased free radical activity which contributes to ageing and the development or worsening of degenerative diseases. Apart from other physiological factors, AGEs are also an important biomarker for premature ageing. Here we report protein modifications (glycation) in a mouse model of lamin B receptor deficient ic J /ic J mice displaying skin defects similar to those of classical progeria. Therefore, we analysed AGE-modifications in protein extracts from various tissues of ic J /ic J mice. Our results demonstrated that pentosidine as well as argpyrimidine were increased in ic J /ic J mice indicating a modification specific increase in biomarkers of ageing, especially derived from glycolysis dependent methylglyoxal. Furthermore, the expression of AGE-preventing enzymes (Glo1, Fn3k) differed between ic J /ic J and control mice. The results indicate that not only lamin A but also the lamin B receptor may be involved in ageing processes.

  14. Mas receptor deficiency exacerbates lipopolysaccharide-induced cerebral and systemic inflammation in mice.

    Science.gov (United States)

    Oliveira-Lima, Onésia C; Pinto, Mauro C X; Duchene, Johan; Qadri, Fatimunnisa; Souza, Laura L; Alenina, Natalia; Bader, Michael; Santos, Robson A S; Carvalho-Tavares, Juliana

    2015-12-01

    Beyond the classical actions of the renin-angiotensin system on the regulation of cardiovascular homeostasis, several studies have shown its involvement in acute and chronic inflammation. The G protein-coupled receptor Mas is a functional binding site for the angiotensin-(1-7); however, its role in the immune system has not been fully elucidated. In this study, we evaluated the effect of genetic deletion of Mas receptor in lipopolysaccharide (LPS)-induced systemic and cerebral inflammation in mice. Inflammatory response was triggered in Mas deficient (Mas(-/-)) and C57BL/6 wild-type (WT) mice (8-12 weeks-old) by intraperitoneal injection of LPS (5 mg/kg). Mas(-/-) mice presented more intense hypothermia compared to WT mice 24 h after LPS injection. Systemically, the bone marrow of Mas(-/-) mice contained a lower number of neutrophils and monocytes 3 h and 24 h after LPS injection, respectively. The plasma levels of inflammatory mediators KC, MCP-1 and IL-10 were higher in Mas(-/-) mice 24 h after LPS injection in comparison to WT. In the brain, Mas(-/-) animals had a significant increase in the number of adherent leukocytes to the brain microvasculature compared to WT mice, as well as, increased number of monocytes and neutrophils recruited to the pia-mater. The elevated number of adherent leukocytes on brain microvasculature in Mas(-/-) mice was associated with increased expression of CD11b - the alpha-subunit of the Mac-1 integrin - in bone marrow neutrophils 3h after LPS injection, and with increased brain levels of chemoattractants KC, MIP-2 and MCP-1, 24 h later. In conclusion, we demonstrated that Mas receptor deficiency results in exacerbated inflammation in LPS-challenged mice, which suggest a potential role for the Mas receptor as a regulator of systemic and brain inflammatory response induced by LPS. Copyright © 2015 Elsevier GmbH. All rights reserved.

  15. Altered glucose homeostasis and hepatic function in obese mice deficient for both kinin receptor genes.

    Directory of Open Access Journals (Sweden)

    Carlos C Barros

    Full Text Available The Kallikrein-Kinin System (KKS has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM, we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO. Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM.

  16. Toll-like receptor 4 deficiency: Smaller infarcts, but nogain in function

    Directory of Open Access Journals (Sweden)

    Hoeft Andreas

    2007-06-01

    Full Text Available Abstract Backgound It has been reported that Toll-like receptor 4 (TLR4 deficiency reduces infarct size after myocardial ischemia/reperfusion (MI/R. However, measurement of MI/R injury was limited and did not include cardiac function. In a chronic closed-chest model we assessed whether cardiac function is preserved in TLR4-deficient mice (C3H/HeJ following MI/R, and whether myocardial and systemic cytokine expression differed compared to wild type (WT. Results Infarct size (IS in C3H/HeJ assessed by TTC staining after 60 min ischemia and 24h reperfusion was significantly smaller than in WT. Despite a smaller infarct size, echocardiography showed no functional difference between C3H/HeJ and WT. Left-ventricular developed pressure measured with a left-ventricular catheter was lower in C3H/HeJ (63.0 ± 4.2 mmHg vs. 77.9 ± 1.7 mmHg in WT, p Conclusion These results demonstrate that, although a mutant TLR4 signaling cascade reduces myocardial IS and serum cytokine levels, it does not preserve myocardial function. The change in inflammatory response, secondary to a non-functional TLR-4 receptor, may contribute to the observed dichotomy between infarct size and function in the TLR-4 mutant mouse.

  17. Granulocytic nuclear differentiation of lamin B receptor-deficient mouse EPRO cells.

    Science.gov (United States)

    Zwerger, Monika; Herrmann, Harald; Gaines, Peter; Olins, Ada L; Olins, Donald E

    2008-08-01

    Lamin B receptor (LBR) is an integral protein of the inner nuclear membrane. Recent studies have demonstrated that genetic deficiency of LBR during granulopoiesis results in hypolobulation of the mature neutrophil nucleus, as observed in human Pelger-Huët anomaly and mouse ichthyosis (ic). In this study, we utilized differentiated early promyelocytes (EPRO cells) that were derived from the bone marrow of homozygous and heterozygous ichthyosis mice to examine changes to the expression of nuclear envelope proteins and heterochromatin structure that result from deficient LBR expression. Wild-type (+/+), heterozygous (+/ic), and homozygous (ic/ic) granulocytic forms of EPRO cells were analyzed for the expression of multiple lamins and inner nuclear envelope proteins by immunostaining and immunoblotting techniques. The heterochromatin architecture was also examined by immunostaining for histone lysine methylation. Wild-type (+/+) and heterozygous (+/ic) granulocytic forms revealed ring-shaped nuclei and contained LBR within the nuclear envelope; ic/ic granulocytes exhibited smaller ovoid nuclei devoid of LBR. The pericentric heterochromatin of undifferentiated and granulocytic ic/ic cells was condensed into larger spots and shifted away from the nuclear envelope, compared to +/+ and +/ic cell forms. Lamin A/C, which is normally not present in mature granulocytes, was significantly elevated in LBR-deficient EPRO cells. Our observations suggest roles for LBR during granulopoiesis, which can involve augmenting nuclear membrane growth, facilitating compartmentalization of heterochromatin, and promoting downregulation of lamin A/C expression.

  18. Depletion of endothelial or smooth muscle cell-specific angiotensin II type 1a receptors does not influence aortic aneurysms or atherosclerosis in LDL receptor deficient mice.

    Directory of Open Access Journals (Sweden)

    Debra L Rateri

    Full Text Available Whole body genetic deletion of AT1a receptors in mice uniformly reduces hypercholesterolemia and angiotensin II-(AngII induced atherosclerosis and abdominal aortic aneurysms (AAAs. However, the role of AT1a receptor stimulation of principal cell types resident in the arterial wall remains undefined. Therefore, the aim of this study was to determine whether deletion of AT1a receptors in either endothelial cells or smooth muscle cells influences the development of atherosclerosis and AAAs.AT1a receptor floxed mice were developed in an LDL receptor -/- background. To generate endothelial or smooth muscle cell specific deficiency, AT1a receptor floxed mice were bred with mice expressing Cre under the control of either Tie2 or SM22, respectively. Groups of males and females were fed a saturated fat-enriched diet for 3 months to determine effects on atherosclerosis. Deletion of AT1a receptors in either endothelial or smooth muscle cells had no discernible effect on the size of atherosclerotic lesions. We also determined the effect of cell-specific AT1a receptor deficiency on atherosclerosis and AAAs using male mice fed a saturated fat-enriched diet and infused with AngII (1,000 ng/kg/min. Again, deletion of AT1a receptors in either endothelial or smooth muscle cells had no discernible effects on either AngII-induced atherosclerotic lesions or AAAs.Although previous studies have demonstrated whole body AT1a receptor deficiency diminishes atherosclerosis and AAAs, depletion of AT1a receptors in either endothelial or smooth muscle cells did not affect either of these vascular pathologies.

  19. Melanocortin 1 Receptor Deficiency Promotes Atherosclerosis in Apolipoprotein E-/-Mice.

    Science.gov (United States)

    Rinne, Petteri; Kadiri, James J; Velasco-Delgado, Mauricio; Nuutinen, Salla; Viitala, Miro; Hollmén, Maija; Rami, Martina; Savontaus, Eriika; Steffens, Sabine

    2018-02-01

    The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transporter subfamily G member 1). In this study, we aimed to investigate whether global deficiency in MC1-R signaling affects the development of atherosclerosis. Apoe -/- (apolipoprotein E deficient) mice were crossed with recessive yellow (Mc1r e/e ) mice carrying dysfunctional MC1-R and fed a high-fat diet to induce atherosclerosis. Apoe -/- Mc1r e/e mice developed significantly larger atherosclerotic lesions in the aortic sinus and in the whole aorta compared with Apoe -/- controls. In terms of plaque composition, MC1-R deficiency was associated with less collagen and smooth muscle cells and increased necrotic core, indicative of more vulnerable lesions. These changes were accompanied by reduced Abca1 and Abcg1 expression in the aorta. Furthermore, Apoe -/- Mc1r e/e mice showed a defect in bile acid metabolism that aggravated high-fat diet-induced hypercholesterolemia and hepatic lipid accumulation. Flow cytometric analysis of leukocyte profile revealed that dysfunctional MC1-R enhanced arterial accumulation of classical Ly6C high monocytes and macrophages, effects that were evident in mice fed a normal chow diet but not under high-fat diet conditions. In support of enhanced arterial recruitment of Ly6C high monocytes, these cells had increased expression of L-selectin and P-selectin glycoprotein ligand 1. The present study highlights the importance of MC1-R in the development of atherosclerosis. Deficiency in MC1-R signaling exacerbates atherosclerosis by disturbing cholesterol handling and by increasing arterial monocyte accumulation. © 2017 The Authors.

  20. Receptor-mediated transport of oligodeoxynucleotides into hepatic cells.

    Science.gov (United States)

    Reinis, M; Damková, M; Korec, E

    1993-04-01

    Receptor-mediated endocytosis was employed for a highly efficient transport of oligodeoxynucleotides into hepatoma cell line PLC/PRF/5. The oligodeoxynucleotides were bound to the asialofetuin-poly-L-lysine conjugate and this complex was internalized by the cells via asialoglycoprotein receptor, an endocytic receptor unique for hepatocytes. Binding of the oligodeoxynucleotides to the complex dramatically increased their cellular uptake more than 20-fold. Chloroquine, a lysosomatropic agent, further increased the transport of the complex but not of the free oligodeoxynucleotides.

  1. [Correlation between vitamin D receptor genetic polymorphism and 25-hydroxyvitamin D3 in vitamin D deficiency rickets].

    Science.gov (United States)

    Gong, Yi-Gu; Li, Yu-Ning; Zhang, Wei-Hua; Liu, Li-Jun; Kang, Xi-Guang

    2010-07-01

    To study the correlation between vitamin D receptor genetic polymorphism Fokand vitamin D deficiency rickets in children between 1 to 3 years old, and to explore the significance of hereditary factors in the development of vitamin D deficiency rickets. Sixty-two children with vitamin D deficiency rickets and 60 healthy children as a control group were enrolled. Serum levels of 25-hydroxyvitamin D3 were measured using ELISA. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genetic analysis method was used. A restriction fragment length polymorphism in the vitamin D receptor genetic polymorphism Fok I was tested. The frequencies of the vitamin D receptor genotype and allele were compared between the two groups. Serum 25-hydroxyvitamin D3 levels in the rickets group were significantly lower than those in the control group ( 9.1+/-4.1 ng/mL vs 16.1+/-6.9 ng/mL; Ppolymorphism Fok I was more common in the rickets group than in the control group (53% vs 25%; Ppolymorphism Fok I and vitamin D deficiency rickets. This suggests that vitamin D receptor genetic polymorphism might play an important role in determining susceptibility to development of vitamin D deficiency rickets.

  2. Protease-activated receptor 4 deficiency offers cardioprotection after acute ischemia reperfusion injury.

    Science.gov (United States)

    Kolpakov, Mikhail A; Rafiq, Khadija; Guo, Xinji; Hooshdaran, Bahman; Wang, Tao; Vlasenko, Liudmila; Bashkirova, Yulia V; Zhang, Xiaoxiao; Chen, Xiongwen; Iftikhar, Sahar; Libonati, Joseph R; Kunapuli, Satya P; Sabri, Abdelkarim

    2016-01-01

    Protease-activated receptor (PAR)4 is a low affinity thrombin receptor with less understood function relative to PAR1. PAR4 is involved in platelet activation and hemostasis, but its specific actions on myocyte growth and cardiac function remain unknown. This study examined the role of PAR4 deficiency on cardioprotection after myocardial ischemia-reperfusion (IR) injury in mice. When challenged by in vivo or ex vivo IR, PAR4 knockout (KO) mice exhibited increased tolerance to injury, which was manifest as reduced infarct size and a more robust functional recovery compared to wild-type mice. PAR4 KO mice also showed reduced cardiomyocyte apoptosis and putative signaling shifts in survival pathways in response to IR. Inhibition of PAR4 expression in isolated cardiomyocytes by shRNA offered protection against thrombin and PAR4-agonist peptide-induced apoptosis, while overexpression of wild-type PAR4 significantly enhanced the susceptibility of cardiomyocytes to apoptosis, even under low thrombin concentrations. Further studies implicate Src- and epidermal growth factor receptor-dependent activation of JNK on the proapoptotic effect of PAR4 in cardiomyocytes. These findings reveal a pivotal role for PAR4 as a regulator of cardiomyocyte survival and point to PAR4 inhibition as a therapeutic target offering cardioprotection after acute IR injury. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Excessive penile norepinephrine level underlies impaired erectile function in adenosine A1 receptor deficient mice.

    Science.gov (United States)

    Ning, Chen; Qi, Lin; Wen, Jiaming; Zhang, Yujin; Zhang, Weiru; Wang, Wei; Blackburn, Michael; Kellems, Rodney; Xia, Yang

    2012-10-01

    Penile erection is a complex neurovascular physiological event controlled by multiple factors and signaling pathways. A considerable amount of evidence indicates that adenosine plays a significant role in cavernosal smooth muscle relaxation. However, the specific role of adenosine and its receptors in erectile physiology and pathology is not fully understood. To determine the role of the adenosine A1 receptor (ADORA1) in penile erection. Adenosine A1 receptor deficient (Adora1-/-) mice and aged-matched wild-type (WT) mice were utilized. We evaluated the in vivo erectile function by measuring the intracavernosal pressure (ICP) in response to cavernous nerve stimulation (CNS). Enzyme-linked immunosorbent assay was used to measure the norepinephrine (NE) plasma concentration in the corpus cavernosum and systemic circulation. We also evaluated the myosin light chain phosphorylation (p-MLC) in penile tissue pre- and post-CNS. The main outcome measurement of this research was the evaluation of in vivo erectile response to CNS by measuring the ICP in Adora1-/- mice and WT mice and to identify the localization and specific neuron types of ADORA1 expression by dual immunostaining and immunofluorescence co-localization. In vivo, both the ratio of CNS-induced Maximum ICP to mean arterial pressure and CNS-induced slope in Adora1-/- mice were significantly lower than WT mice. At the cellular level in penile tissue, we determined that ADORA1 was highly abundant in neuronal cells. During penile erection, Adora1-/- mice exhibited a higher level of NE plasma concentration in the penis than WT mice. And WT mice had a significantly greater reduction in p-MLC compared to Adora1-/- mice. Our results show that ADORA1 is enriched on neuron cells where it functions to control NE release. Activation of this receptor during penile erection results in reduced NE release and reduced cavernosal smooth muscle contraction, therefore facilitating penile erection. © 2012 International Society for

  4. A common susceptibility factor of both autism and epilepsy: functional deficiency of GABA A receptors.

    Science.gov (United States)

    Kang, Jing-Qiong; Barnes, Gregory

    2013-01-01

    Autism and epilepsy are common childhood neurological disorders with a great heterogeneity of clinical phenotypes as well as risk factors. There is a high co-morbidity of autism and epilepsy. The neuropathology of autism and epilepsy has similar histology implicating the processes of neurogenesis, neural migration, programmed cell death, and neurite outgrowth. Genetic advances have identified multiple molecules that participate in neural development, brain network connectivity, and synaptic function which are involved in the pathogenesis of autism and epilepsy. Mutations in GABA(A) receptor subunit have been frequently associated with epilepsy, autism, and other neuropsychiatric disorders. In this paper, we address the hypothesis that functional deficiency of GABAergic signaling is a potential common molecular mechanism underpinning the co-morbidity of autism and epilepsy.

  5. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin induced cardiac injury in mice

    Directory of Open Access Journals (Sweden)

    Yousif Nasser

    2011-10-01

    Full Text Available Abstract Background Cardiac inflammation and generation of oxidative stress are known to contribute to trastuzumab (herceptin induced cardiac toxicity. Toll-like receptors (TLRs are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signaling, we investigated whether or not TLR4 is involved in trastuzumab induced cardiotoxicity. Methods Seven days after a single injection of herceptin (2 mg/kg; i.p., left ventricular pressure volume loops were measured in HeN compotent (TLR4+/+ and HeJ mutant (TLR4-/- treated with trastuzumab and control mice. Immunofluorescent staining for monocyte infiltration and analyses of plasma by (ELISAs for different chemokines including: MCP-1and tumor necrosis factor-α (TNF-α, Western immunoblotting assay for ICAM-1, and used troponin I for cardiac injury marker. Results Trastuzumab injection resulted in an impairment of left ventricular function in TLR-4 competent (HeN, in contrast TLR4-/- trastuzumab mice showed improved left ventricular function EF%, CO; p -/-; p -/-, marked reduction of myocardial troponin-I levels in TLR4-deficient mice. Data are presented as means ± SE; n = 8 in each group p Conclusions Treatment with trastuzumab induces an inflammatory response that contributes to myocardial tissue TLR4 mediates chemokine expression (TNF-α, MCP-1and ICAM-1, so in experimental animals TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in trastuzumab induced cardiomyopathy.

  6. A bovine papillomavirus-1 based vector restores the function of the low-density lipoprotein receptor in the receptor-deficient CHO-ldlA7 cell line

    Directory of Open Access Journals (Sweden)

    Ustav Mart

    2002-04-01

    Full Text Available Abstract Background The rationale of using bovine papillomavirus-1 (BPV-1 derived vectors in gene therapy protocols lies in their episomal maintenance at intermediate to high copy number, and stable, high-level expression of the gene products. We constructed the BPV-1 based vector harbouring the human low-density lipoprotein receptor (LDLR gene cDNA and tested its ability to restore the function of the LDLR in the receptor-deficient cell line CHO-ldlA7. Results The introduced vector p3.7LDL produced functionally active LDL receptors in the receptor-deficient cell line CHO-ldlA7 during the 32-week period of observation as determined by the internalisation assay with the labelled LDL particles. Conclusion Bovine papillomavirus type-1 (BPV-1-derived vectors could be suitable for gene therapy due to their episomal maintenance at intermediate to high copy number and stable, high-level expression of the gene products. The constructed BPV-1 based vector p3.7LDL produced functionally active LDL receptors in the LDLR-deficient cell line CHO-ldlA7 during the 32-week period of observation. In vivo experiments should reveal, whether 1–5% transfection efficiency obtained in the current work is sufficient to bring about detectable and clinically significant lowering of the amount of circulating LDL cholesterol particles.

  7. Role of PCSK9 and IDOL in the pathogenesis of acquired LDL receptor deficiency and hypercholesterolemia in nephrotic syndrome.

    Science.gov (United States)

    Liu, Shuman; Vaziri, Nosratola D

    2014-03-01

    Nephrotic syndrome (NS) leads to elevation of serum total and LDL cholesterol. This is largely due to impaired LDL clearance, which is caused by hepatic LDL receptor (LDLR) deficiency despite normal LDLR mRNA expression, pointing to a post-transcriptional process. The mechanism(s) by which NS causes LDLR deficiency is not known. By promoting degradation of LDLR, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and inducible degrader of the LDL receptor (IDOL) play a major role in post-translational regulation of LDLR. We, therefore, tested the hypothesis that LDLR deficiency despite its normal gene expression in NS may be due to upregulation of hepatic PCSK9 and IDOL. LDLR, IDOL and PCSK9 expressions and nuclear translocation of liver X receptor (LXR) that regulates IDOL expression were determined in the liver of rats with puromycin-induced NS and control (CTL) rats. Compared with the CTLs, the NS rats showed marked elevation of serum total and LDL cholesterol and a significant reduction in hepatic LDLR protein expression. This was accompanied by marked upregulation of hepatic PCSK9 and IDOL expressions and heightened LXR activation. LDLR deficiency, hypercholesterolemia and elevated plasma LDL in NS are associated with upregulation of PCSK9 and IDOL. Interventions targeting these pathways may be effective in the management of hypercholesterolemia and the associated cardiovascular and other complications of NS.

  8. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice.

    Science.gov (United States)

    Yousif, Nasser Ghaly; Al-Amran, Fadhil G

    2011-10-14

    Cardiac inflammation and generation of oxidative stress are known to contribute to trastuzumab (herceptin) induced cardiac toxicity. Toll-like receptors (TLRs) are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signaling, we investigated whether or not TLR4 is involved in trastuzumab induced cardiotoxicity. Seven days after a single injection of herceptin (2 mg/kg; i.p.), left ventricular pressure volume loops were measured in HeN compotent (TLR4+/+) and HeJ mutant (TLR4-/-) treated with trastuzumab and control mice. Immunofluorescent staining for monocyte infiltration and analyses of plasma by (ELISAs) for different chemokines including: MCP-1and tumor necrosis factor-α (TNF-α), Western immunoblotting assay for ICAM-1, and used troponin I for cardiac injury marker. Trastuzumab injection resulted in an impairment of left ventricular function in TLR-4 competent (HeN), in contrast TLR4-/- trastuzumab mice showed improved left ventricular function EF%, CO; p < 0.05, attenuation of mononuclear cell infiltration in TLR4 -/-; p < 0.05 vs.TLR-4 competent (HeN), reduced level of cytokines TNF-α, MCP-1 and ICAM-1 expression in TLR4-/-, marked reduction of myocardial troponin-I levels in TLR4-deficient mice. Data are presented as means ± SE; n = 8 in each group p < 0.05 vs.TLR-4 competent (HeN). Treatment with trastuzumab induces an inflammatory response that contributes to myocardial tissue TLR4 mediates chemokine expression (TNF-α, MCP-1and ICAM-1), so in experimental animals TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in trastuzumab induced cardiomyopathy.

  9. Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice

    NARCIS (Netherlands)

    Espirito Santo, S.M.S.; Rensen, P.C.N.; Goudriaan, J.R.; Bensadoun, A.; Bovenschen, N.; Voshol, P.J.; Havekes, L.M.; Vlijmen, B.J.M. van

    2005-01-01

    The very low density lipoprotein receptor (VLDLR), low density lipoprotein receptor (LDLR), and low density lipoprotein receptor-related protein (LRP) are the three main apolipoprotein E-recognizing endocytic receptors involved in the clearance of triglyceride (TG)-rich lipoproteins from plasma.

  10. Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1

    Science.gov (United States)

    Lelliott, Patrick M.; McMorran, Brendan J.; Foote, Simon J.

    2015-01-01

    The treatment of iron deficiency in areas of high malaria transmission is complicated by evidence which suggests that iron deficiency anemia protects against malaria, while iron supplementation increases malaria risk. Iron deficiency anemia results in an array of pathologies, including reduced systemic iron bioavailability and abnormal erythrocyte physiology; however, the mechanisms by which these pathologies influence malaria infection are not well defined. In the present study, the response to malaria infection was examined in a mutant mouse line, TfrcMRI24910, identified during an N-ethyl-N-nitrosourea (ENU) screen. This line carries a missense mutation in the gene for transferrin receptor 1 (TFR1). Heterozygous mice exhibited reduced erythrocyte volume and density, a phenotype consistent with dietary iron deficiency anemia. However, unlike the case in dietary deficiency, the erythrocyte half-life, mean corpuscular hemoglobin concentration, and intraerythrocytic ferritin content were unchanged. Systemic iron bioavailability was also unchanged, indicating that this mutation results in erythrocytic iron deficiency without significantly altering overall iron homeostasis. When infected with the rodent malaria parasite Plasmodium chabaudi adami, mice displayed increased parasitemia and succumbed to infection more quickly than their wild-type littermates. Transfusion of fluorescently labeled erythrocytes into malaria parasite-infected mice demonstrated an erythrocyte-autonomous enhanced survival of parasites within mutant erythrocytes. Together, these results indicate that TFR1 deficiency alters erythrocyte physiology in a way that is similar to dietary iron deficiency anemia, albeit to a lesser degree, and that this promotes intraerythrocytic parasite survival and an increased susceptibility to malaria in mice. These findings may have implications for the management of iron deficiency in the context of malaria. PMID:26303393

  11. In vivo neutralization of IL-6 receptors ameliorates gastrointestinal dysfunction in dystrophin-deficient mdx mice.

    Science.gov (United States)

    Manning, J; Buckley, M M; O'Halloran, K D; O'Malley, D

    2016-07-01

    Duchenne muscular dystrophy (DMD) is a fatal disease characterized by progressive deterioration and degeneration of striated muscle. A mutation resulting in the loss of dystrophin, a structural protein which protects cells from contraction-induced damage, underlies DMD pathophysiology. Damage to muscle fibers results in chronic inflammation and elevated levels of proinflammatory cytokines such as interleukin-6 (IL-6). However, loss of cellular dystrophin also affects neurons and smooth muscle in the gastrointestinal (GI) tract with complaints such as hypomotility, pseudo-obstruction, and constipation reported in DMD patients. Using dystrophin-deficient mdx mice, studies were carried out to examine colonic morphology and function compared with wild-type mice. Treatment with neutralizing IL-6 receptor antibodies (xIL-6R) and/or the corticotropin-releasing factor (CRF) 2 receptor agonist, urocortin 2 (uro2) was tested to determine if they ameliorated GI dysfunction in mdx mice. Mdx mice exhibited thickening of colonic smooth muscle layers and delayed stress-induced defecation. In organ bath studies, neurally mediated IL-6-evoked contractions were larger in mdx colons. In vivo treatment of mdx mice with xIL-6R normalized defecation rates and colon lengths. Uro2 treatment did not affect motility or morphology. The potentiated colonic contractile response to IL-6 was attenuated by treatment with xIL-6R. These findings confirm the importance of dystrophin in normal GI function and implicate IL-6 as an important regulator of GI motility in the mdx mouse. Inhibition of IL-6 signaling may offer a potential new therapeutic strategy for treating DMD-associated GI symptoms. © 2016 John Wiley & Sons Ltd.

  12. Emotional response in dopamine D2L receptor-deficient mice.

    Science.gov (United States)

    Hranilovic, Dubravka; Bucan, Maja; Wang, Yanyan

    2008-12-22

    The dopamine D2 receptor (D2R) system has been implicated in emotional processing which is often impaired in neuropsychiatric disorders. The long (D2L) and the short (D2S) isoforms of D2R are generated by alternative splicing of the same gene. To study differential roles of the two D2R isoforms, D2L-deficient mice (D2L-/-) expressing functional D2S were previously generated. In this study the contribution of D2L isoform to emotional response was investigated by examining behaviors that reflect emotionality (exploratory behavior, anxiety-like behavior and learned helplessness) in D2L-/- and (wild-type) WT mice. While the thigmotactic, locomotor and general components of anxiety in zero maze did not differ among the genotypes, D2L-/- mice displayed significantly lower level of exploration in a hole board and zero maze, and significantly higher increase in latency to escape from a foot-shock after the learned helplessness training, compared with WT mice. These results suggest that D2L may play a more prominent role than D2S in mediating emotional response, such as behavioral reactions to novelty and inescapable stress. Our findings contribute to a better understanding of the molecular and cellular mechanisms underlying emotional responses.

  13. The dual effect of cannabinoid receptor-1 deficiency on the murine postoperative ileus.

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    Yong-yu Li

    Full Text Available INTRODUCTION: Intestinal inflammatory responses play a critical role in the pathogenesis of postoperative ileus (POI. As cannabinoid receptor-1 (CB1 is involved in inhibiting gastrointestinal (GI motility and anti-inflammation, we aimed to explore its contribution to POI. METHODS: Experimental POI was induced in adult female CB1-deficient (CB1-/- mice and wild-type littermates (C57BL/6N by standardized small bowel manipulation. Twenty-four hours after surgery, GI transit was assessed by charcoal transport. FITC avidin, F4/80, and myeloperoxidase immunohistochemistry techniques were used to evaluate the inflammatory response in the muscularis of ileum and colon. Expressions of p38MAPK and its phosphorylated form (pp38 in the intestine were determined. Plasma levels of proinflammatory cytokines and chemokines were measured by ELISA as well. RESULTS: POI was characterized by decreased GI transit (p<0.01 and accompanied by a marked intestinal and systematic inflammatory response in wild-type and CB1-/- mice. Increased numbers of inflammatory cells, including macrophages, neutrophils, and mast cells were observed in the muscularis of ileum and colon (p<0.01, or p<0.05. Plasma levels of interleukin-6 (IL-6, cytokine-induced neutrophil chemoattractant-1 (CINC-1/KC, and monocyte chemoattractant protein-1 (MCP-1 were elevated (p<0.01, or p<0.05. Expression of p38 and pp38 increased in the intestine (p<0.01, or p<0.05. CB1-/- mice showed an increased inflammatory response during POI, especially the systemic inflammatory markers, such as IL-6, KC, CINC1, and pp38 expression were increased as compared to those in WT mice (p<0.05. CONCLUSIONS: Intestinal motility was inhibited during POI. In this condition, inhibition of motility did not seem to be altered by the absence of CB1 receptors, however, an increased inflammatory response was observed in CB1-/- mice. Hence, CB1 receptor activation rather than inhibition may reduce the inflammatory response in POI

  14. Megalin is a receptor for apolipoprotein M, and kidney-specific megalin-deficiency confers urinary excretion of apolipoprotein M

    DEFF Research Database (Denmark)

    Faber, Kirsten; Hvidberg, Vibeke; Moestrup, Søren K

    2006-01-01

    . In addition, apoM is expressed at high levels in the kidney tubule cells. In this study, we show that the multiligand receptor megalin, which is expressed in kidney proximal tubule cells, is a receptor for apoM and mediates its uptake in the kidney. To examine apoM binding to megalin, a recombinant apo....... To examine the importance of apoM binding by megalin in vivo, we analyzed mice with a tissue-specific deficiency of megalin in the kidney. Megalin deficiency was associated with pronounced urinary excretion of apoM, whereas apoM was not detected in normal mouse, human, or rat urine. Gel filtration analysis...... showed that the urinary apoM-containing particles were small and devoid of apoA-I. The results suggest that apoM binds to megalin and that megalin-mediated endocytosis in kidney proximal tubules prevents apoM excretion in the urine....

  15. Deficiency of Toll-like receptors 2, 3 or 4 extends life expectancy in Huntington’s disease mice

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    Kathleen Griffioen

    2018-01-01

    Full Text Available Huntington’s disease (HD, an autosomal dominant neurodegenerative disorder characterized by progressive striatal and cortical atrophy, has been strongly linked with neuroinflammation. Toll-like receptors, a family of innate immune receptors, are a major pathway for neuroinflammation with pleiotropic effects on neuronal plasticity and neurodevelopment. We assessed whether deficiency for TLRs 2, 3 or 4 affects life expectancy in the N171-82Q mouse model of HD. Our data indicate that homozygous TLRs 2 and 3 as well as heterozygous TLR4 deficiency significantly extends the life expectancy of HD mice. Our data suggest that multiple TLR pathways may be involved in the neuroinflammatory and degenerative processes during HD.

  16. Abnormalities in osteoclastogenesis and decreased tumorigenesis in mice deficient for ovarian cancer G protein-coupled receptor 1.

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    Hui Li

    2009-05-01

    Full Text Available Ovarian cancer G protein-coupled receptor 1 (OGR1 has been shown to be a proton sensing receptor in vitro. We have shown that OGR1 functions as a tumor metastasis suppressor gene when it is over-expressed in human prostate cancer cells in vivo. To examine the physiological functions of OGR1, we generated conditional OGR1 deficient mice by homologous recombination. OGR1 deficient mice were viable and upon gross-inspection appeared normal. Consistent with in vitro studies showing that OGR1 is involved in osteoclastogenesis, reduced osteoclasts were detected in OGR1 deficient mice. A pH-dependent osteoclasts survival effect was also observed. However, overall abnormality in the bones of these animals was not observed. In addition, melanoma cell tumorigenesis was significantly inhibited in OGR1 deficient mice. OGR1 deficient mice in the mixed background produced significantly less peritoneal macrophages when stimulated with thioglycolate. These macrophages also showed altered extracellular signal-regulated kinases (ERK activation and nitric oxide (NO production in response to lipopolysaccharide. OGR1-dependent pH responses assessed by cAMP production and cell survival in macrophages or brown fat cells were not observed, presumably due to the presence of other proton sensing receptors in these cells. Our results indicate that OGR1's role in osteoclastogenesis is not strong enough to affect overall bone development and its role in tumorigenesis warrants further investigation. The mice generated can be potentially used for several disease models, including cancers or osteoclast-related diseases.

  17. Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

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    Wu, Weibin; Liu, Xijun; Peng, Xiaomin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Xue, Ruyi [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Ji, Lingling [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Shen, Xizhong [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Chen, She, E-mail: shechen@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhang, Si, E-mail: zhangsi@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China)

    2014-05-23

    Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR{sup −/−}) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR{sup −/−} mice fed MCD diet (FXR{sup −/−}/MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR{sup −/−}/MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR{sup −/−}/MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR{sup −/−}/MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection.

  18. Impaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice.

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    Philip L S M Gordts

    Full Text Available OBJECTIVE: Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1 dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE. METHODS AND RESULTS: LRP1 knock-in mice carrying an inactivating mutation in the NPxYxxL motif were crossed with apoE-deficient mice. In the absence of apoE, relative to LRP1 wild-type animals, LRP1 mutated mice showed an increased clearance of postprandial lipids despite a compromised LRP1 endocytosis rate and inefficient insulin-mediated translocation of the receptor to the plasma membrane, likely due to inefficient slow recycling of the mutated receptor. Postprandial lipoprotein improvement was explained by increased hepatic clearance of triglyceride-rich remnant lipoproteins and accompanied by a compensatory 1.6-fold upregulation of LDLR expression in hepatocytes. One year-old apoE-deficient mice having the dysfunctional LRP1 revealed a 3-fold decrease in spontaneous atherosclerosis development and a 2-fold reduction in LDL-cholesterol levels. CONCLUSION: These findings demonstrate that the NPxYxxL motif in LRP1 is important for insulin-mediated translocation and slow perinuclear endosomal recycling. These LRP1 impairments correlated with reduced atherogenesis and cholesterol levels in apoE-deficient mice, likely via compensatory LDLR upregulation.

  19. Temperature dependence of the sodium pump is altered in the cerebral cortex of CCK2 receptor-deficient mice.

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    Salum, T; Kõks, S; Kairane, C; Mahlapuu, R; Zilmer, M; Vasar, E

    2010-05-01

    Previously we have shown that the temperature dependence of the sodium pump (Na(+),K(+)-ATPase) is altered under different neuropathological conditions. In this study we compared temperature dependence of the Na(+),K(+)-ATPase in the fronto-parietal cortex of CCK(2) receptor-deficient (homo- and heterozygous) and normal (wild-type) mice. The Arrhenius plot for Na(+),K(+)-ATPase from wild-type brain is non-linear with a breakpoint at 20.3 +/- 0.4 degrees C. In case of the brain cell membrane of CCK(2) receptor-deficient mice (homo- and heterozygous) the breakpoint on Arrhenius plot was detected at 26.0 +/- 1.1 degrees C and 25.4 +/- 0.4 degrees C, respectively. The shift of the breakpoint on the Arrhenius plot established in CCK(2) receptor-deficiency as well as in case of some other pathological conditions confirms that such kind of alteration in the Na(+),K(+)-ATPase temperature dependence is likely related to the homeostatic adjustment of altered function of the sodium pump.

  20. Fractalkine receptor (CX3CR1 deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide

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    Kelley Keith W

    2010-12-01

    Full Text Available Abstract Background Interactions between fractalkine (CX3CL1 and fractalkine receptor (CX3CR1 regulate microglial activation in the CNS. Recent findings indicate that age-associated impairments in CX3CL1 and CX3CR1 are directly associated with exaggerated microglial activation and an impaired recovery from sickness behavior after peripheral injection of lipopolysaccharide (LPS. Therefore, the purpose of this study was to determine the extent to which an acute LPS injection causes amplified and prolonged microglial activation and behavioral deficits in CX3CR1-deficient mice (CX3CR1-/-. Methods CX3CR1-/- mice or control heterozygote mice (CX3CR1+/- were injected with LPS (0.5 mg/kg i.p. or saline and behavior (i.e., sickness and depression-like behavior, microglial activation, and markers of tryptophan metabolism were determined. All data were analyzed using Statistical Analysis Systems General Linear Model procedures and were subjected to one-, two-, or three-way ANOVA to determine significant main effects and interactions. Results LPS injection caused a prolonged duration of social withdrawal in CX3CR1-/- mice compared to control mice. This extended social withdrawal was associated with enhanced mRNA expression of IL-1β, indolamine 2,3-dioxygenase (IDO and kynurenine monooxygenase (KMO in microglia 4 h after LPS. Moreover, elevated expression of IL-1β and CD14 was still detected in microglia of CX3CR1-/- mice 24 h after LPS. There was also increased turnover of tryptophan, serotonin, and dopamine in the brain 24 h after LPS, but these increases were independent of CX3CR1 expression. When submitted to the tail suspension test 48 and 72 h after LPS, an increased duration of immobility was evident only in CX3CR1-/- mice. This depression-like behavior in CX3CR1-/- mice was associated with a persistent activated microglial phenotype in the hippocampus and prefrontal cortex. Conclusions Taken together, these data indicate that a deficiency of CX3CR1

  1. Tumor necrosis factor (TNF) ligand and TNF receptor deficiency affects sleep and the sleep EEG.

    Science.gov (United States)

    Deboer, Tom; Fontana, Adriano; Tobler, Irene

    2002-08-01

    Tumor necrosis factor (TNF) and lymphotoxin-alpha (LT-alpha) are proinflammatory cytokines involved in host defense and pathogenesis of various diseases. In addition, there is evidence that TNF is involved in sleep. TNF and LT-alpha both bind to the tumor necrosis factor receptors (TNFR). Recently, it was shown that TNF receptor 1 (TNFR1) knockout mice (R1KO) sleep less during the light period than controls. We investigated the effect of a TNF and LT-alpha double deficiency on sleep in mice (Ligand KO) and compared their sleep with that of R1KO, TNFR2 knockout (R2KO) mice, and wild-type (WT) controls. All mice were adapted to a 12:12 h light:dark cycle and their electroencephalographs (EEG) and electromyographs (EMG) were continuously recorded during a baseline day, 6-h sleep deprivation (SD), and 18-h recovery. Ligand KO and R2KO had 15% less rapid eye movement (REM) sleep during the baseline light period due to a reduction in REM sleep episode frequency. After SD, all genotypes showed an initial increase in slow-wave activity (SWA) (EEG power density between 0.75 and 4.0 Hz) in non-REM sleep, which gradually declined in the following hours. In Ligand KO the increase was mainly caused by an increase in fast SWA (2.75-4.0 Hz), which was also increased in R2KO. In contrast, in R1KO mice the increase was limited to the slow portion of SWA (0.75-2.5 Hz). R2KO and WT mice showed increases in both frequency ranges. The sub-division into fast and slow SWA frequencies corresponds to previous electrophysiological data where the two types of slow-waves were induced by either excitatory or inhibitory stimuli. Our data suggest that in Ligand KO the SWA increase is caused by an increase in excitatory input to the cortex, whereas in R1KO this input seems to be almost absent.

  2. Effects of high affinity leptin antagonist on prolactin receptor deficient male mouse.

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    Nadège Carré

    Full Text Available Hyperprolactinemia occurs during gestation and lactation with marked hyperphagia associated with leptin resistance. Prolactin (PRL induces the expression of orexigenic neuropeptide Y (NPY in hypothalamic dorsomedial nucleus (DMH leading to hyperphagia. Along this line prolactin receptor deficient (PRLR-/- mice are resistant to obesity under high fat diet due to increased energy expenditure. As these mice have an altered food intake, our objective was to test whether leptin is responsible for these characteristics. PRLR-/- male mice and control littermates were injected subcutaneously every other day with 12 mg/kg pegylated superactive mouse leptin antagonist (PEG-SMLA for 3 weeks. We tested the effect of PEG-SMLA on body weight, food intake and metabolic parameters. The antagonist led to a rapid increase in body weight (20% but increased adipose mass in PEG-SMLA treated mice was less pronounced in PRLR-/- than in WT mice. Food intake of PEG-SMLA-injected animals increased during the first week period of the experiment but then declined to a similar level of the control animals during the second week. Interestingly, PRLR-/- mice were found to have the same bone volume than those of control mice although PEG-SMLA increased bone mass by 7% in both strains. In addition, PEG-SMLA led to insulin resistance and glucose intolerance as well as an altered lipid profile in treated mice. Altogether, these results suggest that PRLR-/- mice respond to leptin antagonist similarly to the control mice, indicating no interaction between the actions of the two hormones.

  3. Impaired glucose and lipid metabolism in ageing aryl hydrocarbon receptor deficient mice

    Science.gov (United States)

    Biljes, Daniel; Hammerschmidt-Kamper, Christiane; Kadow, Stephanie; Diel, Patrick; Weigt, Carmen; Burkart, Volker; Esser, Charlotte

    2015-01-01

    Disturbed homeostasis of glucose and lipid metabolism are dominant features of the so-called metabolic syndrome (MetS) and can increase the risk for the development of type 2 diabetes (T2D), a severe metabolic disease. T2D prevalence increases with age. The aryl hydrocarbon receptor (AHR) is a sensor of small molecules including dietary components. AHR has been identified as potential regulator of glucose homeostasis and lipid metabolism. Epidemiologically, exposure to xenobiotic AHR ligands such as polycyclic aromatic hydrocarbons is linked to T2D. We assess here the potential role of the AHR in disturbances of glucose and lipid metabolism in young (age 2-5 months) and old (age > 1,5 years) AHR-deficient (AHR KO) mice. Fasted young wildtype (WT) and AHR-KO mice displayed similar blood glucose kinetics after challenge with intra-peritoneal glucose injection. However, old AHR-KO mice showed lower tolerance than WT to i.p. administered glucose, i.e. glucose levels rose higher and returned more slowly to normal levels. Old mice had overall higher insulin levels than young mice, and old AHR-KO had a somewhat disturbed insulin kinetic in the serum after glucose challenge. Surprisingly, young AHR-KO mice had significantly lower triglycerides, cholesterol, high density lipoprotein values than WT, i.e., a dyslipidemic profile. With ageing, AHR-KO and WT mice did not differ in these lipid levels, except for slightly reduced levels of triglycerides and cholesterol. In conclusion, our findings in AHR KO mice suggest that AHR expression is relevant for the maintenance of glucose and lipid homeostasis in old mice. PMID:26664351

  4. Oats (Avena sativa) reduce atherogenesis in LDL-receptor-deficient mice.

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    Andersson, K E; Svedberg, K A; Lindholm, M W; Oste, R; Hellstrand, P

    2010-09-01

    The cholesterol-lowering properties of oats, largely ascribed to its contents of soluble fibers, beta-glucans, are well established, whereas effects on atherogenesis are less well elucidated. Oats also contains components with reported antioxidant and anti-inflammatory effects that may affect atherogenesis. In this work we examined effects of oat bran on plasma cholesterol, markers of inflammation, eNOS expression and development of atherosclerosis in LDL-receptor-deficient (LDLr(-/-)) mice. Female LDLr(-/-) mice were fed Western diet+/-oat bran. Two concentrations of oat bran (40 and 27%) were compared regarding effects on plasma lipids. There was a dose-dependent reduction of plasma cholesterol by 42 and 20% with 40 and 27% oat bran, respectively. Both concentrations also lowered plasma triglycerides (by 45 and 33%) and relative levels of plasma LDL+VLDL. The reduction of plasma lipids was accompanied by increased faecal excretion of cholesterol and bile acids. Oat bran (40%) efficiently reduced atherosclerotic lesion area in the descending aorta (-77%) and aortic root (-33%). Plasma levels of fibrinogen and soluble vascular cell adhesion molecule-1 (VCAM-1) were significantly lower, and immunofluorescence of aortic sections revealed a 75% lower expression of VCAM-1 in oat-fed mice. The expression of eNOS protein in the aortic wall was increased in mice fed oat bran. Oat bran supplemented to a Western diet lowers plasma cholesterol, reduces levels of some inflammatory markers, increases eNOS expression and inhibits atherosclerotic lesion development in LDLr(-/-) mice. It remains to be investigated which components in oats contribute to these effects. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  5. C5a receptor deficiency alters energy utilization and fat storage.

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    Christian Roy

    Full Text Available To investigate the impact of whole body C5a receptor (C5aR deficiency on energy metabolism and fat storage.Male wildtype (WT and C5aR knockout (C5aRKO mice were fed a low fat (CHOW or a high fat high sucrose diet-induced obesity (DIO diet for 14 weeks. Body weight and food intake were measured weekly. Indirect calorimetry, dietary fatload clearance, insulin and glucose tolerance tests were also evaluated. Liver, muscle and adipose tissue mRNA gene expression were measured by RT-PCR.At week one and 12, C5aRKO mice on DIO had increased oxygen consumption. After 12 weeks, although food intake was comparable, C5aRKO mice had lower body weight (-7% CHOW, -12% DIO as well as smaller gonadal (-38% CHOW, -36% DIO and inguinal (-29% CHOW, -30% DIO fat pads than their WT counterparts. Conversely, in WT mice, C5aR was upregulated in DIO vs CHOW diets in gonadal adipose tissue, muscle and liver, while C5L2 mRNA expression was lower in C5aRKO on both diet. Furthermore, blood analysis showed lower plasma triglyceride and non-esterified fatty acid levels in both C5aRKO groups, with faster postprandial triglyceride clearance after a fatload. Additionally, C5aRKO mice showed lower CD36 expression in gonadal and muscle on both diets, while DGAT1 expression was higher in gonadal (CHOW and liver (CHOW and DIO and PPARγ was increased in muscle and liver.These observations point towards a role (either direct or indirect for C5aR in energy expenditure and fat storage, suggesting a dual role for C5aR in metabolism as well as in immunity.

  6. Postprandial fatty acid uptake and adipocyte remodeling in angiotensin type 2 receptor-deficient mice fed a high-fat/high-fructose diet.

    Science.gov (United States)

    Noll, Christophe; Labbé, Sébastien M; Pinard, Sandra; Shum, Michael; Bilodeau, Lyne; Chouinard, Lucie; Phoenix, Serge; Lecomte, Roger; Carpentier, André C; Gallo-Payet, Nicole

    2016-01-01

    The role of the angiotensin type-2 receptor in adipose physiology remains controversial. The aim of the present study was to demonstrate whether genetic angiotensin type-2 receptor-deficiency prevents or worsens metabolic and adipose tissue morphometric changes observed following a 6-week high-fat/high-fructose diet with injection of a small dose of streptozotocin. We compared tissue uptake of nonesterified fatty acid and dietary fatty acid in wild-type and angiotensin type-2 receptor-deficient mice by using the radiotracer 14(R,S)-[(1) (8)F]-fluoro-6-thia-heptadecanoic acid in mice fed a standard or high-fat diet. Postprandial fatty acid uptake in the heart, liver, skeletal muscle, kidney and adipose tissue was increased in wild-type mice after a high-fat diet and in angiotensin type-2 receptor-deficient mice on both standard and high-fat diets. Compared to the wild-type mice, angiotensin type-2 receptor-deficient mice had a lower body weight, an increase in fasting blood glucose and a decrease in plasma insulin and leptin levels. Mice fed a high-fat diet exhibited increased adipocyte size that was prevented by angiotensin type-2 receptor-deficiency. Angiotensin type-2 receptor-deficiency abolished the early hypertrophic adipocyte remodeling induced by a high-fat diet. The small size of adipocytes in the angiotensin type-2 receptor-deficient mice reflects their inability to store lipids and explains the increase in fatty acid uptake in non-adipose tissues. In conclusion, a genetic deletion of the angiotensin type-2 receptor is associated with metabolic dysfunction of white adipose depots, and indicates that adipocyte remodeling occurs before the onset of insulin resistance in the high-fat fed mouse model.

  7. Leptin Increases Striatal Dopamine D2 Receptor Binding in Leptin-Deficient Obese (ob/ob) Mice

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    Pfaffly, J.; Michaelides, M.; Wang, G-J.; Pessin, J.E.; Volkow, N.D.; Thanos, P.K.

    2010-06-01

    Peripheral and central leptin administration have been shown to mediate central dopamine (DA) signaling. Leptin-receptor deficient rodents show decreased DA D2 receptor (D2R) binding in striatum and unique DA profiles compared to controls. Leptin-deficient mice show increased DA activity in reward-related brain regions. The objective of this study was to examine whether basal D2R-binding differences contribute to the phenotypic behaviors of leptin-deficient ob/ob mice, and whether D2R binding is altered in response to peripheral leptin treatment in these mice. Leptin decreased body weight, food intake, and plasma insulin concentration in ob/ob mice but not in wild-type mice. Basal striatal D2R binding (measured with autoradiography [{sup 3}H] spiperone) did not differ between ob/ob and wild-type mice but the response to leptin did. In wild-type mice, leptin decreased striatal D2R binding, whereas, in ob/ob mice, leptin increased D2R binding. Our findings provide further evidence that leptin modulates D2R expression in striatum and that these effects are genotype/phenotype dependent.

  8. P2X7 receptor-deficient mice are susceptible to bone cancer pain

    DEFF Research Database (Denmark)

    Hansen, RR; Nielsen, CK; Nasser, A

    2011-01-01

    The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice ...

  9. Validity of leptin receptor-deficiency (db/db) type 2 diabetes mellitus mice as a model of secondary osteoporosis

    Science.gov (United States)

    Huang, Le; You, Yong-Ke; Zhu, Tracy Y.; Zheng, Li-Zhen; Huang, Xiao-Ru; Chen, Hai-Yong; Yao, Dong; Lan, Hui-Yao; Qin, Ling

    2016-06-01

    This study aimed to evaluate the validation of the leptin receptor-deficient mice model for secondary osteoporosis associated with type 2 diabetes mellitus (T2DM) at bone micro-architectural level. Thirty three 36-week old male mice were divided into four groups: normal control (db/m) (n = 7), leptin receptor-deficient T2DM (db/db) (n = 8), human C-reactive protein (CRP) transgenic normal control (crp/db/m) (n = 7), and human CRP transgenic T2DM (crp/db/db) (n = 11). Lumber vertebrae (L5) and bilateral lower limbs were scanned by micro-CT to analyze trabecular and cortical bone quality. Right femora were used for three-point bending to analyze the mechanical properties. Trabecular bone quality at L5 was better in db/db or crp/db/db group in terms of bone mineral density (BMD), bone volume fraction, connectivity density, trabecular number and separation (all p  0.05). Maximum loading and energy yield in mechanical test were similar among groups while the elastic modulus in db/db and crp/db/db significantly lower than db/m. The leptin-receptor mice is not a proper model for secondary osteoporosis associated with T2DM.

  10. Nicotine Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice by Activating α7 Nicotinic Acetylcholine Receptor on Mast Cells.

    Science.gov (United States)

    Wang, Chen; Chen, Han; Zhu, Wei; Xu, Yinchuan; Liu, Mingfei; Zhu, Lianlian; Yang, Fan; Zhang, Ling; Liu, Xianbao; Zhong, Zhiwei; Zhao, Jing; Jiang, Jun; Xiang, Meixiang; Yu, Hong; Hu, Xinyang; Lu, Hong; Wang, Jian'an

    2017-01-01

    Cigarette smoking is an independent risk factor for atherosclerosis. Nicotine, the addictive component of cigarettes, induces mast cell (MC) release and contributes to atherogenesis. The purpose of this study was to determine whether nicotine accelerates atherosclerosis through MC-mediated mechanisms and whether MC stabilizer prevents this pathological process. Nicotine administration increased the size of atherosclerotic lesions in apolipoprotein E-deficient (Apoe-/-) mice fed a fat-enriched diet. This was accompanied by enhanced intraplaque macrophage content and lipid deposition but reduced collagen and smooth muscle cell contents. MC deficiency in Apoe-/- mice (Apoe-/-KitW-sh/W-sh) diminished nicotine-induced atherosclerosis. Nicotine activated bone marrow-derived MCs in vitro, which was inhibited by a MC stabilizer disodium cromoglycate or a nonselective nicotinic acetylcholine receptor blocker mecamylamine. Further investigation revealed that α7 nicotinic acetylcholine receptor was a target for nicotine activation in MCs. Nicotine did not change atherosclerotic lesion size of Apoe-/-KitW-sh/W-sh mice reconstituted with MCs from Apoe-/-α7nAChR-/- animals. Activation of α7 nicotinic acetylcholine receptor on MCs is a mechanism by which nicotine enhances atherosclerosis. © 2016 American Heart Association, Inc.

  11. Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

    Science.gov (United States)

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-01-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB1-dependent manner, whereas pharmacological blockade of CB1 receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB1 receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB1-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB1 receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission. PMID:23563893

  12. Receptor-Interacting Protein Kinase 3 Deficiency Delays Cutaneous Wound Healing.

    Directory of Open Access Journals (Sweden)

    Andrew Godwin

    Full Text Available Wound healing consists of a complex, dynamic and overlapping process involving inflammation, proliferation and tissue remodeling. A better understanding of wound healing process at the molecular level is needed for the development of novel therapeutic strategies. Receptor-interacting protein kinase 3 (RIPK3 controls programmed necrosis in response to TNF-α during inflammation and has been shown to be highly induced during cutaneous wound repair. However, its role in wound healing remains to be demonstrated. To study this, we created dorsal cutaneous wounds on male wild-type (WT and RIPK3-deficient (Ripk3-/- mice. Wound area was measured daily until day 14 post-wound and skin tissues were collected from wound sites at various days for analysis. The wound healing rate in Ripk3-/- mice was slower than the WT mice over the 14-day course; especially, at day 7, the wound size in Ripk3-/- mice was 53% larger than that of WT mice. H&E and Masson-Trichrome staining analysis showed impaired quality of wound closure in Ripk3-/- wounds with delayed re-epithelialization and angiogenesis and defected granulation tissue formation and collagen deposition compared to WT. The neutrophil infiltration pattern was altered in Ripk3-/- wounds with less neutrophils at day 1 and more neutrophils at day 3. This altered pattern was also reflected in the differential expression of IL-6, KC, IL-1β and TNF-α between WT and Ripk3-/- wounds. MMP-9 protein expression was decreased with increased Timp-1 mRNA in the Ripk3-/- wounds compared to WT. The microvascular density along with the intensity and timing of induction of proangiogenic growth factors VEGF and TGF-β1 were also decreased or delayed in the Ripk3-/- wounds. Furthermore, mouse embryonic fibroblasts (MEFs from Ripk3-/- mice migrated less towards chemoattractants TGF-β1 and PDGF than MEFs from WT mice. These results clearly demonstrate that RIPK3 is an essential molecule to maintain the temporal manner of the

  13. Altered Rhythm of Adrenal Clock Genes, StAR and Serum Corticosterone in VIP Receptor 2-Deficient Mice

    DEFF Research Database (Denmark)

    Fahrenkrug, Jan; Georg, Birgitte; Hannibal, Jens

    2012-01-01

    RNA expression and serum corticosterone concentration. Double immunohistochemistry showed that the PER1 protein and StAR were co-localised in the same steroidogenic cells. Circulating corticosterone plays a role in the circadian timing system and the misaligned corticosterone rhythm in the VPAC2 receptor......The circadian time-keeping system consists of clocks in the suprachiasmatic nucleus (SCN) and in peripheral organs including an adrenal clock linked to the rhythmic corticosteroid production by regulating steroidogenic acute regulatory protein (StAR). Clock cells contain an autonomous molecular......) the adrenal Star mRNA and (3) the serum corticosterone concentration both during a light/dark (L/D) cycle and at constant darkness in wild type (WT) and VPAC2 receptor-deficient mice (VPAC2-KO). We also examined if PER1 and StAR were co-localised in the adrenal steroidogenic cells. Per1 and Bmal1 mRNA showed...

  14. Platelet-activating factor receptor-deficient mice are protected from experimental sleep apnea-induced learning deficits.

    Science.gov (United States)

    Row, Barry W; Kheirandish, Leila; Li, Richard C; Guo, Shang Z; Brittian, Kenneth R; Hardy, Mattie; Bazan, Nicolas G; Gozal, David

    2004-04-01

    Intermittent hypoxia (IH) during sleep, a hallmark of sleep apnea, is associated with neurobehavioral impairments, regional neurodegeneration and increased oxidative stress and inflammation in rodents. Platelet-activating factor (PAF) is an important mediator of both normal neural plasticity and brain injury. We report that mice deficient in the cell surface receptor for PAF (PAFR-/-), a bioactive mediator of oxidative stress and inflammation, are protected from the spatial reference learning deficits associated with IH. Furthermore, PAFR-/- exhibit attenuated elevations in inflammatory signaling (cyclo-oxygenase-2 and inducible nitric oxide synthase activities), degradation of the ubiquitin-proteasome pathway and apoptosis observed in wild-type littermates (PAFR+/+) exposed to IH. Collectively, these findings indicate that inflammatory signaling and neurobehavioral impairments induced by IH are mediated through PAF receptors.

  15. Effect of deficiency of tumor necrosis factor alpha or both of its receptors on Streptococcus pneumoniae central nervous system infection and peritonitis.

    Science.gov (United States)

    Wellmer, A; Gerber, J; Ragheb, J; Zysk, G; Kunst, T; Smirnov, A; Brück, W; Nau, R

    2001-11-01

    Tumor necrosis factor alpha (TNF-alpha) and TNF-beta are key mediators in bacterial inflammation. We therefore examined the role of TNF-alpha and its two receptors in murine pneumococcal central nervous system infection. TNF-alpha knockout mice and age- and sex-matched controls and TNF receptor (p55 and p75)-deficient mice and heterozygous littermates were infected intracerebrally with a Streptococcus pneumoniae type 3 strain. Mice were monitored until death or were killed 36 h after infection. Bacterial titers in blood, spleen, and brain homogenates were determined. Leukocyte infiltration and neuronal damage were assessed by histological scores. TNF-alpha-deficient mice died earlier than the controls after intracerebral infection although overall survival was similar. TNF-alpha deficiency did not inhibit leukocyte recruitment into the subarachnoid space and did not lead to an increased density of bacteria in brain homogenates. However, it caused a substantial rise of the concentration of S. pneumoniae cells in blood and spleen. Spleen bacterial titers were also increased in p55- and p75-deficient mice. TNF receptor-deficient mice showed decreased meningeal inflammation. Neuronal damage was not affected by either TNF-alpha or TNF receptor deficiency. In a murine model of pneumococcal peritonitis, 10(2) CFU of S. pneumoniae produced fatal peritonitis in TNF-alpha-deficient, but not wild-type, mice. Early leukocyte influx into the peritoneum was impaired in TNF-alpha-deficient mice. The lack of TNF-alpha or its receptors renders mice more susceptible to S. pneumoniae infections.

  16. Ectopic expression of retinoic acid receptors and change of myocardial structure in the offspring heart with vitamin A deficiency.

    Science.gov (United States)

    Feng, Yi; Yu, Ya-mei; Yin, Min-zhi; Hong, Li; Cai, Wei

    2012-01-01

    Vitamin A is a key micronutrient required during crucial stages of embryonic development and vitamin A deficiency (VAD) results in embryonic heart malformation. The pleiotropic functions of vitamin A are mediated by specific nuclear receptors: the retinoic acid receptors (RARα, -β, and -γ) and the retinoic X receptors (RXRα, -β, and -γ). The action of nuclear receptors has been implicated in controlling of cell proliferation, differentiation and apoptosis, and the expressions of these receptor genes are regulated by retinoic acid levels during the early stages of embryonic development. GATA-4 is one of the earliest transcription factors expressed in developing cardiac cells. However, the functional links of specific nuclear receptors to heart development in VAD embryos are not clearly understood. In our study, weaning female Sprague-Dawley rats were fed a modified diet containing different concentrations of vitamin A according to the American Institute of Nutrition 93 Growth Purified Diet. After 10-wk feeding, the female rats were mated with normal male rats, and a portion of them were transferred to a diet with enough added vitamin A for the pregnancy cycle. The embryo hearts were dissected out at embryonic day 13.5 (E13.5) to study the expression of RARs, RXRs and GATA-4. The embryo hearts from E18.5 were for observation of ultrastructural changes. In comparison to vitamin A supplemented groups, the embryo hearts from vitamin A insufficient groups exhibited ultrastructural changes and significantly lower expression of GATA-4, RARα, and -γ, and higher expression of RXRα and -β. Our findings suggest that the down-regulation of RARs and the up-regulation of RXRs resulted from VAD affected GATA-4 gene expression, which resulted in ultrastructural changes in embryo hearts due to maternal insufficiency of vitamin A during pregnancy.

  17. Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice

    NARCIS (Netherlands)

    Kritikou, E.; Puijvelde, van G.H.M.; Heijden, van der T.; Santbrink, van P.J.; Swart, M.; Schaftenaar, F.H.; Kroner, M.J.; Kuiper, J.; Bot, I.

    2016-01-01

    Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA

  18. Farnesoid X Receptor Deficiency Improves Glucose Homeostasis in Mouse Models of Obesity

    NARCIS (Netherlands)

    Prawitt, Janne; Abdelkarim, Mouaadh; Stroeve, Johanna H. M.; Popescu, Iuliana; Duez, Helene; Velagapudi, Vidya R.; Dumont, Julie; Bouchaert, Emmanuel; van Dijk, Theo H.; Lucas, Anthony; Dorchies, Emilie; Daoudi, Mehdi; Lestavel, Sophie; Gonzalez, Frank J.; Oresic, Matej; Cariou, Bertrand; Kuipers, Folkert; Caron, Sandrine; Staels, Bart

    OBJECTIVE-Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role

  19. Pycnogenol Reduces Toll-Like Receptor 4 Signaling Pathway-Mediated Atherosclerosis Formation in Apolipoprotein E-Deficient Mice.

    Science.gov (United States)

    Liu, Rui; Fan, Bin; Cong, Huiying; Ikuyama, Shoichiro; Guan, Haixia; Gu, Jianqiu

    2016-10-01

    Pycnogenol (PYC) is an extract from French maritime pine bark. Its antioxidative and anti-inflammatory effects have been shown to be beneficial for atherosclerosis. Here, we tested whether PYC could suppress high cholesterol and fat diet (HCD)-induced atherosclerosis formation in apolipoprotein E (apoE)-deficient mice. In our study, PYC suppressed oxidized low-density lipoprotein (ox-LDL)-induced lipid accumulation in peritoneal macrophages. Apolipoprotein E-deficient mice were orally administered PYC or a control solvent for ten weeks, and these mice were fed a standard diet or high cholesterol and fat diet during the latter eight weeks. Pycnogenol markedly decreased the size of atherosclerotic lesions induced by high cholesterol and fat diet compared with the nontreated controls. In addition, TLR4 expression in aortic sinus was stimulated by high cholesterol and fat diet feeding and was significantly reduced by PYC. A mechanistic analysis indicated that lipopolysaccharide (LPS) significantly increased expression of fatty acid binding protein (aP2) and macrophage scavenger receptor class A (SR-A), which were blocked by a JNK inhibitor. Furthermore, PYC inhibited the lipopolysaccharide-induced upregulation of aP2 and scavenger receptor class A via the JNK pathway. In conclusion, PYC administration effectively attenuates atherosclerosis through the TLR4-JNK pathway. Our results suggest that PYC could be a potential prophylaxis or treatment for atherosclerosis in humans.

  20. Vitamin D receptor deficiency and low vitamin D diet stimulate aortic calcification and osteogenic key factor expression in mice.

    Directory of Open Access Journals (Sweden)

    Nadine Schmidt

    Full Text Available Low levels of 25-hydroxy vitamin D (25(OHD are associated with cardiovascular diseases. Herein, we tested the hypothesis that vitamin D deficiency could be a causal factor in atherosclerotic vascular changes and vascular calcification. Aortic root sections of vitamin D receptor knockout (VDR(-/- mice that were stained for vascular calcification and immunostained for osteoblastic differentiation factors showed more calcified areas and a higher expression of the osteogenic key factors Msx2, Bmp2, and Runx2 than the wild-type mice (P<0.01. Data from LDL receptor knockout (LDLR(-/- mice that were fed western diet with either low (50 IU/kg, recommended (1,000 IU/kg, or high (10,000 IU/kg amounts of vitamin D(3 over 16 weeks revealed increasing plasma concentrations of 25(OHD (P<0.001 with increasing intake of vitamin D, whereas levels of calcium and phosphorus in plasma and femur were not influenced by the dietary treatment. Mice treated with the low vitamin D diet had more calcified lesions and a higher expression of Msx2, Bmp2, and Runx2 in aortic roots than mice fed recommended or high amounts of vitamin D (P<0.001. Taken together, these findings indicate vitamin D deficiency as a risk factor for aortic valve and aortic vessel calcification and a stimulator of osteogenic key factor expression in these vascular areas.

  1. Hypocretin Receptor Expression in Canine and Murine Narcolepsy Models and in Hypocretin-Ligand Deficient Human Narcolepsy

    Science.gov (United States)

    Mishima, Kazuo; Fujiki, Nobuhiro; Yoshida, Yasushi; Sakurai, Takeshi; Honda, Makoto; Mignot, Emmanuel; Nishino, Seiji

    2008-01-01

    Study Objective: To determine whether hypocretin receptor gene (hcrtR1 and hcrtR2) expression is affected after long-term hypocretin ligand loss in humans and animal models of narcolepsy. Design: Animal and human study. We measured hcrtR1 and hcrtR2 expression in the frontal cortex and pons using the RT-PCR method in murine models (8-week-old and 27-week-old orexin/ataxin-3 transgenic (TG) hypocretin cell ablated mice and wild-type mice from the same litter, 10 mice for each group), in canine models (8 genetically narcoleptic Dobermans with null mutations in the hcrtR2, 9 control Dobermans, 3 sporadic ligand-deficient narcoleptics, and 4 small breed controls), and in humans (5 narcolepsy-cataplexy patients with hypocretin deficiency (average age 77.0 years) and 5 control subjects (72.6 years). Measurement and Results: 27-week-old (but not 8-week-old) TG mice showed significant decreases in hcrtR1 expression, suggesting the influence of the long-term ligand loss on the receptor expression. Both sporadic narcoleptic dogs and human narcolepsy-cataplexy subjects showed a significant decrease in hcrtR1 expression, while declines in hcrtR2 expression were not significant in these cases. HcrtR2-mutated narcoleptic Dobermans (with normal ligand production) showed no alteration in hcrtR1 expression. Conclusions: Moderate declines in hcrtR expressions, possibly due to long-term postnatal loss of ligand production, were observed in hypocretin-ligand deficient narcoleptic subjects. These declines are not likely to be progressive and complete. The relative preservation of hcrtR2 expression also suggests that hypocretin based therapies are likely to be a viable therapeutic options in human narcolepsy-cataplexy. Citation: Mishima K; Fujiki N; Yoshida Y; Sakurai T; Honda M; Mignot E; Nishino S. Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. SLEEP 2008;31(8):1119-1126. PMID:18714784

  2. PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking.

    Science.gov (United States)

    Nakamura, Tsutomu; Arima-Yoshida, Fumiko; Sakaue, Fumika; Nasu-Nishimura, Yukiko; Takeda, Yasuko; Matsuura, Ken; Akshoomoff, Natacha; Mattson, Sarah N; Grossfeld, Paul D; Manabe, Toshiya; Akiyama, Tetsu

    2016-03-16

    Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface γ-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.

  3. Reduced lymphocyte longevity and homeostatic proliferation in lamin B receptor-deficient mice results in profound and progressive lymphopenia.

    Science.gov (United States)

    Verhagen, Anne M; de Graaf, Carolyn A; Baldwin, Tracey M; Goradia, Ankita; Collinge, Janelle E; Kile, Benjamin T; Metcalf, Donald; Starr, Robyn; Hilton, Douglas J

    2012-01-01

    The lamin B receptor (LBR) is a highly unusual inner nuclear membrane protein with multiple functions. Reduced levels are associated with decreased neutrophil lobularity, whereas complete absence of LBR results in severe skeletal dysplasia and in utero/perinatal lethality. We describe a mouse pedigree, Lym3, with normal bone marrow and thymic development but profound and progressive lymphopenia particularly within the T cell compartment. This defect arises from a point mutation within the Lbr gene with only trace mutant protein detectable in homozygotes, albeit sufficient for normal development. Reduced T cell homeostatic proliferative potential and life span in vivo were found to contribute to lymphopenia. To investigate the role of LBR in gene silencing in hematopoietic cells, we examined gene expression in wild-type and mutant lymph node CD8 T cells and bone marrow neutrophils. Although LBR deficiency had a very mild impact on gene expression overall, for common genes differentially expressed in both LBR-deficient CD8 T cells and neutrophils, gene upregulation prevailed, supporting a role for LBR in their suppression. In summary, this study demonstrates that LBR deficiency affects not only nuclear architecture but also proliferation, cell viability, and gene expression of hematopoietic cells.

  4. Ghrelin receptor deficiency does not affect diet-induced atherosclerosis in low-density lipoprotein receptor-null mice

    Directory of Open Access Journals (Sweden)

    Kirk M. Habegger

    2011-11-01

    Full Text Available Objective: Ghrelin, a stomach-derived, secreted peptide, and its receptor (growth hormone secretagogue receptor, GHSR are known to modulate food intake and energy homeostasis. The ghrelin system is also expressed broadly in cardiovascular tissues. Since ghrelin has been associated with anti-inflammatory and anti-atherogenic properties, but is also well known to promote obesity and impair glucose metabolism, we investigated whether ghrelin has any impact on the development of atherosclerosis. The hypothesis that endogenous ghrelin signaling may be involved in atherosclerosis has not been tested previously Methods and Results: We crossed ghrelin receptor knockout mice (GHSr-/- into a low-density lipoprotein receptor-null (Ldlr-/- mouse line. In this model, atherosclerotic lesions were promoted by feeding a high-fat, high-cholesterol Western-type diet for 13 months, following a standard protocol. Body composition and glucose homeostasis were similar between Ldlr-/- and Ldlr/GHSR -/- ko mice throughout the study. Absence or presence of GHSr did not alter the apolipoprotein profile changes in response to diet exposure on an LDLRko background. Atherosclerotic plaque volume in the aortic arch and thoracic aorta were also not affected differentially in mice without ghrelin signaling due to GHSR gene disruption as compared to control LDLRko littermates. In light of the associations reported for ghrelin with cardiovascular disease in humans, the lack of a phenotype in these loss-of- function studies in mice suggests no directly functional role for endogenous ghrelin in either the inhibition or the promotion of diet-induced atherosclerosis.Conclusions: These data indicate that, surprisingly, the complex and multifaceted actions of endogenous ghrelin signaling on the cardiovascular system have minimal direct impact on atherosclerotic plaque progression as based on loss-of-function in a mouse model of the disease.

  5. Intact attentional processing but abnormal responding in M1 muscarinic receptor-deficient mice using an automated touchscreen method.

    Science.gov (United States)

    Bartko, Susan J; Romberg, Carola; White, Benjamin; Wess, Jürgen; Bussey, Timothy J; Saksida, Lisa M

    2011-12-01

    Cholinergic receptors have been implicated in schizophrenia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. However, to better target therapeutically the appropriate receptor subsystems, we need to understand more about the functions of those subsystems. In the current series of experiments, we assessed the functional role of M(1) receptors in cognition by testing M(1) receptor-deficient mice (M1R(-/-)) on the five-choice serial reaction time test of attentional and response functions, carried out using a computer-automated touchscreen test system. In addition, we tested these mice on several tasks featuring learning, memory and perceptual challenges. An advantage of the touchscreen method is that each test in the battery is carried out in the same task setting, using the same types of stimuli, responses and feedback, thus providing a high level of control and task comparability. The surprising finding, given the predominance of the M(1) receptor in cortex, was the complete lack of effect of M(1) deletion on measures of attentional function per se. Moreover, M1R(-/-) mice performed relatively normally on tests of learning, memory and perception, although they were impaired in object recognition memory with, but not without an interposed delay interval. They did, however, show clear abnormalities on a variety of response measures: M1R(-/-) mice displayed fewer omissions, more premature responses, and increased perseverative responding compared to wild-types. These data suggest that M1R(-/-) mice display abnormal responding in the face of relatively preserved attention, learning and perception. Copyright © 2011 Elsevier Ltd. All rights reserved.

  6. Mas receptor deficiency is associated with worsening of lipid profile and severe hepatic steatosis in ApoE-knockout mice.

    Science.gov (United States)

    Silva, Analina R; Aguilar, Edenil C; Alvarez-Leite, Jacqueline I; da Silva, Rafaela F; Arantes, Rosa M E; Bader, Michael; Alenina, Natalia; Pelli, Graziano; Lenglet, Sébastien; Galan, Katia; Montecucco, Fabrizio; Mach, François; Santos, Sérgio H S; Santos, Robson A S

    2013-12-01

    The classical renin-angiotensin system pathway has been recently updated with the identification of additional molecules [such as angiotensin converting enzyme 2, ANG-(1-7), and Mas receptor] that might improve some pathophysiological processes in chronic inflammatory diseases. In the present study, we focused on the potential protective role of Mas receptor activation on mouse lipid profile, liver steatosis, and atherogenesis. Mas/apolipoprotein E (ApoE)-double-knockout (DKO) mice (based on C57BL/6 strain of 20 wk of age) were fed under normal diet and compared with aged-matched Mas and ApoE-single-knockout (KO), as well as wild-type mice. Mas/ApoE double deficiency was associated with increased serum levels of atherogenic fractions of cholesterol, triglycerides, and fasting glucose compared with wild-type or single KO. Serum levels of HDL or leptin in DKO were lower than in other groups. Hepatic lipid content as well as alanine aminotransferase serum levels were increased in DKO compared with wild-type or single-KO animals. Accordingly, the hepatic protein content of mediators related to atherosclerotic inflammation, such as peroxisome proliferator-activated receptor-α and liver X receptor, was altered in an adverse way in DKO compared with ApoE-KO. On the other hand, DKO mice did not display increased atherogenesis and intraplaque inflammation compared with ApoE-KO group. In conclusion, Mas deletion in ApoE-KO mice was associated with development of severe liver steatosis and dyslipidemia without affecting concomitant atherosclerosis. Mas receptor activation might represent promising strategies for future treatments targeting both hepatic and metabolic alterations in chronic conditions clustering these disorders.

  7. Hypersensitivity to thromboxane receptor mediated cerebral vasomotion and CBF oscillations during acute NO-deficiency in rats.

    Directory of Open Access Journals (Sweden)

    Béla Horváth

    Full Text Available BACKGROUND: Low frequency (4-12 cpm spontaneous fluctuations of the cerebrovascular tone (vasomotion and oscillations of the cerebral blood flow (CBF have been reported in diseases associated with endothelial dysfunction. Since endothelium-derived nitric oxide (NO suppresses constitutively the release and vascular effects of thromboxane A(2 (TXA(2, NO-deficiency is often associated with activation of thromboxane receptors (TP. In the present study we hypothesized that in the absence of NO, overactivation of the TP-receptor mediated cerebrovascular signaling pathway contributes to the development of vasomotion and CBF oscillations. METHODOLOGY/PRINCIPAL FINDINGS: Effects of pharmacological modulation of TP-receptor activation and its downstream signaling pathway have been investigated on CBF oscillations (measured by laser-Doppler flowmetry in anesthetized rats and vasomotion (measured by isometric tension recording in isolated rat middle cerebral arteries, MCAs both under physiological conditions and after acute inhibition of NO synthesis. Administration of the TP-receptor agonist U-46619 (1 µg/kg i.v. to control animals failed to induce any changes of the systemic or cerebral circulatory parameters. Inhibition of the NO synthesis by nitro-L-arginine methyl ester (L-NAME, 100 mg/kg i.v. resulted in increased mean arterial blood pressure and a decreased CBF accompanied by appearance of CBF-oscillations with a dominant frequency of 148±2 mHz. U-46619 significantly augmented the CBF-oscillations induced by L-NAME while inhibition of endogenous TXA(2 synthesis by ozagrel (10 mg/kg i.v. attenuated it. In isolated MCAs U-46619 in a concentration of 100 nM, which induced weak and stable contraction under physiological conditions, evoked sustained vasomotion in the absence of NO, which effect could be completely reversed by inhibition of Rho-kinase by 10 µM Y-27632. CONCLUSION/SIGNIFICANCE: These results suggest that hypersensitivity of the TP-receptor

  8. GABAB receptor deficiency causes failure of neuronal homeostasis in hippocampal networks.

    Science.gov (United States)

    Vertkin, Irena; Styr, Boaz; Slomowitz, Edden; Ofir, Nir; Shapira, Ilana; Berner, David; Fedorova, Tatiana; Laviv, Tal; Barak-Broner, Noa; Greitzer-Antes, Dafna; Gassmann, Martin; Bettler, Bernhard; Lotan, Ilana; Slutsky, Inna

    2015-06-23

    Stabilization of neuronal activity by homeostatic control systems is fundamental for proper functioning of neural circuits. Failure in neuronal homeostasis has been hypothesized to underlie common pathophysiological mechanisms in a variety of brain disorders. However, the key molecules regulating homeostasis in central mammalian neural circuits remain obscure. Here, we show that selective inactivation of GABAB, but not GABA(A), receptors impairs firing rate homeostasis by disrupting synaptic homeostatic plasticity in hippocampal networks. Pharmacological GABA(B) receptor (GABA(B)R) blockade or genetic deletion of the GB(1a) receptor subunit disrupts homeostatic regulation of synaptic vesicle release. GABA(B)Rs mediate adaptive presynaptic enhancement to neuronal inactivity by two principle mechanisms: First, neuronal silencing promotes syntaxin-1 switch from a closed to an open conformation to accelerate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly, and second, it boosts spike-evoked presynaptic calcium flux. In both cases, neuronal inactivity removes tonic block imposed by the presynaptic, GB(1a)-containing receptors on syntaxin-1 opening and calcium entry to enhance probability of vesicle fusion. We identified the GB(1a) intracellular domain essential for the presynaptic homeostatic response by tuning intermolecular interactions among the receptor, syntaxin-1, and the Ca(V)2.2 channel. The presynaptic adaptations were accompanied by scaling of excitatory quantal amplitude via the postsynaptic, GB(1b)-containing receptors. Thus, GABA(B)Rs sense chronic perturbations in GABA levels and transduce it to homeostatic changes in synaptic strength. Our results reveal a novel role for GABA(B)R as a key regulator of population firing stability and propose that disruption of homeostatic synaptic plasticity may underlie seizure's persistence in the absence of functional GABA(B)Rs.

  9. Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice.

    Science.gov (United States)

    Kritikou, Eva; van Puijvelde, Gijs H M; van der Heijden, Thomas; van Santbrink, Peter J; Swart, Maarten; Schaftenaar, Frank H; Kröner, Mara J; Kuiper, Johan; Bot, Ilze

    2016-11-24

    Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3 antagonism using the small molecule Ki16425. We show that LPA1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA1/3 blockade enhanced the percentage of non-inflammatory, Ly6C(low) monocytes and CD4(+) CD25(+) FoxP3(+) T-regulatory cells. Finally, we demonstrate that LPA1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA1/3 receptors may prove a promising approach to diminish atherosclerosis development.

  10. P2X7 receptor-deficient mice are susceptible to bone cancer pain

    DEFF Research Database (Denmark)

    Hansen, Rikke Rie; Nielsen, Christian K.; Nasser, Arafat

    2011-01-01

    The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice...... were susceptible to bone cancer pain and moreover had an earlier onset of pain-related behaviours compared with cancer-bearing, wild-type mice. Furthermore, acute treatment with the selective P2X7 receptor antagonist, A-438079, failed to alleviate pain-related behaviours in models of bone cancer pain...... with and without astrocyte activation (BALB/cJ or C3H mice inoculated with 4T1 mammary cancer cells or NCTC 2472 osteosarcoma cells, respectively), suggesting that astrocytic P2X7 receptors play a negligible role in bone cancer pain. The results support the hypothesis that bone cancer pain is a separate pain state...

  11. Impaired wake-promoting mechanisms in ghrelin receptor-deficient mice.

    Science.gov (United States)

    Esposito, Matthew; Pellinen, Jacob; Kapás, Levente; Szentirmai, Éva

    2012-01-01

    Ghrelin receptors are expressed by key components of the arousal system. Exogenous ghrelin induces behavioral activation, promotes wakefulness and stimulates eating. We hypothesized that ghrelin-sensitive mechanisms play a role in the arousal system. To test this, we investigated the responsiveness of ghrelin receptor knockout (KO) mice to two natural wake-promoting stimuli. Additionally, we assessed the integrity of their homeostatic sleep-promoting system using sleep deprivation. There was no significant difference in the spontaneous sleep-wake activity between ghrelin receptor KO and wild-type (WT) mice. WT mice mounted robust arousal responses to a novel environment and food deprivation. Wakefulness increased for 6 h after cage change accompanied by increases in body temperature and locomotor activity. Ghrelin receptor KO mice completely lacked the wake and body temperature responses to new environment. When subjected to 48 h food deprivation, WT mice showed marked increases in their waking time during the dark periods of both days. Ghrelin receptor KO mice failed to mount an arousal response on the first night and wake increases were attenuated on the second day. The responsiveness to sleep deprivation did not differ between the two genotypes. These results indicate that the ghrelin-receptive mechanisms play an essential role in the function of the arousal system but not in homeostatic sleep-promoting mechanisms. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  12. Urate crystal induced inflammation and joint pain are reduced in transient receptor potential ankyrin 1 deficient mice--potential role for transient receptor potential ankyrin 1 in gout.

    Science.gov (United States)

    Moilanen, Lauri J; Hämäläinen, Mari; Lehtimäki, Lauri; Nieminen, Riina M; Moilanen, Eeva

    2015-01-01

    In gout, monosodium urate (MSU) crystals deposit intra-articularly and cause painful arthritis. In the present study we tested the hypothesis that Transient Receptor Poten-tial Ankyrin 1 (TRPA1), an ion channel mediating nociceptive signals and neurogenic in-flammation, is involved in MSU crystal-induced responses in gout by utilizing three experi-mental murine models. The effects of selective pharmacological inhibition (by HC-030031) and genetic depletion of TRPA1 were studied in MSU crystal-induced inflammation and pain by using 1) spontaneous weight-bearing test to assess MSU crystal-induced joint pain, 2) subcutaneous air-pouch model resembling joint inflammation to measure MSU crystal-induced cytokine production and inflammatory cell accumulation, and 3) MSU crystal-induced paw edema to assess acute vascular inflammatory responses and swelling. Intra-articularly injected MSU crystals provoked spontaneous weight shift off from the affected limb in wild type but not in TRPA1 knock-out mice referring alleviated joint pain in TRPA1 deficient animals. MSU crystal-induced inflammatory cell infiltration and accumulation of cytokines MCP-1, IL-6, IL-1beta, MPO, MIP-1alpha and MIP-2 into subcu-taneous air-pouch (resembling joint cavity) was attenuated in TRPA1 deficient mice and in mice treated with the selective TRPA1 inhibitor HC-030031 as compared to control animals. Further, HC-030031 treated and TRPA1 deficient mice developed tempered inflammatory edema when MSU crystals were injected into the paw. TRPA1 mediates MSU crystal-induced inflammation and pain in experimental models supporting the role of TRPA1 as a potential mediator and a drug target in gout flare.

  13. Altered circadian food anticipatory activity rhythms in PACAP receptor 1 (PAC1) deficient mice

    DEFF Research Database (Denmark)

    Hannibal, Jens; Georg, Birgitte; Fahrenkrug, Jan

    2016-01-01

    Light signals from intrinsically photosensitive retinal ganglion cells (ipRGCs) entrain the circadian clock and regulate negative masking. Two neurotransmitters, glutamate and Pituitary Adenylate Cyclase Activating Polypeptide (PACAP), found in the ipRGCs transmit light signals to the brain via...... glutamate receptors and the specific PACAP type 1 (PAC1) receptor. Light entrainment occurs during the twilight zones and has little effect on clock phase during daytime. When nocturnal animals have access to food only for a few hours during the resting phase at daytime, they adapt behavior...

  14. Galactose-specific recognition system of mammalian liver: receptor distribution on the hepatocyte cell surface

    OpenAIRE

    1981-01-01

    An isolated perfused liver system was used to study the distribution of asialoglycoprotein (ASGP) binding sites on rat hepatocyte cell surfaces. The number of surface receptors was quantitated by monitoring clearance of 125I-labeled ligands from the perfusate medium under two conditions that blocked their internalization: low temperature (less than 5 degrees C) or brief formaldehyde fixation. The cell surface distribution of binding sites was visualized in the electron microscope with either ...

  15. Paternal uniparental isodisomy of chromosome 6 causing a complex syndrome including complete IFN-gamma receptor 1 deficiency.

    Science.gov (United States)

    Prando, Carolina; Boisson-Dupuis, Stéphanie; Grant, Audrey V; Kong, Xiao-Fei; Bustamante, Jacinta; Feinberg, Jacqueline; Chapgier, Ariane; Rose, Yoann; Jannière, Lucile; Rizzardi, Elena; Zhang, Qiuping; Shanahan, Catherine M; Viollet, Louis; Lyonnet, Stanislas; Abel, Laurent; Ruga, Ezia Maria; Casanova, Jean-Laurent

    2010-03-01

    Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency associated with clinical disease caused by weakly virulent mycobacterial species. Interferon gamma receptor 1 (IFN-gammaR1) deficiency is a genetic etiology of MSMD. We describe the clinical and genetic features of a 7-year-old Italian boy suffering from MSMD associated with a complex phenotype, including neonatal hyperglycemia, neuromuscular disease, and dysmorphic features. The child also developed necrotizing pneumonia caused by Rhodococcus equi. The child is homozygous for a nonsense mutation in exon 3 of IFNGR1 as a result of paternal uniparental disomy (UPD) of the entire chromosome 6. This is the first reported case of uniparental disomy resulting in a complex phenotype including MSMD. (c) 2010 Wiley-Liss, Inc.

  16. Working Memory Deficits in Retinoid X receptor [gamma]-Deficient Mice

    Science.gov (United States)

    Wietrzych, Marta; Meziane, Hamid; Sutter, Anne; Ghyselinck, Norbert; Chapman, Paul F.; Chambon, Pierre; Krezel, Wojciech

    2005-01-01

    Retinoid signaling has been recently shown to be required for mnemonic functions in rodents. To dissect the behavioral and molecular mechanisms involved in this requirement, we have analyzed the spatial and recognition working memory in mice carrying null mutations of retinoid receptors RAR[subscript [beta

  17. Effect of vertical sleeve gastrectomy in melanocortin receptor 4-deficient rats

    NARCIS (Netherlands)

    Mul, J.D.; Begg, D.P.; Alsters, S.I.; van Haaften, G.; Duran, K.J.; D'Alessio, D.A.; le Roux, C.W.; Woods, S.C.; Sandoval, D.A.; Blakemore, A.I.; Cuppen, E.; van Haelst, M.M.; Seeley, R.J.

    2012-01-01

    Bariatric surgery is currently the most effective treatment for obesity. Vertical sleeve gastrectomy (VSG), a commonly applied bariatric procedure, involves surgically incising most of the volume of the stomach. In humans, partial loss of melanocortin receptor-4 (MC4R) activity is the most common

  18. LDL receptor deficiency results in decreased cell proliferation and presynaptic bouton density in the murine hippocampus

    NARCIS (Netherlands)

    Mulder, M.; Koopmans, G.; Wassink, G.; Mansouri, G.A.; Simard, M.-L.; Havekes, L.M.; Prickaerts, J.; Blokland, A.

    2007-01-01

    An aberrant cholesterol metabolism in the brain may contribute to the pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) regulates plasma cholesterol levels and recently we and others obtained evidence that it is also involved in regulating brain cholesterol homeostasis. Moreover, we

  19. Effects of radiation combined injury on hippocampal function are modulated in mice deficient in chemokine receptor 2 (CCR2).

    Science.gov (United States)

    Allen, Antiño R; Eilertson, Kirsten; Sharma, Sourabh; Schneider, Danielle; Baure, Jennifer; Allen, Barrett; Rosi, Susanna; Raber, Jacob; Fike, John R

    2013-07-01

    Chemokines and their receptors play a crucial role in normal brain function as well as in pathological conditions such as injury and disease-associated neuroinflammation. Chemokine receptor-2 (CCR2), which mediates the recruitment of infiltrating and resident microglia to sites of central nervous system (CNS) inflammation, is upregulated by ionizing irradiation and traumatic brain injury. Our objective was to determine if a deficiency in CCR2 and subsequent effects on brain microglia affect neurogenesis and cognitive function after radiation combined injury (RCI). CCR2 knock-out ⁻/⁻ and wild-type (WT) mice received 4 Gy of whole body ¹³⁷Cs irradiation. Immediately after irradiation, unilateral traumatic brain injury was induced using a controlled cortical impact system. Forty-four days postirradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water-maze. After cognitive testing, animals were euthanized and their brains snap frozen for immunohistochemical assessment of neuroinflammation (activated microglia) and neurogenesis in the hippocampal dentate gyrus. All animals were able to locate the visible and hidden platform locations in the water maze; however, treatment effects were seen when spatial memory retention was assessed in the probe trials (no platform). In WT animals that received combined injury, a significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden platform training (first probe trial). This impairment was associated with increased neurogenesis in the ipsilateral hemisphere of the dentate gyrus. In contrast, CCR2⁻/⁻ mice, independent of insult showed significant memory retention in the first probe trial and there were no differences in the numbers of newly born neurons in the animals receiving irradiation, trauma or combined injury. Although the mechanisms involved are not clear, our data suggests that CCR2 deficiency can exert a protective

  20. SKP2 Activation by Thyroid Hormone Receptor β2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells.

    Science.gov (United States)

    Xu, Xiaoliang L; Li, Zhengke; Liu, Aihong; Fan, Xianqun; Hu, Dan-Ning; Qi, Dong-Lai; Chitty, David W; Jia, Renbing; Qui, Jianping; Wang, Justin Q; Sharaf, Jake; Zou, Jun; Weiss, Rebecca; Huang, Hongyan; Joseph, Walter J; Ng, Lily; Rosen, Richard; Shen, Binghui; Reid, Mark W; Forrest, Douglas; Abramson, David H; Singer, Samuel; Cobrinik, David; Jhanwar, Suresh C

    2017-12-15

    Germline RB1 mutations strongly predispose humans to cone precursor-derived retinoblastomas and strongly predispose mice to pituitary tumors, yet shared cell type-specific circuitry that sensitizes these different cell types to the loss of RB1 has not been defined. Here we show that the cell type-restricted thyroid hormone receptor isoform TRβ2 sensitizes to RB1 loss in both settings by antagonizing the widely expressed and tumor-suppressive TRβ1. TRβ2 promoted expression of the E3 ubiquitin ligase SKP2, a critical factor for RB1-mutant tumors, by enabling EMI1/FBXO5-dependent inhibition of SKP2 degradation. In RB1 wild-type neuroblastoma cells, endogenous Rb or ectopic TRβ2 was required to sustain SKP2 expression as well as cell viability and proliferation. These results suggest that in certain contexts, Rb loss enables TRβ1-dependent suppression of SKP2 as a safeguard against RB1-deficient tumorigenesis. TRβ2 counteracts TRβ1, thus disrupting this safeguard and promoting development of RB1-deficient malignancies. Cancer Res; 77(24); 6838-50. ©2017 AACR. ©2017 American Association for Cancer Research.

  1. Regression of atherosclerosis in apolipoprotein E-deficient mice is feasible using high-dose angiotensin receptor blocker, candesartan.

    Science.gov (United States)

    Hayashi, Kaori; Sasamura, Hiroyuki; Azegami, Tatsuhiko; Itoh, Hiroshi

    2012-01-01

    Clinical studies have suggested that renin-angiotensin inhibitors are effective for the prevention of atherosclerosis progression, but the results for the regression of established lesions are equivocal. The aim of this study was to examine the effects of different doses of the angiotensin receptor blocker (ARB) candesartan on the regression of atherosclerosis and lipid-induced nephropathy in apolipoprotein E (apoE)-deficient spontaneously hyperlipidemic (SHL) mice. Male SHL were given an atherogenic diet together with salt loading to induce atherosclerosis. The mice were then treated with various doses of candesartan (0-50 mg/kg/d) for 12 weeks. Treatment with high-dose candesartan caused clear regression of atherosclerotic plaques in the aorta, which was not observed with normal-dose candesartan. Biglycan and ACAT1 expression were significantly decreased, and aortic free cholesterol: cholesterol ester ratios were increased in these mice. Treatment of cultured THP-1 macrophages in vitro with candesartan resulted in a similar decrease in ACAT1 expression. In the kidney, glomerular lipid accumulation, mesangial expansion, and albuminuria were significantly regressed after treatment with high-dose candesartan, while biglycan and ACAT1 expressions were decreased. These results suggest that regression of established atherosclerosis lesions in ApoE-deficient mice is feasible using high-dose candesartan, by mechanisms involving (i) a decrease in the lipid-retaining proteoglycan biglycan, and (ii) suppression of ACAT1 expression resulting in increased free cholesterol for lipid release.

  2. P2Y2 receptor deficiency aggravates chronic kidney disease progression

    Directory of Open Access Journals (Sweden)

    Sebastian Alexander Potthoff

    2013-09-01

    Full Text Available Purinergic signaling is involved in a variety of physiological states. P2 receptors are mainly activated by adenosine triphosphate (ATP. Activation of specific P2Y receptor subtypes might influence progression of kidney disease. To investigate the in vivo effect of a particular P2 receptor subtype on chronic kidney disease progression, subtotal nephrectomy was performed on wild type (WT and P2Y2 receptor knockout (KO mice.During the observational period of 56 ± 2 days, survival of KO mice was inferior compared to WT mice after SNX. Subtotal nephrectomy reduced creatinine clearance in both groups of mice, but the decrease was significantly more pronounced in KO compared to WT mice (53.9±7.7 vs. 84.3±8.7µl/min at day 56. The KO mice also sustained a greater increase in systolic blood pressure after SNX compared to WT mice (177±2 vs. 156±7 mmHg and a 2.5-fold increase in albuminuria compared to WT. In addition, WT kidneys showed a significant increase in remnant kidney mass 56 days after SNX, but significant attenuation of hypertrophy in KO mice was observed. In line with the observed hypertrophy in WT SNX mice, a significant dose-dependent increase in DNA synthesis, a marker of proliferation, was present in cultured WT glomerular epithelial cells upon ATP stimulation. Markers for tissue damage (TGF-β1, PAI-1 and proinflammatory target genes (MCP1 were significantly upregulated in KO mice after SNX compared to WT SNX mice. In summary, deletion of the P2Y2 receptor leads to greater renal injury after SNX compared to WT mice. Higher systolic blood pressure and inability of compensatory hypertrophy in KO mice are likely causes for the accelerated progression of chronic kidney disease.

  3. Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Florian Willecke

    Full Text Available We tested whether a high fat diet (HFD containing the inflammatory dietary fatty acid palmitate or insulin deficient diabetes altered the remodeling of atherosclerotic plaques in LDL receptor knockout (Ldlr-/- mice. Cholesterol reduction was achieved by using a helper-dependent adenovirus (HDAd carrying the gene for the low-density lipoprotein receptor (Ldlr; HDAd-LDLR. After injection of the HDAd-LDLR, mice consuming either HFD, which led to insulin resistance but not hyperglycemia, or low fat diet (LFD, showed regression compared to baseline. However there was no difference between the two groups in terms of atherosclerotic lesion size, or CD68+ cell and lipid content. Because of the lack of effects of these two diets, we then tested whether viral-mediated cholesterol reduction would lead to defective regression in mice with greater hyperglycemia. In both normoglycemic and streptozotocin (STZ-treated hyperglycemic mice, HDAd-LDLR significantly reduced plasma cholesterol levels, decreased atherosclerotic lesion size, reduced macrophage area and lipid content, and increased collagen content of plaque in the aortic sinus. However, reductions in anti-inflammatory and ER stress-related genes were less pronounced in STZ-diabetic mice compared to non-diabetic mice. In conclusion, HDAd-mediated Ldlr gene therapy is an effective and simple method to induce atherosclerosis regression in Ldlr-/- mice in different metabolic states.

  4. Altered mRNA editing and expression of ionotropic glutamate receptors after kainic acid exposure in cyclooxygenase-2 deficient mice.

    Directory of Open Access Journals (Sweden)

    Luca Caracciolo

    2011-05-01

    Full Text Available Kainic acid (KA binds to the AMPA/KA receptors and induces seizures that result in inflammation, oxidative damage and neuronal death. We previously showed that cyclooxygenase-2 deficient (COX-2(-/- mice are more vulnerable to KA-induced excitotoxicity. Here, we investigated whether the increased susceptibility of COX-2(-/- mice to KA is associated with altered mRNA expression and editing of glutamate receptors. The expression of AMPA GluR2, GluR3 and KA GluR6 was increased in vehicle-injected COX-2(-/- mice compared to wild type (WT mice in hippocampus and cortex, whereas gene expression of NMDA receptors was decreased. KA treatment decreased the expression of AMPA, KA and NMDA receptors in the hippocampus, with a significant effect in COX-2(-/- mice. Furthermore, we analyzed RNA editing levels and found that the level of GluR3 R/G editing site was selectively increased in the hippocampus and decreased in the cortex in COX-2(-/- compared with WT mice. After KA, GluR4 R/G editing site, flip form, was increased in the hippocampus of COX-2(-/- mice. Treatment of WT mice with the COX-2 inhibitor celecoxib for two weeks decreased the expression of AMPA/KA and NMDAR subunits after KA, as observed in COX-2(-/- mice. After KA exposure, COX-2(-/- mice showed increased mRNA expression of markers of inflammation and oxidative stress, such as cytokines (TNF-α, IL-1β and IL-6, inducible nitric oxide synthase (iNOS, microglia (CD11b and astrocyte (GFAP. Thus, COX-2 gene deletion can exacerbate the inflammatory response to KA. We suggest that COX-2 plays a role in attenuating glutamate excitotoxicity by modulating RNA editing of AMPA/KA and mRNA expression of all ionotropic glutamate receptor subunits and, in turn, neuronal excitability. These changes may contribute to the increased vulnerability of COX-2(-/- mice to KA. The overstimulation of glutamate receptors as a consequence of COX-2 gene deletion suggests a functional coupling between COX-2 and the

  5. Clinical features of Candidiasis in patients with inherited interleukin 12 receptor β1 deficiency.

    Science.gov (United States)

    Ouederni, Monia; Sanal, Ozden; Ikinciogullari, Aydan; Tezcan, Ilhan; Dogu, Figen; Sologuren, Ithaisa; Pedraza-Sánchez, Sigifredo; Keser, Melike; Tanir, Gonul; Nieuwhof, Chris; Colino, Elena; Kumararatne, Dinakantha; Levy, Jacov; Kutukculer, Necil; Aytekin, Caner; Herrera-Ramos, Estefanía; Bhatti, Micah; Karaca, Neslihan; Barbouche, Ridha; Broides, Arnon; Goudouris, Ekaterini; Franco, José Luis; Parvaneh, Nima; Reisli, Ismail; Strickler, Alexis; Shcherbina, Anna; Somer, Ayper; Segal, Anthony; Angel-Moreno, Alfonso; Lezana-Fernandez, José Luis; Bejaoui, Mohamed; Bobadilla-Del Valle, Miriam; Kachboura, Salem; Sentongo, Timothy; Ben-Mustapha, Imen; Bustamante, Jacinta; Picard, Capucine; Puel, Anne; Boisson-Dupuis, Stéphanie; Abel, Laurent; Casanova, Jean-Laurent; Rodríguez-Gallego, Carlos

    2014-01-01

    Interleukin 12Rβ1 (IL-12Rβ1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon γ production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rβ1 deficiency. Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin. Patients who are deficient in IL-12Rβ1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients.

  6. Nutritional Omega-3 Deficiency Alters Glucocorticoid Receptor-Signaling Pathway and Neuronal Morphology in Regionally Distinct Brain Structures Associated with Emotional Deficits

    Directory of Open Access Journals (Sweden)

    Thomas Larrieu

    2016-01-01

    Full Text Available Extensive evidence suggests that long term dietary n-3 polyunsaturated fatty acids (PUFAs deficiency results in altered emotional behaviour. We have recently demonstrated that n-3 PUFAs deficiency induces emotional alterations through abnormal corticosterone secretion which leads to altered dendritic arborisation in the prefrontal cortex (PFC. Here we show that hypothalamic-pituitary-adrenal (HPA axis feedback inhibition was not compromised in n-3 deficient mice. Rather, glucocorticoid receptor (GR signaling pathway was inactivated in the PFC but not in the hippocampus of n-3 deficient mice. Consequently, only dendritic arborisation in PFC was affected by dietary n-3 PUFAs deficiency. In addition, occlusion experiment with GR blockade altered GR signaling in the PFC of control mice, with no further alterations in n-3 deficient mice. In conclusion, n-3 PUFAs deficiency compromised PFC, leading to dendritic atrophy, but did not change hippocampal GR function and dendritic arborisation. We argue that this GR sensitivity contributes to n-3 PUFAs deficiency-related emotional behaviour deficits.

  7. Down-regulation of microRNA-155 promotes selenium deficiency-induced apoptosis by tumor necrosis factor receptor superfamily member 1B in the broiler spleen.

    Science.gov (United States)

    Liu, Ci; Sun, Zhepeng; Xu, Zhe; Liu, Tianqi; Pan, Tingru; Li, Shu

    2017-08-29

    The aim of this work was to explore the microRNA profile and the effect of microRNA-155 on apoptosis in the spleen of selenium-deficient broilers. We replicated the splenic-apoptotic model in selenium-deficient broilers. In vitro , microRNA-155 oligonucleotides were transfected into lymphocytes and subsequently treated with H 2 O 2 . We observed that selenium deficiency altered the microRNA profile and decreased the expression of microRNA-155 in the broiler spleens. Tumor necrosis factor receptor superfamily member 1B was verified as a target of microRNA-155 in the splenocytes. Morphological changes, increased levels of tumor necrosis factor receptor superfamily member 1B, c-Jun N-terminal kinase, Bak, Bax, Cyt-c, caspase9 and caspase3 and decreased levels of Bcl-2 demonstrated that selenium deficiency induced apoptosis in the spleen tissues. In vitro , microRNA-155 m inhibited the levels of ROS and reduced apoptosis compared with microRNA-155i in the lymphocytes. These results suggested that the reduced levels of microRNA-155 due to selenium deficiency could promote oxidative stress-induced apoptosis by increased tumor necrosis factor receptor superfamily member 1B in splenic cells.

  8. Lowbush blueberries inhibit scavenger receptors CD36 and SR-A expression and attenuate foam cell formation in ApoE-deficient mice

    Science.gov (United States)

    Blueberries have recently been reported to reduce atherosclerotic lesion progression in apoE deficient (apoE-/-) mice. However, the underlying mechanisms are not fully understood. The objective of this study was to determine whether blueberries altered scavenger receptors expression and foam cell fo...

  9. Combined IL-12 receptor and IgA deficiency in an adult man intestinally infested by an unknown, non-cultivable mycobacterium

    DEFF Research Database (Denmark)

    Schejbel, L; Rasmussen, E M; Kemp, Helle Bruunsgaard

    2011-01-01

    Interleukin-12 receptor deficiency is a well-described cause of human susceptibility to infection with low-virulent mycobacteria and Salmonella species. We identified a male patient presenting in his late forties with severe gastroenteropathy because of outbred infestation by a previously unknown...

  10. Deficiency of Lipoprotein Lipase in Neurons Decreases AMPA Receptor Phosphorylation and Leads to Neurobehavioral Abnormalities in Mice.

    Directory of Open Access Journals (Sweden)

    Tian Yu

    Full Text Available Alterations in lipid metabolism have been found in several neurodegenerative disorders, including Alzheimer's disease. Lipoprotein lipase (LPL hydrolyzes triacylglycerides in lipoproteins and regulates lipid metabolism in multiple organs and tissues, including the central nervous system (CNS. Though many brain regions express LPL, the functions of this lipase in the CNS remain largely unknown. We developed mice with neuron-specific LPL deficiency that became obese on chow by 16 wks in homozygous mutant mice (NEXLPL-/- and 10 mo in heterozygous mice (NEXLPL+/-. In the present study, we show that 21 mo NEXLPL+/- mice display substantial cognitive function decline including poorer learning and memory, and increased anxiety with no difference in general motor activities and exploratory behavior. These neurobehavioral abnormalities are associated with a reduction in the 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl propanoic acid (AMPA receptor subunit GluA1 and its phosphorylation, without any alterations in amyloid β accumulation. Importantly, a marked deficit in omega-3 and omega-6 polyunsaturated fatty acids (PUFA in the hippocampus precedes the development of the neurobehavioral phenotype of NEXLPL+/- mice. And, a diet supplemented with n-3 PUFA can improve the learning and memory of NEXLPL+/- mice at both 10 mo and 21 mo of age. We interpret these findings to indicate that LPL regulates the availability of PUFA in the CNS and, this in turn, impacts the strength of synaptic plasticity in the brain of aging mice through the modification of AMPA receptor and its phosphorylation.

  11. Deficiency in type 1 insulin-like growth factor receptor in mice protects against oxygen-induced lung injury

    Directory of Open Access Journals (Sweden)

    Flejou Jean-François

    2005-04-01

    Full Text Available Abstract Background Cellular responses to aging and oxidative stress are regulated by type 1 insulin-like growth factor receptor (IGF-1R. Oxidant injury, which is implicated in the pathophysiology of a number of respiratory diseases, acutely upregulates IGF-1R expression in the lung. This led us to suspect that reduction of IGF-1R levels in lung tissue could prevent deleterious effects of oxygen exposure. Methods Since IGF-1R null mutant mice die at birth from respiratory failure, we generated compound heterozygous mice harboring a hypomorphic (Igf-1rneo and a knockout (Igf-1r- receptor allele. These IGF-1Rneo/- mice, strongly deficient in IGF-1R, were subjected to hyperoxia and analyzed for survival time, ventilatory control, pulmonary histopathology, morphometry, lung edema and vascular permeability. Results Strikingly, after 72 h of exposure to 90% O2, IGF-1Rneo/- mice had a significantly better survival rate during recovery than IGF-1R+/+ mice (77% versus 53%, P neo/- mice which developed conspicuously less edema and vascular extravasation than controls. Also, hyperoxia-induced abnormal pattern of breathing which precipitated respiratory failure was elicited less frequently in the IGF-1Rneo/- mice. Conclusion Together, these data demonstrate that a decrease in IGF-1R signaling in mice protects against oxidant-induced lung injury.

  12. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7

    Science.gov (United States)

    Sierro, Frederic; Biben, Christine; Martínez-Muñoz, Laura; Mellado, Mario; Ransohoff, Richard M.; Li, Meizhang; Woehl, Blanche; Leung, Helen; Groom, Joanna; Batten, Marcel; Harvey, Richard P.; Martínez-A, Carlos; Mackay, Charles R.; Mackay, Fabienne

    2007-01-01

    Chemotactic cytokines (chemokines) attract immune cells, although their original evolutionary role may relate more closely with embryonic development. We noted differential expression of the chemokine receptor CXCR7 (RDC-1) on marginal zone B cells, a cell type associated with autoimmune diseases. We generated Cxcr7−/− mice but found that CXCR7 deficiency had little effect on B cell composition. However, most Cxcr7−/− mice died at birth with ventricular septal defects and semilunar heart valve malformation. Conditional deletion of Cxcr7 in endothelium, using Tie2-Cre transgenic mice, recapitulated this phenotype. Gene profiling of Cxcr7−/− heart valve leaflets revealed a defect in the expression of factors essential for valve formation, vessel protection, or endothelial cell growth and survival. We confirmed that the principal chemokine ligand for CXCR7 was CXCL12/SDF-1, which also binds CXCR4. CXCL12 did not induce signaling through CXCR7; however, CXCR7 formed functional heterodimers with CXCR4 and enhanced CXCL12-induced signaling. Our results reveal a specialized role for CXCR7 in endothelial biology and valve development and highlight the distinct developmental role of evolutionary conserved chemokine receptors such as CXCR7 and CXCR4. PMID:17804806

  13. Peroxisomal proliferator activated receptordeficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3

    Directory of Open Access Journals (Sweden)

    Cao Henian

    2006-01-01

    Full Text Available Abstract Background Familial partial lipodystrophy (Dunnigan type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367 results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-γ. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition. Methods We present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol. Results The mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable. Conclusion Taken together with previous studies of human PPARG mutations, these findings suggest that PPAR-γ deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.

  14. Did hypocretin receptor 2 autoantibodies cause narcolepsy with hypocretin deficiency in Pandemrix-vaccinated children? Comment on “Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2”

    OpenAIRE

    Vassalli Anne

    2015-01-01

    Abstract Did hypocretin receptor 2 auto antibodies cause narcolepsy with hypocretin deficiency in Pandemrix vaccinated children as suggested by Ahmed et al.? Using newly developed mouse models to report and inactivate hypocretin receptor expression Vassalli et al. now show that hypocretin neurons (whose loss causes narcolepsy) do not express hypocretin autoreceptors raising questions to the interpretation of Ahmed et al.’s findings. Mouse Genome Informatics: www.informatics.jax.org/reference/...

  15. Natural Killer Cell Receptors and Cytotoxic Activity in Phosphomannomutase 2 Deficiency (PMM2-CDG.

    Directory of Open Access Journals (Sweden)

    Roberto García-López

    Full Text Available PMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder.To evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors.We studied fresh and activated NK cells from twelve PMM2-CDG cells. The number and expression of lymphoid surface receptors were studied by flow cytometry. The NK responsiveness (frequency of degranulated NK cells and killing activity against K562 target cells was determined in the NK cytotoxicity assay.We found an increase of blood NK cells in three patients with a severe phenotype. Two of them, who had suffered from moderate/severe viral infections during their first year of life, also had reduced T lymphocyte numbers. Patient activated NK cells showed increased expression of CD54 adhesion molecule and NKG2D and NKp46 activating receptors. NKp46 and 2B4 expression was inversely correlated with the expression of NKG2D in activated PMM2-CDG cells. Maximal NK activity against K562 target cells was similar in control and PMM2-CDG cells. Interestingly, the NK cell responsiveness was higher in patient cells. NKG2D and specially CD54 increased surface expression significantly correlated with the increased NK cell cytolytic activity according to the modulation of the killer activity by expression of triggering receptors and adhesion molecules.Our results indicate that hypoglycosylation in PMM2-CDG altered NK cell reactivity against target cells and the expression of CD54 and NKG2D, NKp46 and 2B4 activating receptors during NK cell activation. This suggests a defective control of NK cell killing activity and the overall anti-viral immune response in PMM2-CDG patients. The present

  16. Modulators of vascular sex hormone receptors and their effects in estrogen-deficiency states associated with menopause.

    Science.gov (United States)

    Serock, Michelle R; Wells, Amanda K; Khalil, Raouf A

    2008-11-01

    Cardiovascular disease (CVD) is more prevalent in postmenopausal than premenopausal women, suggesting vascular protective effects of estrogen. Also, experimental studies have demonstrated beneficial effects of estrogen in improving vascular function and reducing vascular injury. However, clinical trials including HERS I, HERS II, WHI and WISDOM have demonstrated minimal beneficial vascular effects of menopausal hormone therapy (MHT) in postmenopausal women with CVD. The discrepancies between the experimental findings and clinical data may be related to the vascular estrogen receptors (ER), the type, route of administration, or dosage of MHT, and subject's age. Vascular ERs mediate both genomic and non-genomic effects of estrogen on the endothelium, vascular smooth muscle (VSM), and extracellular matrix (ECM). Postmenopausal changes in vascular ER structure, polymorphisms, amount, subcellular location, affinity or signaling could modify their responsiveness to estrogen and thereby the outcome of MHT. Recent investigations and patents have been centered on developing new ER modulators and alternatives for the traditional natural and synthetic forms of MHT which carry the risk of invasive breast cancer and venous thromoboembolism. Phytoestrogens may have similar effects as traditional MHT and have not demonstrated harmful side effects. Specific estrogen receptor modulators (SERMs) such as raloxifene and tamoxifen have also been tested. ER agonists that selectively target ERalpha, ERbeta and perhaps GPR30 may modify specific vascular signaling pathways. Also, the dose, route of administration, and timing of MHT are integral to optimizing the beneficial effects and minimizing the side effects of MHT. Progesterone, testosterone and modulators of their specific receptors may also affect the overall vascular effects of MHT in estrogen-deficiency states associated with menopause.

  17. Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict.

    Science.gov (United States)

    Li, Chunlu; Yan, Yixiu; Cheng, Jingjing; Xiao, Gang; Gu, Jueqing; Zhang, Luqi; Yuan, Siyu; Wang, Junlu; Shen, Yi; Zhou, Yu-Dong

    2016-04-01

    Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine (DA) system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4 (TLR4), an important pattern-recognition receptor in the innate immune system, can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient (TLR4(-/-)) and wild-type (WT) mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed, large spaces. We found that TLR4(-/-) mice exhibited reduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4(-/-) mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approach-avoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4(-/-) mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly, the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell (NAcSh) in TLR4(-/-) mice than in WT mice. Partially inactivating the NAcSh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4(-/-) mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAcSh may contribute to this phenomenon.

  18. Increased Intimal Hyperplasia After Vascular Injury in Male Androgen Receptor-Deficient Mice

    DEFF Research Database (Denmark)

    Wilhelmson, Anna S; Fagman, Johan B; Johansson, Inger

    2016-01-01

    replacement to castrated male mice increased p27 mRNA in an AR-dependent manner. In conclusion, AR deficiency in male mice increases intimal hyperplasia in response to vascular injury, potentially related to the effects of androgens/AR to inhibit proliferation and migration of smooth muscle cells....... evaluated formation of intimal hyperplasia in male AR knockout (ARKO) mice using a vascular injury model. Two weeks after ligation of the carotid artery, male ARKO mice showed increased intimal area and intimal thickness compared with controls. After endothelial denudation by an in vivo scraping injury......, there was no difference in the reendothelialization in ARKO compared with control mice. Ex vivo, we observed increased outgrowth of vascular smooth muscle cells from ARKO compared with control aortic tissue explants; the number of outgrown cells was almost doubled in ARKO. In vitro, stimulation of human aortic vascular...

  19. Impact of PACAP and PAC1 Receptor Deficiency on the Neurochemical and Behavioral Effects of Acute and Chronic Restraint Stress in Male C57BL/6 Mice

    Science.gov (United States)

    Mustafa, Tomris; Jiang, Sunny Zhihong; Eiden, Adrian M.; Weihe, Eberhard; Thistlethwaite, Ian; Eiden, Lee E.

    2016-01-01

    Acute restraint stress (ARS) for 3 hours causes CORT elevation in venous blood, which is accompanied by Fos up-regulation in the paraventricular nucleus (PVN) of male C57BL/6 mice. CORT elevation by ARS is attenuated in PACAP-deficient mice, but unaffected in PAC1-deficient mice. Correspondingly, Fos up-regulation by ARS is greatly attenuated in PACAP-deficient mice, but much less so in PAC1-deficient animals. We noted that both PACAP- and PAC1-deficiency greatly attenuate CORT elevation after ARS when CORT measurements are performed on trunk blood following euthanasia by abrupt cervical separation: this latter observation is of critical importance in assessing the role of PACAP neurotransmission in ARS, based on previous reports in which serum CORT was sampled from trunk blood. Seven days of chronic restraint stress (CRS) induces non-habituating CORT elevation, and weight loss consequent to hypophagia, in wild-type male C57BL/6 mice. Both CORT elevation and weight loss following seven day CRS are severely blunted in PACAP-deficient mice, but only slightly in PAC1 deficient mice. However, longer periods of daily restraint (14–21 days) resulted in sustained weight loss and elevated CORT in wild-type mice, and these effects of long-term chronic stress were attenuated or abolished in both PACAP- and PAC1-deficient mice. We conclude that while a PACAP receptor in addition to PAC1 may mediate some of the PACAP-dependent central effects of acute restraint stress and short-term (restraint stress on the HPA axis, the PAC1 receptor plays a prominent role in mediating PACAP-dependent HPA axis activation, and hypophagia, during long-term (>7 days) chronic restraint stress. PMID:25853791

  20. Morphological and behavioral evidence for impaired prefrontal cortical function in female CB1 receptor deficient mice.

    Science.gov (United States)

    Lee, Tiffany T-Y; Filipski, Sarah B; Hill, Matthew N; McEwen, Bruce S

    2014-09-01

    The medial prefrontal cortex (mPFC) is known to regulate higher order processes like cognitive flexibility. Accumulating behavioral evidence suggests that endocannabinoid (eCB) signaling regulates neuronal architecture within the PFC, as well as certain forms of cognitive flexibility; however, all of these studies have been performed in male rodents and it is currently unknown whether the eCB system performs a similar role in females. To this extent, dendritic morphology of layer II/III neurons in the infra- and prelimbic regions of the mPFC was analyzed and cognitive ability and flexibility in a fixed-platform Morris water maze task was assessed in adult female CB1 receptor knockout (CB1KO) mice. Similar to data generated in male mice, female mice exhibited no difference in acquisition relative to wildtype (WT); however, during reversal learning, CB1KO females spent more time in the original training quadrant and took significantly longer to learn the location of the new platform relative to WT. Within the mPFC, female mice had reduced length and complexity of layer II/III neurons within the prelimbic, but not infralimbic region of the PFC. Taken together, these findings indicate that the role of eCB signaling in cognitive flexibility is independent of sex and disrupted CB1 receptor signaling results in compromised structure and function of the PFC, at least within the prelimbic division. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Altered Circadian Food Anticipatory Activity Rhythms in PACAP Receptor 1 (PAC1 Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Jens Hannibal

    Full Text Available Light signals from intrinsically photosensitive retinal ganglion cells (ipRGCs entrain the circadian clock and regulate negative masking. Two neurotransmitters, glutamate and Pituitary Adenylate Cyclase Activating Polypeptide (PACAP, found in the ipRGCs transmit light signals to the brain via glutamate receptors and the specific PACAP type 1 (PAC1 receptor. Light entrainment occurs during the twilight zones and has little effect on clock phase during daytime. When nocturnal animals have access to food only for a few hours during the resting phase at daytime, they adapt behavior to the restricted feeding (RF paradigm and show food anticipatory activity (FAA. A recent study in mice and rats demonstrating that light regulates FAA prompted us to investigate the role of PACAP/PAC1 signaling in the light mediated regulation of FAA. PAC1 receptor knock out (PAC1-/- and wild type (PAC1+/+ mice placed in running wheels were examined in a full photoperiod (FPP of 12:12 h light/dark (LD and a skeleton photoperiod (SPP 1:11:1:11 h L:DD:L:DD at 300 and 10 lux light intensity. Both PAC1-/- mice and PAC1+/+ littermates entrained to FPP and SPP at both light intensities. However, when placed in RF with access to food for 4-5 h during the subjective day, a significant change in behavior was observed in PAC1-/- mice compared to PAC1+/+ mice. While PAC1-/- mice showed similar FAA as PAC1+/+ animals in FPP at 300 lux, PAC1-/- mice demonstrated an advanced onset of FAA with a nearly 3-fold increase in amplitude compared to PAC1+/+ mice when placed in SPP at 300 lux. The same pattern of FAA was observed at 10 lux during both FPP and SPP. The present study indicates a role of PACAP/PAC1 signaling during light regulated FAA. Most likely, PACAP found in ipRGCs mediating non-image forming light information to the brain is involved.

  2. Abolished tubuloglomerular feedback and increased plasma renin in adenosine A1 receptor deficient mice

    DEFF Research Database (Denmark)

    Brown, R.; Ollerstam, A.; Johansson, B.

    2001-01-01

    The hypothesis that adenosine acting on adenosine A1 receptors (A1R) regulates several renal functions and mediates tubuloglomerular feedback (TGF) was examined using A1R knockout mice. We anesthetized knockout, wild-type, and heterozygous mice and measured glomerular filtration rate, TGF response...... greater in the A1R knockout mice [74.2 +/- 14.3 milli-Goldblatt units (mGU)/ml] mice compared with the wild-type and A1R+/- mice (36.3 +/- 8.5 and 34.1 +/- 9.6 mGU/ml), respectively. The results demonstrate that adenosine acting on A1R is required for TGF and modulates renin release....

  3. Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation.

    Science.gov (United States)

    Obici, Silvana; Magrisso, I Jack; Ghazarian, Armen S; Shirazian, Alireza; Miller, Jonas R; Loyd, Christine M; Begg, Denovan P; Krawczewski Carhuatanta, Kimberly A; Haas, Michael K; Davis, Jon F; Woods, Stephen C; Sandoval, Darleen A; Seeley, Randy J; Goodyear, Laurie J; Pothos, Emmanuel N; Mul, Joram D

    2015-10-01

    Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome. Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4r (K314X) (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTB (Mc4r) mice, wild-type mice body weight-matched to loxTB (Mc4r) mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats. Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ΔFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners. Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.

  4. Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation☆

    Science.gov (United States)

    Obici, Silvana; Magrisso, I. Jack; Ghazarian, Armen S.; Shirazian, Alireza; Miller, Jonas R.; Loyd, Christine M.; Begg, Denovan P.; Krawczewski Carhuatanta, Kimberly A.; Haas, Michael K.; Davis, Jon F.; Woods, Stephen C.; Sandoval, Darleen A.; Seeley, Randy J.; Goodyear, Laurie J.; Pothos, Emmanuel N.; Mul, Joram D.

    2015-01-01

    Objective Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome. Methods Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4rK314X (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTBMc4r mice, wild-type mice body weight-matched to loxTBMc4r mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats. Results Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ΔFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners. Conclusions Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive

  5. Dietary isoflavones reduce plasma cholesterol and atherosclerosis in C57BL/6 mice but not LDL receptor-deficient mice.

    Science.gov (United States)

    Kirk, E A; Sutherland, P; Wang, S A; Chait, A; LeBoeuf, R C

    1998-06-01

    Susceptibility to atherosclerosis is determined by a combination of genetic and environmental factors, including diet. Consumption of diets rich in soy protein has been claimed to protect against the development of atherosclerosis. Potential mechanisms include cholesterol lowering, inhibition of lipoprotein oxidation and inhibition of cell proliferation by soy proteins or isoflavones, such as genistein, that are present in soy. This study was designed to determine whether soy isoflavones confer protection against atherosclerosis in mice and whether they reduce serum cholesterol levels and lipoprotein oxidation. C57BL/6 and LDL receptor-deficient (LDLr-null) mice were fed soy protein-based, high fat diets with isoflavones present (IF+, 20.85 g/100 g protein, 0.027 g/100 g genistein, 0.009 g/100 g daidzein) or diets from which isoflavones, and possibly other components, had been extracted (IF-, 20.0 g/100 g protein, 0.002 g/100 g genistein, 0.001 g/100 g daidzein). Because LDLr-null mice develop extensive atherosclerosis and hypercholesterolemia after minimal time on a high fat diet, they were fed the diets for 6 wk, whereas C57BL/6 mice were fed the diets for 10 wk. Plasma cholesterol levels did not differ between LDLr-null mice fed IF- and those fed IF+, but were 30% lower in C57BL/6 mice fed the IF+ diet than in those fed the IF- diet. Susceptibility of LDL to oxidative modification, measured as the lag phase of conjugated diene formation in LDLr-null mice, was not altered by isoflavone consumption. All LDLr-null mice developed atherosclerosis, and the presence or deficiency of dietary isoflavones did not influence atherosclerotic lesion area. In contrast, atherosclerotic lesion area was significantly reduced in C57BL/6 mice fed IF+ compared with those fed IF-. Thus, this study demonstrates that although the isoflavone-containing diet resulted in a reduction in cholesterol levels in C57BL/6 mice, it had no effect on cholesterol levels or on susceptibility of LDL

  6. CD8α+ Dendritic Cells Improve Collagen-Induced Arthritis In CC Chemokine Receptor (CCR)-2 Deficient Mice

    Science.gov (United States)

    Ibarra, Jessica M.; Quinones, Marlon P.; Estrada, Carlos A.; Jimenez, Fabio; Martinez, Hernan G.; Ahuja, Seema S.

    2012-01-01

    Objective Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3+ regulatory T cells (Treg), which in turn exert immunosuppression by increasing TGFβ-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2−/−) mice had impaired DCs migration and reduced CD8α+ DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2−/− mice, we tested the hypothesis that CD8α+ DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8α+ DCs in Ccr2−/− and SKG mice. Methods To examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant Flt3L-injections to expand endogenous DCs populations or adoptive transfers of CD8α+ DCs. Results Flt3L-mediated expansion of endogenous CD8α+ DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8α+ DCs ameliorated arthritis in Ccr2−/− mice and enhanced TGFβ1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype. Conclusion CD8α+ DCs were tolerogenic to the development of arthritis. CD8α+ DCs deficiency heightened the sensitivity to arthritis in Ccr2−/− mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2−/− mice was T cell

  7. Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors.

    Science.gov (United States)

    Friel, Anne M; Zhang, Ling; Pru, Cindy A; Clark, Nicole C; McCallum, Melissa L; Blok, Leen J; Shioda, Toshi; Peluso, John J; Rueda, Bo R; Pru, James K

    2015-01-28

    Endometrial cancer is the leading gynecologic cancer in women in the United States with 52,630 women predicted to be diagnosed with the disease in 2014. The objective of this study was to determine if progesterone (P4) receptor membrane component 1 (PGRMC1) influenced endometrial cancer cell viability in response to chemotherapy in vitro and in vivo. A lentiviral-based shRNA knockdown approach was used to generate stable PGRMC1-intact and PGRMC1-deplete Ishikawa endometrial cancer cell lines that also lacked expression of the classical progesterone receptor (PGR). Progesterone treatment inhibited mitosis of PGRMC1-intact, but not PGRMC1-deplete cells, suggesting that PGRMC1 mediates the anti-mitotic actions of P4. To test the hypothesis that PGRMC1 attenuates chemotherapy-induced apoptosis, PGRMC1-intact and PGRMC1-deplete cells were treated in vitro with vehicle, P4 (1 µM), doxorubicin (Dox, 2 µg/ml), or P4 + Dox for 48 h. Doxorubicin treatment of PGRMC1-intact cells resulted in a significant increase in cell death; however, co-treatment with P4 significantly attenuated Dox-induced cell death. This response to P4 was lost in PGRMC1-deplete cells. To extend these observations in vivo, a xenograft model was employed where PGRMC1-intact and PGRMC1-deplete endometrial tumors were generated following subcutaneous and intraperitoneal inoculation of immunocompromised NOD/SCID and nude mice, respectively. Tumors derived from PGRMC1-deplete cells grew slower than tumors from PGRMC1-intact cells. Mice harboring endometrial tumors were then given three treatments of vehicle (1:1 cremophor EL: ethanol + 0.9% saline) or chemotherapy [Paclitaxel (15 mg/kg, i.p.) followed after an interval of 30 minutes by CARBOplatin (50 mg/kg)] at five day intervals. In response to chemotherapy, tumor volume decreased approximately four-fold more in PGRMC1-deplete tumors when compared with PGRMC1-intact control tumors, suggesting that PGRMC1 promotes tumor cell viability

  8. Diazepam improves aspects of social behaviour and neuron activation in NMDA receptor-deficient mice

    Science.gov (United States)

    Mielnik, C. A.; Horsfall, W.; Ramsey, A. J.

    2017-01-01

    NR1 knockdown (NR1KD) mice are genetically modified to express low levels of the NR1 subunit of N-methyl-D-aspartate (NMDA) receptors, and show deficits in affiliative social behaviour. In this study, we determined which brain regions were selectively activated in response to social stimulation and asked whether differences in neuronal activation could be observed in mice with reduced sociability. Furthermore, we aimed to determine whether brain activation patterns correlated with the amelioration of social deficits through pharmacological intervention. The cingulate cortex, lateral septal nuclei, hypothalamus, thalamus and amygdala showed an increase in c-Fos immunoreactivity that was selective for exposure to social stimuli. NR1KD mice displayed a reduction in social behaviour and a reduction in c-Fos immunoreactivity in the cingulate cortex and septal nuclei. Acute clozapine did not significantly alter sociability; however, diazepam treatment did increase sociability and neuronal activation in the lateral septal region. This study has identified the lateral septal region as a neural substrate of social behaviour and the GABA system as a potential therapeutic target for social dysfunction. PMID:25040071

  9. Salidroside Decreases Atherosclerotic Plaque Formation in Low-Density Lipoprotein Receptor-Deficient Mice

    Directory of Open Access Journals (Sweden)

    Bu-Chun Zhang

    2012-01-01

    Full Text Available Salidroside is isolated from Rhodiola rosea and is one of the main active components in Rhodiola species. The present study was designed to evaluate the effects of Salidroside on atherosclerotic plaque formation in high-fat diet-(HFD- fed female LDL receptor knockout (LDLr-/- mice. LDLr-/- mice fed an atherogenic HFD for 12 weeks were divided into two groups. One group was administered Salidroside (50 mg/kg/oral gavage daily for 8 weeks, while the control group was administered saline. Salidroside treatment reduced serum lipids levels and the plaque area through the arch to the abdominal aorta. Furthermore, Salidroside improved macrophage content and enhanced collagen and smooth muscle cells contents in the aortic sinus. These changes were associated with reduced MCP-1, VCAM-1, and VCAM-1 protein expression in atherosclerotic aortas. All these results suggest that Salidroside decreases atherosclerotic plaques formation via effects on lipid lowering and anti-inflammation in HFD-fed LDLr−/− mice.

  10. Dysbiosis caused by vitamin D receptor deficiency confers colonization resistance to Citrobacter rodentium through modulation of innate lymphoid cells.

    Science.gov (United States)

    Chen, J; Waddell, A; Lin, Y-D; Cantorna, M T

    2015-05-01

    Vitamin D receptor (VDR) knockout (KO) mice had fewer Citrobacter rodentium in the feces than wild-type (WT) mice and the kinetics of clearance was faster in VDR KO than WT mice. VDR KO mice had more interleukin-22 (IL-22)-producing innate lymphoid cells (ILCs) and more antibacterial peptides than WT mice. The increased ILCs in the VDR KO mice was a cell-autonomous effect of VDR deficiency on ILC frequencies. Bone marrow (BM) transplantation from VDR KO mice into WT resulted in higher ILCs and colonization resistance of the WT mice. Disruption of the gut microbiota using antibiotics in VDR KO mice reversed colonization resistance to C. rodentium infection. Confirming the role of the microbiota in the colonization resistance of VDR KO mice, transfer of the VDR KO microbiota to WT germ-free mice resulted in colonization resistance. Once colonization resistance was overcome, VDR KO mice had increased susceptibility to C. rodentium. VDR expression is a regulator of ILC frequencies, IL-22, dysbiosis, and C. rodentium susceptibility.

  11. Establishment of a bluetongue virus infection model in mice that are deficient in the alpha/beta interferon receptor.

    Directory of Open Access Journals (Sweden)

    Eva Calvo-Pinilla

    Full Text Available Bluetongue (BT is a noncontagious, insect-transmitted disease of ruminants caused by the bluetongue virus (BTV. A laboratory animal model would greatly facilitate the studies of pathogenesis, immune response and vaccination against BTV. Herein, we show that adult mice deficient in type I IFN receptor (IFNAR((-/- are highly susceptible to BTV-4 and BTV-8 infection when the virus is administered intravenously. Disease was characterized by ocular discharges and apathy, starting at 48 hours post-infection and quickly leading to animal death within 60 hours of inoculation. Infectious virus was recovered from the spleen, lung, thymus, and lymph nodes indicating a systemic infection. In addition, a lymphoid depletion in spleen, and severe pneumonia were observed in the infected mice. Furthermore, IFNAR((-/- adult mice immunized with a BTV-4 inactivated vaccine showed the induction of neutralizing antibodies against BTV-4 and complete protection against challenge with a lethal dose of this virus. The data indicate that this mouse model may facilitate the study of BTV pathogenesis, and the development of new effective vaccines for BTV.

  12. Depleted iron stores and iron deficiency anemia associated with reduced ferritin and hepcidin and elevated soluble transferrin receptors in a multiethnic group of preschool-age children.

    Science.gov (United States)

    Weiler, Hope A; Jean-Philippe, Sonia; Cohen, Tamara R; Vanstone, Catherine A; Agellon, Sherry

    2015-09-01

    Iron deficiency anemia is prevalent in subgroups of the Canadian population. The objective of this study was to examine iron status and anemia in preschool-age children. Healthy children (n = 430, 2-5 years old, Montreal, Quebec, Canada) were sampled from randomly selected daycares. Anthropometry, demographics, and diet were assessed. Biochemistry included hemoglobin, ferritin, soluble transferrin receptors (sTfR), ferritin index, markers of inflammation (C-reactive protein, interleukin 6 (IL-6), and tumour necrosis factor alpha (TNFα)), and hepcidin. Iron deficiency and anemia cutoffs conformed to the World Health Organization criteria. Differences among categories were tested using mixed-model ANOVA or χ(2) tests. Children were 3.8 ± 1.0 years of age, with a body mass index z score of 0.48 ± 0.97, and 51% were white. Adjusted intakes of iron indicated children, whereas ferritin was higher with greater age and female sex. Inflammatory markers and hepcidin did not vary with any demographic variable. The prevalence of iron deficiency was 16.5% (95% confidence interval (CI), 13.0-20.0). Three percent (95% CI, 1.4-4.6) of children had iron deficiency anemia and 12.8% (95% CI, 9.6-16.0) had unexplained anemia. Children with iron deficiency, with and without anemia, had lower plasma ferritin and hepcidin but higher sTfR, ferritin index, and IL-6, whereas those with unexplained anemia had elevated TNFα. We conclude that iron deficiency anemia is not very common in young children in Montreal. While iron deficiency without anemia is more common than iron deficiency with anemia, the correspondingly reduced circulating hepcidin would have enabled heightened absorption of dietary iron in support of erythropoiesis.

  13. NCAM-mimetic, FGL peptide, restores disrupted fibroblast growth factor receptor (FGFR) phosphorylation and FGFR mediated signaling in neural cell adhesion molecule (NCAM)-deficient mice

    DEFF Research Database (Denmark)

    Aonurm-Helm, Anu; Berezin, Vladimir; Bock, Elisabeth

    2010-01-01

    ), a member of Src family of tyrosine kinases, Fyn and Raf1 kinase which all activate different intracellular signaling pathways. The objective was to clarify, which signaling pathways are being disrupted in NCAM knockout mice and whether FGL peptide is able to restore observed disruptions. Therefore we...... in all isoforms of NCAM have decreased basal phosphorylation levels of FGFR1 and CaMKII and CaMKIV. Furthermore, NCAM-mimetic, FGL peptide, is found to be able to restore FGFR1, CaMKII and CaMKIV phosphorylation levels and thereby mimic the interactions of NCAM at this receptor in NCAM deficient mice....... Also, we found that Fyn(Tyr530), Raf1, MAP kinases and Akt kinase phosphorylation in adult animals is not affected by NCAM deficiency but interestingly, we found an over-expression of another cell adhesion molecule L1. We conclude that in NCAM deficient mice FGFR1-dependent signaling is disrupted...

  14. Development of occlusive neointimal lesions in distal pulmonary arteries of endothelin B receptor-deficient rats: a new model of severe pulmonary arterial hypertension.

    Science.gov (United States)

    Ivy, D Dunbar; McMurtry, Ivan F; Colvin, Kelley; Imamura, Masatoshi; Oka, Masahiko; Lee, Dong-Seok; Gebb, Sarah; Jones, Peter Lloyd

    2005-06-07

    Human pulmonary arterial hypertension (PAH) is characterized by proliferation of vascular smooth muscle and, in its more severe form, by the development of occlusive neointimal lesions. However, few animal models of pulmonary neointimal proliferation exist, thereby limiting a complete understanding of the pathobiology of PAH. Recent studies of the endothelin (ET) system demonstrate that deficiency of the ET(B) receptor predisposes adult rats to acute and chronic hypoxic PAH, yet these animals fail to develop neointimal lesions. Herein, we determined and thereafter showed that exposure of ET(B) receptor-deficient rats to the endothelial toxin monocrotaline (MCT) leads to the development of neointimal lesions that share hallmarks of human PAH. The pulmonary hemodynamic and morphometric effects of 60 mg/kg MCT in control (MCT(+/+)) and ET(B) receptor-deficient (MCT(sl/sl)) rats at 6 weeks of age were assessed. MCT(sl/sl) rats developed more severe PAH, characterized by elevated pulmonary artery pressure, diminished cardiac output, and right ventricular hypertrophy. In MCT(sl/sl) rats, morphometric evaluation revealed the presence of neointimal lesions within small distal pulmonary arteries, increased medial wall thickness, and decreased arterial-to-alveolar ratio. In keeping with this, barium angiography revealed diminished distal pulmonary vasculature of MCT(sl/sl) rat lungs. Cells within neointimal lesions expressed smooth muscle and endothelial cell markers. Moreover, cells within neointimal lesions exhibited increased levels of proliferation and were located in a tissue microenvironment enriched with vascular endothelial growth factor, tenascin-C, and activated matrix metalloproteinase-9, factors already implicated in human PAH. Finally, assessment of steady state mRNA showed that whereas expression of ET(B) receptors was decreased in MCT(sl/sl) rat lungs, ET(A) receptor expression increased. Deficiency of the ET(B) receptor markedly accelerates the progression of

  15. Re-expression of the mannose 6-phosphate receptors in receptor-deficient fibroblasts. Complementary function of the two mannose 6-phosphate receptors in lysosomal enzyme targeting.

    Science.gov (United States)

    Munier-Lehmann, H; Mauxion, F; Bauer, U; Lobel, P; Hoflack, B

    1996-06-21

    We have previously generated primary embryonic fibroblasts lacking either the cation-independent mannose 6-phosphate/insulin-like growth factor II receptor (MPR) or the cation-dependent MPR, two trans-membrane proteins that bind the mannose 6-phosphate (Man-6-P) recognition marker on soluble lysosomal enzymes (Ludwig, T., Munier-Lehmann, H., Bauer, U., Hollinshead, M., Ovitt, C., Lobel, P., and Hoflack, B.(1994) EMBO J. 13, 3430-3437). These two cell types partially missort phosphorylated lysosomal enzymes. Using two-dimensional gel electrophoresis, we show here that they secrete, in a large part, different phosphorylated ligands. In order to better understand the sorting function of the MPRs, we have re-expressed each MPR in MPR-negative fibroblasts. We show that the MPRs have similar capacities for transporting the bulk of the newly synthesized lysosomal enzymes and that they target individual ligands with various efficiencies. However, high levels of one MPR do not fully compensate for the absence of the other, demonstrating that the two MPRs have complementary targeting functions, perhaps by recognizing different features on lysosomal enzymes. The analysis of the phosphorylated oligosaccharides shows that the ligands missorted in the absence of the cation-dependent MPR are slightly but significantly depleted in oligosaccharides with two Man-6-P residues, when compared with those missorted in the absence of the cation-independent MPR. While these results could explain some differences between the structure and the sorting function of the two MPRs, they strongly suggest that the reason why cells express two different but related MPRs is to maintain an efficient Man-6-P-dependent targeting process that could be potentially regulated by MPR expression.

  16. IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation.

    Science.gov (United States)

    Fellmann, Florence; Angelini, Federica; Wassenberg, Jacqueline; Perreau, Matthieu; Arenas Ramirez, Natalia; Simon, Gregoire; Boyman, Onur; Demaria, Olivier; Christen-Zaech, Stephanie; Hohl, Daniel; Belfiore, Marco; von Scheven-Gete, Annette; Gilliet, Michel; Bochud, Pierre-Yves; Perrin, Yannick; Beck Popovic, Maya; Bart, Pierre-Alexandre; Beckmann, Jacques S; Martinet, Danielle; Hofer, Michaël

    2016-04-01

    Data on patients affected by chronic mucocutaneous candidiasis underscore the preponderant role of IL-17 receptor A (IL-17RA) in preserving mucocutaneous immunity. Little is known about the role of adenosine deaminase (ADA) 2 in regulation of immune responses, although recent reports linked ADA2 deficiency with inflammation and vasculitis. We sought to investigate the mechanisms of chronic inflammation and vasculitis in a child lacking IL-17RA and ADA2 to identify therapeutic targets. We report a family with 2 siblings who have had recurrent mucocutaneous infections with Candida albicans and Staphylococcus aureus and chronic inflammatory disease and vasculitis since early childhood, which were refractory to classical treatments. Array-based comparative genomic hybridization analysis showed that both siblings are homozygous for a 770-kb deletion on chr22q11.1 encompassing both IL17RA and cat eye critical region 1 (CECR1). Immunologic studies were carried out by means of flow cytometry, ELISA, and RIA. As expected, in the affected child we found a lack of IL-17RA expression, which implies a severe malfunction in the IL-17 signaling pathway, conferring susceptibility to recurrent mucocutaneous infections. Surprisingly, we detected an in vitro and in vivo upregulation of proinflammatory cytokines, notably IL-1β and TNF-α, which is consistent with the persistent systemic inflammation. This work emphasizes the utility of whole-genome analyses combined with immunologic investigation in patients with unresolved immunodeficiency. This approach is likely to provide an insight into immunologic pathways and mechanisms of disease. It also provides molecular evidence for more targeted therapies. In addition, our report further corroborates a potential role of ADA2 in modulating immunity and inflammation. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  17. Transcriptional profiling of Toll-like receptor 2-deficient primary murine brain cells during Toxoplasma gondii infection.

    Directory of Open Access Journals (Sweden)

    Kousuke Umeda

    Full Text Available Toxoplasma gondii is capable of persisting in the brain, although it is efficiently eliminated by cellular immune responses in most other sites. While Toll-like receptor 2 (TLR2 reportedly plays important roles in protective immunity against the parasite, the relationship between neurological disorders induced by T. gondii infection and TLR2 function in the brain remains controversial with many unknowns. In this study, primary cultured astrocytes, microglia, neurons, and peritoneal macrophages obtained from wild-type and TLR2-deficient mice were exposed to T. gondii tachyzoites. To characterize TLR2-dependent functional pathways activated in response to T. gondii infection, gene expression of different cell types was profiled by RNA sequencing.During T. gondii infection, a total of 611, 777, 385, and 1105 genes were upregulated in astrocytes, microglia, neurons, and macrophages, respectively, while 163, 1207, 158, and 1274 genes were downregulated, respectively, in a TLR2-dependent manner. Overrepresented Gene Ontology (GO terms for TLR2-dependently upregulated genes were associated with immune and stress responses in astrocytes, immune responses and developmental processes in microglia, metabolic processes and immune responses in neurons, and metabolic processes and gene expression in macrophages. Overrepresented GO terms for downregulated genes included ion transport and behavior in astrocytes, cell cycle and cell division in microglia, metabolic processes in neurons, and response to stimulus, signaling and cell motility in macrophages.To our knowledge, this is the first transcriptomic study of TLR2 function across different cell types during T. gondii infection. Results of RNA-sequencing demonstrated roles for TLR2 varied by cell type during T. gondii infection. Our findings facilitate understanding of the detailed relationship between TLR2 and T. gondii infection, and elucidate mechanisms underlying neurological changes during infection.

  18. SOD2 Deficient Erythroid Cells Up-Regulate Transferrin Receptor and Down-Regulate Mitochondrial Biogenesis and Metabolism

    Science.gov (United States)

    Martin, Florent M.; Xu, Xiuling; von Löhneysen, Katharina; Gilmartin, Timothy J.; Friedman, Jeffrey S.

    2011-01-01

    Background Mice irradiated and reconstituted with hematopoietic cells lacking manganese superoxide dismutase (SOD2) show a persistent hemolytic anemia similar to human sideroblastic anemia (SA), including characteristic intra-mitochondrial iron deposition. SA is primarily an acquired, clonal marrow disorder occurring in individuals over 60 years of age with uncertain etiology. Methodology/Principal Findings To define early events in the pathogenesis of this murine model of SA, we compared erythroid differentiation of Sod2-/- and normal bone marrow cells using flow cytometry and gene expression profiling of erythroblasts. The predominant transcriptional differences observed include widespread down-regulation of mitochondrial metabolic pathways and mitochondrial biogenesis. Multiple nuclear encoded subunits of complexes I-IV of the electron transport chain, ATP synthase (complex V), TCA cycle and mitochondrial ribosomal proteins were coordinately down-regulated in Sod2-/- erythroblasts. Despite iron accumulation within mitochondria, we found increased expression of transferrin receptor, Tfrc, at both the transcript and protein level in SOD2 deficient cells, suggesting deregulation of iron delivery. Interestingly, there was decreased expression of ABCb7, the gene responsible for X-linked hereditary SA with ataxia, a component required for iron-sulfur cluster biogenesis. Conclusions/Significance These results indicate that in erythroblasts, mitochondrial oxidative stress reduces expression of multiple nuclear genes encoding components of the respiratory chain, TCA cycle and mitochondrial protein synthesis. An additional target of particular relevance for SA is iron:sulfur cluster biosynthesis. By decreasing transcription of components of cluster synthesis machinery, both iron utilization and regulation of iron uptake are impacted, contributing to the sideroblastic phenotype. PMID:21326867

  19. SOD2 deficient erythroid cells up-regulate transferrin receptor and down-regulate mitochondrial biogenesis and metabolism.

    Directory of Open Access Journals (Sweden)

    Florent M Martin

    2011-02-01

    Full Text Available Mice irradiated and reconstituted with hematopoietic cells lacking manganese superoxide dismutase (SOD2 show a persistent hemolytic anemia similar to human sideroblastic anemia (SA, including characteristic intra-mitochondrial iron deposition. SA is primarily an acquired, clonal marrow disorder occurring in individuals over 60 years of age with uncertain etiology.To define early events in the pathogenesis of this murine model of SA, we compared erythroid differentiation of Sod2⁻/⁻ and normal bone marrow cells using flow cytometry and gene expression profiling of erythroblasts. The predominant transcriptional differences observed include widespread down-regulation of mitochondrial metabolic pathways and mitochondrial biogenesis. Multiple nuclear encoded subunits of complexes I-IV of the electron transport chain, ATP synthase (complex V, TCA cycle and mitochondrial ribosomal proteins were coordinately down-regulated in Sod2⁻/⁻ erythroblasts. Despite iron accumulation within mitochondria, we found increased expression of transferrin receptor, Tfrc, at both the transcript and protein level in SOD2 deficient cells, suggesting deregulation of iron delivery. Interestingly, there was decreased expression of ABCb7, the gene responsible for X-linked hereditary SA with ataxia, a component required for iron-sulfur cluster biogenesis.These results indicate that in erythroblasts, mitochondrial oxidative stress reduces expression of multiple nuclear genes encoding components of the respiratory chain, TCA cycle and mitochondrial protein synthesis. An additional target of particular relevance for SA is iron:sulfur cluster biosynthesis. By decreasing transcription of components of cluster synthesis machinery, both iron utilization and regulation of iron uptake are impacted, contributing to the sideroblastic phenotype.

  20. Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron-deficient anemia.

    Science.gov (United States)

    Rishi, Gautam; Secondes, Eriza S; Wallace, Daniel F; Subramaniam, V Nathan

    2016-08-01

    Iron metabolism and erythropoiesis are inherently interlinked physiological processes. Regulation of iron metabolism is mediated by the iron-regulatory hormone hepcidin. Hepcidin limits the amount of iron released into the blood by binding to and causing the internalization of the iron exporter, ferroportin. A number of molecules and physiological stimuli, including erythropoiesis, are known to regulate hepcidin. An increase in erythropoietic demand decreases hepcidin, resulting in increased bioavailable iron in the blood. Transferrin receptor 2 (TFR2) is involved in the systemic regulation of iron metabolism. Patients and mice with mutations in TFR2 develop hemochromatosis due to inappropriate hepcidin levels relative to body iron. Recent studies from our laboratory and others have suggested an additional role for TFR2 in response to iron-restricted erythropoiesis. These studies used mouse models with perturbed systemic iron metabolism: anemic mice lacking matriptase-2 and Tfr2, or bone marrow transplants from iron-loaded Tfr2 null mice. We developed a novel transgenic mouse model which lacks Tfr2 in the hematopoietic compartment, enabling the delineation of the role of Tfr2 in erythroid development without interfering with its role in systemic iron metabolism. We show that in the absence of hematopoietic Tfr2 immature polychromatic erythroblasts accumulate with a concordant reduction in the percentage of mature erythroid cells in the spleen and bone marrow of anemic mice. These results demonstrate that erythroid Tfr2 is essential for an appropriate erythropoietic response in iron-deficient anemia. These findings may be of relevance in clinical situations in which an immediate and efficient erythropoietic response is required. Am. J. Hematol. 91:812-818, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Divergent impact of Toll-like receptor 2 deficiency on repair mechanisms in healthy muscle versus Duchenne muscular dystrophy.

    Science.gov (United States)

    Mojumdar, Kamalika; Giordano, Christian; Lemaire, Christian; Liang, Feng; Divangahi, Maziar; Qureshi, Salman T; Petrof, Basil J

    2016-05-01

    Injury to skeletal muscle, whether acute or chronic, triggers macrophage-mediated innate immunity in a manner which can be either beneficial or harmful for subsequent repair. Endogenous ligands for Toll-like receptor 2 (TLR2) are released by damaged tissues and might play an important role in activating the innate immune system following muscle injury. To test this hypothesis, we compared macrophage behaviour and muscle repair mechanisms in mice lacking TLR2 under conditions of either acute (cardiotoxin-induced) or chronic (mdx mouse genetic model of Duchenne muscular dystrophy; DMD) muscle damage. In previously healthy muscle subjected to acute damage, TLR2 deficiency reduced macrophage numbers in the muscle post-injury but did not alter the expression pattern of the prototypical macrophage polarization markers iNOS and CD206. In addition, there was abnormal persistence of necrotic fibres and impaired regeneration in TLR2-/- muscles after acute injury. In contrast, TLR2 ablation in chronically diseased muscles of mdx mice not only resulted in significantly reduced macrophage numbers but additionally modified their phenotype by shifting from inflammatory (iNOS(pos) CD206(neg) ) to more anti-inflammatory (iNOS(neg) CD206(pos) ) characteristics. This decrease in macrophage-mediated inflammation was associated with ameliorated muscle histopathology and improved force-generating capacity of the dystrophic muscle. Our results suggest that the role of TLR2 in macrophage function and skeletal muscle repair depends greatly upon the muscle injury context, and raise the possibility that inhibition of TLR2 could serve as a useful therapeutic measure in DMD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  2. miR-34a deficiency in APP/PS1 mice promotes cognitive function by increasing synaptic plasticity via AMPA and NMDA receptors.

    Science.gov (United States)

    Xu, Yuelong; Chen, Ping; Wang, Xianjun; Yao, Jinguo; Zhuang, Sujing

    2018-02-06

    MicroRNA (miR)-34a was recently determined to contribute to the pathological development of Alzheimer's disease (AD). miR-34a deficiency significantly attenuates cognitive deficits in amyloid precursor protein (APP)/presenilin 1 (PS1) mice; however, its role in early AD pathology and the underlying mechanisms remain elusive. Here, we confirmed that the increase of miR-34a expression in APP/PS1 mice was earlier than the relevant AD pathological characteristics, such as amyloid-β production, amyloid plaque deposition, and cognitive deficits. Furthermore, because predicted miR-34a target genes were broadly linked to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors, we evaluated synaptic plasticity by investigating high-frequency conditioning tetanus-induced excitatory postsynaptic potential, which revealed that synaptic plasticity was promoted in miR-34a knockout/APP/PS1 mice. Therefore, we assessed the expression of the presynaptic components synaptophysin and postsynaptic density protein 95 (PSD95) and found that synaptophysin and PSD95 were not altered by miR-34a deficiency. Additionally, the synaptic strength (vesicular fusion, vesicular docking, and transporting) was either not significantly changed. We also evaluated the levels of AMPA and NMDA receptors, which showed that the expression of AMPA and NMDA receptors was markedly upregulated in APP/PS1 mice with miR-34a deficiency. We conclude that miR-34a is involved in synaptic deficits in AD pathological development, which was, at least in part, due to the inhibition of NMDA (by miR-34a-5p) and AMPA (by miR-34a-3p) receptor expression. Copyright © 2018. Published by Elsevier B.V.

  3. The Role of Vitamin D Deficiency and Vitamin D Receptor Genotypes on the Degree of Collateralization in Patients with Suspected Coronary Artery Disease

    Directory of Open Access Journals (Sweden)

    Arash Hossein-Nezhad

    2014-01-01

    Full Text Available We determined the association of vitamin D deficiency and the FokI polymorphism of the vitamin D receptor (VDR gene in 760 patients who underwent angiography due to suspected coronary artery disease (CAD. Angiography and the Rentrop scoring system were used to classify the severity of CAD in each patient and to grade the extent of collateral development, respectively. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP was used to determine the FokI VDR gene polymorphism. The prevalence of severe vitamin D deficiency (serum 25(OHD < 10 ng/mL was significantly higher in patients with at least one stenotic coronary artery compared to those without any stenotic coronary arteries. Severe vitamin D deficiency was not independently associated with collateralization, but it was significantly associated with the VDR genotypes. In turn, VDR genotype was independently associated with the degree of collateralization; the Rentrop scores were the highest in FF, intermediate in Ff, and the lowest in the ff genotype. The results show that FokI polymorphism is independently associated with collateralization. Additionally, vitamin D deficiency is more prevalent in patients with CAD that may result from FokI polymorphism. Therefore, maintaining a normal vitamin D status should be a high priority for patients with CAD.

  4. Demonstration by transfection studies that mutations in the adrenocorticotropin receptor gene are one cause of the hereditary syndrome of glucocorticoid deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Naville, D.; Barjhoux, L.; Jaillard, C. [Hopital Debrousse, Tours (France)] [and others

    1996-04-01

    The hereditary syndrome of unresponsiveness to ACTH is a rare autosomal recessive disorder characterized by low levels of serum cortisol and high levels of plasma ACTH. There is no cortisol response to exogenous ACTH. Recent cloning of the human ACTH receptor gene has enabled us to study this gene in patients with glucocorticoid deficiency. By using the PCR to amplify the coding sequence of the ACTH receptor gene, we identified three mutations in two unrelated patients. One mutation present in homozygous form converted the negatively charged Asp{sup 107}, located in the third transmembrane domain, to an uncharged Asn residue. The second patient was a compound heterozygote: the paternal allele contained a one-nucleotide insertion leading to a stop codon within the third extracellular loop, and the maternal allele contained a point mutation converting Cys{sup 235} to Phe, also in the third extracellular loop. Normal and mutant ACTH receptor genes were expressed in the M3 cell line, and intracellular cAMP production in response to ACTH was measured. For the mutant receptors, no response to physiological ACTH concentrations was detected, suggesting an impaired binding of ACTH to the receptors and/or an altered coupling to the adenylate cyclase effector. 24 refs., 6 figs., 2 tabs.

  5. Induction of experimental autoimmune encephalomyelitis in C57BL/6 mice deficient in either the chemokine macrophage inflammatory protein-1alpha or its CCR5 receptor

    DEFF Research Database (Denmark)

    Tran, E H; Kuziel, W A; Owens, T

    2000-01-01

    Macrophage inflammatory protein (MIP)-1alpha is a chemokine that is associated with Th1 cytokine responses. Expression and antibody blocking studies have implicated MIP-1alpha in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). We examined the role of MIP-1alpha...... and its CCR5 receptor in the induction of EAE by immunizing C57BL / 6 mice deficient in either MIP-1alpha or CCR5 with myelin oligodendrocyte glycoprotein (MOG). We found that MIP-1alpha-deficient mice were fully susceptible to MOG-induced EAE. These knockout animals were indistinguishable from wild-type...... mice in Th1 cytokine gene expression, the kinetics and severity of disease, and infiltration of the central nervous system by lymphocytes, macrophages and granulocytes. RNase protection assays showed comparable accumulation of mRNA for the chemokines interferon-inducible protein-10, RANTES, macrophage...

  6. ApoE-dependent modulation of HDL and atherosclerosis by G2A in LDL receptor-deficient mice independent of bone marrow-derived cells.

    Science.gov (United States)

    Parks, Brian W; Srivastava, Roshni; Yu, Shaohua; Kabarowski, Janusz H S

    2009-04-01

    Deletion of the lysophospholipid-sensitive receptor, G2A, in low-density lipoprotein receptor knockout (LDLR(-/-)) mice elevates plasma high-density lipoprotein (HDL) cholesterol and suppresses atherosclerosis. However, chemotactic action of G2A in monocytes/macrophages, in addition to its modulatory effect on HDL, may contribute to the proatherogenic action of G2A. We determined that deletion of G2A in LDLR(-/-) mice increases the ApoA1, ApoE, and cholesterol content of plasma HDL fractions. Hepatocytes were shown to express G2A and hepatocytes from G2A-deficient LDLR(-/-) mice secreted more ApoA1 and ApoE in HDL fractions compared to their G2A-sufficient counterparts. The atheroprotective and HDL modulatory effects of G2A deficiency were dependent on the presence of ApoE, as deletion of G2A in ApoE(-/-) and ApoE(-/-)LDLR(-/-) mice failed to raise HDL and did not suppress atherosclerosis. G2A deficiency in bone marrow-derived cells of LDLR(-/-) mice had no effect on atherosclerosis or HDL, whereas G2A deficiency in resident tissues was sufficient to raise HDL and suppress atherosclerosis. These data demonstrate that the chemotactic function of G2A in bone marrow-derived monocytes does not modulate atherosclerosis in LDLR(-/-) mice and suggest an ApoE-dependent function for G2A in the control of hepatic HDL metabolism that might contribute to its proatherogenic action.

  7. Acyl-coenzyme A:cholesterol acyltransferase inhibition ameliorates proteinuria, hyperlipidemia, lecithin-cholesterol acyltransferase, SRB-1, and low-denisty lipoprotein receptor deficiencies in nephrotic syndrome.

    Science.gov (United States)

    Vaziri, N D; Liang, K H

    2004-07-27

    Nephrotic syndrome (NS) is associated with hyperlipidemia, altered lipid regulatory enzymes and receptors, and increased risk of progressive renal and cardiovascular diseases. Acyl-coenzyme A:cholesterol acyltransferase (ACAT) catalyzes intracellular esterification of cholesterol and plays an important role in production of apolipoprotein B-containing lipoproteins, regulation of cholesterol-responsive proteins, and formation of foam cells. Because hepatic ACAT-2 is markedly upregulated in NS, we tested the hypothesis that inhibition of ACAT may improve cholesterol metabolism in NS. Rats with puromycin-induced NS were treated with either the ACAT inhibitor CI-976 or placebo for 2 weeks. Normal rats served as controls. Plasma lipids, renal function, and key lipid regulatory factors were measured. Untreated NS rats showed heavy proteinuria; hypoalbuminemia; elevated plasma cholesterol, triglyceride, LDL, VLDL, and total cholesterol-to-HDL cholesterol ratio; increased hepatic ACAT activity, ACAT-2 mRNA, and ACAT-2 protein; and reduced LDL receptor, HDL receptor, otherwise known as scavenger receptor B-1 (SRB-1) and plasma lecithin-cholesterol acyltransferase (LCAT). ACAT inhibitor reduced plasma cholesterol and triglycerides, normalized total cholesterol-to-HDL cholesterol ratio, and lowered hepatic ACAT activity without changing ACAT-2 mRNA or protein. This was accompanied by near normalizations of plasma LCAT, hepatic SRB-1, and LDL receptor and a significant amelioration of proteinuria and hypoalbuminemia. Pharmacological inhibition of ACAT reverses NS-induced LDL receptor, HDL receptor, and LCAT deficiencies; improves plasma lipid profile; and ameliorates proteinuria in nephrotic animals. Further studies are needed to explore the effect of ACAT inhibition in nephrotic humans.

  8. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism.

    NARCIS (Netherlands)

    Steinfeld, R.; Grapp, M.; Kraetzner, R.; Dreha-Kulaczewski, S.; Helms, G.; Dechent, P.; Wevers, R.A.; Grosso, S.; Gartner, J.

    2009-01-01

    Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited

  9. Impaired LDL Receptor-Related Protein 1 Translocation Correlates with Improved Dyslipidemia and Atherosclerosis in apoE-Deficient Mice

    DEFF Research Database (Denmark)

    Gordts, Philip L S M; Bartelt, Alexander; Nilsson, Stefan K

    2012-01-01

    Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1) dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE.......Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1) dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE....

  10. Effects of a n-3 PUFA deficient diet on the expression of retinoid nuclear receptors, neurogranin and neuromodulin in rat brain

    Directory of Open Access Journals (Sweden)

    Buaud Benjamin

    2007-05-01

    Full Text Available A lot of studies performed in rodents revealed that n-3 polyunsaturated fatty acid (PUFA deficient diets could induce deficits of learning capacities but the mechanisms involved are not well known. Retinoic acid (RA and its nuclear receptors (RAR and RXR play a central role in the maintenance of cognitive processes and synaptic plasticity via its action on target genes that are neurogranin (RC3 and neuromodulin (GAP43. Given some interferences were described between the retinoid and fatty acid signaling pathways, we investigated the effects of a _α-linolenic acid (18: 3 n-3 deficient diet on retinoic acid nuclear receptors (RAR, and RXR, on GAP43 and RC3, and on blood and brain fatty acid composition in rats at three times of diet: 3, 9 and 18 weeks. In blood and brain of these animals, we observed a severe n-3 PUFA deficit (18:3 n-3, 20:5 n-3 and particularly 22:6 n-3 associated with an increase in the n-6 PUFA content (mainly 22:5 n-6. Real-time PCR and western blot analysis allowed us to note that retinoid signaling, GAP43 and RC3 expression were affected in the striatum of the n-3 PUFA deprived rats.

  11. BCG Lymphadenitis and Recurrent Oral Candidiasis in an Infant with a New Mutation Leading to Interleukin-12 Receptor Beta-1 Deficiency

    Science.gov (United States)

    Aytekin, Caner; Dogu, Figen; Tuygun, Nilden; Tanir, Gonul; Guloglu, Deniz; Boisson-Dupuis, Stephanie; Bustamante, Jacinta; Feinberg, Jacqueline; Casanova, Jean-Laurent; Ikinciogullari, Aydan

    2012-01-01

    Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome characterized by the predisposition to infections caused by weakly virulent mycobacteria, such as bacille Calmette-Guérin (BCG) vaccines and environmental mycobacteria. Salmonellosis has been reported in almost half of affected patients. Patients are also vulnerable to Mycobacterium tuberculosis. Various other infectious diseases occurred, albeit each rarely, but mucocutaneous candidiasis have been reported in more patients. Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most frequent genetic cause of MSMD. Here, we describe an infant with a single episode of BCG lymphadenitis (BCG-itis) who also suffered from recurrent oral candidiasis. Genetic analysis revealed a new homozygous mutation (64+1G>T) in the IL12RB1 gene that caused complete IL-12Rβ1 deficiency. IL12Rβ1 deficiency should be considered in patients with BCG infection, even a single episode of BCG-itis or recurrent mucocutaneous candidiasis. Nevertheless, awareness should be increased in countries where BCG vaccination is performed. PMID:21905505

  12. Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer's disease leads to enhanced cognitive impairment despite of a reduction in amyloid deposition.

    Science.gov (United States)

    Stumm, Christoph; Hiebel, Christof; Hanstein, Regina; Purrio, Martin; Nagel, Heike; Conrad, Andrea; Lutz, Beat; Behl, Christian; Clement, Angela B

    2013-11-01

    Alzheimer's disease (AD) is characterized by amyloid-β deposition in amyloid plaques, neurofibrillary tangles, inflammation, neuronal loss, and cognitive deficits. Cannabinoids display neuromodulatory and neuroprotective effects and affect memory acquisition. Here, we studied the impact of cannabinoid receptor type 1 (CB1) deficiency on the development of AD pathology by breeding amyloid precursor protein (APP) Swedish mutant mice (APP23), an AD animal model, with CB1-deficient mice. In addition to the lower body weight of APP23/CB1(-/-) mice, most of these mice died at an age before typical AD-associated changes become apparent. The surviving mice showed a reduced amount of APP and its fragments suggesting a regulatory influence of CB1 on APP processing, which was confirmed by modulating CB1 expression in vitro. Reduced APP levels were accompanied by a reduced plaque load and less inflammation in APP23/CB1(-/-) mice. Nevertheless, compared to APP23 mice with an intact CB1, APP23/CB1(-/-) mice showed impaired learning and memory deficits. These data argue against a direct correlation of amyloid plaque load with cognitive abilities in this AD mouse model lacking CB1. Furthermore, the findings indicate that CB1 deficiency can worsen AD-related cognitive deficits and support a potential role of CB1 as a pharmacologic target. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study.

    Science.gov (United States)

    Wilkinson, R J; Llewelyn, M; Toossi, Z; Patel, P; Pasvol, G; Lalvani, A; Wright, D; Latif, M; Davidson, R N

    2000-02-19

    Susceptibility to disease after infection by Mycobacterium tuberculosis is influenced by environmental and host genetic factors. Vitamin D metabolism leads to activation of macrophages and restricts the intracellular growth of M. tuberculosis. This effect may be influenced by polymorphisms at three sites in the vitamin D receptor (VDR) gene. We investigated the interaction between serum vitamin D (25-hydroxycholecalciferol) concentrations and VDR genotype on susceptibility to tuberculosis. This study was a hospital-based case-control analysis of Asians of Gujarati origin, a mainly vegetarian immigrant population with a high rate of tuberculosis. We typed three VDR polymorphisms (defined by the presence of restriction endonuclease sites for Taq1, Bsm1, and Fok1) in 91 of 126 untreated patients with tuberculosis and 116 healthy contacts who had been sensitised to tuberculosis. Serum 25-hydroxycholecalciferol was recorded in 42 contacts and 103 patients. 25-hydroxycholecalciferol deficiency was associated with active tuberculosis (odds ratio 2.9 [95% CI 1.3-6.5], p=0.008), and undetectable serum 25-hydroxycholecalciferol (<7 nmol/L) carried a higher risk of tuberculosis (9.9 [1.3-76.2], p=0.009). Although there was no significant independent association between VDR genotype and tuberculosis, the combination of genotype TT/Tt and 25-hydroxycholecalciferol deficiency was associated with disease (2.8 [1.2-6.5]) and the presence of genotype ff or undetectable serum 25-hydroxycholecalciferol was strongly associated with disease (5.1 [1.4-18.4]). 25-hydroxycholecalciferol deficiency may contribute to the high occurrence of tuberculosis in this population. Polymorphisms in the VDR gene also contribute to susceptibility when considered in combination with 25-hydroxycholecalciferol deficiency.

  14. Firing properties of dopamine neurons in freely moving dopamine-deficient mice: Effects of dopamine receptor activation and anesthesia

    OpenAIRE

    Robinson, Siobhan; Smith, David M.; Mizumori, Sheri J. Y.; Palmiter, Richard D.

    2004-01-01

    To examine the regulation of midbrain dopamine neurons, recordings were obtained from single neurons of freely moving, genetically engineered dopamine-deficient (DD) mice. DD mice were tested without dopamine signaling (basal state) and with endogenous dopamine signaling (after L-dopa administration). In the basal state, when dopamine concentration in DD mice is

  15. Impaired vascular contractility and aortic wall degeneration in fibulin-4 deficient mice: effect of angiotensin II type 1 (AT1 receptor blockade.

    Directory of Open Access Journals (Sweden)

    Els Moltzer

    Full Text Available Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang II type 1 (AT(1 receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4(+/R and 4-fold (homozygous Fibulin-4(R/R reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT(1 receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4(R/R mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT(1 receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic

  16. The Unique Functions of the Type-II IL-4 Receptor are revealed in IL-13R¿1-deficient mice

    Science.gov (United States)

    The IL-4 receptor is a central mediator of Th2-mediated diseases and associates with either the common gamma chain (type-I IL-4R) or IL-13Ra1 (type-II IL-4R) to form two receptor complexes. Here, using IL-13Ra1-/- mice, we characterized the distinct functions of the type-II IL-4R. In contrast to IL-...

  17. A platelet-activating factor (PAF) receptor deficiency exacerbates diet-induced obesity but PAF/PAF receptor signaling does not contribute to the development of obesity-induced chronic inflammation.

    Science.gov (United States)

    Yamaguchi, Masahiko; Matsui, Masakazu; Higa, Ryoko; Yamazaki, Yasuhiro; Ikari, Akira; Miyake, Masaki; Miwa, Masao; Ishii, Satoshi; Sugatani, Junko; Shimizu, Takao

    2015-02-15

    Platelet-activating factor (PAF) is a well-known phospholipid that mediates acute inflammatory responses. In the present study, we investigated whether PAF/PAF receptor signaling contributed to chronic inflammation in the white adipose tissue (WAT) of PAF receptor-knockout (PAFR-KO) mice. Body and epididymal WAT weights were higher in PAFR-KO mice fed a high-fat diet (HFD) than in wild-type (WT) mice. TNF-α mRNA expression levels in epididymal WAT and the infiltration of CD11c-positive macrophages into epididymal WAT, which led to chronic inflammation, were also elevated in HFD-fed PAFR-KO mice. HFD-fed PAFR-KO mice had higher levels of fasting serum glucose than HFD-fed WT mice as well as impaired glucose tolerance. Although PAF receptor signaling up-regulated the expression of TNF-α and lipopolysaccharide induced the expression of acyl-CoA:lysophosphatidylcholine acyltransferase 2 (LPCAT2) mRNA in bone marrow-derived macrophages, no significant differences were observed in the expression of LPCAT2 mRNA and PAF levels in epididymal WAT between HFD-fed mice and normal diet-fed mice. In addition to our previous finding in which energy expenditure in PAF receptor (PAFR)-deficient mice was low due to impaired brown adipose tissue function, the present study demonstrated that PAF/PAF receptor signaling up-regulated the expression of Ucp1 mRNA, which is essential for cellular thermogenesis, in 3T3-L1 adipocytes. We concluded that the marked accumulation of abdominal fat due to HFD feeding led to more severe chronic inflammation in WAT, which is associated with glucose metabolism disorders, in PAFR-KO mice than in WT mice, and PAF/PAF receptor signaling may regulate energy expenditure and adiposity. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Mutations in Prokineticin 2 and Prokineticin receptor 2genes in Human Gonadotrophin-Releasing Hormone Deficiency: Molecular Genetics and Clinical Spectrum

    Science.gov (United States)

    Cole, Lindsay W.; Sidis, Yisrael; Zhang, ChengKang; Quinton, Richard; Plummer, Lacey; Pignatelli, Duarte; Hughes, Virginia A.; Dwyer, Andrew A.; Raivio, Taneli; Hayes, Frances J.; Seminara, Stephanie B.; Huot, Celine; Alos, Nathalie; Speiser, Phyllis; Takeshita, Akira; VanVliet, Guy; Pearce, Simon; Crowley, William F.; Zhou, Qun-Yong; Pitteloud, Nelly

    2008-01-01

    Context: Mice deficient in prokineticin 2(PROK2) and prokineticin receptor2 (PROKR2) exhibit variable olfactory bulb dysgenesis and GnRH neuronal migration defects reminiscent of human GnRH deficiency. Objectives: We aimed to screen a large cohort of patients with Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (IHH) for mutations in PROK2/PROKR2, evaluate their prevalence, define the genotype/phenotype relationship, and assess the functionality of these mutant alleles in vitro. Design: Sequencing of the PROK2 and PROKR2 genes was performed in 170 KS patients and 154 nIHH. Mutations were examined using early growth response 1-luciferase assays in HEK 293 cells and aequorin assays in Chinese hamster ovary cells. Results: Four heterozygous and one homozygous PROK2 mutation (p.A24P, p.C34Y, p.I50M, p.R73C, and p.I55fsX1) were identified in five probands. Four probands had KS and one nIHH, and all had absent puberty. Each mutant peptide impaired receptor signaling in vitro except the I50M. There were 11 patients who carried a heterozygous PROKR2 mutation (p.R85C, p.Y113H, p.V115M, p.R164Q, p.L173R, p.W178S, p.S188L, p.R248Q, p.V331M, and p.R357W). Among them, six had KS, four nIHH, and one KS proband carried both a PROKR2 (p.V115M) and PROK2 (p.A24P) mutation. Reproductive phenotypes ranged from absent to partial puberty to complete reversal of GnRH deficiency after discontinuation of therapy. All mutant alleles appear to decrease intracellular calcium mobilization; seven exhibited decreased MAPK signaling, and six displayed decreased receptor expression. Nonreproductive phenotypes included fibrous dysplasia, sleep disorder, synkinesia, and epilepsy. Finally, considerable variability was evident in family members with the same mutation, including asymptomatic carriers. Conclusion: Loss-of-function mutations in PROK2 and PROKR2 underlie both KS and nIHH. PMID:18559922

  19. Temporal phasing of locomotor activity, heart rate rhythmicity, and core body temperature is disrupted in VIP receptor 2-deficient mice

    DEFF Research Database (Denmark)

    Hannibal, Jens; Hsiung, Hansen M; Fahrenkrug, Jan

    2011-01-01

    Neurons of the brain's biological clock located in the hypothalamic suprachiasmatic nucleus (SCN) generate circadian rhythms of physiology (core body temperature, hormone secretion, locomotor activity, sleep/wake, and heart rate) with distinct temporal phasing when entrained by the light/dark (LD...... these observations with observations made from mice examined by wheel-running activity. The study demonstrates that VPAC2 signaling is necessary for a functional circadian clock driving locomotor activity, core body temperature, and heart rate rhythmicity, since VPAC2-deficient mice lose the rhythms in all three...... parameters when placed under constant conditions (of either light or darkness). Furthermore, although 24-h rhythms for three parameters are retained in VPAC2-deficient mice during the LD cycle, the temperature rhythm displays markedly altered time course and profile, rising earlier and peaking ~4-6 h prior...

  20. Temporal phasing of locomotor activity, heart rate rhythmicity, and core body temperature is disrupted in VIP receptor 2-deficient mice

    DEFF Research Database (Denmark)

    Hannibal, Jens; Hsiung, Hansen M; Fahrenkrug, Jan

    2011-01-01

    Neurons of the brain's biological clock located in the hypothalamic suprachiasmatic nucleus (SCN) generate circadian rhythms of physiology (core body temperature, hormone secretion, locomotor activity, sleep/wake, and heart rate) with distinct temporal phasing when entrained by the light/dark (LD...... these observations with observations made from mice examined by wheel-running activity. The study demonstrates that VPAC2 signaling is necessary for a functional circadian clock driving locomotor activity, core body temperature, and heart rate rhythmicity, since VPAC2-deficient mice lose the rhythms in all three...... parameters when placed under constant conditions (of either light or darkness). Furthermore, although 24-h rhythms for three parameters are retained in VPAC2-deficient mice during the LD cycle, the temperature rhythm displays markedly altered time course and profile, rising earlier and peaking ∼4-6 h prior...

  1. CB2 receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer's disease.

    Science.gov (United States)

    Koppel, Jeremy; Vingtdeux, Valerie; Marambaud, Philippe; d'Abramo, Cristina; Jimenez, Heidy; Stauber, Mark; Friedman, Rachel; Davies, Peter

    2014-03-14

    The endocannabinoid CB2 receptor system has been implicated in the neuropathology of Alzheimer's disease (AD). In order to investigate the impact of the CB2 receptor system on AD pathology, a colony of mice with a deleted CB2 receptor gene, CNR2, was established on a transgenic human mutant APP background for pathological comparison with CB2 receptor-sufficient transgenic mice. J20 APP (PDGFB-APPSwInd) mice were bred over two generations with CNR2(-/-) (Cnr2(tm1Dgen)/J) mice to produce a colony of J20 CNR2(+/+) and J20 CNR2(-/-) mice. Seventeen J20 CNR2(+/+) mice (12 females, 5 males) and 16 J20 CNR2(-/-) mice (11 females, 5 males) were killed at 12 months, and their brains were interrogated for AD-related pathology with both biochemistry and immunocytochemistry (ICC). In addition to amyloid-dependent endpoints such as soluble Aβ production and plaque deposition quantified with 6E10 staining, the effect of CB2 receptor deletion on total soluble mouse tau production was assayed by using a recently developed high-sensitivity assay. Results revealed that soluble Aβ42 and plaque deposition were significantly increased in J20 CNR2(-/-) mice relative to CNR2(+/+) mice. Microgliosis, quantified with ionized calcium-binding adapter molecule 1 (Iba-1) staining, did not differ between groups, whereas plaque associated microglia was more abundant in J20 CNR2(-/-) mice. Total tau was significantly suppressed in J20 CNR2(-/-) mice relative to J20 CNR2(+/+) mice. The results confirm the constitutive role of the CB2 receptor system both in reducing amyloid plaque pathology in AD and also support tehpotential of cannabinoid therapies targeting CB2 to reduce Aβ; however, the results suggest that interventions may have a divergent effect on tau pathology.

  2. Rapid Phosphoproteomic Effects of Abscisic Acid (ABA) on Wild-Type and ABA Receptor-Deficient A. thaliana Mutants*

    Science.gov (United States)

    Minkoff, Benjamin B.; Stecker, Kelly E.; Sussman, Michael R.

    2015-01-01

    Abscisic acid (ABA)1 is a plant hormone that controls many aspects of plant growth, including seed germination, stomatal aperture size, and cellular drought response. ABA interacts with a unique family of 14 receptor proteins. This interaction leads to the activation of a family of protein kinases, SnRK2s, which in turn phosphorylate substrates involved in many cellular processes. The family of receptors appears functionally redundant. To observe a measurable phenotype, four of the fourteen receptors have to be mutated to create a multilocus loss-of-function quadruple receptor (QR) mutant, which is much less sensitive to ABA than wild-type (WT) plants. Given these phenotypes, we asked whether or not a difference in ABA response between the WT and QR backgrounds would manifest on a phosphorylation level as well. We tested WT and QR mutant ABA response using isotope-assisted quantitative phosphoproteomics to determine what ABA-induced phosphorylation changes occur in WT plants within 5 min of ABA treatment and how that phosphorylation pattern is altered in the QR mutant. We found multiple ABA-induced phosphorylation changes that occur within 5 min of treatment, including three SnRK2 autophosphorylation events and phosphorylation on SnRK2 substrates. The majority of robust ABA-dependent phosphorylation changes observed were partially diminished in the QR mutant, whereas many smaller ABA-dependent phosphorylation changes observed in the WT were not responsive to ABA in the mutant. A single phosphorylation event was increased in response to ABA treatment in both the WT and QR mutant. A portion of the discovery data was validated using selected reaction monitoring-based targeted measurements on a triple quadrupole mass spectrometer. These data suggest that different subsets of phosphorylation events depend upon different subsets of the ABA receptor family to occur. Altogether, these data expand our understanding of the model by which the family of ABA receptors directs

  3. Melatonin Attenuates Memory Impairment Induced by Klotho Gene Deficiency Via Interactive Signaling Between MT2 Receptor, ERK, and Nrf2-Related Antioxidant Potential

    Science.gov (United States)

    Shin, Eun-Joo; Chung, Yoon Hee; Le, Hoang-Lan Thi; Jeong, Ji Hoon; Dang, Duy-Khanh; Nam, Yunsung; Wie, Myung Bok; Nah, Seung-Yeol; Nabeshima, Yo-Ichi; Nabeshima, Toshitaka; Kim, Hyoung-Chun

    2015-01-01

    Background: We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down-regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment. Methods: First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin. Results: Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatonin-mediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice. Conclusions: Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2-related antioxidant potential. PMID

  4. Impact of tumor necrosis factor receptor p55 deficiency in susceptibility of C57BL/6 mice to infection with Leishmania (Leishmania) amazonensis.

    Science.gov (United States)

    Cargnelutti, Diego Esteban; Salomón, María Cristina; Celedon, Verónica; Cuello-Carrión, Fernando Darío; Gea, Susana; Di Genaro, María Silvia; Scodeller, Eduardo Alberto

    2016-04-01

    Tumor necrosis factor (TNF) is involved in host resistance to several intracellular pathogens. Although the critical role of TNF receptor (TNFR)p55 in Leishmania (Leishmania) major infection has been demonstrated, the impact of TNFRp55 deficiency on L. (L.) amazonensis infection has not been explored. L. (L.) amazonensis-infected TNFRp55(-/-) mice failed to resolve lesions, whereas C57BL/6 wild-type mice completely healed. The susceptibility of the TNFRp55(-/-) mice was characterized by higher lesion size and histopathological damage in comparison with the wild-type mice. A marked increased of the splenic index was observed in the TNFRp55(-/-) mice after 15 weeks infection. These results show that in the absence of TNFRp55, L. (L.) amazonensis-infected knockout mice fail to resolve lesions, whereas wild-type mice completely heal. Copyright © 2014. Published by Elsevier B.V.

  5. Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats

    NARCIS (Netherlands)

    Chen, X.; Walther, F. J.; van Boxtel, R.|info:eu-repo/dai/nl/344456110; Laghmani, E. H.; Sengers, R. M. A.; Folkerts, G.; DeRuiter, M. C.; Cuppen, E.|info:eu-repo/dai/nl/183050487; Wagenaar, G. T. M.

    Aim Blocking of lysophosphatidic acid (LPA) receptor (LPAR) 1 may be a novel therapeutic option for bronchopulmonary dysplasia (BPD) by preventing the LPAR1-mediated adverse effects of its ligand (LPA), consisting of lung inflammation, pulmonary arterial hypertension (PAH) and fibrosis. Methods In

  6. Low-density lipoprotein receptor deficiency resulting in familial hypercholesterolaemia in a black man. A follow-up study

    NARCIS (Netherlands)

    Coetzee, G. A.; van Wingerden, J. J.; van der Westhuyzen, D. R.

    1985-01-01

    The binding and catabolism of low-density lipoprotein (LDL) was measured in cultured skin fibroblasts and Epstein-Barr virus-transformed lymphoblastoid cells from a South African black man. On the basis of LDL receptor activity, the patient was classified as a familial hypercholesterolaemic

  7. The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen improve ANP levels and decrease nuclear translocation of NF-kB in estrogen-deficient rats.

    Science.gov (United States)

    Lamas, Aline Z; Nascimento, Andrews M; Medeiros, Ana Raquel S; Caliman, Izabela F; Dalpiaz, Polyana L M; Firmes, Luciana B; Sousa, Glauciene J; Oliveira, Phablo Wendell C; Andrade, Tadeu U; Reis, Adelina M; Gouvea, Sônia A; Bissoli, Nazaré S

    2017-08-01

    The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are used for the treatment of osteoporosis and cancer, respectively, in women. The impairment of both the Atrial Natriuretic Peptide (ANP) cell signaling system and the translocation of nuclear factor-kappa B (NF-kB) to the cell nucleus are associated with detrimental cardiovascular effects and inflammation. The effects of SERMs on these parameters in the cardiac tissue of estrogen-deficient rats has not been reported. We investigated the effects of raloxifene and tamoxifen on ANP signaling, p65 NF-kB nuclear translocation, cardiac histology and contractility. Female rats were divided into five groups: control (SHAM), ovariectomized (OVX), OVX-treated 17-β-estradiol (E), OVX-treated raloxifene (RLX) and OVX-treated tamoxifen (TAM). The treatments started 21days after ovariectomy and continued for 14days. Ovariectomy reduced ANP mRNA in the left atrium (LA), decreased the content of ANP protein in the LA and in plasma, and increased the level of p65 NF-kB nuclear translocation in the left ventricle. Both 17-β-estradiol and SERMs were able to reverse these alterations, which were induced by the estrogen deficient state. The hemodynamic and cardiac structural parameters analyzed in the present work were not modified by the interventions. Our study demonstrates, for the first time, the additional benefits of raloxifene and tamoxifen in an estrogen-deficient state. These include the normalization of plasmatic and cardiac ANP levels and cardiac p65 NF-kB translocation. Therefore, these treatments promote cardiovascular protection and may contribute to the prevention of cardiac dysfunction observed long-term in postmenopausal women. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

  8. Dichotomy in FcγRIIB deficiency and autoimmune-prone SLAM haplotype clarifies the roles of the Fc receptor in development of autoantibodies and glomerulonephritis.

    Science.gov (United States)

    Kanari, Yasuyoshi; Sugahara-Tobinai, Akiko; Takahashi, Haruka; Inui, Masanori; Nakamura, Akira; Hirose, Sachiko; Takai, Toshiyuki

    2014-10-24

    The significance of a unique inhibitory Fc receptor for IgG, FcγRIIB (RIIB), in the prevention of spontaneous production of autoantibodies remains controversial, due mainly to the fact that the RIIB locus is adjacent to the autoimmune-related SLAM locus harboring the genes coding for signaling lymphocyte activation molecules, making it difficult to isolate the effect of RIIB deletion from that of SLAM in gene-targeted mice. Our objective was to determine the influence of RIIB deletion on the spontaneous development of autoimmune diseases and to compare it with that of potentially pathogenic SLAM. We established two congenic C57BL/6 (B6) strains, one with the RIIB deletion and the other with SLAM, by backcrossing 129/SvJ-based RIIB-deficient mice into the B6 genetic background extensively. The RIIB deficiency indeed led to the production and/or accumulation of a small amount of anti-nuclear autoantibodies (ANAs) and to weak IgG immune-complex deposition in glomeruli without any obvious manifestation of lupus nephritis. In contrast, pathogenic SLAM in the B6 genetic background induced ANAs but no IgG immune-complex deposition in the kidneys. Naïve SLAM mice but not RIIB-deficient mice exhibited hyperplasia of splenic germinal centers. The present results clarify the roles of RIIB in preventing production and/or accumulation of a small amount of ANAs, and development of glomerulonephritis. The combined effects of RIIB deletion and pathogenic SLAM can lead to severe lupus nephritis in the B6 genetic background.

  9. Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene.

    Science.gov (United States)

    Waterham, Hans R; Koster, Janet; Mooyer, Petra; Noort Gv, Gerard van; Kelley, Richard I; Wilcox, William R; Wanders, Ronald J A; Hennekam, Raoul C M; Oosterwijk, Jan C

    2003-04-01

    Hydrops-ectopic calcification-"moth-eaten" (HEM) or Greenberg skeletal dysplasia is an autosomal recessive chondrodystrophy with a lethal course, characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification. We found elevated levels of cholesta-8,14-dien-3beta-ol in cultured skin fibroblasts of an 18-wk-old fetus with HEM, compatible with a deficiency of the cholesterol biosynthetic enzyme 3beta-hydroxysterol delta(14)-reductase. Sequence analysis of two candidate genes encoding putative human sterol delta(14)-reductases (TM7SF2 and LBR) identified a homozygous 1599-1605TCTTCTA-->CTAGAAG substitution in exon 13 of the LBR gene encoding the lamin B receptor, which results in a truncated protein. Functional complementation of the HEM cells by transfection with control LBR cDNA confirmed that LBR encoded the defective sterol delta(14)-reductase. Mutations in LBR recently have been reported also to cause Pelger-Huët anomaly, an autosomal dominant trait characterized by hypolobulated nuclei and abnormal chromatin structure in granulocytes. The fact that the healthy mother of the fetus showed hypolobulated nuclei in 60% of her granulocytes confirms that classic Pelger-Huët anomaly represents the heterozygous state of 3beta-hydroxysterol delta(14)-reductase deficiency.

  10. Development of an autoimmune syndrome affecting the skin and internal organs in P-selectin glycoprotein ligand 1 leukocyte receptor-deficient mice.

    Science.gov (United States)

    Pérez-Frías, A; González-Tajuelo, R; Núñez-Andrade, N; Tejedor, R; García-Blanco, M J; Vicente-Rabaneda, E; Castañeda, S; Gamallo, C; Silván, J; Esteban-Villafruela, A; Cubero-Rueda, L; García-García, C; Muñoz-Calleja, C; García-Diez, A; Urzainqui, A

    2014-11-01

    To define and characterize the progression of the spontaneous autoimmune disease that develops in mice in the absence of the leukocyte adhesion receptor P-selectin glycoprotein ligand 1 (PSGL-1). Skin-resident immune cells from PSGL-1-deficient mice and C57BL/6 control mice of different ages were isolated and analyzed by flow cytometry. Biochemical parameters were analyzed in mouse serum and urine, and the presence of serum autoantibodies was investigated. Skin and internal organs were extracted, and their structure was analyzed histologically. Skin-resident innate and adaptive immune cells from PSGL-1(-/-) mice had a proinflammatory phenotype with an imbalanced T effector cell:Treg cell ratio. Sera from PSGL-1(-/-) mice had circulating autoantibodies commonly detected in connective tissue-related human autoimmune diseases. Biochemical and histologic analysis of skin and internal organs revealed skin fibrosis and structural and functional abnormalities in the lungs and kidneys. Furthermore, PSGL-1(-/-) mice exhibited vascular alterations, showing loss of dermal vessels, small vessel medial layer remodeling in the lungs and kidneys, and ischemic processes in the kidney that promote renal infarcts. Our study demonstrates that immune system overactivation due to PSGL-1 deficiency triggers an autoimmune syndrome with characteristics similar to systemic sclerosis, including skin fibrosis, vascular alterations, and systemic organ involvement. These results suggest that PSGL-1 expression contributes to the maintenance of the homeostasis of the immune system and could act as a barrier for autoimmunity in mice. Copyright © 2014 by the American College of Rheumatology.

  11. Coupling of receptor interference and a host-dependent post-binding entry deficiency in a gammaretroviral envelope protein

    Directory of Open Access Journals (Sweden)

    Sørensen Karina

    2010-02-01

    Full Text Available Abstract Background SL3-2 is a unique polytropic murine gammaretroviral isolate that is only able to infect murine cells. We have previously shown that two mutations R212G and T213I located on the surface of the receptor binding domain in a region designated the VR3 loop can alter the species tropism of this envelope protein. This location suggests that the VR3 loop composition has an influence on receptor interaction and thereby affects binding as well as superinfection resistance. In order to investigate this further, we have studied the binding and interference patterns of the SL3-2 envelope and its mutants. Results We find unexpectedly that wild type SL3-2 envelope binds equally well to both permissive and non-permissive cells, indicating a post binding defect when interacting with the human Xpr1. Using replication competent viruses containing envelopes from SL3-2 or its mutants we find that the same amino acid mutations can dramatically alter the interference profile of this polytropic ENV, suggesting that the same amino acid changes that cause the post binding defect also influence interaction with the receptor. Conclusions The envelope protein of SL3-2 MLV shows an entry defect on non-murine cells. This is coupled to a dramatically reduced ability to interfere with entry of other polytropic viruses. Two point mutations in the VR3 loop of the receptor binding domain of this envelope result both in a much increased interference ability and in removing the post-binding defect on non-murine cells, suggesting that both of these phenotypes are a consequence of insufficient interaction between the envelope and the receptor

  12. CRISPR/Cas9 in locusts: Successful establishment of an olfactory deficiency line by targeting the mutagenesis of an odorant receptor co-receptor (Orco).

    Science.gov (United States)

    Li, Yan; Zhang, Jie; Chen, Dafeng; Yang, Pengcheng; Jiang, Feng; Wang, Xianhui; Kang, Le

    2016-12-01

    Locusts are important agricultural pests worldwide and regarded as study models for entomology. However, the absence of targeted gene manipulation systems for locusts has restricted their applications for research. Herein, we report the successful use of the CRISPR/Cas9 system to induce a targeted heritable mutagenesis of the migratory locust, Locusta migratoria. The target sequence of gRNA was designed to disrupt the gene encoding the odorant receptor co-receptor (Orco) and examine the roles of the odorant receptor pathway in the locust. Microinjection of the mixture of Cas9-mRNA and Orco-gRNA into the locust eggs resulted in efficient target-gene editing at a rate of 71.7% in G0 animals and achieved a germline efficiency of up to 88.1% in G1 animals. By a crossing strategy, we successfully established stable Orco mutant lines. EAGs and SSRs indicated that the fourth-instar nymphs of the Orco mutants showed severely impaired electrophysiological responses to multiple odors. The Orco mutant locusts lost an attraction response to aggregation pheromones under the crowding conditions. The locomotor activity and body coloration of the Orco mutant locusts did not significantly differ from those of the two other genotypes. This study provides an easy and effective approach by using the CRISPR/Cas9 system for generating loss-of-function mutants for functional genetic studies of locusts and for managing insect pests. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Fibromodulin-deficiency alters temporospatial expression patterns of transforming growth factor-β ligands and receptors during adult mouse skin wound healing.

    Directory of Open Access Journals (Sweden)

    Zhong Zheng

    Full Text Available Fibromodulin (FMOD is a small leucine-rich proteoglycan required for scarless fetal cutaneous wound repair. Interestingly, increased FMOD levels have been correlated with decreased transforming growth factor (TGF-β1 expression in multiple fetal and adult rodent models. Our previous studies demonstrated that FMOD-deficiency in adult animals results in delayed wound closure and increased scar size accompanied by loose package collagen fiber networks with increased fibril diameter. In addition, we found that FMOD modulates in vitro expression and activities of TGF-β ligands in an isoform-specific manner. In this study, temporospatial expression profiles of TGF-β ligands and receptors in FMOD-null and wild-type (WT mice were compared by immunohistochemical staining and quantitative reverse transcriptase-polymerase chain reaction using a full-thickness, primary intention wound closure model. During the inflammatory stage, elevated inflammatory infiltration accompanied by increased type I TGF-β receptor levels in individual inflammatory cells was observed in FMOD-null wounds. This increased inflammation was correlated with accelerated epithelial migration during the proliferative stage. On the other hand, significantly more robust expression of TGF-β3 and TGF-β receptors in FMOD-null wounds during the proliferative stage was associated with delayed dermal cell migration and proliferation, which led to postponed granulation tissue formation and wound closure and increased scar size. Compared with WT controls, expression of TGF-β ligands and receptors by FMOD-null dermal cells was markedly reduced during the remodeling stage, which may have contributed to the declined collagen synthesis capability and unordinary collagen architecture. Taken together, this study demonstrates that a single missing gene, FMOD, leads to conspicuous alternations in TGF-β ligand and receptor expression at all stages of wound repair in various cell types. Therefore

  14. Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice

    Science.gov (United States)

    The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob (Ghrelin(-/-):ob/ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth ...

  15. Cardioprotective Effect of Selective Estrogen Receptor Modulator Raloxifene Are Mediated by Heme Oxygenase in Estrogen-Deficient Rat

    Directory of Open Access Journals (Sweden)

    Anikó Posa

    2017-01-01

    Full Text Available Estrogens and raloxifene (RAL have beneficial effects on certain cardiovascular indices in postmenopausal women characterized by estrogen deficiency. Heme oxygenase (HO activity is increased by 17β-estradiol (E2 and RAL in estrogen-deficient rat resulting in vasorelaxation mediated by carbon monoxide. We determined the expressions of HO in cardiac and aortic tissues after ovariectomy (OVX and subsequent RAL or E2 treatment. We investigated the effects of pharmacological inhibition of HO enzyme on the arginine vasopressin- (AVP- induced blood pressure in vivo, the epinephrine- and phentolamine-induced electrocardiogram ST segment changes in vivo, and the myeloperoxidase (MPO enzyme activity. When compared with intact females, OVX decreased the HO-1 and HO-2 expression, aggravated the electrocardiogram signs of heart ischemia and the blood pressure response to AVP, and increased the cardiac MPO. E2 and RAL are largely protected against these negative impacts induced by OVX. The pharmacological inhibition of HO in E2- or RAL-treated OVX animals, however, restored the cardiovascular status close to that observed in nontreated OVX animals. The decreased expression of HO enzymes and the changes in blood pressure ischemia susceptibility and inflammatory state in OVX rat can be reverted by the administration of E2 or RAL partly through its antioxidant and anti-inflammatory roles.

  16. Reduced benzodiazepine tolerance, but increased flumazenil-precipitated withdrawal in AMPA-receptor GluR-A subunit-deficient mice.

    Science.gov (United States)

    Aitta-Aho, Teemu; Vekovischeva, Olga Y; Neuvonen, Pertti J; Korpi, Esa R

    2009-04-01

    Pharmacotherapy with benzodiazepines is compromised by rapid sedative tolerance and diverse withdrawal symptoms. To assess the role of AMPA-type glutamate receptor GluR-A subunits in neuroadaptation to subchronic benzodiazepine treatment, GluR-A subunit-deficient mice were rendered tolerant by a high-dose seven-day flurazepam treatment (40 mg/kg, s.c., twice a day for 4 days, 60 mg/kg twice a day for 3 days). The acute effects to flurazepam were not changed in the GluR-/- mice compared with their littermate control mice. GluR-A-/- mice developed less tolerance than their controls as demonstrated in behavioral tests for muscle relaxation and sensory functions. Actually, the knockout mice exhibited slower recovery than their littermates from impaired gait and pelvic position after an acute 40 mg/kg dose of flurazepam. The apparent elimination of flurazepam was similarly increased in the knockout and control mice as assessed by blood and brain concentrations 2 h after acute and chronic treatments, but the active metabolite desalkylflurazepam cumulated similarly in both mouse lines. Withdrawal symptoms, precipitated by flumazenil (20 mg/kg, s.c.) 48 h after discontinuation of the flurazepam treatment, were enhanced in the GluR-A-/- mice. The results stress the importance of the AMPA-receptor system in neuroadaptation to acute and chronic effects of benzodiazepines.

  17. TRH-receptor-type-2-deficient mice are euthyroid and exhibit increased depression and reduced anxiety phenotypes.

    Science.gov (United States)

    Sun, Yuhua; Zupan, Bojana; Raaka, Bruce M; Toth, Miklos; Gershengorn, Marvin C

    2009-05-01

    Thyrotropin-releasing hormone (TRH) is a neuropeptide that initiates its effects in mice by interacting with two G-protein-coupled receptors, TRH receptor type 1 (TRH-R1) and TRH receptor type 2 (TRH-R2). Two previous reports described the effects of deleting TRH-R1 in mice. TRH-R1 knockout mice exhibit hypothyroidism, hyperglycemia, and increased depression and anxiety-like behavior. Here we report the generation of TRH-R2 knockout mice. The phenotype of these mice was characterized using gross and histological analyses along with blood hematological assays and chemistries. Standard metabolic tests to assess glucose and insulin tolerance were performed. Behavioral testing included elevated plus maze, open field, tail suspension, forced swim, and novelty-induced hypophagia tests. TRH-R2 knockout mice are euthyroid with normal basal and TRH-stimulated serum levels of thyroid-stimulating hormone (thyrotropin), are normoglycemic, and exhibit normal development and growth. Female, but not male, TRH-R2 knockout mice exhibit moderately increased depression-like and reduced anxiety-like phenotypes. Because the behavioral changes in TRH-R1 knockout mice may have been caused secondarily by their hypothyroidism whereas TRH-R2 knockout mice are euthyroid, these data provide the first evidence for the involvement of the TRH/TRH-R system, specifically extrahypothalamic TRH/TRH-R2, in regulating mood and affect.

  18. A calcitonin receptor (CALCR) single nucleotide polymorphism is associated with growth performance and bone integrity in response to dietary phosphorus deficiency.

    Science.gov (United States)

    Alexander, L S; Qu, A; Cutler, S A; Mahajan, A; Rothschild, M F; Cai, W; Dekkers, J C; Stahl, C H

    2010-03-01

    Although concerns over the environmental impact of excess P in the excreta from pig production and governmental regulations have driven research toward reducing dietary supplementation of P to swine diets for over a decade, recent dramatic increases in feed costs have further motivated researchers to identify means to further reduce dietary P supplementation. We have demonstrated that genetic background impacts P utilization in young pigs and have identified genetic polymorphisms in several target genes related to mineral utilization. In this study, we examined the impact of a SNP in the calcitonin receptor gene (CALCR) on P utilization in growing pigs. In Exp. 1, 36 gilts representing the 3 genotypes identified by this CALCR SNP (11, 12, and 22) were fed a P-adequate (PA) or a marginally P-deficient (approximately 20% less available P; PD) diet for 14 wk. As expected, P deficiency reduced plasma P concentration, bone strength, and mineral content (P < 0.05). However, the dietary P deficiency was mild enough to not affect the growth performance of these pigs. A genotype x dietary P interaction (P < 0.05) was observed in measures of bone integrity and mineral content, with the greatest reduction in bone strength and mineral content due to dietary P deficiency being associated with the allele 1. In Exp. 2, 168 pigs from a control line and low residual feed intake (RFI) line were genotyped for the CALCR SNP and fed a PA diet. As expected, pigs from the low RFI line consumed less feed but also gained less BW when compared with the control line (P < 0.05). Although ADFI did not differ between genotypes, pigs having the 11 genotype gained less BW (P < 0.05) than pigs having the 12 or 22 genotypes. Pigs of the 11 and 12 genotypes had bones that tolerated greater load when compared with animals having the 22 genotype (P < 0.05). A similar trend was observed in bone modulus and ash % (P < 0.10). These data are supportive of the association of this CALCR SNP with bone

  19. C-C chemokine receptor type 5 deficiency exacerbates alcoholic fatty liver disease through pro-inflammatory cytokines and chemokines-induced hepatic inflammation.

    Science.gov (United States)

    Park, Ju Ho; Lee, Dong Hun; Park, Mork Soon; Jung, Young Suk; Hong, Jin Tae

    2017-06-01

    Chemokines and chemokine receptors implicated with alcoholic liver disease. Studies have shown that inflammation and oxidative stress induce fat molecules aggregation in liver. We evaluated the relationship between alcoholic fatty liver disease and C-C chemokine receptor 5 (CCR5) and impact of inflammation and oxidative stress in fat molecule deposition. Lieber-DeCarli diet containing ethanol or isocaloric control diets were fed to wild-type and CCR5 knockout mice for 10 days and gavaged with a single dose of ethanol or isocaloric maltose dextrin at 11th day. Cytokine, chemokine, and reactive oxygen species levels were measured in liver tissues to study the role of CCR5 in alcoholic fatty liver disease. C-C chemokine receptor type 5 knockout mice exacerbated ethanol-induced liver injury. Serum levels of aspartate aminotransferase and alanine aminotransferase were higher in CCR5 knockout mice than wild-type mice, and CCR5 knockout mice showed more severe lipid accumulation in liver tissue than wild-type mice after ethanol feeding. Increased expressions of pro-inflammatory cytokines TNF-α and IL-6 and chemokines CCL2, CCL3, CCL4, and CCL5 result in exacerbation of hepatitis in CCR5 knockout mice after ethanol feeding. Oxidative stress induced by reactive oxygen species was more severe in CCR5 knockout mice, and increasing level of fatty acid import and decreasing level of lipid degradation resulted in lipid accumulation in ethanol-fed CCR5 knockout mice. Deficiency of CCR5 exacerbates alcoholic fatty liver disease by hepatic inflammation induced by pro-inflammatory cytokines and chemokines and oxidative stress. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  20. Low E-prostanoid 2 receptor levels and deficient induction of the IL-1β/IL-1 type I receptor/COX-2 pathway: Vicious circle in patients with aspirin-exacerbated respiratory disease.

    Science.gov (United States)

    Machado-Carvalho, Liliana; Martín, Margarita; Torres, Rosa; Gabasa, Marta; Alobid, Isam; Mullol, Joaquim; Pujols, Laura; Roca-Ferrer, Jordi; Picado, Cesar

    2016-01-01

    We hypothesized that the 2 reported alterations in aspirin-exacerbated respiratory disease (AERD), reduced expression/production of COX-2/prostaglandin (PG) E2 and diminished expression of E-prostanoid (EP) 2 receptor, are closely linked. We sought to determine the mechanisms involved in the altered regulation of the COX pathway in patients with AERD. Fibroblasts were obtained from nasal mucosa; samples of control subjects (NM-C, n = 8) and from nasal polyps from patients with aspirin-exacerbated respiratory disease (NP-AERD, n = 8). Expression of the autocrine loop components regulating PGE2 production and signaling, namely IL-1 type I receptor (IL-1RI), COX-2, microsomal prostaglandin E synthase 1 (mPGES-1), and EP receptors, was assessed at baseline and after stimulation with IL-1β, PGE2, and specific EP receptor agonists. Compared with NM-C fibroblasts, basal expression levels of IL-1RI and EP2 receptor were lower in NP-AERD fibroblasts. IL-1β-induced IL-1RI, COX-2, and mPGES-1 expression levels were also lower in these cells. Levels of IL-1RI positively correlated with COX-2 and mPGES-1 expression in both NM-C and NP-AERD fibroblasts. Incubation with either exogenous PGE2 or selective EP2 agonist significantly increased expression of IL-1RI in NM-C fibroblasts and had hardly any effect on NP-AERD fibroblasts. Alterations in IL-1RI, COX-2, and mPGES-1 expression that were found in NP-AERD fibroblasts were corrected when EP2 receptor expression was normalized by transfection of NP-AERD fibroblasts. Altered expression of EP2 in patients with AERD contributes to deficient induction of IL-1RI, reducing the capacity of IL-1β to increase COX-2 and mPGES-1 expression, which results in low PGE2 production. This impairment in the generation of PGE2 subsequently reduces its ability to induce IL-1RI. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  1. 5-HT2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress

    Directory of Open Access Journals (Sweden)

    Minal Jaggar

    2017-12-01

    Full Text Available Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin2A (5-HT2A receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC and hippocampus in 5-HT2A receptor knockout (5-HT2A−/− and wild-type mice of both sexes. While 5-HT2A−/− male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stress-evoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-HT2A−/− female mice with a hyperlipidemic baseline phenotype. 5-HT2A−/− male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes (Crh, Crhr1, Nr3c1, and Nr3c2, trophic factors (Bdnf, Igf1 and immediate early genes (IEGs (Arc, Fos, Fosb, Egr1-4 in the PFC and hippocampus were altered in 5-HT2A−/− mice both under baseline and CUS conditions. Our results support a role for the 5-HT2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT2A receptor to stress-evoked changes is sexually dimorphic. Keywords: 5-HT2A−/− mice, Prefrontal cortex, Hippocampus, Gene expression, Sexual dimorphism, Despair

  2. Reversal of adipose tissue loss by probucol in mice with deficiency of both scavenger receptor class B type 1 and LDL receptor on high fat diet.

    Science.gov (United States)

    Guo, Xin; Liao, Jiawei; Huang, Xiaomin; Wang, Yuhui; Huang, Wei; Liu, George

    2017-05-15

    Scavenger receptor class B type 1(SR-B1) and low density lipoprotein receptor (LDLR) play vital roles in cholesterol homeostasis. Previous studies indicated a strong link between cholesterol and adipose tissue (AT). In this study, adult male SR-B1 and LDLR double knockout (DKO) mice were fed with high fat diet (HFD) for 3 months. Interestingly, we found severe loss of AT in DKO mice fed with HFD. To reverse the AT loss in DKO mice, 1% probucol was added in HFD. In DKO mice on HFD, plasma total cholesterol (TC) and free cholesterol (FC) levels were increased 6 and 15 folds respectively compared with wild type (WT) mice. We found severe loss of AT in whole body of DKO mice compared with WT or single KO mice. In AT of DKO mice, histology showed the very small size of adipocytes and infiltration of inflammatory cells; Genes expressions related to fatty acid uptake, lipogenesis and adipogenesis were decreased; TUNEL analysis and related genes expressions of endoplasmic reticulum (ER) stress and inflammation were significantly higher than those of WT or single KO mice. Probucol could reduce increased TC and FC levels, and reverse the loss of fat and apoptosis of AT in DKO mice. AT loss in DKO mice with HFD was probably due to high levels of FC which led to apoptosis induced by ER stress and inflammation of AT. This study provided a novel utility of probucol in rescue of fat loss in DKO mice. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Differential Expression of Claudin Family Proteins in Mouse Ovarian Serous Papillary Epithelial Adenoma in Aging FSH Receptor-Deficient Mutants

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    Jayaprakash Aravindakshan

    2006-12-01

    Full Text Available Ovarian cancer is a deadly disease with long latency. To understand the consequences of loss of folliclestimulating hormone receptor (FSH-R signaling and to explore why the atrophic and anovulatory ovaries of follitropin receptor knockout (FORKO mice develop different types of ovarian tumors, including serous papillary epithelial adenoma later in life, we used mRNA expression profiling to gain a comprehensive view of misregulated genes. Using real-time quantitative reverse transcription-polymerase chain reaction, protein analysis, and cellular localization, we show, for the first time, in vivo evidence that, in the absence of FSH-R signaling, claudin-3, claudin-4, and claudin-11 are selectively upregulated, whereas claudin-1 decreases in ovarian surface epithelium and tumors in comparison to wild type. In vitro experiments using a mouse ovarian surface epithelial cell line derived from wild-type females reveal direct hormonal influence on claudin proteins. Although recent studies suggest that cell junction proteins are differentially expressed in ovarian tumors in women, the etiology of such changes remains unclear. Our results suggest an altered hormonal environment resulting from FSH-R loss as a cause of early changes in tight junction proteins that predispose the ovary to late-onset tumors that occur with aging. More importantly, this study identifies claudin-11 overexpression in mouse ovarian serous cystadenoma.

  4. Differential expression of claudin family proteins in mouse ovarian serous papillary epithelial adenoma in aging FSH receptor-deficient mutants.

    Science.gov (United States)

    Aravindakshan, Jayaprakash; Chen, Xinlei; Sairam, M Ram

    2006-12-01

    Ovarian cancer is a deadly disease with long latency. To understand the consequences of loss of follicle-stimulating hormone receptor (FSH-R) signaling and to explore why the atrophic and anovulatory ovaries of follitropin receptor knockout (FORKO) mice develop different types of ovarian tumors, including serous papillary epithelial adenoma later in life, we used mRNA expression profiling to gain a comprehensive view of misregulated genes. Using real-time quantitative reverse transcription-polymerase chain reaction, protein analysis, and cellular localization, we show, for the first time, in vivo evidence that, in the absence of FSH-R signaling, claudin-3, claudin-4, and claudin-11 are selectively upregulated, whereas claudin-1 decreases in ovarian surface epithelium and tumors in comparison to wild type. In vitro experiments using a mouse ovarian surface epithelial cell line derived from wild-type females reveal direct hormonal influence on claudin proteins. Although recent studies suggest that cell junction proteins are differentially expressed in ovarian tumors in women, the etiology of such changes remains unclear. Our results suggest an altered hormonal environment resulting from FSH-R loss as a cause of early changes in tight junction proteins that predispose the ovary to late-onset tumors that occur with aging. More importantly, this study identifies claudin-11 overexpression in mouse ovarian serous cystadenoma.

  5. Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity.

    Science.gov (United States)

    Nice, Timothy J; Osborne, Lisa C; Tomov, Vesselin T; Artis, David; Wherry, E John; Virgin, Herbert W

    2016-06-01

    In order for a virus to persist, there must be a balance between viral replication and immune clearance. It is commonly believed that adaptive immunity drives clearance of viral infections and, thus, dysfunction or viral evasion of adaptive immunity is required for a virus to persist. Type I interferons (IFNs) play pleiotropic roles in the antiviral response, including through innate control of viral replication. Murine norovirus (MNoV) replicates in dendritic cells (DCs) and type I IFN signaling in DCs is important for early control of MNoV replication. We show here that the non-persistent MNoV strain CW3 persists systemically when CD11c positive DCs are unable to respond to type I IFN. Persistence in this setting is associated with increased early viral titers, maintenance of DC numbers, increased expression of DC activation markers and an increase in CD8 T cell and antibody responses. Furthermore, CD8 T cell function is maintained during the persistent phase of infection and adaptive immune cells from persistently infected mice are functional when transferred to Rag1-/- recipients. Finally, increased early replication and persistence are also observed in mixed bone marrow chimeras where only half of the CD11c positive DCs are unable to respond to type I IFN. These findings demonstrate that increased early viral replication due to a cell-intrinsic innate immune deficiency is sufficient for persistence and a functional adaptive immune response is not sufficient for viral clearance.

  6. Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity.

    Directory of Open Access Journals (Sweden)

    Timothy J Nice

    2016-06-01

    Full Text Available In order for a virus to persist, there must be a balance between viral replication and immune clearance. It is commonly believed that adaptive immunity drives clearance of viral infections and, thus, dysfunction or viral evasion of adaptive immunity is required for a virus to persist. Type I interferons (IFNs play pleiotropic roles in the antiviral response, including through innate control of viral replication. Murine norovirus (MNoV replicates in dendritic cells (DCs and type I IFN signaling in DCs is important for early control of MNoV replication. We show here that the non-persistent MNoV strain CW3 persists systemically when CD11c positive DCs are unable to respond to type I IFN. Persistence in this setting is associated with increased early viral titers, maintenance of DC numbers, increased expression of DC activation markers and an increase in CD8 T cell and antibody responses. Furthermore, CD8 T cell function is maintained during the persistent phase of infection and adaptive immune cells from persistently infected mice are functional when transferred to Rag1-/- recipients. Finally, increased early replication and persistence are also observed in mixed bone marrow chimeras where only half of the CD11c positive DCs are unable to respond to type I IFN. These findings demonstrate that increased early viral replication due to a cell-intrinsic innate immune deficiency is sufficient for persistence and a functional adaptive immune response is not sufficient for viral clearance.

  7. Deficiency in EP4 Receptor-Associated Protein Ameliorates Abnormal Anxiety-Like Behavior and Brain Inflammation in a Mouse Model of Alzheimer Disease.

    Science.gov (United States)

    Fujikawa, Risako; Higuchi, Sei; Nakatsuji, Masato; Yasui, Mika; Ikedo, Taichi; Nagata, Manabu; Hayashi, Kosuke; Yokode, Masayuki; Minami, Manabu

    2017-08-01

    Microglia are thought to play key roles in the progression of Alzheimer disease (AD). Overactivated microglia produce proinflammatory cytokines, such as tumor necrosis factor-α, which appear to contribute to disease progression. Previously, we reported that prostaglandin E2 type 4 receptor-associated protein (EPRAP) promotes microglial activation. We crossed human amyloid precursor protein transgenic mice from strain J20+/- onto an EPRAP-deficient background to determine the role of EPRAP in AD. Behavioral tests were performed in 5-month-old male J20+/-EPRAP+/+ and J20+/-EPRAP-/- mice. EPRAP deficiency reversed the reduced anxiety of J20+/- mice but did not affect hyperactivity. No differences in spatial memory were observed between J20+/-EPRAP+/+ and J20+/-EPRAP-/- mice. In comparison with J20+/-EPRAP+/+, J20+/-EPRAP-/- mice exhibited less microglial accumulation and reductions in the Cd68 and tumor necrosis factor-α mRNAs in the prefrontal cortex and hippocampus. No significant differences were found between the two types of mice in the amount of amyloid-β 40 or 42 in the cortex and hippocampus. J20+/-EPRAP-/- mice reversed the reduced anxiety-like behavior and had reduced microglial activation compared with J20+/-EPRAP+/+ mice. Further research is required to identify the role of EPRAP in AD, but our results indicate that EPRAP may be related to behavioral and psychological symptoms of dementia and inflammation in patients with AD. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  8. Quaking Deficiency Amplifies Inflammation in Experimental Endotoxemia via the Aryl Hydrocarbon Receptor/Signal Transducer and Activator of Transcription 1–NF-κB Pathway

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    Li Wang

    2017-12-01

    Full Text Available Macrophages, characterized by considerable diversity and plasticity, play a crucial role in a broad spectrum of biological processes, including inflammation. However, the molecular mechanisms underlying the diverse phenotypes of macrophages are not well defined. Here, we show that the RNA-binding protein, quaking (QKI, dynamically modulates macrophage polarization states. After lipopolysaccharide (LPS stimulation, QKI-silenced RAW 264.7 cells displayed a pro-inflammatory M1 phenotype characterized by increased expression of iNOS, TNF-α, and IL-6 and decreased expression of anti-inflammatory factors, such as IL-10, found in inflammatory zone (Fizz1, and chitinase-like 3 (Chil3 or Ym1. By contrast, QKI5 overexpression led to a suppressive phenotype resembling M2 macrophages, even under M1 differentiation conditions. Moreover, myeloid-specific QKI-deficient mice tended to be more susceptible to LPS-induced endotoxic shock, while the exogenous transfer of macrophages overexpressing QKI5 exerted a significant improving effect. This improvement corresponded to a higher proportion of M2 macrophages, in line with elevated levels of IL-10, and a decrease in levels of pro-inflammatory mediators, such as IL-6, TNF-α, and IL-1β. Further mechanistic studies disclosed that QKI was a potent inhibitor of the nuclear factor-kappa B (NF-κB pathway, suppressing p65 expression and phosphorylation. Strikingly, reduced expression of the aryl hydrocarbon receptor (Ahr and reduced phosphorylation of signal transducer and activator of transcription 1 in QKI-deficient cells failed to restrain the transcriptional activity of NF-κB and NRL pyrin domain containing 3 (NLRP3 activation, while restoring QKI expression skewed the above M1-like response toward an anti-inflammatory M2 state. Taken together, these findings suggest a role for QKI in restraining overt innate immune responses by regulating the Ahr/STAT1–NF-κB pathway.

  9. Targeted next generation sequencing of the entire vitamin D receptor gene reveals polymorphisms correlated with vitamin D deficiency among older Filipino women with and without fragility fracture.

    Science.gov (United States)

    Zumaraga, Mark Pretzel; Medina, Paul Julius; Recto, Juan Miguel; Abrahan, Lauro; Azurin, Edelyn; Tanchoco, Celeste C; Jimeno, Cecilia A; Palmes-Saloma, Cynthia

    2017-03-01

    This study aimed to discover genetic variants in the entire 101 kB vitamin D receptor (VDR) gene for vitamin D deficiency in a group of postmenopausal Filipino women using targeted next generation sequencing (TNGS) approach in a case-control study design. A total of 50 women with and without osteoporotic fracture seen at the Philippine Orthopedic Center were included. Blood samples were collected for determination of serum vitamin D, calcium, phosphorus, glucose, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase and as primary source for targeted VDR gene sequencing using the Ion Torrent Personal Genome Machine. The variant calling was based on the GATK best practice workflow and annotated using Annovar tool. A total of 1496 unique variants in the whole 101-kb VDR gene were identified. Novel sequence variations not registered in the dbSNP database were found among cases and controls at a rate of 23.1% and 16.6% of total discovered variants, respectively. One disease-associated enhancer showed statistically significant association to low serum 25-hydroxy vitamin D levels (Pearson chi-square P-value=0.009). The transcription factor binding site prediction program PROMO predicted the disruption of three transcription factor binding sites in this enhancer region. These findings show the power of TNGS in identifying sequence variations in a very large gene and the surprising results obtained in this study greatly expand the catalog of known VDR sequence variants that may represent an important clue in the emergence of vitamin D deficiency. Such information will also provide the additional guidance necessary toward a personalized nutritional advice to reach sufficient vitamin D status. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Tandem mass spectrometry, but not T-cell receptor excision circle analysis, identifies newborns with late-onset adenosine deaminase deficiency.

    Science.gov (United States)

    la Marca, Giancarlo; Canessa, Clementina; Giocaliere, Elisa; Romano, Francesca; Duse, Marzia; Malvagia, Sabrina; Lippi, Francesca; Funghini, Silvia; Bianchi, Leila; Della Bona, Maria Luisa; Valleriani, Claudia; Ombrone, Daniela; Moriondo, Maria; Villanelli, Fabio; Speckmann, Carsten; Adams, Stuart; Gaspar, Bobby H; Hershfield, Michael; Santisteban, Ines; Fairbanks, Lynette; Ragusa, Giovanni; Resti, Massimo; de Martino, Maurizio; Guerrini, Renzo; Azzari, Chiara

    2013-06-01

    Adenosine deaminase (ADA)-severe combined immunodeficiency (SCID) is caused by genetic variants that disrupt the function of ADA. In its early-onset form, it is rapidly fatal to infants. Delayed or late-onset ADA-SCID is characterized by insidious progressive immunodeficiency that leads to permanent organ damage or death. Quantification of T-cell receptor excision circles (TRECs) or tandem mass spectrometry (tandem-MS) analysis of dried blood spots (DBSs) collected at birth can identify newborns with early-onset ADA-SCID and are used in screening programs. However, it is not clear whether these analyses can identify newborns who will have delayed or late-onset ADA-SCID before symptoms appear. We performed a retrospective study to evaluate whether tandem-MS and quantitative TREC analyses of DBSs could identify newborns who had delayed-onset ADA-SCID later in life. We tested stored DBSs collected at birth from 3 patients with delayed-onset ADA-SCID using tandem-MS (PCT EP2010/070517) to evaluate levels of adenosine and 2'-deoxyadenosine and real-time PCR to quantify TREC levels. We also analyzed DBSs from 3 newborns with early-onset ADA-SCID and 2 healthy newborn carriers of ADA deficiency. The DBSs taken at birth from the 3 patients with delayed-onset ADA-SCID had adenosine levels of 10, 25, and 19 μmol/L (normal value, <1.5 μmol/L) and 2'-deoxyadenosine levels of 0.7, 2.7, and 2.4 μmol/L (normal value, <0.07 μmol/L); the mean levels of adenosine and 2'-deoxyadenosine were respectively 12.0- and 27.6-fold higher than normal values. DBSs taken at birth from all 3 patients with delayed-onset ADA deficiency had normal TREC levels, but TRECs were undetectable in blood samples taken from the same patients at the time of diagnosis. Tandem-MS but not TREC quantification identifies newborns with delayed- or late-onset ADA deficiency. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  11. New evidence of mitochondria dysfunction in the female Alzheimer’s brain: deficiency of estrogen receptor

    Science.gov (United States)

    Long, Jiangang; He, Ping; Shen, Yong; Li, Rena

    2012-01-01

    Accumulating evidence suggests that mitochondria are important targets for the actions of estrogens and studies indicated that localization of ERβ in neuronal mitochondrial ERβ (mtERβ) might directly affect neuronal mitochondrial function in vitro. However, it is unknown what expression levels and how important of mtERβ in the human brain, particularly in the brain with Alzheimer’s disease (AD). In the present study, by using rapidly autopsied human brain tissue, we found that the frontal cortices of female AD patients exhibited significantly reduced mtERβ, along with reduced mitochondrial cytochrome C oxidase activity, and increased protein carbonylation compared to that in normal controls. The correlation between the mtERβ expression and mitochondrial cytochrome C oxidase activity in the female human brain is significant. To understand the possible mechanisms of mtERβ in AD-related mitochondrial dysfunction, using ERβKO mice as a model, we found that lacking of ERβ enhanced brain reactive oxygen species generation and reduced mitochondrial membrane potential under Aβ peptide insult compared to brain mitochondria from wild-type control mice. Our studies for the first time, demonstrated neuronal mtERβ expression in the human brain and the deficiency of mtERβ in the female AD brain is associated with the dysfunction of mitochondria. Our results from ERβKO mice demonstrated that ERβ depletion-induced mitochondrial dysfunction is mediated through increasing reactive oxygen generation and reduction of mitochondria membrane potential. These results indicate that ERβ depletion has the ability to impair mitochondrial function in mice and reduction of brain mtERβ may significantly contribute to the mitochondrial dysfunction involved in AD pathogenesis in women. PMID:22451324

  12. Gamma interferon (IFN-γ) receptor restricts systemic dengue virus replication and prevents paralysis in IFN-α/β receptor-deficient mice.

    Science.gov (United States)

    Prestwood, Tyler R; Morar, Malika M; Zellweger, Raphaël M; Miller, Robyn; May, Monica M; Yauch, Lauren E; Lada, Steven M; Shresta, Sujan

    2012-12-01

    We previously reported that mice lacking alpha/beta and gamma interferon receptors (IFN-α/βR and -γR) uniformly exhibit paralysis following infection with the dengue virus (DENV) clinical isolate PL046, while only a subset of mice lacking the IFN-γR alone and virtually no mice lacking the IFN-α/βR alone develop paralysis. Here, using a mouse-passaged variant of PL046, strain S221, we show that in the absence of the IFN-α/βR, signaling through the IFN-γR confers approximately 140-fold greater resistance against systemic vascular leakage-associated dengue disease and virtually complete protection from dengue-induced paralysis. Viral replication in the spleen was assessed by immunohistochemistry and flow cytometry, which revealed a reduction in the number of infected cells due to IFN-γR signaling by 2 days after infection, coincident with elevated levels of IFN-γ in the spleen and serum. By 4 days after infection, IFN-γR signaling was found to restrict DENV replication systemically. Clearance of DENV, on the other hand, occurred in the absence of IFN-γR, except in the central nervous system (CNS) (brain and spinal cord), where clearance relied on IFN-γ from CD8(+) T cells. These results demonstrate the roles of IFN-γR signaling in protection from initial systemic and subsequent CNS disease following DENV infection and demonstrate the importance of CD8(+) T cells in preventing DENV-induced CNS disease.

  13. Mineralocorticoid Receptor Deficiency in T Cells Attenuates Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction Through Modulating T-Cell Activation.

    Science.gov (United States)

    Li, Chao; Sun, Xue-Nan; Zeng, Meng-Ru; Zheng, Xiao-Jun; Zhang, Yu-Yao; Wan, Qiangyou; Zhang, Wu-Chang; Shi, Chaoji; Du, Lin-Juan; Ai, Tang-Jun; Liu, Yuan; Liu, Yan; Du, Li-Li; Yi, Yi; Yu, Ying; Duan, Sheng-Zhong

    2017-07-01

    Although antagonists of mineralocorticoid receptor (MR) have been widely used to treat heart failure, the underlying mechanisms are incompletely understood. Recent reports show that T cells play important roles in pathologic cardiac hypertrophy and heart failure. However, it is unclear whether and how MR functions in T cells under these pathologic conditions. We found that MR antagonist suppressed abdominal aortic constriction-induced cardiac hypertrophy and decreased the accumulation and activation of CD4 + and CD8 + T cells in mouse heart. T-cell MR knockout mice manifested suppressed cardiac hypertrophy, fibrosis, and dysfunction compared with littermate control mice after abdominal aortic constriction. T-cell MR knockout mice had less cardiac inflammatory response, which was illustrated by decreased accumulation of myeloid cells and reduced expression of inflammatory cytokines. Less amounts and activation of T cells were observed in the heart of T-cell MR knockout mice after abdominal aortic constriction. In vitro studies showed that both MR antagonism and deficiency repressed activation of T cells, whereas MR overexpression elevated activation of T cells. These results demonstrated that MR blockade in T cells protected against abdominal aortic constriction-induced cardiac hypertrophy and dysfunction. Mechanistically, MR directly regulated T-cell activation and modulated cardiac inflammation. Targeting MR in T cells specifically may be a feasible strategy for more effective treatment of pathologic cardiac hypertrophy and heart failure. © 2017 American Heart Association, Inc.

  14. Triggering receptor expressed on myeloid cells 2 knockdown exacerbates aging-related neuroinflammation and cognitive deficiency in senescence-accelerated mouse prone 8 mice.

    Science.gov (United States)

    Jiang, Teng; Yu, Jin-Tai; Zhu, Xi-Chen; Tan, Meng-Shan; Gu, Li-Ze; Zhang, Ying-Dong; Tan, Lan

    2014-06-01

    As a major characteristic of aging process, neuroinflammation is involved in the pathogenesis of several aging-related diseases including Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a newly identified risk gene for AD, which regulates inflammatory process in peripheral tissues via modulating the release of inflammatory cytokines. However, the role of TREM2 in aging-related neuroinflammation, cognitive deficiency, and AD-like neuropathology is unclear so far. Here, we detected the protein levels of TREM2 in brain of 3-, 7-, and 11-month-old senescence-accelerated mouse prone 8 (SAMP8) mice and observed that TREM2 levels were increased during aging process. We then knocked down TREM2 expression in brain of SAMP8 mice by nonviral RNA interference and found a significant increase in proinflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-6, which was accompanied by a reduction in IL-10. Meanwhile, more obvious neuronal and synaptic losses and cognitive impairment were observed. These findings indicate that TREM2 may play a protective role against aging-related neuroinflammation and cognitive impairment. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Sleep Homeostatic and Waking Behavioral Phenotypes in Egr3-Deficient Mice Associated with Serotonin Receptor 5-HT2 Deficits.

    Science.gov (United States)

    Grønli, Janne; Clegern, William C; Schmidt, Michelle A; Nemri, Rahmi S; Rempe, Michael J; Gallitano, Amelia L; Wisor, Jonathan P

    2016-12-01

    The expression of the immediate early gene early growth response 3 (Egr3) is a functional marker of brain activity including responses to novelty, sustained wakefulness, and sleep. We examined the role of this gene in regulating wakefulness and sleep. Electroencephalogram/electromyogram (EEG/EMG) were recorded in Egr3-/- and wild-type (WT) mice during 24 h baseline, 6 h sleep disruption and 6 h recovery. Serotonergic signaling was assessed with 6 h EEG/EMG recordings after injections of nonselective 5-HT2 antagonist (clozapine), selective 5-HT2 antagonists (5-HT2A; MDL100907 and 5-HT2BC; SB206553) and a cocktail of both selective antagonists, administered in a randomized order to each animal. Egr3-/- mice did not exhibit abnormalities in the timing of wakefulness and slow wave sleep (SWS); however, EEG dynamics in SWS (suppressed 1-3 Hz power) and in quiet wakefulness (elevated 3-8 Hz and 15-35 Hz power) differed in comparison to WT-mice. Egr3-/- mice showed an exaggerated response to sleep disruption as measured by active wakefulness, but with a blunted increase in homeostatic sleep drive (elevated 1-4 Hz power) relative to WT-mice. Egr3-/-mice exhibit greatly reduced sedative effects of clozapine at the electroencephalographic level. In addition, clozapine induced a previously undescribed dissociated state (low amplitude, low frequency EEG and a stable, low muscle tone) lasting up to 2 h in WT-mice. Egr3-/- mice did not exhibit this phenomenon. Selective 5-HT2A antagonist, alone or in combination with selective 5-HT2BC antagonist, caused EEG slowing coincident with behavioral quiescence in WT-mice but not in Egr3-/- mice. Egr3 has an essential role in regulating cortical arousal, wakefulness, and sleep, presumably by its regulation of 5-HT2 receptors.

  16. An investigation into ‘two hit’ effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice

    Directory of Open Access Journals (Sweden)

    Maren eKlug

    2013-10-01

    Full Text Available Reduced brain-derived neurotrophic factor (BDNF signalling has been shown in the frontal cortex and hippocampus in schizophrenia. The aim of the present study was to investigate whether a BDNF deficit would modulate effects of chronic cannabis intake, a well-described risk factor for schizophrenia development. BDNF heterozygous mice (HET and wild-type controls were chronically treated during weeks 6, 7 and 8 of life with the cannabinoid CB1 receptor agonist, CP55,940 (CP. After a 2-week delay, there were no CP-induced deficits in any of the groups in short-term spatial memory in a Y-maze task or novel object recognition memory. Baseline prepulse inhibition (PPI was lower but average startle was increased in BDNF HET compared to wild-type controls. Acute CP administration before the PPI session caused a marked increase in PPI in male HET mice pre-treated with CP but not in any of the other male groups. In females, there were small increases of PPI in all groups upon acute CP administration. Acute CP administration furthermore reduced startle and this effect was greater in HET mice irrespective of chronic CP pre-treatment. Analysis of the levels of [3H]CP55,940 binding by autoradiography revealed a significant increase in the nucleus accumbens of male BDNF HET mice previously treated with CP but not in any of the other groups or in the caudate nucleus.These results show that BDNF deficiency and chronic young-adult cannabinoid receptor stimulation do not interact in this model on learning and memory later in life. In contrast, male ‘two hit’ mice, but not females, were hypersensitive to the effect of acute CP on sensorimotor gating. These effects may be related to a selective increase of [3H]CP55,940 binding in the nucleus accumbens, reflecting up-regulation of CB1 receptor density in this region. These data could be of relevance to our understanding of differential ‘two hit’ neurodevelopmental mechanisms in schizophrenia.

  17. Plasma ferritin and soluble transferrin receptor concentrations and body iron stores identify similar risk factors for iron deficiency but result in different estimates of the national prevalence of iron deficiency and iron-deficiency anemia among women and children in Cameroon.

    Science.gov (United States)

    Engle-Stone, Reina; Nankap, Martin; Ndjebayi, Alex O; Erhardt, Juergen G; Brown, Kenneth H

    2013-03-01

    Available iron status indicators reflect different aspects of metabolism. We compared the prevalence and distribution of iron deficiency (ID) and iron-deficiency anemia (IDA) among Cameroonian women and children, as measured by plasma ferritin, and soluble transferrin receptor concentrations, body iron stores (BIS), and hemoglobin, and evaluated the impact of adjustments for inflammation on these measures. In a nationally representative survey, we randomly selected 30 clusters in each of 3 zones (north, south, and large cities) and 10 households/ cluster, each with a child aged 12-59 mo and a woman 15-49 y. Ferritin and BIS were mathematically adjusted for inflammation, using plasma C-reactive protein and α(1)-acid glycoprotein both as continuous and categorical variables. Inflammation was present in 48.0% of children and 20.8% of women and anemia was diagnosed in 57.6% of children and 38.8% of women. Depending on the iron status indicator applied, the prevalence of ID ranged from 14.2 to 68.4% among children and 11.5 to 31.8% among women, and the prevalence of IDA ranged from 12.0 to 47.4% among children and 9.0 to 19.4% among women; the proportion of anemia associated with ID ranged from 20.8 to 82.3% among children and 23.2 to 50.0% among women. The different iron indicators generally identified similar groups at greatest risk of deficiency, using both conventional and derived cutoffs: younger children, pregnant women, and women and children in the north and rural areas. Research is needed to clarify the relationships between iron status indicators, particularly in the presence of inflammation, to harmonize global data on prevalence of ID.

  18. Uptake by J774 macrophages of very-low-density lipoproteins isolated from apoE-deficient mice is mediated by a distinct receptor and stimulated by lipoprotein lipase.

    Science.gov (United States)

    Hendriks, W L; van der Sman-de Beer, F; van Vlijmen, B J; van Vark, L C; Hofker, M H; Havekes, L M

    1997-03-01

    Apolipoprotein (apo) E-deficient mice display marked accumulation in the plasma of VLDL deficient in both apoE and apoB100 but containing apoB48, apoA-I, apoCs, and apoA-IV. Since apoE-deficient mice develop severe atherosclerotic lesions with lipid-laden macrophages, we reasoned that the uptake of lipoproteins by intimal macrophages can take place in the absence of both apoE and apoB100. To get more insight into the mechanism of foam cell formation in apoE-deficient mice, we measured the interaction of VLDL from apoE-deficient mice (apoEnull VLDL) with the murine macrophage cell line J774. Scatchard analysis revealed that apoEnull VLDL is bound to J774 cells with a Kd value comparable to that of control VLDL (8.1 versus 4.7 micrograms/mL) and with a Bmax value about half that of control VLDL (40 versus 70 ng/mg cell protein, respectively). ApoEnull VLDL is also taken up and degraded by J774 macrophages via a high-affinity process less efficiently than control mouse VLDL (6-fold and 50-fold less efficiently, respectively). In line with this observation, incubation of J774 cells with 50 micrograms/mL apoEnull VLDL for 24 hours resulted in an increase in intracellular cholesteryl ester (CE) content, although 5-fold less pronounced than after incubation with 50 micrograms/mL control mouse VLDL. Under the conditions applied, simultaneous addition of 5 micrograms/mL lipoprotein lipase (LPL) stimulated the cellular uptake and degradation of apoEnull VLDL about 10-fold and resulted in a 5-fold stimulation of the intracellular CE accumulation, from 9 +/- 2 to 46 +/- 5 micrograms CE per milligram cell protein. In contrast to control mouse VLDL, apoEnull VLDL could not compete with 125I-labeled LDL for binding to the LDL receptor of J774 cells. Furthermore, neither LDL nor acetylated LDL could compete with 125I-labeled apoEnull VLDL for binding to these cells, whereas control mouse VLDL, VLDL from a hypertriglyceridemic patient, and apoEnull VLDL itself were efficient

  19. 5-HT2C Receptor Desensitization Moderates Anxiety in 5-HTT Deficient Mice: From Behavioral to Cellular Evidence

    Science.gov (United States)

    Martin, Cédric BP; Martin, Vincent S.; Trigo, José M.; Chevarin, Caroline; Maldonado, Rafael; Fink, Latham H.; Cunningham, Kathryn A.; Hamon, Michel; Lanfumey, Laurence

    2015-01-01

    Background: Desensitization and blockade of 5-HT2C receptors (5-HT2CR) have long been thought to be central in the therapeutic action of antidepressant drugs. However, besides behavioral pharmacology studies, there is little in vivo data documenting antidepressant-induced 5-HT2CR desensitization in specific brain areas. Methods: Mice lacking the 5-HT reuptake carrier (5-HTT-/-) were used to model the consequences of chronic 5-HT reuptake inhibition with antidepressant drugs. The effect of this mutation on 5-HT2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding, and 5-HT2CR–induced hypolocomotion tests), the neurochemical, and the cellular (RT-qPCR, mRNA editing, and c-fos–induced expression) levels. Results: Although 5-HTT-/- mice had an anxiogenic profile in the novelty-suppressed feeding test, they displayed less 5-HT2CR–mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT2CR–mediated inhibition of a stress-induced increase in 5-HT turnover, measured in various brain areas, was markedly reduced in 5-HTT-/- mutants. These indices of tolerance to 5-HT2CR stimulation were associated neither with altered levels of 5-HT2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c-fos mRNA production in cells expressing 5-HT2CR was higher in 5-HTT-/- mutants, suggesting an altered basal activity of these cells following sustained 5-HT reuptake carrier inactivation. Furthermore, the increased c-fos mRNA expression in 5-HT2CR–like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT2CR agonist RO-60,0175 was absent in 5-HTT-/- mutants. Conclusions: Such blunted responsiveness of the 5-HT2CR system, observed at the cell signaling level, probably contributes to the moderation of the anxiety phenotype in 5-HTT-/- mice. PMID:25522398

  20. Expression of an IRF-3 fusion protein and mouse estrogen receptor, inhibits hepatitis C viral replication in RIG-I-deficient Huh 7.5 cells

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    Liu Chen

    2011-09-01

    Full Text Available Abstract Interferon Regulatory Factor-3 (IRF-3 plays a central role in the induction of interferon (IFN production and succeeding interferon-stimulated genes (ISG expression en route for restraining hepatitis C virus (HCV infection. Here, we established a stable Huh7.5-IRF3ER cell line expressing a fusion protein of IRF-3 and mouse estrogen receptor (ER to examine IFN production and anti-HCV effects of IRF-3 in retinoic acid inducible-gene-I (RIG-I deficient Huh 7.5 cells. Homodimerization of the IRF-3ER fusion protein was detected by Western blotting after treatment with the estrogen receptor agonist 4-hydrotamoxifen (4-HT in Huh7.5-IRF3ER cells. Expression of IFN-α, IFN-β, and their inhibitory effects on HCV replication were demonstrated by real-time polymerase chain reaction (PCR. Peak expression of IFN-α and IFN-β was achieved 24-hours post 4-HT treatment, coinciding with the appearance of phosphorylated signal transducer and activator of transcription (STAT proteins. Additionally, HCV viral replication declined in time-dependent fashion. In previous studies, a novel IFN-mediated pathway regulating expression of 1-8U and heterogeneous nuclear ribonucleoprotein M (hnRNP M inhibited HCV internal ribosomal entry site (IRES-dependent translation. When expression of ISGs such as 1-8U and hnRNP M were measured in 4-HT-treated Huh7.5-IRF3ER cells, both genes were positively regulated by activation of the IRF-3ER fusion protein. In conclusion, the anti-HCV effects of IRF-3ER homodimerization inhibited HCV RNA replication as well as HCV IRES-dependent translation in Huh7.5-IRF3ER cells. The results of this study indicate that IRF-3ER homodimerization is a key step to restore IFN expression in Huh7.5-IRF3ER cells and in achieving its anti-HCV effects.

  1. Loading-related regulation of gene expression in bone in the contexts of estrogen deficiency, lack of estrogen receptor alpha and disuse.

    Science.gov (United States)

    Zaman, Gul; Saxon, Leanne K; Sunters, Andrew; Hilton, Helen; Underhill, Peter; Williams, Debbie; Price, Joanna S; Lanyon, Lance E

    2010-03-01

    Loading-related changes in gene expression in resident cells in the tibia of female mice in the contexts of normality (WT), estrogen deficiency (WT-OVX), absence of estrogen receptor alpha (ERalpha(-/-)) and disuse due to sciatic neurectomy (WT-SN) were established by microarray. Total RNA was extracted from loaded and contra-lateral non-loaded tibiae at selected time points after a single, short period of dynamic loading sufficient to engender an osteogenic response. There were marked changes in the expression of many genes according to context as well as in response to loading within those contexts. In WT mice at 3, 8, 12 and 24 h after loading the expression of 642, 341, 171 and 24 genes, respectively, were differentially regulated compared with contra-lateral bones which were not loaded. Only a few of the genes differentially regulated by loading in the tibiae of WT mice have recognized roles in bone metabolism or have been linked previously to osteogenesis (Opn, Sost, Esr1, Tgfb1, Lrp1, Ostn, Timp, Mmp, Ctgf, Postn and Irs1, BMP and DLX5). The canonical pathways showing the greatest loading-related regulation were those involving pyruvate metabolism, mitochondrial dysfunction, calcium-induced apoptosis, glycolysis/gluconeogenesis, aryl hydrocarbon receptor and oxidative phosphorylation. In the tibiae from WT-OVX, ERalpha(-/-) and WT-SN mice, 440, 439 and 987 genes respectively were differentially regulated by context alone compared to WT. The early response to loading in tibiae of WT-OVX mice involved differential regulation compared to their contra-lateral non-loaded pair of fewer genes than in WT, more down-regulation than up-regulation and a later response. This was shared by WT-SN. In tibiae of ERalpha(-/-) mice, the number of genes differentially regulated by loading was markedly reduced at all time points. These data indicate that in resident bone cells, both basal and loading-related gene expression is substantially modified by context. Many of the

  2. Vitamin A deficiency impairs spatial learning and memory: the mechanism of abnormal CBP-dependent histone acetylation regulated by retinoic acid receptor alpha.

    Science.gov (United States)

    Hou, Nali; Ren, Lan; Gong, Min; Bi, Yang; Gu, Yan; Dong, Zhifang; Liu, Youxue; Chen, Jie; Li, Tingyu

    2015-04-01

    Vitamin A (VA) is an essential micronutrient. Numerous studies have confirmed that VA deficiency (VAD) leads to a decline in learning and memory function. Our previous studies have demonstrated that retinoic acid nuclear receptor α (RARα) in the hippocampus plays a crucial role in learning and memory, but the exact mechanism for this process is unclear. Epigenetic modifications, particularly histone acetylation, are involved in nervous system development, learning and memory function, and the pathogenesis of neurodegenerative diseases. Histone acetyltransferases (HATs), such as CREB-binding protein (CBP), E1A-binding protein p300 (p300), and p300/CBP-associated factor (PCAF), are critical for regulating memory function. The current study uses RARα and CBP as examples to study the connections between the RA signaling pathway and histone acetylation modification and to reveal the epigenetic mechanism in VAD-induced learning and memory impairment. This study examined the expression of RARα, HATs, acetylated histone H3/H4, and memory-related genes (Zif268, cFos, FosB), as well as the interaction of RARα and CBP in the hippocampus of 8-week-old rats. Additionally, the changes shown in vivo were further assessed in primary cultured neurons with the inhibition or overexpression of RARα. We found significantly lower levels of histone acetylation in the VAD rats. Furthermore, this downregulation, which impairs learning and memory, is induced by the dysregulation of CBP-dependent histone acetylation that is mediated by RARα. This work provides a solid theoretical foundation and experimental basis for the importance of ensuring sufficient nutritional VA during pregnancy and early life to prevent impairments of learning and memory in adulthood.

  3. CER-001, a HDL-mimetic, stimulates the reverse lipid transport and atherosclerosis regression in high cholesterol diet-fed LDL-receptor deficient mice.

    Science.gov (United States)

    Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Ackermann, Rose; Sy, Gavin; Bluteau, Alice; Cholez, Guy; Keyserling, Constance; Lalwani, Narendra; Paolini, John F; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

    2014-01-01

    CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and phospholipids that was designed to mimic the beneficial properties of nascent pre-β HDL. In this study, we have evaluated the capacity of CER-001 to perform reverse lipid transport in single dose studies as well as to regress atherosclerosis in LDLr(-/-) mice after short-term multiple-dose infusions. CER-001 induced cholesterol efflux from macrophages and exhibited anti-inflammatory response similar to natural HDL. Studies with HUVEC demonstrated CER-001 at a concentration of 500 μg/mL completely suppressed the secretion of cytokines IL-6, IL-8, GM-CSF and MCP-1. Following infusion of CER-001 (10mg/kg) in C57Bl/6J mice, we observed a transient increase in the mobilization of unesterified cholesterol in HDL particles containing recombinant human apoA-I. Finally we show that cholesterol elimination was stimulated in CER-001 treated animals as demonstrated by the increased cholesterol concentration in liver and feces. In a familial hypercholesterolemia mouse model (LDL-receptor deficient mice), the infusion of CER-001 caused 17% and 32% reductions in plaque size, 17% and 23% reductions in lipid content after 5 and 10 doses given every 2 days, respectively. Also, there was an 80% reduction in macrophage content in the plaque following 5 doses, and decreased VCAM-1 expression by 16% and 22% in the plaque following 5 and 10 intravenous doses of CER-001, respectively. These data demonstrate that CER-001 rapidly enhances reverse lipid transport in the mouse, reducing vascular inflammation and promoting regression of diet-induced atherosclerosis in LDLr(-/-) mice upon a short-term multiple dose treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation.

    Science.gov (United States)

    Aguiar-Oliveira, Manuel H; Souza, Anita H O; Oliveira, Carla R P; Campos, Viviane C; Oliveira-Neto, Luíz A; Salvatori, Roberto

    2017-08-01

    Twenty years ago, we described kindred of 105 individuals with isolated GH deficiency (IGHD) in Itabaianinha County, in northeast Brazil, carrying a homozygous mutation in the GH-releasing hormone receptor gene. These subjects exhibit markedly reduced GH responsiveness to stimulatory tests, and anterior pituitary hypoplasia. Serum concentrations of IGF-I, IGF binding protein type 3 and the acid-labile subunit are markedly reduced, with a lesser reduction of IGF-II. The most striking physical findings of these IGHD individuals are the proportionate short stature, doll facies, high-pitched voice and visceral obesity with reduced fat-free mass. There is neither microphallus, nor neonatal hypoglycemia. Puberty is delayed, menopause anticipated, but fertility is preserved in both genders. The reduction in bone sizes is not even, with mean standard deviation scores for height of -7.2, total maxillary length of -6.5, total facial height of -4.3 and cephalic perimeter of -2.7. In addition, the non-osseous growth is not uniform, preserving some organs, like pancreas, liver, kidney, brain and eyes, and compromising others such as thyroid, heart, uterus and spleen. These subjects present higher prevalence of dizziness, mild high-tones sensorineural hearing loss, reduction of vascular retinal branching points, increase of optic disk, genu valgum and increased systolic blood pressure. Biochemically, they have high low density lipoprotein cholesterol and C-reactive protein levels, but maintain increased insulin sensitivity, and do not show premature atherosclerosis. Finally, they have normal immune function, and normal longevity. This review details the findings and summarizes 20 years of clinical research carried out in this unique population. © 2017 European Society of Endocrinology.

  5. Left ventricular dysfunction with reduced functional cardiac reserve in diabetic and non-diabetic LDL-receptor deficient apolipoprotein B100-only mice.

    Science.gov (United States)

    Heinonen, Suvi E; Merentie, Mari; Hedman, Marja; Mäkinen, Petri I; Loponen, Elina; Kholová, Ivana; Bosch, Fatima; Laakso, Markku; Ylä-Herttuala, Seppo

    2011-06-30

    Lack of suitable mouse models has hindered the studying of diabetic macrovascular complications. We examined the effects of type 2 diabetes on coronary artery disease and cardiac function in hypercholesterolemic low-density lipoprotein receptor-deficient apolipoprotein B100-only mice (LDLR-/-ApoB100/100). 18-month-old LDLR-/-ApoB100/100 (n = 12), diabetic LDLR-/-ApoB100/100 mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells (IGF-II/LDLR-/-ApoB100/100, n = 14) and age-matched C57Bl/6 mice (n = 15) were studied after three months of high-fat Western diet. Compared to LDLR-/-ApoB100/100 mice, diabetic IGF-II/LDLR-/-ApoB100/100 mice demonstrated more calcified atherosclerotic lesions in aorta. However, compensatory vascular enlargement was similar in both diabetic and non-diabetic mice with equal atherosclerosis (cross-sectional lesion area ~60%) and consequently the lumen area was preserved. In coronary arteries, both hypercholesterolemic models showed significant stenosis (~80%) despite positive remodeling. Echocardiography revealed severe left ventricular systolic dysfunction and anteroapical akinesia in both LDLR-/-ApoB100/100 and IGF-II/LDLR-/-ApoB100/100 mice. Myocardial scarring was not detected, cardiac reserve after dobutamine challenge was preserved and ultrasructural changes revealed ischemic yet viable myocardium, which together with coronary artery stenosis and slightly impaired myocardial perfusion suggest myocardial hibernation resulting from chronic hypoperfusion. LDLR-/-ApoB100/100 mice develop significant coronary atherosclerosis, severe left ventricular dysfunction with preserved but diminished cardiac reserve and signs of chronic myocardial hibernation. However, the cardiac outcome is not worsened by type 2 diabetes, despite more advanced aortic atherosclerosis in diabetic animals.

  6. Status of 25-hydroxyvitamin D deficiency and effect of vitamin D receptor gene polymorphisms on bone mineral density in thalassemia patients of North India.

    Science.gov (United States)

    Singh, Kritanjali; Kumar, Ravindra; Shukla, Anju; Phadke, Shubha R; Agarwal, Sarita

    2012-09-01

    Bone disease comprising of low bone mineral density (BMD), bone pain, and fractures is a characteristic feature of thalassemia. Vitamin D receptors (VDRs - FokI, TaqI, and Bsml) polymorphisms are closely related to low BMD at the lumbar spine and hips which can be used as a useful genetic marker in predicting bone disease in these patients. To find out the status of VDRs gene polymorphisms and its effect on osteoporosis in thalassemia patients of North Indian origin. BMD was measured in 40 beta-thalassemia major patients by dual-energy X-ray densitometry (DXA). Serum vitamin D levels were estimated by enzyme linked immunosorbant assay. VDR gene polymorphisms (FokI, TaqI, and BsmI) were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. About 80.6% cases were found to be vitamin D deficient. Z score of BMD of lumbar spine and hips were -2.31 ± 1.18 and -2.09 ± 0.89. Osteoporotic lumbar spine was observed in 42.5% cases of thalassemia. A positive correlation of vitamin D level was found with Z score of BMD of lumbar spine (r = 0.398, P value = 0.027). Polymorphisms of FokI and BsmI were found significantly correlated with BMD of lumbar spine. However, no association of BMD was observed with TaqI polymorphism. The present study showed a high prevalence of low BMD in thalassemia, suggesting that they should be targeted for DXA screening and osteoporosis prevention before permanent end organ bone damage occurs. The VDR genotyping can be used as additional test in individuals who are susceptible to osteoporosis so that early preventive measurements can be taken.

  7. Left ventricular dysfunction with reduced functional cardiac reserve in diabetic and non-diabetic LDL-receptor deficient apolipoprotein B100-only mice

    Directory of Open Access Journals (Sweden)

    Bosch Fatima

    2011-06-01

    Full Text Available Abstract Background Lack of suitable mouse models has hindered the studying of diabetic macrovascular complications. We examined the effects of type 2 diabetes on coronary artery disease and cardiac function in hypercholesterolemic low-density lipoprotein receptor-deficient apolipoprotein B100-only mice (LDLR-/-ApoB100/100. Methods and results 18-month-old LDLR-/-ApoB100/100 (n = 12, diabetic LDLR-/-ApoB100/100 mice overexpressing insulin-like growth factor-II (IGF-II in pancreatic beta cells (IGF-II/LDLR-/-ApoB100/100, n = 14 and age-matched C57Bl/6 mice (n = 15 were studied after three months of high-fat Western diet. Compared to LDLR-/-ApoB100/100 mice, diabetic IGF-II/LDLR-/-ApoB100/100 mice demonstrated more calcified atherosclerotic lesions in aorta. However, compensatory vascular enlargement was similar in both diabetic and non-diabetic mice with equal atherosclerosis (cross-sectional lesion area ~60% and consequently the lumen area was preserved. In coronary arteries, both hypercholesterolemic models showed significant stenosis (~80% despite positive remodeling. Echocardiography revealed severe left ventricular systolic dysfunction and anteroapical akinesia in both LDLR-/-ApoB100/100 and IGF-II/LDLR-/-ApoB100/100 mice. Myocardial scarring was not detected, cardiac reserve after dobutamine challenge was preserved and ultrasructural changes revealed ischemic yet viable myocardium, which together with coronary artery stenosis and slightly impaired myocardial perfusion suggest myocardial hibernation resulting from chronic hypoperfusion. Conclusions LDLR-/-ApoB100/100 mice develop significant coronary atherosclerosis, severe left ventricular dysfunction with preserved but diminished cardiac reserve and signs of chronic myocardial hibernation. However, the cardiac outcome is not worsened by type 2 diabetes, despite more advanced aortic atherosclerosis in diabetic animals.

  8. Infection of type I interferon receptor-deficient mice with various old world arenaviruses: a model for studying virulence and host species barriers.

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    Toni Rieger

    Full Text Available Lassa virus causes hemorrhagic Lassa fever in humans, while the related Old World arenaviruses Mopeia, Morogoro, and Mobala are supposedly apathogenic to humans and cause only inapparent infection in non-human primates. Here, we studied whether the virulence of Old World arenaviruses in humans and non-human primates is reflected in type I interferon receptor deficient (IFNAR(-/- mice by testing several strains of Lassa virus vs. the apathogenic viruses Mopeia, Morogoro, and Mobala. All Lassa virus strains tested-Josiah, AV, BA366, and Nig04-10-replicated to high titers in blood, lung, kidney, heart, spleen, brain, and liver and caused disease as evidenced by weight loss and elevation of aspartate and alanine aminotransferase (AST and ALT levels with a high AST/ALT ratio. Lassa fever-like pathology included acute hepatitis, interstitial pneumonia, and pronounced disturbance of splenic cytoarchitecture. Infiltrations of activated monocytes/macrophages expressing inducible nitric oxide synthase and T cells were found in liver and lung. In contrast, Mopeia, Morogoro, and Mobala virus replicated poorly in the animals and acute inflammatory alterations were not noted. Depletion of CD4(+ and CD8(+ T cells strongly enhanced susceptibility of IFNAR(-/- mice to the apathogenic viruses. In conclusion, the virulence of Old World arenaviruses in IFNAR(-/- mice correlates with their virulence in humans and non-human primates. In addition to the type I interferon system, T cells seem to regulate whether or not an arenavirus can productively infect non-host rodent species. The observation that Lassa virus overcomes the species barrier without artificial depletion of T cells suggests it is able to impair T cell functionality in a way that corresponds to depletion.

  9. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  10. A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Tsigos, C.; Arai, K.; Latronico, A.C. [National Inst. of Child Health and Human Development, Bethesda, MD (United States)]|[Temple Univ. School of Medicine, Philadelphia, PA (United States)]|[Children`s Hospital of New Jersey, Newark, NJ (United States)] [and others

    1995-07-01

    Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by primary adrenocortical insufficiency, usually without mineralocorticoid deficiency. Occasionally, the disorder is associated with alacrima and achalasia of the esophagus (triple A syndrome), suggesting potential heterogeneity in its etiology. Mutations in the ACTH receptor gene have been reported in several families with IGD. We have amplified and directly sequenced the entire intronless ACTH receptor gene in 1 other family with IGD and 2 famlies with triple A syndrome. The proband with IGD was a homozygote for an A {r_arrow}G substitution, changing tyrosine 254 to cysteine in the third extracellular loop of the receptor protein, probably interfering with ligand binding. Both of her parents were heterozygotes for this mutation, which was not detected in 100 normal alleles. No mutations were identified in the entire coding area of the ACTH receptor in the 2 families with triple A syndrome, supporting the idea of a developmental or postreceptor defect in this syndrome. 19 refs., 1 fig.

  11. Bile acid receptor agonists. INT747 and INT777 decrease oestrogen deficiency-related postmenopausal obesity and hepatic steatosis in mice

    NARCIS (Netherlands)

    de Oliveira, Monique C.; Gilglioni, Eduardo H.; de Boer, Bouke A.; Runge, Jurgen H.; de Waart, Dirk R.; Salgueiro, Clairce L.; Ishii-Iwamoto, Emy L.; Oude Elferink, Ronald P. J.; Gaemers, Ingrid C.

    2016-01-01

    Menopause is often followed by obesity and, related to this, non-alcoholic fatty liver disease (NAFLD). Two bile acid (BA) receptors, farnesoid X receptor (FXR) and G-protein-coupled receptor TGR5, have emerged as putative therapeutic targets for obesity and NAFLD. Aim of this study: to evaluate the

  12. Detection of early stage atherosclerotic plaques using PET and CT fusion imaging targeting P-selectin in low density lipoprotein receptor-deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Ikuko, E-mail: nakamuri@riken.jp [RIKEN Center for Molecular Imaging Science, Kobe (Japan); Department of Cardiovascular Medicine, Saga University, Saga (Japan); Hasegawa, Koki [RIKEN Center for Molecular Imaging Science, Kobe (Japan); Department of Pathology and Experimental Medicine, Kumamoto University, Kumamoto (Japan); Wada, Yasuhiro [RIKEN Center for Molecular Imaging Science, Kobe (Japan); Hirase, Tetsuaki; Node, Koichi [Department of Cardiovascular Medicine, Saga University, Saga (Japan); Watanabe, Yasuyoshi, E-mail: yywata@riken.jp [RIKEN Center for Molecular Imaging Science, Kobe (Japan)

    2013-03-29

    Highlights: ► P-selectin regulates leukocyte recruitment as an early stage event of atherogenesis. ► We developed an antibody-based molecular imaging probe targeting P-selectin for PET. ► This is the first report on successful PET imaging for delineation of P-selectin. ► P-selectin is a candidate target for atherosclerotic plaque imaging by clinical PET. -- Abstract: Background: Sensitive detection and qualitative analysis of atherosclerotic plaques are in high demand in cardiovascular clinical settings. The leukocyte–endothelial interaction mediated by an adhesion molecule P-selectin participates in arterial wall inflammation and atherosclerosis. Methods and results: A {sup 64}Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid conjugated anti-P-selectin monoclonal antibody ({sup 64}Cu-DOTA-anti-P-selectin mAb) probe was prepared by conjugating an anti-P-selectin monoclonal antibody with DOTA followed by {sup 64}Cu labeling. Thirty-six hours prior to PET and CT fusion imaging, 3 MBq of {sup 64}Cu-DOTA-anti-P-selectin mAb was intravenously injected into low density lipoprotein receptor-deficient Ldlr-/- mice. After a 180 min PET scan, autoradiography and biodistribution of {sup 64}Cu-DOTA-anti-P-selectin monoclonal antibody was examined using excised aortas. In Ldlr-/- mice fed with a high cholesterol diet for promotion of atherosclerotic plaque development, PET and CT fusion imaging revealed selective and prominent accumulation of the probe in the aortic root. Autoradiography of aortas that demonstrated probe uptake into atherosclerotic plaques was confirmed by Oil red O staining for lipid droplets. In Ldlr-/- mice fed with a chow diet to develop mild atherosclerotic plaques, probe accumulation was barely detectable in the aortic root on PET and CT fusion imaging. Probe biodistribution in aortas was 6.6-fold higher in Ldlr-/- mice fed with a high cholesterol diet than in those fed with a normal chow diet. {sup 64}Cu-DOTA-anti-P-selectin m

  13. Loss of mRor1 Enhances the Heart and Skeletal Abnormalities in mRor2-Deficient Mice: Redundant and Pleiotropic Functions of mRor1 and mRor2 Receptor Tyrosine Kinases

    OpenAIRE

    Nomi, Masashi; Oishi, Isao; Kani, Shuichi; Suzuki, Hiroaki; Matsuda, Takeru; Yoda, Akinori; Kitamura, Makiko; Itoh, Kyoko; Takeuchi, Shigeto; Takeda, Kiyoshi; Akira, Shizuo; Ikeya, Makoto; Takada, Shinji; Minami, Yasuhiro

    2001-01-01

    The mammalian Ror family of receptor tyrosine kinases consists of two structurally related proteins, Ror1 and Ror2. We have shown that mRor2-deficient mice exhibit widespread skeletal abnormalities, ventricular septal defects in the heart, and respiratory dysfunction, leading to neonatal lethality (S. Takeuchi, K. Takeda, I. Oishi, M. Nomi, M. Ikeya, K. Itoh, S. Tamura, T. Ueda, T. Hatta, H. Otani, T. Terashima, S. Takada, H. Yamamura, S. Akira, and Y. Minami, Genes Cells 5:71–78, 2000). Here...

  14. Effect of iron deficiency on the expression of insulin-like growth factor-II and its receptor in neuronal and glial cells.

    Science.gov (United States)

    Morales González, E; Contreras, I; Estrada, J A

    2014-09-01

    Many studies have demonstrated that iron deficiency modifies the normal function of the central nervous system and alters cognitive abilities. When cellular damage occurs in the central nervous system, neuroprotective mechanisms, such as the production of neurotrophic factors, are essential in order for nervous tissue to function correctly. Insulin-like growth factor II (IGF- II) is a neurotrophic factor that was recently shown to be involved in the normal functioning of cognitive processes in animal models. However, the impact of iron deficiency on the expression and function of this molecule has not yet been clarified. Mixed primary cell cultures from the central nervous system were collected to simulate iron deficiency using deferoxamine. The expression of IGF-I, IGF-II, IGF-IR, and IGF-IIR was determined with the western blot test. We observed increased expression of IGF-II, along with a corresponding decrease in the expression of IGF-IIR, in iron-deficient mixed primary cell cultures. We did not observe alterations in the expression of these proteins in isolated microglia or neuronal cultures under the same conditions. We did not detect differences in the expression of IGF-I and IGF-IR in iron-deficient cultures. In vitro iron deficiency increases the expression of IGF-II in mixed glial cell cultures, which may have a beneficial effect on brain tissue homeostasis in a situation in which iron availability is decreased. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  15. Antibody production in mice deficient for complement receptors 1 and 2 can be induced by IgG/Ag and IgE/Ag, but not IgM/Ag complexes.

    Science.gov (United States)

    Applequist, S E; Dahlström, J; Jiang, N; Molina, H; Heyman, B

    2000-09-01

    Deficiencies in C factors C2, C3, or C4 as well as lack of C receptors 1 and 2 (CR1/2) lead to impaired Ab production. Classical pathway activation plays a major role, as mice deficient in factor B, a key factor in the alternative pathway, have normal Ab production. Abs in complex with their specific Ag are known to feedback regulate the Ab response, and enhanced responses are initiated by IgM, IgE, and IgG. IgM acts via the C system, whereas IgE and IgG can operate independently of C via Fc receptors. Here we have investigated whether these isotypes are able to enhance Ab responses in mice lacking CR1/2. SRBC-specific IgM, administered with SRBC, does not enhance Ab responses in these animals. In contrast, 2,4, 6-trinitrophenyl-specific IgE and IgG2a, administered with BSA-2,4, 6-trinitrophenyl, induce potent Ab responses in CR1/2-deficient mice. Additionally, BSA administered with CFA or alum induced strong Ab responses in the absence of CR1/2. These results indicate that CR1/2 is needed to promote IgM-mediated induction of primary Ab responses. The data also show that the need for CR1/2 can be circumvented by Abs typical of a secondary immune response forming complexes with Ag or by conventional adjuvants, presumably mimicking physiological inflammatory reactions.

  16. Iodine Deficiency

    NARCIS (Netherlands)

    Zimmermann, M.B.

    2009-01-01

    Iodine deficiency has multiple adverse effects in humans, termed iodine deficiency disorders, due to inadequate thyroid hormone production. Globally, it is estimated that 2 billion individuals have an insufficient iodine intake, and South Asia and sub-Saharan Africa are particularly affected.

  17. Expression of the sodium channel transcripts Na(v)1.8 and Na(v)1.9 in injured dorsal root ganglion neurons of interferon-gamma or interferon-gamma receptor deficient mice.

    Science.gov (United States)

    Eriksson, Jonas; Fried, Kaj

    2003-03-06

    Changes in the dorsal root ganglion (DRG) expression of the sodium channels Na(v)1.8 and Na(v)1.9 may contribute to injury-induced hyperexcitability and pain. Interferon (IFN)-gamma receptor -/- mice display a reduced pain-related behavior after nerve injury as compared to wild-type mice (NeuroReport 8 (1997) 1311). To elucidate a possible role for IFN-gamma in the regulation of sodium channels, we have studied the DRG mRNA expression of Na(v)1.8/Na(v)1.9 in IFN-gamma- or IFN-gamma receptor-deficient mice. In both types of mice, nerve damage induced a downregulation of Na(v)1.8 as well as Na(v)1.9. The magnitude of this reduction was similar to that observed in wild-type animals. These results indicate that the downregulation of Na(v)1.8/Na(v)1.9 in damaged DRG neurons is not influenced by IFN-gamma. Thus, the reduced pain-related behavior of nerve-injured IFN-gamma receptor null mice is not due to differential changes in the regulation of Na(v)1.8/Na(v)1.9 mRNA.

  18. Vitamin D deficiency in girls from South Brazil: a cross-sectional study on prevalence and association with vitamin D receptor gene variants.

    Science.gov (United States)

    Santos, Betânia R; Mascarenhas, Luis P G; Satler, Fabíola; Boguszewski, Margaret C S; Spritzer, Poli Mara

    2012-06-08

    Vitamin D deficiency has been associated with a multitude of disorders including diabetes, defective insulin secretion as well as rickets and poor bone health. Vitamin D is also a concern during childhood and adolescence and has been reported in girls from South Brazil. We determined the prevalence of vitamin D deficiency in girls from South Brazil and investigated whether the genotypic distribution of the BsmI, ApaI and TaqI polymorphisms of the VDR gene and their haplotypes were associated with vitamin D levels. Cross-sectional study including 234 apparently healthy girls aged 7 to 18 years. Height and weight were measured for calculation of body mass index (BMI) percentiles for age. Plasma levels of 25-hydroxyvitamin D [25(OH)D] were assessed. Participants were genotyped for ApaI (rs7975232), TaqI (rs731236), and BsmI (rs1544410) SNPs. The median and interquartile range (25-75%) of BMI percentile was 62.0 (33.3 - 84.9). The frequency of overweight/obesity was 24.9%. Circulating levels of 25(OH)D (≥ 30 ng/mL) were adequate in 9.4%; insufficient in 54.3% (20-29 ng/mL); and deficient in 36.3% (children and adolescents.

  19. Vitamin D deficiency in girls from South Brazil: a cross-sectional study on prevalence and association with vitamin D receptor gene variants

    Directory of Open Access Journals (Sweden)

    Santos Betânia R

    2012-06-01

    Full Text Available Abstract Background Vitamin D deficiency has been associated with a multitude of disorders including diabetes, defective insulin secretion as well as rickets and poor bone health. Vitamin D is also a concern during childhood and adolescence and has been reported in girls from South Brazil. We determined the prevalence of vitamin D deficiency in girls from South Brazil and investigated whether the genotypic distribution of the BsmI, ApaI and TaqI polymorphisms of the VDR gene and their haplotypes were associated with vitamin D levels. Methods Cross-sectional study including 234 apparently healthy girls aged 7 to 18 years. Height and weight were measured for calculation of body mass index (BMI percentiles for age. Plasma levels of 25-hydroxyvitamin D [25(OHD] were assessed. Participants were genotyped for ApaI (rs7975232, TaqI (rs731236, and BsmI (rs1544410 SNPs. Results The median and interquartile range (25-75% of BMI percentile was 62.0 (33.3 – 84.9. The frequency of overweight/obesity was 24.9%. Circulating levels of 25(OHD (≥ 30 ng/mL were adequate in 9.4%; insufficient in 54.3% (20–29 ng/mL; and deficient in 36.3% (vs. GA + AA, two-tailed Student’s t-test p vs. GT + TT, two-tailed Student’s t-test p = 0.031 and TaqI (TT vs. TC + CC, two-tailed Student’s t-test p = 0.005 SNPs and the GGT haplotype (two-tailed Student’s t-test p = 0.036 were significantly associated with lower 25(OHD levels. Conclusions 25-hydroxyvitamin D deficiency and insufficiency were highly prevalent in this sample. The BsmI, ApaI and TaqI wild variants of the VDR gene, as well as the GGT haplotype, were associated with lower vitamin D levels, suggesting that VDR gene polymorphisms could be linked to higher susceptibility to vitamin D deficiency in a sub-population of children and adolescents.

  20. Impaired virus control and severe CD8+ T-cell-mediated immunopathology in chimeric mice deficient in gamma interferon receptor expression on both parenchymal and hematopoietic cells

    DEFF Research Database (Denmark)

    Henrichsen, Pernille; Bartholdy, Christina; Christensen, Jan Pravsgaard

    2005-01-01

    Bone marrow chimeras were used to determine the cellular target(s) for the antiviral activity of gamma interferon (IFN-gamma). By transfusing such mice with high numbers of naive virus-specific CD8(+) T cells, a system was created in which the majority of virus-specific CD8(+) T cells would...... be capable of responding to IFN-gamma, but expression of the relevant receptor on non-T cells could be experimentally controlled. Only when the IFN-gamma receptor is absent on both radioresistant parenchymal and bone marrow-derived cells will chimeric mice challenged with a highly invasive, noncytolytic...

  1. Macrophage ABCG1 deletion disrupts lipid homeostasis in alveolar macrophages and moderately influences atherosclerotic lesion development in LDL receptor-deficient mice

    NARCIS (Netherlands)

    Out, Ruud; Hoekstra, Menno; Hildebrand, Reeni B.; Kruit, Janine K.; Meurs, Illiana; Li, Zhaosha; Kuipers, Folkert; Van Berkel, Theo J. C.; Van Eck, Miranda

    2006-01-01

    Objective - ABCG1 has recently been identified as a facilitator of cellular cholesterol and phospholipid efflux to high-density lipoprotein (HDL). Its expression in macrophages is induced during cholesterol uptake in macrophages and by liver X receptor (LXR). The role of macrophage ABCG1 in

  2. D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI

    DEFF Research Database (Denmark)

    Santini, Martin A; Balu, Darrick T; Puhl, Matthew D

    2014-01-01

    Both the serotonin and glutamate systems have been implicated in the pathophysiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. Psychedelic drugs act through the serotonin 2A receptor (5-HT2AR), and elicit a head-twitch response (HTR) in mice, which directly...

  3. Elevated interferon gamma expression in the central nervous system of tumour necrosis factor receptor 1-deficient mice with experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Wheeler, Rachel D; Zehntner, Simone P; Kelly, Lisa M

    2006-01-01

    Inflammation in the central nervous system (CNS) can be studied in experimental autoimmune encephalomyelitis (EAE). The proinflammatory cytokines interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) are implicated in EAE pathogenesis. Signals through the type 1 TNF receptor (TNFR1) are r...

  4. Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor γ function (P465L PPARγ) in mice

    NARCIS (Netherlands)

    Gray, S.L.; Dalla Nora, E.; Grosse, J.; Manieri, M.; Stoeger, T.; Medina-Gomez, G.; Burling, K.; Wattler, S.; Russ, A.; Yeo, G.S.H.; Chatterjee, V.K.; O'Rahilly, S.; Voshol, P.J.; Cinti, S.; Vidal-Puig, A.

    2006-01-01

    Peroxisome proliferator-activated receptor (PPAR)γ is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPARγ display lipodystrophy and extreme insulin resistance. For this

  5. Gene expression of a truncated and the full-length growth hormone (GH) receptor in subcutaneous fat and skeletal muscle in GH-deficient adults

    DEFF Research Database (Denmark)

    Fisker, Sidse; Kristensen, K; Rosenfalck, A M

    2001-01-01

    the relationship of circulating GHBP and body composition to GHR and GHRtr gene expression. Eleven adult GH-deficient patients were studied before and after 4 months of GH substitution therapy. Abdominal fat obtained by liposuction and femoral muscle biopsies were taken at baseline and after 4 months. Gene...... expression of GHR and GHRtr in adipose tissue and skeletal muscle was determined and expressed relative to the expression of beta-actin. Gene expression of GHR in abdominal sc adipose tissue was not altered, whereas the expression of GHRtr increased significantly. In skeletal muscle inverse changes were seen...

  6. Autosomal Recessive HEM/Greenberg Skeletal Dysplasia Is Caused by 3β-Hydroxysterol Δ14-Reductase Deficiency Due to Mutations in the Lamin B Receptor Gene

    OpenAIRE

    Waterham, Hans R.; Koster, Janet; Mooyer, Petra; Noort, Gerard van; Kelley, Richard I.; Wilcox, William R.; Ronald Wanders, J.A.; Raoul Hennekam, C.M.; Jan Oosterwijk, C.

    2003-01-01

    Hydrops-ectopic calcification-“moth-eaten” (HEM) or Greenberg skeletal dysplasia is an autosomal recessive chondrodystrophy with a lethal course, characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification. We found elevated levels of cholesta-8,14-dien-3β-ol in cultured skin fibroblasts of an 18-wk-old fetus with HEM, compatible with a deficiency of the cholesterol biosynthetic enzyme 3β-hydroxysterol Δ14-reductase. Sequence analysis of two candidate genes encodin...

  7. Growth hormone receptor deficiency in mice results in reduced systolic blood pressure and plasma renin, increased aortic eNOS expression, and altered cardiovascular structure and function

    DEFF Research Database (Denmark)

    Egecioglu, E; Andersson, I J; Bollano, E

    2007-01-01

    To study the role of the growth hormone receptor (GHR) in the development of cardiovascular structure and function, female GHR gene-disrupted or knockout (KO) and wild-type (WT) mice at age 18 wk were used. GHR KO mice had lower plasma renin levels (12 +/- 2 vs. 20 +/- 4 mGU/ml, P .... These data suggest an important role for an intact GH/IGF-I axis in the maintenance of a normal cardiovascular system....

  8. [Niacin deficiency and cutaneous immunity].

    Science.gov (United States)

    Ikenouchi-Sugita, Atsuko; Sugita, Kazunari

    2015-01-01

    Niacin, also known as vitamin B3, is required for the synthesis of coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin binds with G protein-coupled receptor (GPR) 109A on cutaneous Langerhans cells and causes vasodilation with flushing in head and neck area. Niacin deficiency due to excessive alcohol consumption, certain drugs or inadequate uptake in diet causes pellagra, a photosensitivity dermatitis. Recently several studies have revealed the mechanism of photosensitivity in niacin deficiency, which may pave a way for new therapeutic approaches. The expression level of prostaglandin E synthase (PTGES) is up-regulated in the skin of both pellagra patients and niacin deficient pellagra mouse models. In addition, pellagra is mediated through prostaglandin E₂-EP4 (PGE₂-EP4) signaling via reactive oxygen species (ROS) production in keratinocytes. In this article, we have reviewed the role of niacin in immunity and the mechanism of niacin deficiency-induced photosensitivity.

  9. The Leucine-Rich Repeat Receptor-Like Kinase BRASSINOSTEROID INSENSITIVE1-ASSOCIATED KINASE1 and the Cytochrome P450 PHYTOALEXIN DEFICIENT3 Contribute to Innate Immunity to Aphids in Arabidopsis1[C][W][OPEN

    Science.gov (United States)

    Prince, David C.; Drurey, Claire; Zipfel, Cyril; Hogenhout, Saskia A.

    2014-01-01

    The importance of pathogen-associated molecular pattern-triggered immunity (PTI) against microbial pathogens has been recently demonstrated. However, it is currently unclear if this layer of immunity mediated by surface-localized pattern recognition receptors (PRRs) also plays a role in basal resistance to insects, such as aphids. Here, we show that PTI is an important component of plant innate immunity to insects. Extract of the green peach aphid (GPA; Myzus persicae) triggers responses characteristic of PTI in Arabidopsis (Arabidopsis thaliana). Two separate eliciting GPA-derived fractions trigger induced resistance to GPA that is dependent on the leucine-rich repeat receptor-like kinase BRASSINOSTEROID INSENSITIVE1-ASSOCIATED KINASE1 (BAK1)/SOMATIC-EMBRYOGENESIS RECEPTOR-LIKE KINASE3, which is a key regulator of several leucine-rich repeat-containing PRRs. BAK1 is required for GPA elicitor-mediated induction of reactive oxygen species and callose deposition. Arabidopsis bak1 mutant plants are also compromised in immunity to the pea aphid (Acyrthosiphon pisum), for which Arabidopsis is normally a nonhost. Aphid-derived elicitors induce expression of PHYTOALEXIN DEFICIENT3 (PAD3), a key cytochrome P450 involved in the biosynthesis of camalexin, which is a major Arabidopsis phytoalexin that is toxic to GPA. PAD3 is also required for induced resistance to GPA, independently of BAK1 and reactive oxygen species production. Our results reveal that plant innate immunity to insects may involve early perception of elicitors by cell surface-localized PRRs, leading to subsequent downstream immune signaling. PMID:24586042

  10. Pharmacological evaluation of pioglitazone and candesartan cilexetil in a novel mouse model of non-alcoholic steatohepatitis, modified choline-deficient, amino acid-defined diet fed low-density lipoprotein receptor knockout mice.

    Science.gov (United States)

    Tsuchiya, Shuntarou; Amano, Yuichiro; Isono, Osamu; Imai, Mayumi; Shimizu, Fumi; Asada, Mari; Imai, Shigemitsu; Harada, Ayako; Yasuhara, Yoshitaka; Tozawa, Ryuichi; Nagabukuro, Hiroshi

    2017-05-01

    Low-density lipoprotein receptor knockout (LDLR-KO) mice fed a modified choline-deficient and amino acid-defined (mCDAA) diet show non-alcoholic steatohepatitis (NASH)-like pathophysiology. In order to pharmacologically benchmark this model, effects of pioglitazone (a thiazolidinedione) and candesartan cilexetil (an angiotensin II type 1 receptor blocker) on steatosis and liver fibrosis were examined. Pioglitazone (10 mg/kg) and candesartan cilexetil (3 mg/kg) were given orally once daily to LDLR-KO mice under mCDAA diet for 7 weeks. Blood biochemistry and hepatic histology were assessed, and hepatic gene expression levels and triglyceride content were measured. Pioglitazone suppressed hepatic COL1A1 gene expression by 43% and attenuated hepatic fibrosis areas by 49%. Pioglitazone also decreased plasma alanine aminotransferase levels, liver weight, hepatic triglyceride content, and hepatic expression of other fibrosis-related genes such as TGFB1, SPP1, TIMP1, and IL6. Candesartan cilexetil suppressed hepatic COL1A1 gene expression by 33%, whereas the other end-points including hepatic fibrosis areas were not affected. Pioglitazone showed anti-fibrotic effects accompanied by improving hepatic transaminase activity and hepatic lipid accumulation, but the effect of candesartan cilexetil was only limited, unlike previous reports for angiotensin II type 1 receptor blockers. As the pharmacological effects of pioglitazone in the current animal model are similar to those reported in patients with NASH, this model may represent some aspects of the pathophysiology of NASH. Further profiling using other agents or mechanisms that have been tested in the clinic will better clarify the utility of the animal model. © 2016 The Japan Society of Hepatology.

  11. 3,5,3’-triiodo-L-thyronine- and 3,5-diiodo-L-thyronine- affected metabolic pathways in liver of LDL receptor deficient mice

    Directory of Open Access Journals (Sweden)

    Maria Moreno

    2016-11-01

    Full Text Available 3,5,3’-triiodo-L-thyronine (T3 and 3,5-diiodo-L-thyronine (T2, when administered to a model of familial hypercholesterolemia, i.e. low density lipoprotein receptor (LDLr-knockout (Ldlr-/- mice fed with a Western type diet (WTD, dramatically reduce circulating total and very low-density lipoprotein/LDL cholesterol with decreased liver apolipoprotein B (ApoB production. The aim of the study was to highlight putative molecular mechanisms to manage cholesterol levels in the absence of LDLr. A comprehensive comparative profiling of changes in expression of soluble proteins in livers from Ldlr-/- mice treated with either T3 or T2 was performed. From a total proteome of 450 liver proteins, 25 identified proteins were affected by both T2 and T3, 18 only by T3 and 9 only by T2. Using in silico analyses, an overlap was observed with 11/14 pathways common to both iodothyronines, with T2 and T3 preferentially altering sub-networks centered around hepatocyte nuclear factor 4 α (HNF4α and peroxisome proliferator-activated receptor α (PPARα, respectively. Both T2 and T3 administration significantly reduced nuclear HNF4α protein content, while T2, but not T3, decreased the expression levels of the HNFα transcriptional coactivator PGC-1α. Lower PPARα levels were found only following T3 treatment while both T3 and T2 lowered liver X receptor α (LXRα nuclear content. Overall, this study, although it was not meant to investigate the use of T2 and T3 as a therapeutic agent, provides novel insights into the regulation of hepatic metabolic pathways involved in T3- and T2-driven cholesterol reduction in Ldlr-/- mice.

  12. Impaired Mobilization of Vascular Reparative Bone Marrow Cells in Streptozotocin-Induced Diabetes but not in Leptin Receptor-Deficient db/db Mice

    Science.gov (United States)

    Vasam, Goutham; Joshi, Shrinidh; Jarajapu, Yagna P. R.

    2016-01-01

    Diabetes is associated with impaired mobilization of bone marrow stem/progenitor cells that accelerate vascularization of ischemic areas. This study characterized mobilization of vascular reparative bone marrow progenitor cells in mouse models of diabetes. Age-matched control or streptozotocin (STZ)-induced diabetic, and db/db mice with lean-controls were studied. Mobilization induced by G-CSF, AMD3100 or ischemia was evaluated by flow cytometric enumeration of circulating Lin−Sca-1+cKit+ (LSK) cells, and by colony forming unit (CFU) assay. The circulating WBCs and LSKs, and CFUs were reduced in both models with a shorter duration (10–12 weeks) of diabetes compared to their respective controls. Longer duration of STZ-diabetes (≥20 weeks) induced impairment of G-CSF- or AMD3100-mobilization (P mobilization by G-CSF or AMD3100 was either increased or unaffected (P mobilization, of LSK cells were impaired in both models. Leptin receptor antagonist, PESLAN-1, increased G-CSF- or AMD3100-mobilization of WBCs and LSKs, compared to the untreated. Leptin increased basal WBCs, decreased basal and AMD3100-mobilized LSK cells, and had no effect on G-CSF. These results suggest that mobilopathy is apparent in STZ-diabetes but not in db/db mice. Leptin receptor antagonism would be a promising approach for reversing diabetic bone marrow mobilopathy. PMID:27188595

  13. Differential Expression of Claudin Family Proteins in Mouse Ovarian Serous Papillary Epithelial Adenoma in Aging FSH Receptor-Deficient Mutants1

    Science.gov (United States)

    Aravindakshan, Jayaprakash; Chen, Xinlei; Sairam, M Ram

    2006-01-01

    Abstract Ovarian cancer is a deadly disease with long latency. To understand the consequences of loss of folliclestimulating hormone receptor (FSH-R) signaling and to explore why the atrophic and anovulatory ovaries of follitropin receptor knockout (FORKO) mice develop different types of ovarian tumors, including serous papillary epithelial adenoma later in life, we used mRNA expression profiling to gain a comprehensive view of misregulated genes. Using real-time quantitative reverse transcription-polymerase chain reaction, protein analysis, and cellular localization, we show, for the first time, in vivo evidence that, in the absence of FSH-R signaling, claudin-3, claudin-4, and claudin-11 are selectively upregulated, whereas claudin-1 decreases in ovarian surface epithelium and tumors in comparison to wild type. In vitro experiments using a mouse ovarian surface epithelial cell line derived from wild-type females reveal direct hormonal influence on claudin proteins. Although recent studies suggest that cell junction proteins are differentially expressed in ovarian tumors in women, the etiology of such changes remains unclear. Our results suggest an altered hormonal environment resulting from FSH-R loss as a cause of early changes in tight junction proteins that predispose the ovary to late-onset tumors that occur with aging. More importantly, this study identifies claudin-11 overexpression in mouse ovarian serous cystadenoma. PMID:17217615

  14. D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT2A receptor agonist DOI

    Science.gov (United States)

    Santini, Martin A.; Balu, Darrick T.; Puhl, Matthew D.; Hill-Smith, Tiffany E.; Berg, Alexandra R.; Lucki, Irwin; Mikkelsen, Jens D.; Coyle, Joseph T.

    2014-01-01

    Both the serotonin and glutamate systems have been implicated in the pathophysiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. Psychedelic drugs act through the serotonin 2A receptor (5-HT2AR), and elicit a head-twitch response (HTR) in mice, which directly correlates to 5-HT2AR activation and is absent in 5-HT2AR knockout mice. The precise mechanism of this response remains unclear, but both an intrinsic cortico-cortical pathway and a thalamo-cortical pathway involving glutamate release have been proposed. Here, we used a genetic model of NMDAR hypofunction, a serine racemase knockout (SRKO) mouse, to explore the role of glutamatergic transmission in regulating the 5-HT2AR-mediated cellular and behavioral responses. SRKO mice treated with the 5-HT2AR agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished HTR and lower induction of c-fos mRNA. These altered functional responses in SRKO mice were not associated with changes in cortical or hippocampal 5-HT levels or in 5-HT2AR and metabotropic glutamate-2 receptor (mGluR2) mRNA and protein expression. Together, these findings suggest that D-serine-dependent NMDAR activity is involved in mediating the cellular and behavioral effects of 5-HT2AR activation. PMID:24269270

  15. Administration of anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody for the treatment of osteoporosis was associated with amelioration of hepatitis in a female patient with growth hormone deficiency: a case report.

    Science.gov (United States)

    Takeno, Ayumu; Yamamoto, Masahiro; Notsu, Masakazu; Sugimoto, Toshitsugu

    2016-11-24

    Growth hormone deficiency (GHD) is associated with non-alcoholic fatty liver disease (NAFLD). A recent animal study showed that hepatocyte-specific receptor activator of nuclear factor-kappa B (RANK) knockout mice had significantly lower liver fat content compared with control mice concomitant with a decrease in production of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) from hepatocytes and kupffer cells. The role of anti-RANK ligand (RANKL) antibody for osteoporosis on hepatitis in patients with aGHD is still unknown. A forty-seven-year-old female patient was referred to our hospital to investigate chronic hepatitis caused by unknown etiology. She had past history of craniopharyngioma treated with craniotomy and post-surgical radiotherapy. She was for the first time diagnosed as panhypopituitarism including growth hormone deficiency and osteoporosis by endocrine examinations and bone mineral densitometry, respectively. In addition, non-alcoholic steatohepatitis (NASH) was histologically confirmed by liver biopsy in this time. Sixty mg anti-RANKL antibody, which was subcutaneously injected to treat the osteoporosis every six months after replacement of 5 mg hydrocortisone and 30 μg oral desmopressin, rapidly decreased the levels of her liver enzymes (ALT and γGTP were 133 to 72 U/L and 284 to 99 U/L at 16 months after the beginning of the treatment, respectively). Additional amelioration of liver dysfunction was not observed after growth hormone replacement. The clinical course of the present case suggested that RANKL-RANK signaling may be a key pathological mechanism in establishment or development of NAFLD or NASH in patients with panhypopituitarism including GHD.

  16. A large increase of sour taste receptor cells in Skn-1-deficient mice does not alter the number of their sour taste signal-transmitting gustatory neurons.

    Science.gov (United States)

    Maeda, Naohiro; Narukawa, Masataka; Ishimaru, Yoshiro; Yamamoto, Kurumi; Misaka, Takumi; Abe, Keiko

    2017-05-01

    The connections between taste receptor cells (TRCs) and innervating gustatory neurons are formed in a mutually dependent manner during development. To investigate whether a change in the ratio of cell types that compose taste buds influences the number of innervating gustatory neurons, we analyzed the proportion of gustatory neurons that transmit sour taste signals in adult Skn-1a -/- mice in which the number of sour TRCs is greatly increased. We generated polycystic kidney disease 1 like 3-wheat germ agglutinin (pkd1l3-WGA)/Skn-1a +/+ and pkd1l3-WGA/Skn-1a -/- mice by crossing Skn-1a -/- mice and pkd1l3-WGA transgenic mice, in which neural pathways of sour taste signals can be visualized. The number of WGA-positive cells in the circumvallate papillae is 3-fold higher in taste buds of pkd1l3-WGA/Skn-1a -/- mice relative to pkd1l3-WGA/Skn-1a +/+ mice. Intriguingly, the ratio of WGA-positive neurons to P2X 2 -expressing gustatory neurons in nodose/petrosal ganglia was similar between pkd1l3-WGA/Skn-1a +/+ and pkd1l3-WGA/Skn-1a -/- mice. In conclusion, an alteration in the ratio of cell types that compose taste buds does not influence the number of gustatory neurons that transmit sour taste signals. Copyright © 2017. Published by Elsevier B.V.

  17. Aryl Hydrocarbon Receptor Deficiency in an Exon 3 Deletion Mouse Model Promotes Hematopoietic Stem Cell Proliferation and Impacts Endosteal Niche Cells

    Directory of Open Access Journals (Sweden)

    Zeenath Unnisa

    2016-01-01

    Full Text Available The aryl hydrocarbon receptor (AHR is a ligand-activated transcription factor belonging to the Per-Arnt-Sim (PAS family of proteins. The AHR is involved in hematopoietic stem cell (HSC functions including self-renewal, proliferation, quiescence, and differentiation. We hypothesize that AHR impacts HSC functions by influencing genes that have roles in HSC maintenance and function and that this may occur through regulation of bone marrow (BM niche cells. We examined BM and niche cells harvested from 8-week-old AHR null-allele (KO mice in which exon 3 was deleted in the Ahr gene and compared these data to cells from B6 control mice; young and old (10 months animals were also compared. We report changes in HSCs and peripheral blood cells in mice lacking AHR. Serial transplantation assays revealed a significant increase in long term HSCs. There was a significant increase in mesenchymal stem cells constituting the endosteal BM niche. Gene expression analyses of HSCs revealed an increase in expression of genes involved in proliferation and maintenance of quiescence. Our studies infer that loss of AHR results in increased proliferation and self-renewal of long term HSCs, in part, by influencing the microenvironment in the niche regulating the balance between quiescence and proliferation in HSCs.

  18. The Group 3 Innate Lymphoid Cell Defect in Aryl Hydrocarbon Receptor Deficient Mice Is Associated with T Cell Hyperactivation during Intestinal Infection.

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    Sagie Wagage

    Full Text Available Intestinal infection with the intracellular parasite Toxoplasma gondii results in the translocation of commensal bacteria to peripheral organs and the development of a T cell response specific to the microbiota. In naïve mice, the recently described RORγt+ group 3 innate lymphoid cell (ILC population plays a critical role in promoting intestinal barrier function and limiting responses to gut-resident commensal bacteria. Given this role for group 3 ILCs, studies were performed to evaluate whether these cells might influence the immune response to mucosal infection with T. gondii. Phenotypic characterization of RORγt+ ILCs in T. gondii infected mice revealed that this population decreased following challenge but the population that remained expressed costimulatory molecules and IL-22. One factor that influences the maintenance of RORγt+ ILCs is the aryl hydrocarbon receptor (AHR, a ligand-activated transcription factor, and Ahr-/- mice have a marked defect in the lamina propria group 3 ILC population. When Ahr-/- mice were challenged with T. gondii, they lost more weight than wild type controls. This disease course in Ahr-/- animals was associated with increased T cell responses to Toxoplasma antigen and crude commensal antigen preparations. Together, these data suggest that group 3 ILCs have a role in limiting T cell activation during intestinal infection.

  19. Nrf2 Deficiency Upregulates Intrarenal Angiotensin-converting Enzyme-2 and Angiotensin 1-7 Receptor Expression and Attenuates Hypertension and Nephropathy in Diabetic Mice.

    Science.gov (United States)

    Zhao, Shuiling; Ghosh, Anindya; Lo, Chao-Sheng; Chenier, Isabelle; Scholey, James W; Filep, Janos G; Ingelfinger, Julie R; Zhang, Shao-Ling; Chan, John S D

    2017-12-01

    We investigated the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in renin-angiotensin system (RAS) gene expression in renal proximal tubule cells (RPTCs) and in the development of systemic hypertension and kidney injury in diabetic Akita mice. We used adult male Akita Nrf2 knockout (KO) mice and Akita mice treated with trigonelline (an Nrf2 inhibitor) or oltipraz (an Nrf2 activator). We also examined immortalized rat RPTCs (IRPTCs) stably transfected with control plasmids or plasmids containing rat angiotensinogen (Agt), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (Ace2) or angiotensin 1-7 receptor (MasR) gene promoters. Genetic deletion of Nrf2 or pharmacological inhibition of Nrf2 attenuated hypertension, renal injury, and tubulointerstitial fibrosis, and lowered the urinary albumin/creatinine ratio as well as upregulated RPTC Ace2 and MasR expression, increased urinary angiotensin 1-7 levels parallel with down-regulation of Agt, ACE and pro-fibrotic gene expression compared to non-treated Akita mice. In cultured IRPTCs, Nrf2 small interfering RNA transfection or trigonelline treatment prevented high glucose-stimulation of Nrf2 nuclear translocation, Agt and ACE transcription with augmentation of Ace2 and MasR transcription, which was reversed by oltipraz. These data identify a novel mechanism, Nrf2-mediated stimulation of intrarenal RAS gene expression, by which chronic hyperglycemia induces hypertension and renal injury in diabetes. Copyright © 2017 Endocrine Society.

  20. Increased a-series gangliosides positively regulate leptin/Ob receptor-mediated signals in hypothalamus of GD3 synthase-deficient mice.

    Science.gov (United States)

    Ji, Shuting; Tokizane, Kyohei; Ohkawa, Yuki; Ohmi, Yuhsuke; Banno, Ryoichi; Okajima, Tetsuya; Kiyama, Hiroshi; Furukawa, Koichi; Furukawa, Keiko

    2016-10-21

    Gangliosides are widely involved in the regulation of cells and organs. However, little is known about their roles in adipose tissues and hypothalamus. In GD3 synthase-knockout (GD3S KO) mice, deletion of b-series gangliosides resulted in the reduction of serum leptin due to disturbed secretion from adipocytes. To examine whether leptin signals altered, leptin/leptin receptor (ObR)-mediated signaling in hypothalamus was analyzed. Hypothalamus of GD3S KO mouse showed increased expression of GM1 and GD1a, and increased activation of ObR-mediated signals such as pSTAT3 and c-Fos. Leptin stimulation of hypothalamus-derived N-41 cells and their transfectants with GD3S cDNA showed that a-series gangliosides positively regulate leptin/ObR-mediated signals. Co-precipitation analysis revealed that ObR interacts with a-series gangliosides with increased association by leptin stimulation. In brown adipose tissues (BAT) of GD3S KO mice, their weights and adipocyte numbers were increased, and BAT markers such as PGC1α and UCP-1 were also up-regulated. These results suggested that leptin/ObRb-mediated signals were enhanced in hypothalamus of GD3S KO mice due to increased a-series gangliosides, leading to the apparently similar features of energy expenditure between the KO and wild type mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Iron deficiency

    DEFF Research Database (Denmark)

    Schou, Morten; Bosselmann, Helle; Gaborit, Freja

    2015-01-01

    BACKGROUND: Both iron deficiency (ID) and cardiovascular biomarkers are associated with a poor outcome in heart failure (HF). The relationship between different cardiovascular biomarkers and ID is unknown, and the true prevalence of ID in an outpatient HF clinic is probably overlooked. OBJECTIVES.......043). CONCLUSION: ID is frequent in an outpatient HF clinic. ID is not associated with cardiovascular biomarkers after adjustment for traditional confounders. Inflammation, but not neurohormonal activation is associated with ID in systolic HF. Further studies are needed to understand iron metabolism in elderly HF...

  2. p63 and p73 repress CXCR5 chemokine receptor gene expression in p53-deficient MCF-7 breast cancer cells during genotoxic stress.

    Science.gov (United States)

    Mitkin, Nikita A; Muratova, Alisa M; Sharonov, George V; Korneev, Kirill V; Sviriaeva, Ekaterina N; Mazurov, Dmitriy; Schwartz, Anton M; Kuprash, Dmitry V

    2017-12-01

    Many types of chemotherapeutic agents induce of DNA-damage that is accompanied by activation of p53 tumor suppressor, a key regulator of tumor development and progression. In our previous study we demonstrated that p53 could repress CXCR5 chemokine receptor gene in MCF-7 breast cancer cells via attenuation of NFkB activity. In this work we aimed to determine individual roles of p53 family members in the regulation of CXCR5 gene expression under genotoxic stress. DNA-alkylating agent methyl methanesulfonate caused a reduction in CXCR5 expression not only in parental MCF-7 cells but also in MCF-7-p53off cells with CRISPR/Cas9-mediated inactivation of the p53 gene. Since p53 knockout was associated with elevated expression of its p63 and p73 homologues, we knocked out p63 using CRISPR/Cas9 system and knocked down p73 using specific siRNA. The CXCR5 promoter activity, CXCR5 expression and CXCL13-directed migration in MCF-7 cells with inactivation of all three p53 family genes were completely insensitive to genotoxic stress, while pairwise p53+p63 or p53+p73 inactivation resulted in partial effects. Using deletion analysis and site-directed mutagenesis, we demonstrated that effects of NFkB on the CXCR5 promoter inversely correlated with p63 and p73 levels. Thus, all three p53 family members mediate the effects of genotoxic stress on the CXCR5 promoter using the same mechanism associated with attenuation of NFkB activity. Understanding of this mechanism could facilitate prognosis of tumor responses to chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Sex differences between CRF1 receptor deficient mice following naloxone-precipitated morphine withdrawal in a conditioned place aversion paradigm: implication of HPA axis.

    Directory of Open Access Journals (Sweden)

    Juan-Antonio García-Carmona

    Full Text Available Extinction period of positive affective memory of drug taking and negative affective memory of drug withdrawal, as well as the different response of men and women might be important for the clinical treatment of drug addiction. We investigate the role of corticotropin releasing factor receptor type one (CRF1R and the different response of male and female mice in the expression and extinction of the aversive memory.We used genetically engineered male and female mice lacking functional CRF1R. The animals were rendered dependent on morphine by intraperitoneally injection of increasing doses of morphine (10-60 mg/kg. Negative state associated with naloxone (1 mg/kg s.c.-precipitated morphine withdrawal was examined by using conditioned place aversion (CPA paradigm. No sex differences for CPA expression were found in wild-type (n = 29 or CRF1R knockout (KO mice (n = 29. However, CRF1R KO mice presented less aversion score than wild-type mice, suggesting that CRF1R KO mice were less responsive than wild-type to continuous associations between drug administration and environmental stimuli. In addition, CPA extinction was delayed in wild-type and CRF1R KO male mice compared with females of both genotypes. The genetic disruption of the CRF1R pathway decreased the period of extinction in males and females suggesting that CRF/CRF1R is implicated in the duration of aversive memory. Our results also showed that the increase in adrenocorticotropic hormone (ACTH levels observed in wild-type (n = 11 mice after CPA expression, were attenuated in CRF1R KO mice (n = 10. In addition, ACTH returned to the baseline levels in males and females once CPA extinction was finished.These results suggest that, at least, CPA expression is partially due to an increase in plasma ACTH levels, through activation of CRF1R, which can return when CPA extinction is finished.

  4. Effects of PARP-1 deficiency on airway inflammatory cell recruitment in response to LPS or TNF: differential effects on CXCR2 ligands and Duffy Antigen Receptor for Chemokines.

    Science.gov (United States)

    Zerfaoui, Mourad; Naura, Amarjit S; Errami, Youssef; Hans, Chetan P; Rezk, Bashir M; Park, Jiwon; Elsegeiny, Waleed; Kim, Hogyoung; Lord, Kevin; Kim, Jong G; Boulares, A Hamid

    2009-12-01

    We reported that PARP-1 exhibits differential roles in expression of inflammatory factors. Here, we show that PARP-1 deletion was associated with a significant reduction in inflammatory cell recruitment to mouse airways upon intratracheal administration of LPS. However, PARP-1 deletion exerted little effect in response to TNF exposure. LPS induced massive neutrophilia and moderate recruitment of macrophages, and TNF induced recruitment of primarily macrophages with smaller numbers of neutrophils in the lungs. Following either exposure, macrophage recruitment was blocked severely in PARP-1(-/-) mice, and this was associated with a marked reduction in MCP-1 and MIP-1alpha. This association was corroborated partly by macrophage recruitment in response to intratracheal administration of MCP-1 in PARP-1(-/-) mice. Surprisingly, although neutrophil recruitment was reduced significantly in LPS-treated PARP-1(-/-) mice, neutrophil numbers increased in TNF-treated mice, suggesting that PARP-1 deletion may promote a macrophagic-to-neutrophilic shift in the inflammatory response upon TNF exposure. Neutrophil-specific chemokines mKC and MIP-2 were reduced significantly in lungs of LPS-treated but only partially reduced in TNF-treated PARP-1(-/-) mice. Furthermore, the MIP-2 antagonist abrogated the shift to a neutrophilic response in TNF-exposed PARP-1(-/-) mice. Although CXCR2 expression increased in response to either stimulus in PARP-1(+/+) mice, the DARC increased only in lungs of TNF-treated PARP-1(+/+) mice; both receptors were reduced to basal levels in treated PARP-1(-/-) mice. Our results show that the balance of pro-neutrophilic or pro-macrophagic stimulatory factors and the differential influence of PARP-1 on these factors are critical determinants for the nature of the airway inflammatory response.

  5. Deficiency of the Purinergic Receptor 2X7 Attenuates Nonalcoholic Steatohepatitis Induced by High-Fat Diet: Possible Role of the NLRP3 Inflammasome

    Directory of Open Access Journals (Sweden)

    Claudia Blasetti Fantauzzi

    2017-01-01

    Full Text Available Molecular mechanisms driving transition from simple steatosis to nonalcoholic steatohepatitis (NASH, a critical step in the progression of nonalcoholic fatty liver disease (NAFLD to cirrhosis, are poorly defined. This study aimed at investigating the role of the purinergic receptor 2X7 (PR2X7, through the NLRP3 inflammasome, in the development of NASH. To this end, mice knockout for the Pr2x7 gene (Pr2x7−/− and coeval wild-type (WT mice were fed a high-fat diet (HFD or normal-fat diet for 16 weeks. NAFLD grade and stage were lower in Pr2x7−/− than WT mice, and only 1/7 Pr2x7−/− animals showed evidence of NASH, as compared with 4/7 WT mice. Molecular markers of inflammation, oxidative stress, and fibrosis were markedly increased in WT-HFD mice, whereas no or significantly reduced increments were detected in Pr2x7−/− animals, which showed also decreased modulation of genes of lipid metabolism. Deletion of Pr2x7 gene was associated with blunted or abolished activation of NLRP3 inflammasome and expression of its components, which were induced in liver sinusoidal endothelial cells challenged with appropriate stimuli. These data show that Pr2x7 gene deletion protects mice from HFD-induced NASH, possibly through blunted activation of NLRP3 inflammasome, suggesting that PR2X7 and NLRP3 may represent novel therapeutic targets.

  6. Dietary omega-3 deficiency reduces BDNF content and activation NMDA receptor and Fyn in dorsal hippocampus: implications on persistence of long-term memory in rats.

    Science.gov (United States)

    Bach, Simone Azevedo; de Siqueira, Letícia V; Müller, Alexandre P; Oses, Jean P; Quatrim, Andreia; Emanuelli, Tatiana; Vinadé, Lúcia; Souza, Diogo O; Moreira, Júlia D

    2014-07-01

    Omega-3 (n-3) fatty acids are important for adequate brain function and cognition. The aim of the present study was to evaluate how n-3 fatty acids influence the persistence of long-term memory (LTM) in an aversive memory task and to explore the putative mechanism involved. Female rats received isocaloric diets that included n-3 (n-3 group) or not (D group). The adult litters were subjected to an inhibitory avoidance task (0.7 mA, 1.0 seconds foot shock) to elicit persistent LTM. Twelve hours after the training session, the fatty acid profile and the brain derived neurotrophic factor (BDNF) content of the dorsal hippocampus were assessed. In addition, we measured the activation of the NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor and the SRC family protein Fyn. Despite pronounced learning in both groups, the persistence of LTM was abolished in the D group 7 days after the training session. We also observed that the D group presented reductions in hippocampal DHA (22:6 n-3) and BDNF content. Twelve hours after the training session, the D group showed decreased NR2B and Fyn phosphorylation in the dorsal hippocampus, with no change in the total content of these proteins. Further, there was a decrease in the interaction of Fyn with NR2B in the D group, as observed by co-immunoprecipitation. Taken together, these data suggest that n-3 fatty acids influence the persistence of LTM by maintaining adequate levels of DHA and BDNF as well as by influencing the activation of NR2B and Fyn during the period of memory formation.

  7. Uptake by J774 macrophages of very-low-density lipoproteins isolated from apoE-deficient mice is mediated by a distinct receptor and stimulated by lipoprotein lipase

    NARCIS (Netherlands)

    Hendriks, W.L.; Sman van der - Beer, F. de; Vlijmen, B.J.M. van; Vark, L.C. van; Hofker, M.H.; Havekes, L.M.

    1997-01-01

    Apolipoprotein (apo) E-deficient mice display marked accumulation in the plasma of VLDL deficient in both apoE and apoBl00 but containing apoB48, apoA-1, apoCs, and apoA-IV. Since apoE-deficient mice develop severe atherosclerotic lesions with lipid-laden macrophages, we reasoned that the uptake of

  8. Treatment with the anti-IL-6 receptor antibody attenuates muscular dystrophy via promoting skeletal muscle regeneration in dystrophin-/utrophin-deficient mice.

    Science.gov (United States)

    Wada, Eiji; Tanihata, Jun; Iwamura, Akira; Takeda, Shin'ichi; Hayashi, Yukiko K; Matsuda, Ryoichi

    2017-10-27

    Chronic increases in the levels of the inflammatory cytokine interleukin-6 (IL-6) in serum and skeletal muscle are thought to contribute to the progression of muscular dystrophy. Dystrophin/utrophin double-knockout (dKO) mice develop a more severe and progressive muscular dystrophy than the mdx mice, the most common murine model of Duchenne muscular dystrophy (DMD). In particular, dKO mice have smaller body sizes and muscle diameters, and develop progressive kyphosis and fibrosis in skeletal and cardiac muscles. As mdx mice and DMD patients, we found that IL-6 levels in the skeletal muscle were significantly increased in dKO mice. Thus, in this study, we aimed to analyze the effects of IL-6 receptor (IL-6R) blockade on the muscle pathology of dKO mice. Male dKO mice were administered an initial injection (200 mg/kg intraperitoneally (i.p.)) of either the anti-IL-6R antibody MR16-1 or an isotype-matched control rat IgG at the age of 14 days, and were then given weekly injections (25 mg/kg i.p.) until 90 days of age. Treatment of dKO mice with the MR16-1 antibody successfully inhibited the IL-6 pathway in the skeletal muscle and resulted in a significant reduction in the expression levels of phosphorylated signal transducer and activator of transcription 3 in the skeletal muscle. Pathologically, a significant increase in the area of embryonic myosin heavy chain-positive myofibers and muscle diameter, and reduced fibrosis in the quadriceps muscle were observed. These results demonstrated the therapeutic effects of IL-6R blockade on promoting muscle regeneration. Consistently, serum creatine kinase levels were decreased. Despite these improvements observed in the limb muscles, degeneration of the diaphragm and cardiac muscles was not ameliorated by the treatment of mice with the MR16-1 antibody. As no adverse effects of treatment with the MR16-1 antibody were observed, our results indicate that the anti-IL-6R antibody is a potential therapy for muscular dystrophy

  9. Impact of glucocorticoid receptor gene polymorphisms on the metabolic profile of adult patients with the classical form of 21-hydroxylase deficiency.

    Directory of Open Access Journals (Sweden)

    Ricardo P P Moreira

    Full Text Available BACKGROUND: CAH patients have an increased risk of cardiovascular disease, and it remains unknown if lifelong glucocorticoid (GC treatment is a contributing factor. In the general population, glucocorticoid receptor gene (NR3C1 polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of CAH patients. METHODOLOGY: Sixty-eight adult patients (34SV/34SW with a mean age of 28.4±9 years received dexamethasone (mean 0.27±0.11 mg/day to obtain normal androgen levels. SW patients also received fludrocortisone (50 µg/day. Metabolic syndrome (MetS was defined by the NCEP ATPIII criteria and obesity by BMI ≥30 kg/m². NR3C1 alleles were genotyped, and association analyses with phenotype were carried out with Chi-square, t-test and regression analysis. RESULTS: Obesity and MetS were observed in 23.5% and 7.3% of patients, respectively, and were not correlated with GC doses and treatment duration. BMI was positively correlated with blood pressure (BP, triglycerides (TG, LDL-c levels and HOMA-IR and inversely correlated with HDL-c levels. BclI and A3669G variants were found in 26.4% and 9.6% of alleles, respectively. Heterozygotes for the BclI polymorphism presented with higher BMI (29 kg/m²±5.3 vs. 26 kg/m²±5.3, respectively and waist circumference (89 cm±12.7 vs. 81 cm±13, respectively compared to wild-type subjects. Hypertension was found in 12% of patients and heterozygotes for the BclI polymorphism presented higher systolic BP than wild type subjects. Low HDL-c and high TG levels were identified in 30% and 10% of patients, respectively, and were not associated with the NR3C1 polymorphisms. A3669G carriers and non-carriers did not differ. CONCLUSION: In addition to GC therapy, the BclI GR variant might play an important role in obesity susceptibility in CAH patients. Genotyping of GR polymorphisms could result in the identification of a

  10. Impact of Glucocorticoid Receptor Gene Polymorphisms on the Metabolic Profile of Adult Patients with the Classical Form of 21-Hydroxylase Deficiency

    Science.gov (United States)

    Moreira, Ricardo P. P.; Gomes, Larissa G.; Mendonca, Berenice B.; Bachega, Tânia A. S. S.

    2012-01-01

    Background CAH patients have an increased risk of cardiovascular disease, and it remains unknown if lifelong glucocorticoid (GC) treatment is a contributing factor. In the general population, glucocorticoid receptor gene (NR3C1) polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of CAH patients. Methodology Sixty-eight adult patients (34SV/34SW) with a mean age of 28.4±9 years received dexamethasone (mean 0.27±0.11 mg/day) to obtain normal androgen levels. SW patients also received fludrocortisone (50 µg/day). Metabolic syndrome (MetS) was defined by the NCEP ATPIII criteria and obesity by BMI ≥30 kg/m2. NR3C1 alleles were genotyped, and association analyses with phenotype were carried out with Chi-square, t-test and regression analysis. Results Obesity and MetS were observed in 23.5% and 7.3% of patients, respectively, and were not correlated with GC doses and treatment duration. BMI was positively correlated with blood pressure (BP), triglycerides (TG), LDL-c levels and HOMA-IR and inversely correlated with HDL-c levels. BclI and A3669G variants were found in 26.4% and 9.6% of alleles, respectively. Heterozygotes for the BclI polymorphism presented with higher BMI (29 kg/m2±5.3 vs. 26 kg/m2±5.3, respectively) and waist circumference (89 cm±12.7 vs. 81 cm±13, respectively) compared to wild-type subjects. Hypertension was found in 12% of patients and heterozygotes for the BclI polymorphism presented higher systolic BP than wild type subjects. Low HDL-c and high TG levels were identified in 30% and 10% of patients, respectively, and were not associated with the NR3C1 polymorphisms. A3669G carriers and non-carriers did not differ. Conclusion In addition to GC therapy, the BclI GR variant might play an important role in obesity susceptibility in CAH patients. Genotyping of GR polymorphisms could result in the identification of a subgroup at risk

  11. Aerobic exercise training protects against endothelial dysfunction by increasing nitric oxide and hydrogen peroxide production in LDL receptor-deficient mice.

    Science.gov (United States)

    Guizoni, Daniele M; Dorighello, Gabriel G; Oliveira, Helena C F; Delbin, Maria A; Krieger, Marta H; Davel, Ana P

    2016-07-19

    Endothelial dysfunction associated with hypercholesterolemia is an early event in atherosclerosis characterized by redox imbalance associated with high superoxide production and reduced nitric oxide (NO) and hydrogen peroxide (H2O2) production. Aerobic exercise training (AET) has been demonstrated to ameliorate atherosclerotic lesions and oxidative stress in advanced atherosclerosis. However, whether AET protects against the early mechanisms of endothelial dysfunction in familial hypercholesterolemia remains unclear. This study investigated the effects of AET on endothelial dysfunction and vascular redox status in the aortas of LDL receptor knockout mice (LDLr(-/-)), a genetic model of familial hypercholesterolemia. Twelve-week-old C57BL/6J (WT) and LDLr(-/-) mice were divided into sedentary and exercised (AET on a treadmill 1 h/5 × per week) groups for 4 weeks. Changes in lipid profiles, endothelial function, and aortic NO, H2O2 and superoxide production were examined. Total cholesterol and triglycerides were increased in sedentary and exercised LDLr(-/-) mice. Endothelium-dependent relaxation induced by acetylcholine was impaired in aortas of sedentary LDLr(-/-) mice but not in the exercised group. Inhibition of NO synthase (NOS) activity or H2O2 decomposition by catalase abolished the differences in the acetylcholine response between the animals. No changes were noted in the relaxation response induced by NO donor sodium nitroprusside or H2O2. Neuronal NOS expression and endothelial NOS phosphorylation (Ser1177), as well as NO and H2O2 production, were reduced in aortas of sedentary LDLr(-/-) mice and restored by AET. Incubation with apocynin increased acetylcholine-induced relaxation in sedentary, but not exercised LDLr(-/-) mice, suggesting a minor participation of NADPH oxidase in the endothelium-dependent relaxation after AET. Consistent with these findings, Nox2 expression and superoxide production were reduced in the aortas of exercised compared to

  12. VLCAD deficiency

    DEFF Research Database (Denmark)

    Boneh, A; Andresen, B S; Gregersen, N

    2006-01-01

    We diagnosed six newborn babies with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) through newborn screening in three years in Victoria (prevalence rate: 1:31,500). We identified seven known and two new mutations in our patients (2/6 homozygotes; 4/6 compound heterozygotes). Blood...... samples taken at age 48-72 h were diagnostic whereas repeat samples at an older age were normal in 4/6 babies. Urine analysis was normal in 5/5. We conclude that the timing of blood sampling for newborn screening is important and that it is important to perform mutation analysis to avoid false......-negative diagnoses of VLCADD in asymptomatic newborn babies. In view of the emerging genotype-phenotype correlation in this disorder, the information derived from mutational analysis can be helpful in designing the appropriate follow-up and therapeutic regime for these patients....

  13. Carnitine deficiency.

    Science.gov (United States)

    Răşanu, T; Mehedinţi-Hâncu, Mihaela; Alexianu, Marilena; Mehedinţi, T; Gheorghe, Emma; Damian, Irene

    2012-01-01

    We present the case of a female patient, aged 12 years, with fatigability and exertional myalgias, progressively developed within the last two years. Negative family history, as well as negative personal medical history, were found. At physical examination, short stature, proximal muscle weakness and mild hepatomegaly were noted. Urine ketones level was slightly decreased, serum transaminases, creatine kinase and lactate dehydrogenase levels were increased. Electromyographical examination showed a myopathic non-specific pattern. Deltoid muscle biopsy revealed: small, clear vesicles are present on Hematoxylin-Eosin and modified Gömöri trichrome stains; modified Gömöri trichrome stain also revealed muscle fibers (especially type I of muscle fibers) having mild to moderate mitochondrial proliferation (red rim and speckled sarcoplasm). The lipid storage has been well demonstrated by Sudan Black stain, which revealed small lipid droplets in type I muscle fibers. Abnormal internal architecture with a punctate pattern was showed by adenine dinucleotide tetrazolium reductase and succinate dehydrogenase stains. Electron microscopy showed small inter-myofibrillar accumulations of round, amorphous, homogeneous acellular substances that are not membrane bounded. These features indicate that these are neutral fat (lipid) droplets. Subsarcolemmal accumulations of mitochondria were also revealed. The differential diagnosis of this case is discussed, and the up to date general data concerning carnitine deficiency are presented. The aim of our case-report is to emphasize the role of muscle biopsy in carnitine deficiency, as well as to remind the necessity of keeping in mind such metabolic disorders when doing the differential diagnostic of a muscular weakness.

  14. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Research Home / < Back To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Leer en español What Is Iron-deficiency anemia ... cases, surgery may be advised. Treatments for Severe Iron-Deficiency Anemia Blood Transfusion If your iron-deficiency anemia is ...

  15. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia What Is Iron-deficiency anemia is a common, ... all types of anemia . Signs and Symptoms of Anemia The most common symptom of all types of ...

  16. Vitamin Deficiency Anemia

    Science.gov (United States)

    ... cancer can interfere with the metabolism of folate. Vitamin B-12 deficiency anemia risk factors include: Lack ... vitamin B-12 deficiency anemia called pernicious anemia. Vitamin C deficiency anemia risk factors include: Smoking. Smoking ...

  17. Vitamin Deficiency Anemia

    Science.gov (United States)

    ... are unique to specific vitamin deficiencies. Folate-deficiency anemia risk factors include: Undergoing hemodialysis for kidney failure. ... the metabolism of folate. Vitamin B-12 deficiency anemia risk factors include: Lack of intrinsic factor. Most ...

  18. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Deficiency Anemia Explore Iron-Deficiency Anemia What Is... CAUSES WHO IS AT RISK SIGNS & SYMPTOMS DIAGNOSIS TREATMENTS ... less hemoglobin than normal. Iron-deficiency anemia can cause fatigue (tiredness), shortness of breath, chest pain, and ...

  19. Scavenger Receptor C-Type Lectin Binds to the Leukocyte Cell Surface Glycan Lewis By a Novel Mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Feinberg, H.; Taylor, M.E.; Weis, W.I.; /Stanford U., Med. School /Imperial Coll., London

    2007-07-10

    The scavenger receptor C-type lectin (SRCL) is unique in the family of class A scavenger receptors, because in addition to binding sites for oxidized lipoproteins it also contains a C-type carbohydrate-recognition domain (CRD) that interacts with specific glycans. Both human and mouse SRCL are highly specific for the Lewis(x) trisaccharide, which is commonly found on the surfaces of leukocytes and some tumor cells. Structural analysis of the CRD of mouse SRCL in complex with Lewis(x) and mutagenesis show the basis for this specificity. The interaction between mouse SRCL and Lewis(x) is analogous to the way that selectins and DC-SIGN bind to related fucosylated glycans, but the mechanism of the interaction is novel, because it is based on a primary galactose-binding site similar to the binding site in the asialoglycoprotein receptor. Crystals of the human receptor lacking bound calcium ions reveal an alternative conformation in which a glycan ligand would be released during receptor-mediated endocytosis.

  20. [Effect of copper deficiency on iron metabolism in rats].

    Science.gov (United States)

    Wang, Kebo; Wang, Chaoxu; Liu, Baosheng; Jiang, Shan

    2010-07-01

    To study the effect of copper deficiency on the nutritional status of iron, the expression of hepcidin mRNA and transferrin receptor mRNA in rats. Forty eight clean male SD rats were randomly divided into four groups according to body weight; and there were 12 rats in each group. The groups are normal iron and copper control group (group I), normal iron and copper deficiency group (group II), normal iron and copper slightly deficient group (group III), both iron and copper slightly deficient group (group IV). Serum, liver and spleen of rats were collected by the end of 8th week. Serum copper, serum iron, hemoglobin, serum transferrin receptor, serum ferritin, liver iron and liver copper, spleen iron and spleen copper were determined. The expression of liver transferring receptor mRNA and hepcidin mRNA were measured by reverse transcription polymerase chain reaction (RT-PCR) method. Compared with the controls, the contents of serum iron and serum ferritin decreased (P copper deficiency. The expression of transferrin receptor mRNA in liver increased but the expression of hepcidin mRNA in liver decreased significantly under copper deficiency (P copper deficiency through influencing the absorption, storage and transportation of iron. Under the condition of copper deficiency, the expression of hepcidin mRNA in liver was lowered and the expression of transferrin receptor mRNA was enhanced through the way of iron response element-iron regulatory protein (IRE-IRP) to regulate iron metabolism.

  1. Genetics Home Reference: leptin receptor deficiency

    Science.gov (United States)

    ... B, Lopez-Fernandez J, Ferraz-Amaro I, Dattani MT, Ercan O, Myhre AG, Retterstol L, Stanhope R, Edge JA, McKenzie S, Lessan N, Ghodsi M, De Rosa V, Perna F, Fontana S, Barroso I, Undlien DE, O'Rahilly S. Clinical ...

  2. Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations

    NARCIS (Netherlands)

    Cossins, Judy; Burke, Georgina; Maxwell, Susan; Spearman, Hayley; Man, Somai; Kuks, Jan; Vincent, Angela; Palace, Jackie; Fuhrer, Christian; Beeson, David

    2006-01-01

    Congenital myasthenic syndromes are inherited disorders of neuromuscular transmission characterized by fatigable muscle weakness. Autosomal recessive acetylcholine receptor (AChR) deficiency syndromes, in which levels of this receptor at the neuromuscular junction are severely reduced, may be caused

  3. Iron deficiency and new insights into therapy.

    Science.gov (United States)

    Low, Michael Sy; Grigoriadis, George

    2017-07-17

    Iron deficiency and iron deficiency anaemia remain prevalent in Australia. The groups at highest risk are pre-menopausal women, socially disadvantaged people and those of Indigenous background. Diagnosing iron deficiency using a full blood examination and iron studies can be difficult and can be further complicated by concomitant inflammation. Results of iron studies should always be interpreted as an overall picture rather than focusing on individual parameters. In difficult clinical scenarios, soluble transferrin receptor assays can be useful. Management of iron deficiency involves identification and treatment of the cause of iron deficiency, as well as effective iron replacement. Clinicians should always take a detailed history and perform a comprehensive physical examination of a patient with iron deficiency. Patients should be monitored even if a likely cause of iron deficiency is identified. Patients who fail to respond to iron replacement or maintain iron status should be referred for further investigation, including endoscopy to exclude internal bleeding. Both enteral and parenteral iron are effective at replacing iron. For most adult patients, we recommend trialling daily oral iron (30-100 mg of elemental iron) as the first-line therapy. Safety and efficacy of intravenous iron infusions have improved with the availability of a newer formulation, ferric carboxymaltose. Patients who fail to respond to oral iron replacement can be safely managed with intravenous iron. Blood transfusion for iron deficiency anaemia should be reserved for life-threatening situations and should always be followed by appropriate iron replacement.

  4. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... less hemoglobin than normal. Iron-deficiency anemia can cause fatigue (tiredness), shortness of breath, chest pain, and ... iron-deficiency anemia. Treatment will depend on the cause and severity of the condition. Treatments may include ...

  5. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... food. Overview Iron-deficiency anemia is a common type of anemia . The term "anemia" usually refers to ... also may lead to iron-deficiency anemia. This type of blood loss isn't always obvious, and ...

  6. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... or an inability to absorb enough iron from food. Overview Iron-deficiency anemia is a common type ... of the condition. Treatments may include dietary changes, medicines, and surgery. Severe iron-deficiency anemia may require ...

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... condition. Women Women of childbearing age are at higher risk for iron-deficiency anemia because of blood ... iron-deficiency anemia. Pregnant women also are at higher risk for the condition because they need twice ...

  8. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... help prevent overdosing in children. Because recent research supports concerns that iron deficiency during infancy and childhood ... treat iron-deficiency anemia. These doctors include pediatricians, family doctors, gynecologists/obstetricians, and internal medicine specialists. A ...

  9. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... more information about diet and supplements, go to "How Is Iron-Deficiency Anemia Treated?" Infants and young ... who should be screened for iron deficiency, and how often: Girls aged 12 to 18 and women ...

  10. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... and other symptoms. Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and ... Internal bleeding (bleeding inside the body) also may lead to iron-deficiency anemia. This type of blood ...

  11. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... have iron-deficiency anemia, you'll have a high level of transferrin that has no iron. Other ... may include dietary changes and supplements, medicines, and surgery. Severe iron-deficiency anemia may require a blood ...

  12. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... deficiency anemia if they're underweight or have chronic (ongoing) illnesses. Teenage girls who have heavy periods ... factors for iron-deficiency anemia The Centers for Disease Control and Prevention (CDC) has developed guidelines for ...

  13. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... deficiency anemia apply to all types of anemia . Signs and Symptoms of Anemia The most common symptom ... appetite, slowed growth and development, and behavioral problems. Signs and Symptoms of Iron Deficiency Signs and symptoms ...

  14. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... also may help treat iron-deficiency anemia. Medical History Your doctor will ask about your signs and ... much of the transferrin in your blood isn't carrying iron. If you have iron-deficiency anemia, ...

  15. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... coped with having iron-deficiency anemia. Prior to her diagnosis, Susan had symptoms such as tiredness, poor skin tone, dizziness, and depression. After her doctor diagnosed her with iron-deficiency anemia, Susan ...

  16. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... drawings also can cause iron-deficiency anemia. Poor Diet The best sources of iron are meat, poultry, ... more likely to develop iron-deficiency anemia. Vegetarian diets can provide enough iron if you eat the ...

  17. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Deficiency Anemia What Is... CAUSES WHO IS AT RISK SIGNS & SYMPTOMS DIAGNOSIS TREATMENTS PREVENTION LIVING WITH CLINICAL ... and women are the two groups at highest risk for iron-deficiency anemia. Outlook Doctors usually can ...

  18. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... iron-deficiency anemia may require treatment in a hospital, blood transfusions , iron injections, or intravenous iron therapy. ... Treatment may need to be done in a hospital. The goals of treating iron-deficiency anemia are ...

  19. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Leer en español What Is Iron-deficiency anemia ... all types of anemia . Signs and Symptoms of Anemia The most common symptom of all types of ...

  20. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... page from the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a ... Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented ...

  1. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Tumblr. Share this page from the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency ... Iron-Deficiency Anemia article. Updated: March 26, 2014 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT ...

  2. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, easily ... Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the ...

  3. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... iron-deficiency anemia, especially if they have: A history of iron-deficiency anemia Heavy blood loss during their monthly periods Other risk factors for iron-deficiency anemia The Centers for Disease Control and Prevention (CDC) has developed guidelines for who ...

  4. Carnitine Deficiency and Pregnancy

    Directory of Open Access Journals (Sweden)

    Anouk de Bruyn

    2015-01-01

    Full Text Available We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, supplementation with carnitine is advised. This supplementation should be continued throughout pregnancy according to plasma concentrations.

  5. Beta-Ketothiolase Deficiency

    Directory of Open Access Journals (Sweden)

    Elsayed Abdelkreem MD, MSc

    2016-03-01

    Full Text Available Beta-ketothiolase deficiency is an inherited disorder of ketone body metabolism and isoleucine catabolism. It typically manifests as recurrent ketoacidotic episodes with characteristic abnormalities in the urinary organic acid profile. However, several challenges in the diagnosis of beta-ketothiolase deficiency have been encountered: atypical presentations have been reported and some other disorders, such as succinyl-CoA:3-oxoacid CoA transferase and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiencies, can mimic the clinical and/or biochemical signs of beta-ketothiolase deficiency. A final diagnosis of beta-ketothiolase deficiency requires an enzymatic assay and/or a molecular analysis, but some caveats must be considered. Despite the reported missed cases, screening programs have successfully identified an increasing number of patients with beta-ketothiolase deficiency. Early diagnosis and management of beta-ketothiolase deficiency will enable prevention of its serious acute and chronic complications and ultimately improve the prognosis.

  6. Computing sleep deficiency.

    Science.gov (United States)

    Erren, Thomas C; Groß, J Valerie; Lewis, Philip

    2017-11-20

    Sleep deficiency is a major public health concern. Since epidemiological studies play an important role in public health evaluations, this theoretical paper pursues answers to the question: 'How can we compute sleep deficiency as informative measures of exposures or doses in observational research?' Starting from the social jetlag concept and based on the chronodisruption rationale, we illustrate and discuss five approaches (one established and four untested, each with unique strengths and limitations) to quantify sleep deficiency by focusing on the timing and duration of sleep. Hitherto, social jetlag and chronodisruption rationale were neither explicitly proposed nor developed as assessments of sleep deficiency but, as we suggest, could potentially be utilized to this end. This first foray into computing sleep deficiency in epidemiological studies makes clear that laboratory, field and epidemiological collaboration is pre-requisite to elucidating potential (co-)causal roles of sleep deficiency in disease endpoints. © 2017 European Sleep Research Society.

  7. Acquired color vision deficiency.

    Science.gov (United States)

    Simunovic, Matthew P

    2016-01-01

    Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Manganese deficiency in plants

    DEFF Research Database (Denmark)

    Schmidt, Sidsel Birkelund; Jensen, Poul Erik; Husted, Søren

    2016-01-01

    restricting crop productivity in many places of the world. Hence, timely alleviation of latent Mn deficiency is a challenge in promoting plant growth and quality. We describe here the key mechanisms of Mn deficiency in plants by focusing on the impact of Mn on PSII stability and functionality. We also address...... the mechanisms underlying the differential tolerance towards Mn deficiency observed among plant genotypes, which enable Mn-efficient plants to grow on marginal land with poor Mn availability....

  9. [Effects of copper deficiency on iron metabolism in rats].

    Science.gov (United States)

    Xiao, Fei; Wang, Chaoxu; Yang, Li

    2013-07-01

    To study the effects of copper deficiency on iron metabolism, the expression of IRP mRNA and Fn mRNA and transferrin receptor mRNA in rats. Forty clean male SD rats were randomly divided into four groups according to body weight and there were 10 rats in each group. The groups are normal iron and copper control group (group I), copper deficiency group (group II), normal iron and copper slightly deficient group (group III), both iron and copper slightly deficient group (group IV). After 8 weeks, all the rats were killed by sodium pentobarbital anesthesia and all samples were collected and detected for gene expression. Compared with the controls, the contents of serum iron and serum ferritin in completely copper deficiency group decreased (P copper deficiency (P copper deficiency group was significantly increased (P copper deficiency group was significantly decreased (P copper deficiency through influencing the absorption, the results indicate that copper deficiency influences iron homeostasis in cells through affecting the expression of IRP2 and the activity of IRP-RNA combination which change the expressions of ferritin and transferrin mRNA.

  10. The brown shrimp (Crangon crangon L.) ecdysteroid receptor complex: cloning, structural modeling of the ligand-binding domain and functional expression in an EcR-deficient Drosophila cell line.

    Science.gov (United States)

    Verhaegen, Yves; Parmentier, Koen; Swevers, Luc; Rougé, Pierre; Soin, Thomas; De Coen, Wim; Cooreman, Kris; Smagghe, Guy

    2010-09-15

    cDNAs encoding ecdysteroid receptor (EcR) and retinoid X receptor (RXR) were cloned and sequenced from brown shrimp Crangon crangon (Crustacea: Decapoda), a common faunal species and commercially important in the North-West European coastal waters. A 3D model of the ligand-binding domain (LBD) of EcR was created and docking of ponasterone A (PonA) was simulated in silico. Finally, we report the transfection of expression plasmids for these receptors in the mutant Drosophila L57-3-11 cell line. Through an ecdysteroid responsive reporter assay we clearly prove the functionality of shrimp ecdysteroid receptor in the transfected L57-3-11 cell line. Our results indicate that the Drosophila L57-3-11 cell line and in silico LBD modeling can be used to study the function of crustacean ecdysteroid receptors and be applied to assess endocrine disrupting effects on non-target crustacean species. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  11. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... diet. Young children who drink a lot of cow's milk may be at risk for iron-deficiency anemia. ... her risk for iron-deficiency anemia. For example, cow's milk is low in iron. For this and other ...

  12. Serine-deficiency syndromes

    NARCIS (Netherlands)

    de Koning, Tom J; Klomp, Leo W J

    PURPOSE OF REVIEW: Serine-deficiency disorders comprise a new group of neurometabolic diseases and are caused by defects in the biosynthesis of the amino acid L-serine. In contrast to most neurometabolic disorders, serine-deficiency disorders are potentially treatable. Furthermore, the severe

  13. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Organization NHLBI Director Budget, Planning, & Legislative Advisory Committees Jobs Contact Us FAQs Home » Iron-Deficiency Anemia Explore ... the body. Iron-deficiency anemia usually develops over time if your body doesn't have enough iron ...

  14. Iron deficiency anemia

    Science.gov (United States)

    Anemia - iron deficiency ... iron from old red blood cells. Iron deficiency anemia develops when your body's iron stores run low. ... You may have no symptoms if the anemia is mild. Most of the time, ... slowly. Symptoms may include: Feeling weak or tired more often ...

  15. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... have enough iron stored in your body to make up for the lost iron, you'll develop iron- ... by mouth. This therapy also is given to people who need immediate treatment for iron-deficiency ... have iron-deficiency anemia, get ongoing care to make sure your iron levels are improving. At your ...

  16. Muscle phosphorylase kinase deficiency

    DEFF Research Database (Denmark)

    Preisler, N; Orngreen, M C; Echaniz-Laguna, A

    2012-01-01

    To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD).......To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD)....

  17. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Blood Tests Blood Transfusion Restless Legs Syndrome Send a link to NHLBI to someone by E-MAIL | ... Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, easily treated condition that occurs if you ...

  18. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... shows how Susan, a full-time worker and student, has coped with having iron-deficiency anemia. Prior to her diagnosis, Susan had symptoms such as tiredness, poor skin tone, dizziness, and depression. After her doctor diagnosed her with iron-deficiency ...

  19. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... For more information about diet and supplements, go to "How Is Iron-Deficiency Anemia Treated?" Infants and young ... who should be screened for iron deficiency, and how often: Girls aged 12 to 18 and women of childbearing age who are ...

  20. Nutritional iron deficiency

    NARCIS (Netherlands)

    Zimmermann, M.B.; Hurrell, R.F.

    2007-01-01

    Iron deficiency is one of the leading risk factors for disability and death worldwide, affecting an estimated 2 billion people. Nutritional iron deficiency arises when physiological requirements cannot be met by iron absorption from diet. Dietary iron bioavailability is low in populations consuming

  1. Alpha1-antitrypsin deficiency

    DEFF Research Database (Denmark)

    Stolk, Jan; Seersholm, Niels; Kalsheker, Noor

    2006-01-01

    deficiency and contributes to an international database located in Malmö, Sweden. This database is designed to increase understanding of AAT deficiency. Additionally, AIR members are engaged in active, wide-ranging investigations to improve the diagnosis, monitoring, and treatment of the disease and meet...

  2. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... women of childbearing age has iron-deficiency anemia. Pregnant women also are at higher risk for the condition ... for the fetus' growth. About half of all pregnant women develop iron-deficiency anemia. The condition can increase ...

  3. Maternal vitamin D deficiency

    African Journals Online (AJOL)

    GB

    2017-05-01

    May 1, 2017 ... ABSTRACT. BACKGROUND: A rare but reversible cause of dilated cardiomyopathy occurs in infants born to vitamin D deficient mothers due to hypocalcaemia. CASE REPORT: We report a case of dilated cardiomyopathy due to hypocalcaemia secondary to maternal vitamin D deficiency in an.

  4. G6PD Deficiency

    Science.gov (United States)

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder that is most common in males. About 1 in 10 African American males in the United States has it. G6PD deficiency mainly affects red blood cells, which carry oxygen ...

  5. Iron deficiency in childhood

    NARCIS (Netherlands)

    Uijterschout, L.

    2015-01-01

    Iron deficiency (ID) is the most common micronutrient deficiency in the world. Iron is involved in oxygen transport, energy metabolism, immune response, and plays an important role in brain development. In infancy, ID is associated with adverse effects on cognitive, motor, and behavioral development

  6. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... have RLS often have a hard time sleeping. Iron-deficiency anemia can put children at greater risk for lead poisoning and infections. Some signs and symptoms of iron-deficiency anemia are related to the condition's causes. For ...

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... food. Overview Iron-deficiency anemia is a common type of anemia . The term "anemia" usually refers to a condition ... symptoms of iron-deficiency anemia apply to all types of anemia . Signs and Symptoms of Anemia The most common ...

  8. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... will diagnose iron-deficiency anemia based on your medical history, a physical exam, and the results from tests and procedures. Once ... specialists also may help treat iron-deficiency anemia. Medical ... be pregnant. Physical Exam Your doctor will do a physical exam to ...

  9. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... be advised. Treatments for Severe Iron-Deficiency Anemia Blood Transfusion If your iron-deficiency anemia is severe, you ... get a transfusion of red blood cells. A blood transfusion is a safe, common procedure in which blood ...

  10. Restoration of high-density lipoprotein levels by cholesteryl ester transfer protein expression in scavenger receptor class B type I (SR-BI) knockout mice does not normalize pathologies associated with SR-BI deficiency

    NARCIS (Netherlands)

    Hildebrand, Reeni B; Lammers, Bart; Meurs, Illiana; Korporaal, Suzanne J A; De Haan, Willeke; Zhao, Ying; Kruijt, J Kar; Praticò, Domenico; Schimmel, Alinda W M; Holleboom, Adriaan G; Hoekstra, Menno; Kuivenhoven, Jan Albert; Van Berkel, Theo J C; Rensen, Patrick C N; Van Eck, Miranda

    OBJECTIVE: Disruption of scavenger receptor class B type I (SR-BI) in mice impairs high-density lipoprotein (HDL)-cholesterol (HDL-C) delivery to the liver and induces susceptibility to atherosclerosis. In this study, it was investigated whether introduction of cholesteryl ester transfer protein

  11. The chicken c-erbA alpha-product induces expression of thyroid hormone-responsive genes in 3,5,3'-triiodothyronine receptor-deficient rat hepatoma cells

    DEFF Research Database (Denmark)

    Muñoz, A; Höppner, W; Sap, J

    1990-01-01

    To determine the capacity of the chicken c-erbA (cTR-alpha) gene product in regulating expression of known thyroid hormone-responsive genes, both the cTR-alpha and the viral v-erbA genes were expressed in FAO cells, a rat hepatoma cell line defective for functional thyroid hormone receptors. Upon...

  12. Fatal pneumococcal meningitis in a 7-year-old girl with interleukin-1 receptor activated kinase deficiency (IRAK-4) despite prophylactic antibiotic and IgG responses to Streptococcus pneumoniae vaccines.

    Science.gov (United States)

    McKelvie, Brianna; Top, Karina; McCusker, Christine; Letenyi, Duncan; Issekutz, Thomas B; Issekutz, Andrew C

    2014-04-01

    IRAK-4 deficiency causes IL-1R and TLR signaling failure, resulting in minimal clinical features despite invasive bacterial infection. We report the course of a 7-year-old IRAK-4-deficient girl presenting in the first year with multiple occult Staphylococcus aureus lymphadenitis. She was managed with antibiotic prophylaxis (sulfa/trimethoprim/PenV, then - due to neutropenia - Cefprozil), pneumococcal vaccination (PCV-7, Pneumovax23, PCV-13) and vigilance. Pneumococcal-specific IgG levels were monitored. No bacterial infections occurred on prophylaxis for 6 years after initial presentation. IgG response to pneumococcal polysaccharide was satisfactory but short-lived, requiring frequent boosting. At age 7, patient developed a morning headache and vomited once. Cefprozil was administered and re-dosed. Over 12 h, she was fatigued without other symptoms. Low fever accompanied another emesis. A few hours later she was confused, and purpuric rash appeared. Emergency physicians diagnosed sepsis/meningitis and started vancomycin-ceftriaxone. Respiratory failure and cerebellar herniation occurred IgG4 was increased (3.4 g/L). IgG response to vaccine antigens was satisfactory. IgG to 6A is reported to cross-react with 6C, but this was not the case here. Despite antibiotic prophylaxis and repeated vaccination, even older IRAK-4-deficient patients are at high risk of rapidly fatal infection due to emergence of antibiotic resistance. These patients need early assessment at any age, bacterial culturing, alternative empiric antibiotic therapy and close observation when even vaguely unwell. Based on increasingly recognized immunological and/or clinical impairments in B cell function, and possibly other defects, long-term IgG prophylaxis in addition to antibiotics is recommended.

  13. Congenital IL-12R1β receptor deficiency and thrombophilia in a girl homozygous for an IL12RB1 mutation and compound heterozygous for MTFHR mutations: A case report and literature review

    OpenAIRE

    Akar, H. H.; Kose, M.; Ceylan, O.; Patiroglu, T.; Bustamante, J.; Casanova, J. L.; Akyildiz, B. N.; Doganay, S

    2014-01-01

    Interleukin-12 (IL-12) plays an important role in the production of interferon gamma from T cells and natural killer cells and is essential for protection against intra-macrophagic pathogens such as Mycobacterium and Salmonella. Here, we describe a 16-year-old girl with homozygous mutation in exon 12 of the IL12RB1 gene, which causes complete IL-12Rβ1 deficiency in association with heterozygous mutation (C677T and A1298C) in the methylenetetrahydrofolate reductase gene. She ...

  14. Gastrin-deficient mice have disturbed hematopoiesis in response to iron deficiency.

    Science.gov (United States)

    Kovac, Suzana; Anderson, Gregory J; Alexander, Warren S; Shulkes, Arthur; Baldwin, Graham S

    2011-08-01

    Gastrins are peptide hormones important for gastric acid secretion and growth of the gastrointestinal mucosa. We have previously demonstrated that ferric ions bind to gastrins, that the gastrin-ferric ion complex interacts with the iron transport protein transferrin in vitro, and that circulating gastrin concentrations positively correlate with transferrin saturation in vivo. Here we report the effect of long-term dietary iron modification on gastrin-deficient (Gas(-/-)) and hypergastrinemic cholecystokinin receptor 2-deficient (Cck2r(-/-)) mice, both of which have reduced basal gastric acid secretion. Iron homeostasis in both strains appeared normal unless the animals were challenged by iron deficiency. When fed an iron-deficient diet, Gas(-/-) mice, but not Cck2r(-/-) mice, developed severe anemia. In iron-deficient Gas(-/-) mice, massive splenomegaly was also apparent with an increased number of splenic megakaryocytes accompanied by thrombocytosis. The expression of the mRNA encoding the iron-regulatory peptide hepcidin, Hamp, was down-regulated in both Cck2r(-/-) and Gas(-/-) mice on a low-iron diet, but, interestingly, the reduction was greater in Cck2r(-/-) mice and smaller in Gas(-/-) mice than in the corresponding wild-type strains. These data suggest that gastrins play an important direct role, unrelated to their ability to stimulate acid secretion, in hematopoiesis under conditions of iron deficiency.

  15. Gastrin-Deficient Mice Have Disturbed Hematopoiesis in Response to Iron Deficiency

    Science.gov (United States)

    Anderson, Gregory J.; Alexander, Warren S.; Shulkes, Arthur; Baldwin, Graham S.

    2011-01-01

    Gastrins are peptide hormones important for gastric acid secretion and growth of the gastrointestinal mucosa. We have previously demonstrated that ferric ions bind to gastrins, that the gastrin-ferric ion complex interacts with the iron transport protein transferrin in vitro, and that circulating gastrin concentrations positively correlate with transferrin saturation in vivo. Here we report the effect of long-term dietary iron modification on gastrin-deficient (Gas−/−) and hypergastrinemic cholecystokinin receptor 2-deficient (Cck2r−/−) mice, both of which have reduced basal gastric acid secretion. Iron homeostasis in both strains appeared normal unless the animals were challenged by iron deficiency. When fed an iron-deficient diet, Gas−/− mice, but not Cck2r−/−mice, developed severe anemia. In iron-deficient Gas−/−mice, massive splenomegaly was also apparent with an increased number of splenic megakaryocytes accompanied by thrombocytosis. The expression of the mRNA encoding the iron-regulatory peptide hepcidin, Hamp, was down-regulated in both Cck2r−/− and Gas−/−mice on a low-iron diet, but, interestingly, the reduction was greater in Cck2r−/− mice and smaller in Gas−/− mice than in the corresponding wild-type strains. These data suggest that gastrins play an important direct role, unrelated to their ability to stimulate acid secretion, in hematopoiesis under conditions of iron deficiency. PMID:21652729

  16. Diagnosis of iron deficiency anemia in children of Northeast Brazil.

    Science.gov (United States)

    Carvalho, Antonio Geraldo Cidrão; Lira, Pedro Israel Cabral de; Barros, Maria de Fátima Alcântara; Aléssio, Maria Luiza Martins; Lima, Marília de Carvalho; Carbonneau, Marie Annette; Berger, Jacques; Léger, Claude Louis

    2010-06-01

    To diagnose iron deficiency anemia in children. The study was conducted with a sample of 301 children aged six to 30 months attending public daycare centers in the city of Recife, Northeast Brazil, in 2004. The diagnoses of anemia were based on a combination of different hematological and biochemical parameters: hemoglobin, mean corpuscular volume, ferritin, C-reactive protein, transferrin saturation and transferrin receptor. The chi-square test and ANOVA were used in the statistical analysis. Of all children studied, 92.4% had anemia (Hb<110 g/L) and 28.9% had moderate/severe anemia (Hb<90 g/L). Lower levels of hemoglobin were found in children aged 6-17 months. Iron deficiency was found in 51.5% of children using ferritin (<12 microg/L) as parameter. Taking into consideration the combination of hemoglobin level, ferritin and transferrin receptor, 58.1% had anemia with iron deficiency, 34.2% had anemia without iron deficiency and 2.3% had iron deficiency without anemia. Mean ferritin concentration was significantly higher in children with high C-reactive protein when compared with those with normal levels (22.1 vs. 14.8 microg/L). The use of several biochemical and hematological parameters allowed to diagnosing iron deficiency anemia in two thirds of children, suggesting a need to identify other determinants of anemia without iron deficiency.

  17. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... bleeding. Other At-Risk Groups People who get kidney dialysis treatment may develop iron-deficiency anemia. This ... because blood is lost during dialysis. Also, the kidneys are no longer able to make enough of ...

  18. Iron-Deficiency Anemia

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    Full Text Available ... if you have intestinal surgery (such as gastric bypass) or a disease of the intestine (such as ... produce red blood cells. People who have gastric bypass surgery also may develop iron-deficiency anemia. This ...

  19. Iron-Deficiency Anemia

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    Full Text Available ... Safety Sleep Science and Sleep Disorders Lung Diseases Heart and Vascular Diseases Precision Medicine Activities Obesity, Nutrition, ... symptoms. Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and development in ...

  20. Iron-Deficiency Anemia

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    Full Text Available ... NHLBI About NHLBI Home Mission and Strategic Vision Leadership Scientific Divisions Operations and Administration Advisory Committees Budget ... include poor appetite, slowed growth and development, and behavioral problems. Signs and Symptoms of Iron Deficiency Signs ...

  1. Iron-Deficiency Anemia

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    Full Text Available ... also may help treat iron-deficiency anemia. Medical History Your doctor will ask about your signs and ... It must be done in a hospital or clinic by experienced staff. Iron therapy usually is given ...

  2. Iron-Deficiency Anemia

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    Full Text Available ... re more likely to develop iron-deficiency anemia. Vegetarian diets can provide enough iron if you eat ... which are the best sources of iron. However, vegetarian diets can provide enough iron if you eat ...

  3. Iron-Deficiency Anemia

    Science.gov (United States)

    ... re more likely to develop iron-deficiency anemia. Vegetarian diets can provide enough iron if you eat ... which are the best sources of iron. However, vegetarian diets can provide enough iron if you eat ...

  4. Iron-Deficiency Anemia

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    Full Text Available ... a waste product) from your body. Anemia also can occur if your red blood cells don't ... have less hemoglobin than normal. Iron-deficiency anemia can cause fatigue (tiredness), shortness of breath, chest pain, ...

  5. Iron-Deficiency Anemia

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    Full Text Available ... usually can successfully treat iron-deficiency anemia. Treatment will depend on the cause and severity of the ... about a healthy diet and food choices that will help your child get enough iron. Your child's ...

  6. Iron-Deficiency Anemia

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    Full Text Available ... or soil, or drinking water that contains lead. Teens Teens are at risk for iron-deficiency anemia if ... and bleeding ulcers, can cause blood loss. Some medicines, such as aspirin, also can cause internal bleeding. ...

  7. Iron-Deficiency Anemia

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    Full Text Available ... or soil, or drinking water that contains lead. Teens Teens are at risk for iron-deficiency anemia ... for increased blood volume and for the fetus' growth. About half of all pregnant women develop iron- ...

  8. Iron-Deficiency Anemia

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    Full Text Available ... anemia at 1 year of age. Women and Girls Women of childbearing age may be tested for ... be screened for iron deficiency, and how often: Girls aged 12 to 18 and women of childbearing ...

  9. Iron-Deficiency Anemia

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    Full Text Available ... condition. Treatments may include dietary changes, medicines, and surgery. Severe iron-deficiency anemia may require treatment in ... Urinary tract bleeding Blood loss from severe injuries, surgery, or frequent blood drawings also can cause iron- ...

  10. Iron-Deficiency Anemia

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    Full Text Available ... or soil, or drinking water that contains lead. Teens Teens are at risk for iron-deficiency anemia if ... Visit Children and Clinical Studies to hear experts, parents, and children talk about their experiences with clinical ...

  11. Iron-Deficiency Anemia

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    Full Text Available ... symptoms. Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and development in ... 18/2011 This video—presented by the National Heart, Lung, and Blood Institute, part of the National ...

  12. Iron-Deficiency Anemia

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    Full Text Available ... Digg. Share this page from the NHLBI on Facebook. Add this link to the NHLBI to my ... Deficiency Anemia article. Updated: March 26, 2014 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA ...

  13. Iron-Deficiency Anemia

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    Full Text Available ... and Blood Safety Sleep Science and Sleep Disorders Lung Diseases Heart and Vascular Diseases Precision Medicine Activities ... iron-rich protein that carries oxygen from the lungs to the rest of the body. Iron-deficiency ...

  14. Iron-Deficiency Anemia

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    Full Text Available ... leafy green vegetables like turnip greens and spinach. Treatment To Stop Bleeding If blood loss is causing ... flow. In some cases, surgery may be advised. Treatments for Severe Iron-Deficiency Anemia Blood Transfusion If ...

  15. Alpha-1 Antitrypsin Deficiency

    Science.gov (United States)

    ... seafood, processed soy products, nuts, seeds, beans, and peas. A healthy diet is low in sodium (salt), ... help you cope with stress. Emotional Issues and Support Living with AAT deficiency may cause fear, anxiety, ...

  16. Iron-Deficiency Anemia

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    Full Text Available ... Disorders Lung Diseases Heart and Vascular Diseases Precision Medicine Activities Obesity, Nutrition, and Physical Activity Population and ... of the condition. Treatments may include dietary changes, medicines, and surgery. Severe iron-deficiency anemia may require ...

  17. Vitamin D Deficiency

    Science.gov (United States)

    ... disease osteoporosis. Severe vitamin D deficiency can cause rickets in children and osteomalacia in adults. Both problems cause soft, ... The oral dose is once daily or weekly. Children with rickets or at risk of this disease may get ...

  18. Iron-Deficiency Anemia

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    Full Text Available ... need to be done in a hospital. The goals of treating iron-deficiency anemia are to treat ... and children talk about their experiences with clinical research. More Information Related Health Topics Anemia Blood Tests ...

  19. Iron-Deficiency Anemia

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    Full Text Available ... low iron levels in women. Internal bleeding (bleeding inside the body) also may lead to iron-deficiency ... a diagnosis, look for a cause, and find out how severe the condition is. Complete Blood Count ...

  20. Iron-Deficiency Anemia

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    Full Text Available ... the body. Iron-deficiency anemia usually develops over time if your body doesn't have enough iron ... because your need for iron increases during these times of growth and development. Inability To Absorb Enough ...

  1. Iron-Deficiency Anemia

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    Full Text Available ... People who have RLS often have a hard time sleeping. Iron-deficiency anemia can put children at ... Reticulocytes are young, immature red blood cells. Over time, reticulocytes become mature red blood cells that carry ...

  2. Iron-Deficiency Anemia

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    Full Text Available ... or iron supplements, when used properly, can help prevent iron-deficiency anemia in infants and young children. ... in the diet. Too much milk also may prevent children's bodies from absorbing iron from other foods. ...

  3. Iron-Deficiency Anemia

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    Full Text Available ... Health Topics Education & Awareness Resources Contact The Health Information Center Health Professionals Systematic Evidence Reviews & Clinical Practice ... and see the benefits of treatment. For more information about living with and managing iron-deficiency anemia, ...

  4. Iron-Deficiency Anemia

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    Full Text Available ... the cause and severity of the condition. Treatments may include dietary changes, medicines, and surgery. Severe iron-deficiency anemia may require treatment in a hospital, blood transfusions , iron ...

  5. Iron-Deficiency Anemia

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    Full Text Available ... the first prenatal visit. For pregnant women, medical care during pregnancy usually includes screening for anemia. Also, ... while checking for other problems. Specialists Involved Primary care doctors often diagnose and treat iron-deficiency anemia. ...

  6. Iron-Deficiency Anemia

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    Full Text Available ... green leafy vegetables. Eat poorly because of money, social, health, or other problems. Follow a very low- ... help prevent overdosing in children. Because recent research supports concerns that iron deficiency during infancy and childhood ...

  7. Iron-Deficiency Anemia

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    Full Text Available ... hemoglobin than normal. Iron-deficiency anemia can cause fatigue (tiredness), shortness of breath, chest pain, and other ... common symptom of all types of anemia is fatigue (tiredness). Fatigue occurs because your body doesn't ...

  8. Iron-Deficiency Anemia

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    Full Text Available ... treat iron-deficiency anemia. These doctors include pediatricians, family doctors, gynecologists/obstetricians, and internal medicine specialists. A ... Center for Health Information Email Alerts Jobs and Careers Site Index About NHLBI National Institute of Health ...

  9. Iron-Deficiency Anemia

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    Full Text Available ... Follow a very low-fat diet over a long time. Some higher fat foods, like meat, are ... iron deficiency during infancy and childhood can have long-lasting, negative effects on brain health, the American ...

  10. Iron-Deficiency Anemia

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    Full Text Available ... Anemia What Is... CAUSES WHO IS AT RISK SIGNS & SYMPTOMS DIAGNOSIS TREATMENTS PREVENTION LIVING WITH CLINICAL TRIALS LINKS Related ... with having iron-deficiency anemia. Prior to her diagnosis, Susan had symptoms such as tiredness, poor skin ...

  11. Iron-Deficiency Anemia

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    Full Text Available ... iron-rich protein that carries oxygen from the lungs to the rest of the body. Iron-deficiency ... 2011 This video—presented by the National Heart, Lung, and Blood Institute, part of the National Institutes ...

  12. Iron-Deficiency Anemia

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    Full Text Available ... can cause fatigue (tiredness), shortness of breath, chest pain, and other symptoms. Severe iron-deficiency anemia can ... colon cancer Regular use of aspirin or other pain medicines, such as nonsteroidal anti-inflammatory drugs (for ...

  13. Iron-Deficiency Anemia

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    Full Text Available ... or an inability to absorb enough iron from food. Overview Iron-deficiency anemia is a common type ... or an inability to absorb enough iron from food. Blood Loss When you lose blood, you lose ...

  14. Iron-Deficiency Anemia

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    Full Text Available ... Infants and Young Children A baby's diet can affect his or her risk for iron-deficiency anemia. ... eat grapefruit or drink grapefruit juice. Grapefruit can affect the strength of a few medicines and how ...

  15. Iron-Deficiency Anemia

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    Full Text Available ... carry oxygen and remove carbon dioxide (a waste product) from your body. Anemia also can occur if ... Deficiency Anemia article. Updated: March 26, 2014 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA ...

  16. Iron-Deficiency Anemia

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    Full Text Available ... drawings also can cause iron-deficiency anemia. Poor Diet The best sources of iron are meat, poultry, ... also checks the number of red blood cells, white blood cells, and platelets in your blood. Abnormal ...

  17. Iron-Deficiency Anemia

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    Full Text Available ... also can cause internal bleeding. Other At-Risk Groups People who get kidney dialysis treatment may develop ... and young children and women are the two groups at highest risk for iron-deficiency anemia. Special ...

  18. Iron-Deficiency Anemia

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    Full Text Available ... the signs and symptoms of iron-deficiency anemia apply to all types of anemia . Signs and Symptoms ... rapid or uneven breathing Feel your abdomen to check the size of your liver and spleen Do ...

  19. Iron-Deficiency Anemia

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    Full Text Available ... iron-deficiency anemia may require treatment in a hospital, blood transfusions , iron injections, or intravenous iron therapy. ... beans. Other lifestyle changes, such as getting enough sleep and exercising, also have helped Susan feel better. ...

  20. Iron-Deficiency Anemia

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    Full Text Available ... intestine (such as Crohn's disease or celiac disease). Prescription medicines that reduce acid in the stomach also ... specialists also may help treat iron-deficiency anemia. Medical History Your doctor will ask about your signs ...

  1. Iron-Deficiency Anemia

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    Full Text Available ... specialists also may help treat iron-deficiency anemia. Medical History Your doctor will ask about your signs ... information, go to the Health Topics Blood Transfusion article. Iron Therapy If you have severe anemia, your ...

  2. Iron-Deficiency Anemia

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    Full Text Available ... drawings also can cause iron-deficiency anemia. Poor Diet The best sources of iron are meat, poultry, ... other dark green leafy vegetables Prune juice The Nutrition Facts labels on packaged foods will show how ...

  3. Iron-Deficiency Anemia

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    Full Text Available ... Other At-Risk Groups People who get kidney dialysis treatment may develop iron-deficiency anemia. This is because blood is lost during dialysis. Also, the kidneys are no longer able to ...

  4. Iron-Deficiency Anemia

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    Full Text Available ... for iron-deficiency anemia The Centers for Disease Control and Prevention (CDC) has developed guidelines for who ... heavy menstrual flow, your doctor may prescribe birth control pills to help reduce your monthly blood flow. ...

  5. Iron-Deficiency Anemia

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    Full Text Available ... screened for iron deficiency, and how often: Girls aged 12 to 18 and women of childbearing age ... For this treatment, iron is injected into a muscle or an IV line in one of your ...

  6. Iron-Deficiency Anemia

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    Full Text Available ... factors for iron-deficiency anemia The Centers for Disease Control and Prevention (CDC) has developed guidelines for who should be ... or while checking for other problems. Specialists ... disease specialist), a gastroenterologist (a digestive system specialist), and ...

  7. Iron deficiency anemia

    National Research Council Canada - National Science Library

    Naigamwalla, Dinaz Z; Webb, Jinelle A; Giger, Urs

    2012-01-01

    .... The most important function is oxygen transport in hemoglobin. Iron deficiency anemia in dogs and cats is usually caused by chronic blood loss and can be discovered incidentally as animals may have adapted to the anemia...

  8. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... stomach also can interfere with iron absorption. Risk Factors Infants and Young Children Infants and young children ... blood loss during their monthly periods Other risk factors for iron-deficiency anemia The Centers for Disease ...

  9. Iron-Deficiency Anemia

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    Full Text Available ... some stages of life, such as pregnancy and childhood, it may be hard to get enough iron ... supports concerns that iron deficiency during infancy and childhood can have long-lasting, negative effects on brain ...

  10. Iron-Deficiency Anemia

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    Full Text Available ... For this treatment, iron is injected into a muscle or an IV line in one of your ... body can damage your organs. You may have fatigue (tiredness) and other symptoms of iron-deficiency anemia ...

  11. Iron-Deficiency Anemia

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    Full Text Available ... risk for iron-deficiency anemia if they're underweight or have chronic (ongoing) illnesses. Teenage girls who ... other dark green leafy vegetables Prune juice The Nutrition Facts labels on packaged foods will show how ...

  12. Iron-Deficiency Anemia

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    Full Text Available ... deficiency anemia if they're underweight or have chronic (ongoing) illnesses. Teenage girls who have heavy periods ... in your hands and feet, pale skin, chest pain, weakness, and fatigue (tiredness). If you don't ...

  13. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... intravenous iron therapy. Rate This Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the National Heart, Lung, and Blood ...

  14. Sleep Deprivation and Deficiency

    Science.gov (United States)

    ... adults report falling asleep during the day without meaning to at least once a month. Also, an ... Sleep deficiency also has been linked to depression, suicide, and risk-taking behavior. Children and teens who ...

  15. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... prevent children's bodies from absorbing iron from other foods. Children who have lead in their blood also may be at risk for iron-deficiency anemia. Lead can interfere with ...

  16. Iron-Deficiency Anemia

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    Full Text Available ... Diseases Heart and Vascular Diseases Precision Medicine Activities Obesity, Nutrition, and Physical Activity Population and Epidemiology Studies ... or an inability to absorb enough iron from food. Overview Iron-deficiency anemia is a common type ...

  17. Glucose-6-phosphatase deficiency.

    OpenAIRE

    Labrune Philippe; Gajdos Vincent; Eberschweiler Pascale; Hubert-Buron Aurélie; Petit François; Vianey-Saban Christine; Boudjemline Alix; Piraud Monique; Froissart Roseline

    2011-01-01

    Abstract Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, betw...

  18. AT2 Receptors Targeting Cardiac Protection Post-Myocardial Infarction

    DEFF Research Database (Denmark)

    Kaschina, Elena; Lauer, Dilyara; Schmerler, Patrick

    2014-01-01

    is preserved over periods of up to four months. Depending on the experimental protocol, the AT2R also attenuates post-MI left ventricular remodeling or protects the heart from early left ventricular thinning and rupture. In combination with AT1-receptor blockade or deficiency, post-MI cardiac hypertrophy...... deficiency or overexpression, treatment with an AT1-receptor blocker leading to indirect stimulation of the unopposed AT2-receptor, or studies using AT2-receptor agonists. It is a common finding in these studies that the AT2-receptor improves cardiac function in the early phase post-MI, and that this effect...

  19. Congenital IL-12R1β receptor deficiency and thrombophilia in a girl homozygous for an IL12RB1 mutation and compound heterozygous for MTFHR mutations: A case report and literature review.

    Science.gov (United States)

    Akar, H H; Kose, M; Ceylan, O; Patiroglu, T; Bustamante, J; Casanova, J L; Akyildiz, B N; Doganay, S

    2014-03-01

    Interleukin-12 (IL-12) plays an important role in the production of interferon gamma from T cells and natural killer cells and is essential for protection against intra-macrophagic pathogens such as Mycobacterium and Salmonella. Here, we describe a 16-year-old girl with homozygous mutation in exon 12 of the IL12RB1 gene, which causes complete IL-12Rβ1 deficiency in association with heterozygous mutation (C677T and A1298C) in the methylenetetrahydrofolate reductase gene. She presented with disseminated Mycobacterium tuberculosis complex infection, retroperitoneal fungal abscess and also thrombosis in the superior mesenteric-portal vein junction. This is the first case report of a primary immunodeficiency associated with a genetically determined venous thrombosis.

  20. Iron deficiency in Europe.

    Science.gov (United States)

    Hercberg, S; Preziosi, P; Galan, P

    2001-04-01

    In Europe, iron deficiency is considered to be one of the main nutritional deficiency disorders affecting large fractions of the population, particularly such physiological groups as children, menstruating women and pregnant women. Some factors such as type of contraception in women, blood donation or minor pathological blood loss (haemorrhoids, gynaecological bleeding...) considerably increase the difficulty of covering iron needs. Moreover, women, especially adolescents consuming low-energy diets, vegetarians and vegans are at high risk of iron deficiency. Although there is no evidence that an absence of iron stores has any adverse consequences, it does indicate that iron nutrition is borderline, since any further reduction in body iron is associated with a decrease in the level of functional compounds such as haemoglobin. The prevalence of iron-deficient anaemia has slightly decreased in infants and menstruating women. Some positive factors may have contributed to reducing the prevalence of iron-deficiency anaemia in some groups of population: the use of iron-fortified formulas and iron-fortified cereals; the use of oral contraceptives and increased enrichment of iron in several countries; and the use of iron supplements during pregnancy in some European countries. It is possible to prevent and control iron deficiency by counseling individuals and families about sound iron nutrition during infancy and beyond, and about iron supplementation during pregnancy, by screening persons on the basis of their risk for iron deficiency, and by treating and following up persons with presumptive iron deficiency. This may help to reduce manifestations of iron deficiency and thus improve public health. Evidence linking iron status with risk of cardiovascular disease or cancer is unconvincing and does not justify changes in food fortification or medical practice, particularly because the benefits of assuring adequate iron intake during growth and development are well established

  1. Dopamine Receptors and Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Shin Hisahara

    2011-01-01

    Full Text Available Parkinson's disease (PD is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first choice to delay the starting of L-dopa therapy. In advanced stage of PD, they are also used as adjunct therapy together with L-dopa. DA receptor agonists act by stimulation of presynaptic and postsynaptic DA receptors. Despite the usefulness, they could be causative drugs for valvulopathy and nonmotor complication such as DA dysregulation syndrome (DDS. In this paper, physiological characteristics of DA receptor familyare discussed. We also discuss the validity, benefits, and specific adverse effects of pharmaceutical DA receptor agonist.

  2. Iron, Anemia, and Iron Deficiency Anemia among Young Children in the United States

    OpenAIRE

    Gupta, Priya M.; Perrine, Cria G.; Mei, Zuguo; Scanlon, Kelley S.

    2016-01-01

    Iron deficiency and anemia are associated with impaired neurocognitive development and immune function in young children. Total body iron, calculated from serum ferritin and soluble transferrin receptor concentrations, and hemoglobin allow for monitoring of the iron and anemia status of children in the United States. The purpose of this analysis is to describe the prevalence of iron deficiency (ID), anemia, and iron deficiency anemia (IDA) among children 1–5 years using data from the 2007–201...

  3. Iron deficiency in children | Thejpal | South African Medical Journal

    African Journals Online (AJOL)

    Maternal iron deficiency has negative effects during pregnancy and in the postpartum period, which affects maternal health (e.g. depression, stress, interaction) and has negative effects on the baby (e.g. behavioural and immunological effects). Newer tests include the soluble transferrin receptor, reticulocyte haemoglobin ...

  4. Extraskeletal effects and manifestations of Vitamin D deficiency

    Directory of Open Access Journals (Sweden)

    R Kasi Visweswaran

    2013-01-01

    Full Text Available The actions of vitamin D are not confined to bone. Vitamin D receptors are present in nearly all the nuclei and its actions are manifold. Populations deficient in vitamin D are at higher risk of developing autoimmune diseases, diabetes, cancer, infections, allergies and other chronic illnesses.

  5. Deficiências de minerais Mineral deficiencies

    Directory of Open Access Journals (Sweden)

    Silvia Maria Franciscato Cozzolino

    2007-08-01

    Full Text Available Neste artigo procuramos relatar a situação mundial e brasileira com relação aos micronutrientes, em especial sobre os minerais. Os elementos químicos minerais desempenham funções de grande importância no organismo humano, sendo indispensáveis para o desenvolvimento e a saúde dos indivíduos. Ainda não existe uma avaliação global do estado nutricional dos indivíduos em relação a esses micronutrientes no Brasil, mas os estudos existentes apontam para a necessidade do acompanhamento das tendências alimentares que poderiam levar às suas deficiências com conseqüências adversas para a saúde da população e o desenvolvimento do nosso país.In this paper we will try to report the Brazilian micronutrients status, as well as in worldwide, specifically for minerals. Minerals have major importance on human body, becoming indispensable for the development and health of individuals. There is not yet an integral assessment of micronutrient status in the Brazilian subjects, but there are some studies pointing to the need of observation of alimentary tendencies that might lead to deficiencies, with adverse consequences to the population’s health and the development of our country

  6. Risk factors associated with anemia, iron deficiency and iron deficiency anemia in rural Nepali pregnant women.

    Science.gov (United States)

    Makhoul, Zeina; Taren, Douglas; Duncan, Burris; Pandey, Pooja; Thomson, Cynthia; Winzerling, Joy; Muramoto, Myra; Shrestha, Ram

    2012-05-01

    We conducted a cross sectional study to investigate risk factors associated with severe anemia [hemoglobin (Hb) anemia and the soluble transferrin receptor (sTfR) was measured among a subsample of 479 women. The iron status categories were: 1) normal (Hb> or = 11.0 g/dl and sTfR anemia without iron deficiency (Hbanemia (Hb > or = 11.0 g/dl and sTfR>8.5 mg/l); and 4) iron deficiency anemia (IDA): (Hb8.5 mg/l). Factors associated with severe anemia and poor iron status were determined using logistic regression. Hookworm infection increased the risk for developing severe anemia [adjusted odds ratio (AOR): 4.26; 95% CI 1.67-10.89; panemia. Intake of iron supplements as tablets and/or tonic was protective against severe anemia, anemia without iron deficiency and IDA. Dietary heme iron was significantly associated with iron deficiency without anemia (RRR: 0.1; 95% CI 0.02-0.47; pclassification and multiple approaches are needed to reduce anemia and associated nutrient deficiencies.

  7. Expression of platelet-derived growth factor (PDGF) in the epididymis and analysis of the epididymal development in PDGF-A, PDGF-B, and PDGF receptor beta deficient mice.

    Science.gov (United States)

    Basciani, Sabrina; Mariani, Stefania; Arizzi, Mario; Brama, Marina; Ricci, Andrea; Betsholtz, Christer; Bondjers, Cecilia; Ricci, Giulia; Catizone, Angela; Galdieri, Michela; Spera, Giovanni; Gnessi, Lucio

    2004-01-01

    The platelet-derived growth factor (PDGF) family of ligands and receptors play a pivotal role in the development of various organs. The critical importance of the PDGF-mediated signaling during embryonic development and adult physiology of the kidney and the common mesonephric origin of the epididymis and kidney prompted us to investigate the immunohistochemical localization of PDGF A- and B-chain and PDGF receptor (PDGFR) alpha- and beta-subunit in rat and mouse epididymis, the expression profiles of the corresponding mRNAs, and the consequences of a loss-of-function mutation at the PDGF-A, PDGF-B, and PDGFR-beta loci on mouse epididymis phenotypic appearance. Prenatally, PDGF-A and PDGFR-alpha immunohistochemical staining was seen in both species, whereas PDGF-B and PDGFR-beta were absent. The cellular localization of PDGF-A within the epithelium and the alpha-receptor in the mesenchyme in either mouse or rat before birth suggests that the PDGF-A/PDGFR-alpha system might be involved in the epididymal epithelial-mesenchymal interaction during the fetal period of life. Postnatally, PDGF A- and B-ligand and PDGFR alpha- and beta-subunit were confined in the epithelium. The identity of PDGF and PDGFR proteins were further confirmed by immunoblotting. In line with the immunohistochemical studies, PDGF-A and PDGFR-alpha mRNAs were seen by reverse transcription-polymerase chain reaction in rat and mouse tissue before birth, whereas PDGF-B and PDGFR-beta were almost not detectable. During the first days of life, PDGF-B and PDGFR-beta genes started to appear, and the overall trend in mRNA expression throughout postnatal development showed that the transcripts levels for PDGF-A, PDGF-B, PDGFR-beta, and PDGFR-alpha were constant with the only exception of a progressive decrease of PDGFR-alpha in adult rats. The PDGF-A null mutation strongly influenced the epididymal phenotype starting from puberty; only fetal PDGF-B and PDGFR-beta -/- mice were available, and no differences

  8. Vitamin deficiencies in cattle.

    Science.gov (United States)

    Frye, T M; Williams, S N; Graham, T W

    1991-03-01

    Deficiencies of vitamins A, D, K, E and thiamin can cause severe limitations in beef production. In particular, vitamin A and E can be common causes of lost profit, secondary to limitations of reproductive and growth potential. Prolonged dry periods will reduce available A and E in pasture forage, as can ensiling and prolonged storage of harvested feedstuffs. Polioencephalomalacia is a thiamin responsive disorder, associated with high concentrate feeding and lush pastures. Antimetabolites, such as amprolium, will cause thiamine deficiency when fed in excess. Recent information has shown improved performance with supplemental beta carotene and niacin. The positive responses in reproductive performance, noted with cattle fed supplemental beta carotene, was independent of vitamin A. Supplementation of vitamins above National Research Council recommendations can be justified. However, proper evaluation of feed and animal status, and documentation of a response to supplementation is necessary before diagnosing deficiencies of specific nutrients.

  9. Antepartum Ornithine Transcarbamylase Deficiency

    Directory of Open Access Journals (Sweden)

    Hitoshi Nakajima

    2014-11-01

    Full Text Available Ornithine transcarbamylase deficiency (OTCD is the most common type urea cycle enzyme deficiencies. This syndrome results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase, which catalyzes the conversion of ornithine and carbamoyl phosphate to citrullin. Our case was a 28-year-old female diagnosed with OTCD following neurocognitive deficit during her first pregnancy. Although hyperammonemia was suspected as the cause of the patient's mental changes, there was no evidence of chronic liver disease. Plasma amino acid and urine organic acid analysis revealed OTCD. After combined modality treatment with arginine, sodium benzoate and hemodialysis, the patient's plasma ammonia level stabilized and her mental status returned to normal. At last she recovered without any damage left.

  10. Vitamin B12 deficiency

    DEFF Research Database (Denmark)

    Green, Ralph; Allen, Lindsay H; Bjørke-Monsen, Anne-Lise

    2017-01-01

    Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However...... remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes...

  11. Multiple sulfatase deficiency.

    Science.gov (United States)

    Soong, B W; Casamassima, A C; Fink, J K; Constantopoulos, G; Horwitz, A L

    1988-08-01

    Multiple sulfatase deficiency is an inherited disorder characterized by a deficiency of several sulfatases and the accumulation of sulfatides, glycosaminoglycans, sphingolipids, and steroid sulfates in tissues and body fluids. The clinical manifestations represent the summation of two diseases: late infantile metachromatic leukodystrophy and mucopolysaccharidosis. We present a 9-year-old girl with a phenotype similar to a mucopolysaccharidosis: short stature, microcephaly, and mild facial dysmorphism, along with dysphagia, retinal degeneration, developmental arrest, and ataxia. We discuss the importance of measuring the sulfatase activities in the leukocytes, and the instability of sulfatases in the cultured skin fibroblasts.

  12. Iodine Deficiency and Human Development

    Directory of Open Access Journals (Sweden)

    M A Sviridonova

    2014-03-01

    Full Text Available Iodine is а vital microelements that are essential for the normal human development and functions. Iodine deficiency is a global problem: about 2 billion individuals worldwide suffer from a lack of iodine. Despite goiter is the most visually noticeable manifestation of iodine deficiency, the most significant consequence of the iodine deficiency is impaired neurodevelopment, particularly early in life. Moreover, moderate to severe iodine deficiency increases the risk of spontaneous abortion, low birth weight and infant mortality. Babies in utero affected by iodine deficiency are at increased risk of mental developmental disorders, cretinism is their extreme degree. In addition, moderate to severe iodine deficiency in childhood negatively affects somatic growth. Iodine deficiency compensation improves cognitive and motor function in children. Iodine prophylaxis of deficient populations is an extremely effective approach to reduce the substantial adverse effects of iodine deficiency throughout the life cycle.

  13. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... your red blood cells don't contain enough hemoglobin (HEE-muh-glow-bin). Hemoglobin is an iron-rich protein that carries oxygen ... red blood cells it does make have less hemoglobin than normal. Iron-deficiency anemia can cause fatigue ( ...

  14. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Every 5 to 10 years. Women who have risk factors for iron deficiency: Once a year. Pregnant women: At the first prenatal visit. For pregnant women, medical care during pregnancy usually includes screening for anemia. Also, your doctor ...

  15. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and development in children, and other ... poorly because of money, social, health, or other problems. Follow a very low-fat diet over a ...

  16. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... deficiency anemia if they're underweight or have chronic (ongoing) illnesses. Teenage girls who have heavy periods ... because blood is lost during dialysis. Also, the kidneys are no longer able to make ... Centers for Disease Control and Prevention (CDC) has developed guidelines for ...

  17. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... iron-rich foods in the diet. Too much milk also may prevent children's bodies from absorbing iron from other foods. Children who have lead in their blood also may be at risk for iron-deficiency anemia. Lead can interfere with the body's ability to make hemoglobin. Lead may get into the body from ...

  18. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... also may help treat iron-deficiency anemia. Medical History Your doctor will ask about your signs and symptoms and any past problems you've had with anemia or low iron. He or she also may ask about your diet and whether you're taking any medicines. If ...

  19. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Site Health Topics News & Resources Intramural Research ... Is Iron-deficiency anemia is a common, easily treated condition that occurs if you don't have enough iron in your body. Low iron levels usually are due to blood loss, ...

  20. Deficiency Report Management System

    Science.gov (United States)

    1989-09-28

    The Customer Feedback Office of the Product Assurance Directorate, MICOM has the mission to manage and analyze data in the Deficiency Reporting...capability within the Customer Feedback Office (CFO) of the MICOM Product Assurance Directorate for government comment. The objective of this program is

  1. Partial Biotinidase Deficiency

    OpenAIRE

    J Gordon Millichap

    1990-01-01

    The symptoms, biochemical features and inheritance pattern of partial biotinidase deficiency have been studied at the Departments of Human Genetics and Pediatrics, Medical College of Virginia, Richmond, VA; the State Laboratory Institute, Massachusetts Department of Public Health; Massachusetts General Hospital, Boston; the Lincoln Clinic, NB; and the Division of Human Genetics, university of Maryland School of Medicine, Baltimore.

  2. Iodine-deficiency disorders

    NARCIS (Netherlands)

    Zimmermann, M.B.; Jooste, P.L.; Pandav, C.S.

    2008-01-01

    billion individuals worldwide have insufficient iodine intake, with those in south Asia and sub-Saharan Africa particularly affected. Iodine deficiency has many adverse effects on growth and development. These effects are due to inadequate production of thyroid hormone and are termed

  3. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Activity Population and Epidemiology Studies Women’s Health All Science A-Z ... usually are due to blood loss, poor diet, or an inability to absorb enough iron from food. Overview Iron-deficiency anemia is a common type ...

  4. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... doctor may ask whether you might be pregnant. Physical Exam Your doctor will do a physical exam to look for signs of iron-deficiency ... remove the growth. If you have heavy menstrual flow, your doctor may prescribe birth control pills to ...

  5. Alpha-1 antitrypsin deficiency

    Science.gov (United States)

    ... Tools About MedlinePlus Show Search Search MedlinePlus GO GO About MedlinePlus Site Map FAQs Customer Support Health Topics Drugs & Supplements Videos & Tools Español You Are Here: Home → Medical Encyclopedia → Alpha-1 antitrypsin deficiency URL of this page: //medlineplus. ...

  6. Vitamin B12 deficiency

    Science.gov (United States)

    Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, sub...

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... hospital, blood transfusions , iron injections, or intravenous iron therapy. Causes Not having enough iron in your body causes iron-deficiency anemia. Lack of iron usually is due to blood loss, poor diet, or an inability to absorb enough iron from ...

  8. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... blood transfusions , iron injections, or intravenous iron therapy. Rate This Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the National Heart, Lung, and Blood Institute, part of the National ...

  9. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... who have iron-deficiency anemia develop restless legs syndrome (RLS). RLS is a disorder that causes a ... Topics Anemia Blood Tests Blood Transfusion Restless Legs Syndrome Other Resources Non-NHLBI Resources Anemia (MedlinePlus) "Dietary ...

  10. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the body. Iron-deficiency anemia usually develops over time if your body doesn't have enough iron ... Institutes of Health—shows how Susan, a full-time worker and student, has coped with having iron- ...

  11. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... woman's risk for a premature or low-birth-weight baby. Adults Who Have Internal Bleeding Adults who have internal bleeding, such as intestinal bleeding, can develop iron-deficiency anemia due to blood loss. Certain conditions, such as colon cancer and bleeding ...

  12. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... as larger, full-term infants. Iron-fortified baby food or iron supplements, when used properly, can help prevent iron-deficiency ... Syndrome Other Resources Non-NHLBI Resources Anemia (MedlinePlus) "Dietary Supplement Fact Sheet: Iron" (Office of Dietary Supplements, National ...

  13. Role of activating transcription factor 3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization of p53-deficient human colon cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through up-regulation of death receptor 5 (DR5) by zerumbone and celecoxib.

    Science.gov (United States)

    Edagawa, Makoto; Kawauchi, Junya; Hirata, Manabu; Goshima, Hiroto; Inoue, Makoto; Okamoto, Tatsuro; Murakami, Akira; Maehara, Yoshihiko; Kitajima, Shigetaka

    2014-08-01

    Death receptor 5 (DR5) is a death domain-containing transmembrane receptor that triggers cell death upon binding to its ligand, TNF-related apoptosis-inducing ligand (TRAIL), and a combination of TRAIL and agents that increase the expression of DR5 is expected to be a novel anticancer therapy. In this report, we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells. Both agents activated PERK-eIF2α kinases and induced the expression of activating transcription factor 4 (ATF4)-CCAAT enhancer-binding protein (C/EBP) homologous protein, which were remarkably suppressed by reactive oxygen species scavengers. In the absence of ATF3, the induction of DR5 mRNA and protein was abrogated significantly, and this was associated with reduced cell death by cotreatment of TRAIL with ZER or CCB. By contrast, exogenous expression of ATF3 caused a more rapid and elevated expression of DR5, resulting in enhanced sensitivity to apoptotic cell death by TRAIL/ZER or TRAIL/CCB. A reporter assay demonstrated that at least two ATF/cAMP response element motifs as well as C/EBP homologous protein motif at the proximal region of the human DR5 gene promoter were required for ZER-induced DR5 gene transcription. Taken together, our results provide novel insights into the role of ATF3 as an essential transcription factor for p53-independent DR5 induction upon both ZER and CCB treatment, and this may be a useful biomarker for TRAIL-based anticancer therapy. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Glucose-6-phosphate dehydrogenase deficiency

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000528.htm Glucose-6-phosphate dehydrogenase deficiency To use the sharing features on this page, please enable JavaScript. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a condition ...

  15. Genetics Home Reference: transcobalamin deficiency

    Science.gov (United States)

    ... PH, Nordwall M, Hoffmann-Lücke E, Sorensen BS, Nexo E. Transcobalamin deficiency caused by compound heterozygosity for ... Hung C, Rupar T, Mühl A, Fowler B, Nexo E, Bodamer OA. Transcobalamin II deficiency at birth. ...

  16. Genetics Home Reference: proopiomelanocortin deficiency

    Science.gov (United States)

    ... due to pomc deficiency Orphanet: Obesity due to pro-opiomelanocortin deficiency Patient Support and Advocacy Resources (4 ... HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, ...

  17. Growth Hormone Deficiency in Children

    Science.gov (United States)

    ... c m y one in Children What is growth hormone deficiency? Growth hormone deficiency (GHD) is a rare condition in which the body does not make enough growth hormone (GH). GH is made by the pituitary gland, ...

  18. Growth Hormone Deficiency in Adults

    Science.gov (United States)

    ... Balance › Growth Hormone Deficiency in Adults Patient Guide Growth Hormone Deficiency in Adults June 2011 Download PDFs English ... depression, or moodiness What are the benefits of growth hormone therapy? Growth hormone treatment involves injections (shots) of ...

  19. Influenza virus vaccination induces interleukin-12/23 receptor β1 (IL-12/23Rβ1)-independent production of gamma interferon (IFN-γ) and humoral immunity in patients with genetic deficiencies in IL-12/23Rβ1 or IFN-γ receptor I

    NARCIS (Netherlands)

    T. de Boer (Tjitske); J.T. van Dissel (Jaap); T.W. Kuijpers (Taco W.); G.F. Rimmelzwaan (Guus); F.P. Kroon; T.H.M. Ottenhoff (Tom)

    2008-01-01

    textabstractTo investigate whether protective immune responses can be induced in the absence of normal interleukin-12/23/gamma interferon (IL-12/23/IFN-γ) axis signaling, we vaccinated with the seasonal influenza virus subunit vaccine two patients with 3complete IL-12/23 receptor β1 (IL-12/23Rβ1)

  20. Influenza virus vaccination induces interleukin-12/23 receptor beta 1 (IL-12/23R beta 1)-independent production of gamma interferon (IFN-gamma) and humoral immunity in patients with genetic deficiencies in IL-12/23R beta 1 or IFN-gamma receptor I

    NARCIS (Netherlands)

    de Boer, Tjitske; van Dissel, Jaap T.; Kuijpers, Taco W. J.; Rimmelzwaan, Guus F.; Kroon, Frank P.; Ottenhoff, Tom H. M.

    2008-01-01

    To investigate whether protective immune responses can be induced in the absence of normal interleukin12/23/gamma interferon (IL-12/23/IFN-gamma) axis signaling, we vaccinated with the seasonal influenza virus subunit vaccine two patients with complete IL-12/23 receptor beta 1 (IL-12/23R beta 1)

  1. Influenza virus vaccination induces interleukin-12/23 receptor beta 1 (IL-12/23R beta 1)-independent production of gamma interferon (IFN-gamma) and humoral immunity in patients with genetic deficiencies in IL-12/23R beta 1 or IFN-gamma receptor I.

    NARCIS (Netherlands)

    Boer, T. de; Dissel, J.T. van; Kuijpers, T.W.; Rimmelzwaan, G.F.; Kroon, F.P.; Ottenhoff, T.H.M.

    2008-01-01

    To investigate whether protective immune responses can be induced in the absence of normal interleukin-12/23/gamma interferon (IL-12/23/IFN-gamma) axis signaling, we vaccinated with the seasonal influenza virus subunit vaccine two patients with complete IL-12/23 receptor beta1 (IL-12/23R beta 1)

  2. Iron deficiency and cognitive functions

    Directory of Open Access Journals (Sweden)

    Jáuregui-Lobera I

    2014-11-01

    Full Text Available Ignacio Jáuregui-Lobera Department of Nutrition and Bromatology, Pablo de Olavide University, Seville, Spain Abstract: Micronutrient deficiencies, especially those related to iodine and iron, are linked to different cognitive impairments, as well as to potential long-term behavioral changes. Among the cognitive impairments caused by iron deficiency, those referring to attention span, intelligence, and sensory perception functions are mainly cited, as well as those associated with emotions and behavior, often directly related to the presence of iron deficiency anemia. In addition, iron deficiency without anemia may cause cognitive disturbances. At present, the prevalence of iron deficiency and iron deficiency anemia is 2%–6% among European children. Given the importance of iron deficiency relative to proper cognitive development and the alterations that can persist through adulthood as a result of this deficiency, the objective of this study was to review the current state of knowledge about this health problem. The relevance of iron deficiency and iron deficiency anemia, the distinction between the cognitive consequences of iron deficiency and those affecting specifically cognitive development, and the debate about the utility of iron supplements are the most relevant and controversial topics. Despite there being methodological differences among studies, there is some evidence that iron supplementation improves cognitive functions. Nevertheless, this must be confirmed by means of adequate follow-up studies among different groups. Keywords: iron deficiency, anemia, cognitive functions, supplementation

  3. Biotin and biotinidase deficiency

    OpenAIRE

    Zempleni, Janos; Hassan, Yousef I.; Wijeratne, Subhashinee SK

    2008-01-01

    Biotin is a water-soluble vitamin that serves as an essential coenzyme for five carboxylases in mammals. Biotin-dependent carboxylases catalyze the fixation of bicarbonate in organic acids and play crucial roles in the metabolism of fatty acids, amino acids and glucose. Carboxylase activities decrease substantially in response to biotin deficiency. Biotin is also covalently attached to histones; biotinylated histones are enriched in repeat regions in the human genome and appear to play a role...

  4. Vitamin D receptors and parathyroid glands.

    Science.gov (United States)

    Landry, Christine S; Ruppe, Mary D; Grubbs, Elizabeth G

    2011-01-01

    To describe the function and metabolism of the vitamin D hormone and the role of the vitamin D receptor and the calcium-sensing receptor in the secretion of parathyroid hormone. A review of the literature was undertaken regarding the function and metabolism of vitamin D; the role of the vitamin D receptor and calcium-sensing receptor in the secretion of parathyroid hormone; and the contemporary research regarding the interaction of vitamin D and parathyroid hormone in patients with vitamin D deficiency, primary hyperparathyroidism, and secondary hyperparathyroidism. Over the last several years, great interest has been generated about the interaction of vitamin D and the parathyroid glands, gastrointestinal tract, kidney, and bone in relation to calcium and parathyroid hormone levels. Vitamin D has an important role in calcium and parathyroid hormone metabolism. Likewise, the vitamin D axis appears to be involved with the development of both primary and secondary hyperparathyroidism. The specific mechanism by which vitamin D interacts with the parathyroid gland to bring about observed effects is not yet fully understood. Future studies investigating the relationship of the vitamin D receptor, calcium-sensing receptor, and parathyroid glands are needed to enhance our knowledge of vitamin D deficiency and primary and secondary vitamin D deficiency.

  5. Tall stature in familial glucocorticoid deficiency.

    Science.gov (United States)

    Elias, L L; Huebner, A; Metherell, L A; Canas, A; Warne, G L; Bitti, M L; Cianfarani, S; Clayton, P E; Savage, M O; Clark, A J

    2000-10-01

    Familial glucocorticoid deficiency (FGD) has frequently been associated with tall stature in affected individuals. The clinical, biochemical and genetic features of five such patients were studied with the aim of clarifying the underlying mechanisms of excessive growth in these patients. Five patients with a clinical diagnosis of FGD are described in whom the disorder resulted from a variety of novel or previously described missense or nonsense mutations of the ACTH receptor (MC2-R). All patients demonstrated excessive linear growth over that predicted from parental indices and increased head circumference. Growth hormone and IGF-I-values were normal. Growth charts suggest that the excessive growth is reduced to normal following the introduction of glucocorticoid replacement. A characteristic facial appearance including hypertelorism, marked epicanthic folds and prominent frontal bossing was noted. These findings indicate that ACTH resistance resulting from a defective ACTH receptor may be associated with abnormalities of cartilage and/or bone growth independently of the GH-IGF-I axis, but probably dependent on ACTH actions through other melanocortin receptors.

  6. Development and function of CD94-deficient natural killer cells.

    Directory of Open Access Journals (Sweden)

    Mark T Orr

    Full Text Available The CD94 transmembrane-anchored glycoprotein forms disulfide-bonded heterodimers with the NKG2A subunit to form an inhibitory receptor or with the NKG2C or NKG2E subunits to assemble a receptor complex with activating DAP12 signaling proteins. CD94 receptors expressed on human and mouse NK cells and T cells have been proposed to be important in NK cell tolerance to self, play an important role in NK cell development, and contribute to NK cell-mediated immunity to certain infections including human cytomegalovirus. We generated a gene-targeted CD94-deficient mouse to understand the role of CD94 receptors in NK cell biology. CD94-deficient NK cells develop normally and efficiently kill NK cell-susceptible targets. Lack of these CD94 receptors does not alter control of mouse cytomegalovirus, lymphocytic choriomeningitis virus, vaccinia virus, or Listeria monocytogenes. Thus, the expression of CD94 and its associated NKG2A, NKG2C, and NKG2E subunits is dispensable for NK cell development, education, and many NK cell functions.

  7. Glucose-6-phosphatase deficiency

    Directory of Open Access Journals (Sweden)

    Labrune Philippe

    2011-05-01

    Full Text Available Abstract Glucose-6-phosphatase deficiency (G6P deficiency, or glycogen storage disease type I (GSDI, is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea. Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty, generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency. GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib. Mutations in the genes G6PC (17q21 and SLC37A4 (11q23 respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most

  8. [Iron deficiency and digestive disorders].

    Science.gov (United States)

    Cozon, G J N

    2014-11-01

    Iron deficiency anemia still remains problematic worldwide. Iron deficiency without anemia is often undiagnosed. We reviewed, in this study, symptoms and syndromes associated with iron deficiency with or without anemia: fatigue, cognitive functions, restless legs syndrome, hair loss, and chronic heart failure. Iron is absorbed through the digestive tract. Hepcidin and ferroportin are the main proteins of iron regulation. Pathogenic micro-organisms or intestinal dysbiosis are suspected to influence iron absorption. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  9. Autophagy induction by tetrahydrobiopterin deficiency

    OpenAIRE

    Kwak, Sang Su; Suk, Jinkyu; Choi, Ji Hye; Yang, Seungkyung; Kim, Jin Woo; Sohn, Seonghyang; Chung, Jae Hoon; Hong, Yong Hee; Lee, Dong Hwan; Ahn, Jeong Keun; Min, Hyesun; Fu, Ya-Min; Meadows, Gary G.; Joe, Cheol O.

    2011-01-01

    Tetrahydrobiopterin (BH4) deficiency is a genetic disorder associated with a variety of metabolic syndromes such as phenylketonuria (PKU). In this article, the signaling pathway by which BH4 deficiency inactivates mTORC1 leading to the activation of the autophagic pathway was studied utilizing BH4-deficient Spr-/- mice generated by the knockout of the gene encoding sepiapterin reductase (SR) catalyzing BH4 synthesis. We found that mTORC1 signaling was inactivated and autophagic pathway was ac...

  10. Nutritional deficiencies after bariatric surgery.

    Science.gov (United States)

    Bal, Bikram S; Finelli, Frederick C; Shope, Timothy R; Koch, Timothy R

    2012-09-01

    Lifestyle intervention programmes often produce insufficient weight loss and poor weight loss maintenance. As a result, an increasing number of patients with obesity and related comorbidities undergo bariatric surgery, which includes approaches such as the adjustable gastric band or the 'divided' Roux-en-Y gastric bypass (RYGB). This Review summarizes the current knowledge on nutrient deficiencies that can develop after bariatric surgery and highlights follow-up and treatment options for bariatric surgery patients who develop a micronutrient deficiency. The major macronutrient deficiency after bariatric surgery is protein malnutrition. Deficiencies in micronutrients, which include trace elements, essential minerals, and water-soluble and fat-soluble vitamins, are common before bariatric surgery and often persist postoperatively, despite universal recommendations on multivitamin and mineral supplements. Other disorders, including small intestinal bacterial overgrowth, can promote micronutrient deficiencies, especially in patients with diabetes mellitus. Recognition of the clinical presentations of micronutrient deficiencies is important, both to enable early intervention and to minimize long-term adverse effects. A major clinical concern is the relationship between vitamin D deficiency and the development of metabolic bone diseases, such as osteoporosis or osteomalacia; metabolic bone diseases may explain the increased risk of hip fracture in patients after RYGB. Further studies are required to determine the optimal levels of nutrient supplementation and whether postoperative laboratory monitoring effectively detects nutrient deficiencies. In the absence of such data, clinicians should inquire about and treat symptoms that suggest nutrient deficiencies.

  11. Anaemia, iron status and vitamin A deficiency among adolescent refugees in Kenya and Nepal.

    Science.gov (United States)

    Woodruff, Bradley A; Blanck, Heidi Michels; Slutsker, Laurence; Cookson, Susan T; Larson, Mary Kay; Duffield, Arabella; Bhatia, Rita

    2006-02-01

    To investigate the prevalence of anaemia (haemoglobiniron deficiency (transferrin receptor concentration>8.3 microg ml(-1)) and vitamin A deficiency (serum retinol Kenya and seven refugee camps in Nepal. Adolescent refugee residents in these camps. Anaemia was present in 46% (95% confidence interval (CI): 42-51) of adolescents in Kenya and in 24% (95% CI: 20-28) of adolescents in Nepal. The sensitivity of palmar pallor in detecting anaemia was 21%. In addition, 43% (95% CI: 36-50) and 53% (95% CI: 46-61) of adolescents in Kenya and Nepal, respectively, had iron deficiency. In both surveys, anaemia occurred more commonly among adolescents with iron deficiency. Vitamin A deficiency was found in 15% (95% CI: 10-20) of adolescents in Kenya and 30% (95% CI: 24-37) of adolescents in Nepal. Night blindness was not more common in adolescents with vitamin A deficiency than in those without vitamin A deficiency. In Kenya, one of the seven adolescents with Bitot's spots had vitamin A deficiency. Anaemia, iron deficiency and vitamin A deficiency are common among adolescents in refugee populations. Such adolescents need to increase intakes of these nutrients; however, the lack of routine access makes programmes targeting adolescents difficult. Adolescent refugees should be considered for assessment along with other at-risk groups in displaced populations.

  12. Diagnosis of iron deficiency anemia in children of Northeast Brazil

    OpenAIRE

    Carvalho, Antonio Geraldo Cidrão; Lira, Pedro Israel Cabral de; Barros, Maria de Fátima Alcântara; Aléssio, Maria Luiza Martins; Lima, Marília de Carvalho; Carbonneau, Marie Annette; Berger, Jacques; Léger, Claude Louis

    2010-01-01

    OBJECTIVE: To diagnose iron deficiency anemia in children. METHODS: The study was conducted with a sample of 301 children aged six to 30 months attending public daycare centers in the city of Recife, Northeast Brazil, in 2004. The diagnoses of anemia were based on a combination of different hematological and biochemical parameters: hemoglobin, mean corpuscular volume, ferritin, C-reactive protein, transferrin saturation and transferrin receptor. The chi-square test and ANOVA were used in the ...

  13. Activation of glucocorticoid receptors increases 5-HT2A receptor levels

    DEFF Research Database (Denmark)

    Trajkovska, Viktorija; Kirkegaard, Lisbeth; Krey, Gesa

    2009-01-01

    Major depression is associated with both dysregulation of the hypothalamic pituitary adrenal axis and serotonergic deficiency, not the least of the 5-HT2A receptor. However, how these phenomena are linked to each other, and whether a low 5-HT2A receptor level is a state or a trait marker of depre......Major depression is associated with both dysregulation of the hypothalamic pituitary adrenal axis and serotonergic deficiency, not the least of the 5-HT2A receptor. However, how these phenomena are linked to each other, and whether a low 5-HT2A receptor level is a state or a trait marker...... of depression is unknown. In mice with altered glucocorticoid receptor (GR) expression we investigated 5-HT2A receptor levels by Western blot and 3H-MDL100907 receptor binding. Serotonin fibre density was analyzed by stereological quantification of serotonin transporter immunopositive fibers. To establish...... an effect of GR activation on 5-HT2A levels, mature organotypic hippocampal cultures were exposed to corticosterone with or without GR antagonist mifepristone and mineralocorticoid receptor (MR) antagonist spironolactone. In GR under-expressing mice, hippocampal 5-HT2A receptor protein levels were decreased...

  14. The Nature of Foot Ray Deficiency in Congenital Fibular Deficiency.

    Science.gov (United States)

    Reyes, Bryan A; Birch, John G; Hootnick, David R; Cherkashin, Alex M; Samchukov, Mikhail L

    Absent lateral osseous structures in congenital fibular deficiency, including the distal femur and fibula, have led some authors to refer to the nature of foot ray deficiency as "lateral" as well. Others have suggested that the ray deficiency is in the central portion of the midfoot and forefoot.We sought to determine whether cuboid preservation and/or cuneiform deficiency in the feet of patients with congenital fibular deficiency implied that the ray deficiency is central rather than lateral in patients with congenital fibular deficiency. We identified all patients with a clinical morphologic diagnosis of congenital fibular deficiency at our institution over a 15-year period. We reviewed the records and radiographs of patients who had radiographs of the feet to allow determination of the number of metatarsals, the presence or absence of a cuboid or calcaneocuboid fusion, the number of cuneiforms present (if possible), and any other osseous abnormalities of the foot. We excluded patients with 5-rayed feet, those who had not had radiographs of the feet, or whose radiographs were not adequate to allow accurate assessment of these radiographic features. We defined the characteristic "lateral (fifth) ray present" if there was a well-developed cuboid or calcaneocuboid coalition with which the lateral-most preserved metatarsal articulated. Twenty-six patients with 28 affected feet met radiographic criteria for inclusion in the study. All affected feet had a well-developed cuboid or calcaneocuboid coalition. The lateral-most ray of 25 patients with 26 affected feet articulated with the cuboid or calcaneocuboid coalition. One patient with bilateral fibular deficiency had bilateral partially deficient cuboids, and the lateral-most metatarsal articulated with the medial remnant of the deformed cuboids. Twenty-one of 28 feet with visible cuneiforms had 2 or 1 cuneiform. Although the embryology and pathogenesis of congenital fibular deficiency remain unknown, based on the

  15. MCAD deficiency in Denmark

    DEFF Research Database (Denmark)

    Andresen, Brage Storstein; Lund, Allan Meldgaard; Hougaard, David Michael

    2012-01-01

    Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common defect of fatty acid oxidation. Many countries have introduced newborn screening for MCADD, because characteristic acylcarnitines can easily be identified in filter paper blood spot samples by tandem mass spectrometry (MS...... analysis. This gives an incidence of MCADD detected by newborn screening in Denmark of 1/8954. In sharp contrast to this we found that the incidence of clinically presenting MCADD in Denmark in the 10 year period preceding introduction of MS/MS-based screening was only 1 in 39,691. This means that four...... lower proportion of newborns being homozygous for the prevalent disease-causing c.985A>G mutation. A significant number of the newborns have genotypes with mutations that have not been observed in patients detected clinically. Some of these mutations, like c.199T>C and c.127G>A, are always associated...

  16. Congenital fibular deficiency.

    Science.gov (United States)

    Hamdy, Reggie C; Makhdom, Asim M; Saran, Neil; Birch, John

    2014-04-01

    Congenital fibular deficiency (CFD) is characterized by a wide spectrum of manifestations ranging from mild limb length inequality (LLI) to severe shortening, with foot and ankle deformities and associated anomalies. The etiology of CFD remains unclear. Treatment goals are to achieve normal weight bearing, a functional plantigrade foot, and equal limb length. The recent Birch classification system has been proposed to provide a treatment guide: the functionality of the foot, LLI, and associated anomalies should be taken into account for decision-making. Treatment options include orthosis or epiphysiodesis, Syme or Boyd amputation and prosthetic rehabilitation, limb lengthening procedures, and foot and ankle reconstruction. The outcome of amputation for severe forms of CFD has shown favorable results and fewer complications compared with those of limb lengthening. Nevertheless, advances in the limb lengthening techniques may change our approach to treating patients with CFD and might extend the indications for reconstructive procedures to the treatment of severe LLI and foot deformities.

  17. Mortality and GH deficiency

    DEFF Research Database (Denmark)

    Stochholm, Kirstine; Gravholt, Claus Højbjerg; Laursen, Torben

    2007-01-01

    OBJECTIVE: To estimate the mortality in Denmark in patients suffering from GH deficiency (GHD). DESIGN: Mortality was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in GHD patients were studied and additional morbidity noted. Patients were divided...... into childhood onset (CO) and adult onset (AO), discriminated by an age cutoff below or above 18 years at onset of GHD. METHOD: Data on death were identified in national registries. Sex- and cause-specific mortalities were identified in CO and AO GHD when compared with controls. RESULTS: Mortality was increased...... versus AO males, both compared with controls (P mortality was increased due to cancer in all subgroups, due to circulatory diseases in all age groups for females and for males in the oldest age group. For CO, the increased mortality was due to cancer. CONCLUSIONS: We found...

  18. Orexin receptor-1 mediates brown fat developmental differentiation

    OpenAIRE

    Sellayah, Dyan; Sikder, Devanjan

    2012-01-01

    Orexin A (OX) is a small excitatory neuropeptide hormone that stimulates feeding, wakefulness and energy expenditure via a pair of G-coupled protein receptors, namely orexin receptor-1 (OXR1) and orexin receptor-2 (OXR2). OX-deficient mice are sensitive to obesity despite being hypophagic. The obesogenic effect of OX-deletion is due to brown adipose tissue (BAT) dysfunction, a defect that originates during fetal growth. Brown preadipocytes in OX-null mice display undifferentiated histological...

  19. Prostaglandin E2 is critical for the development of niacin-deficiency-induced photosensitivity via ROS production

    Science.gov (United States)

    Sugita, Kazunari; Ikenouchi-Sugita, Atsuko; Nakayama, Yasuko; Yoshioka, Haruna; Nomura, Takashi; Sakabe, Jun-Ichi; Nakahigashi, Kyoko; Kuroda, Etsushi; Uematsu, Satoshi; Nakamura, Jun; Akira, Shizuo; Nakamura, Motonobu; Narumiya, Shuh; Miyachi, Yoshiki; Tokura, Yoshiki; Kabashima, Kenji

    2013-10-01

    Pellagra is a photosensitivity syndrome characterized by three ``D's'': diarrhea, dermatitis, and dementia as a result of niacin deficiency. However, the molecular mechanisms of photosensitivity dermatitis, the hallmark abnormality of this syndrome, remain unclear. We prepared niacin deficient mice in order to develop a murine model of pellagra. Niacin deficiency induced photosensitivity and severe diarrhea with weight loss. In addition, niacin deficient mice exhibited elevated expressions of COX-2 and PGE syntheses (Ptges) mRNA. Consistently, photosensitivity was alleviated by a COX inhibitor, deficiency of Ptges, or blockade of EP4 receptor signaling. Moreover, enhanced PGE2 production in niacin deficiency was mediated via ROS production in keratinocytes. In line with the above murine findings, human skin lesions of pellagra patients confirmed the enhanced expression of Ptges. Niacin deficiency-induced photosensitivity was mediated through EP4 signaling in response to increased PGE2 production via induction of ROS formation.

  20. Iron deficiency and cardiovascular disease

    NARCIS (Netherlands)

    von Haehling, Stephan; Jankowska, Ewa A.; van Veldhuisen, Dirk J.; Ponikowski, Piotr; Anker, Stefan D.

    2015-01-01

    Iron deficiency affects up to one-third of the world's population, and is particularly common in elderly individuals and those with certain chronic diseases. Iron excess can be detrimental in cardiovascular illness, and research has now also brought anaemia and iron deficiency into the focus of

  1. Vitamin B12 deficiency anemia

    Science.gov (United States)

    ... provide oxygen to body tissues. There are many types of anemia. Vitamin B12 deficiency anemia is a low red ... People with this type of anemia often do well with treatment. Long-term vitamin B12 deficiency can cause nerve damage. This may be permanent if ...

  2. Models of GH deficiency in animal studies.

    Science.gov (United States)

    Gahete, Manuel D; Luque, Raul M; Castaño, Justo P

    2016-12-01

    Growth hormone (GH) is a peptide hormone released from pituitary somatotrope cells that promotes growth, cell division and regeneration by acting directly through the GH receptor (GHR), or indirectly via hepatic insulin-like growth factor 1 (IGF1) production. GH deficiency (GHD) can cause severe consequences, such as growth failure, changes in body composition and altered insulin sensitivity, depending of the origin, time of onset (childhood or adulthood) or duration of GHD. The highly variable clinical phenotypes of GHD can now be better understood through research on transgenic and naturally-occurring animal models, which are widely employed to investigate the origin, phenotype, and consequences of GHD, and particularly the underlying mechanisms of metabolic disorders associated to GHD. Here, we reviewed the most salient aspects of GH biology, from somatotrope development to GH actions, linked to certain GHD types, as well as the animal models employed to reproduce these GHD-associated alterations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Mouse embryonic fibroblasts derived from Odin deficient mice display a hyperproliiferative phenotype

    DEFF Research Database (Denmark)

    Kristiansen, Troels Zaccharias Glahn; Nielsen, Mogens Møller; Blagoev, Blagoy

    2004-01-01

    -induced mitogenesis in cell lines. To further investigate the role of Odin in growth factor receptor signaling and to elucidate its biological function in vivo, we have generated mice deficient in Odin by gene targeting. Odin-deficient mice do not display any obvious phenotype, and histological examination...... of the kidney, lung and liver does not show any major abnormalities as compared to wild-type controls. However, mouse embryonic fibroblasts (MEFs) generated from Odin-deficient mice exhibit a hyperproliferative phenotype compared to wild-type-derived MEFs, consistent with its role as a negative regulator...... of growth factor receptor signaling. Our results confirm that although Odin expression in mice is not essential for any major developmental pathway, it could play a significant functional role to negatively regulate growth factor receptor signaling pathways....

  4. Iron deficiency anemia in children.

    Science.gov (United States)

    Subramaniam, Girish; Girish, Meenakshi

    2015-06-01

    Iron deficiency is not just anemia; it can be responsible for a long list of other manifestations. This topic is of great importance, especially in infancy and early childhood, for a variety of reasons. Firstly, iron need is maximum in this period. Secondly, diet in infancy is usually deficient in iron. Thirdly and most importantly, iron deficiency at this age can result in neurodevelopmental and cognitive deficits, which may not be reversible. Hypochromia and microcytosis in a complete blood count (CBC) makes iron deficiency anemia (IDA) most likely diagnosis. Absence of response to iron should make us look for other differential diagnosis like β thalassemia trait and anemia of chronic disease. Celiac disease is the most important cause of true IDA not responding to oral iron therapy. While oral ferrous sulphate is the cheapest and most effective therapy for IDA, simple nonpharmacological and pharmacological measures can go a long way in prevention of iron deficiency.

  5. Adaptive gene regulation in the Striatum of RGS9-deficient mice.

    Directory of Open Access Journals (Sweden)

    Kathy Busse

    Full Text Available BACKGROUND: RGS9-deficient mice show drug-induced dyskinesia but normal locomotor activity under unchallenged conditions. RESULTS: Genes related to Ca2+ signaling and their functions were regulated in RGS9-deficient mice. CONCLUSION: Changes in Ca2+ signaling that compensate for RGS9 loss-of-function can explain the normal locomotor activity in RGS9-deficient mice under unchallenged conditions. SIGNIFICANCE: Identified signaling components may represent novel targets in antidyskinetic therapy. The long splice variant of the regulator of G-protein signaling 9 (RGS9-2 is enriched in striatal medium spiny neurons and dampens dopamine D2 receptor signaling. Lack of RGS9-2 can promote while its overexpression prevents drug-induced dyskinesia. Other animal models of drug-induced dyskinesia rather pointed towards overactivity of dopamine receptor-mediated signaling. To evaluate changes in signaling pathways mRNA expression levels were determined and compared in wild-type and RGS9-deficient mice. Unexpectedly, expression levels of dopamine receptors were unchanged in RGS9-deficient mice, while several genes related to Ca2+ signaling and long-term depression were differentially expressed when compared to wild type animals. Detailed investigations at the protein level revealed hyperphosphorylation of DARPP32 at Thr34 and of ERK1/2 in striata of RGS9-deficient mice. Whole cell patch clamp recordings showed that spontaneous synaptic events are increased (frequency and size in RGS9-deficient mice while long-term depression is reduced in acute brain slices. These changes are compatible with a Ca2+-induced potentiation of dopamine receptor signaling which may contribute to the drug-induced dyskinesia in RGS9-deficient mice.

  6. Interactions between copper deficiency, selenium deficiency and adriamycin toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, J.; Tackett, R.; Johnson, M.A. (Univ. of Georgia, Athens (United States))

    1991-03-15

    The objective of this study was to test the hypothesis that there are interactions between copper (Cu) and selenium (Se) status, and adriamycin (ADR) toxicity. Male Sprague Dawley rats were fed Cu,Se adequate; Cu deficient, Se adequate ({minus}Cu); Cu adequate, Se deficient; or Cu,Se deficient diets for 38-41 days. ADR or saline (SAL) were administered weekly for the last 4 weeks of the study. Cu deficiency was confirmed by a 3-fold decrease in liver Cu,Zn-superoxide dismutase and liver Cu, and a 5-fold decrease in RBC Cu,Zn-SOD. Se deficiency was confirmed by a 10-fold decrease in liver glutathione peroxidase (GSH-Px). ADR, Cu deficiency and Se deficiency all caused EKG abnormalities. However, Cu and Se deficiencies did not enhance ADR's influence on EKGs. ADR increased lipid peroxidation in liver by 15% and in heart by 18% (NS). Cu deficiency decreased ADR-induced lipid peroxidation in heart tissue by 25%. ADR influenced Se status by significantly increasing heart GSH-Px, and Cu status by increasing liver Cu, plasma ceruloplasmin and liver Cu, Zn-SOD. These elevations in Cu,Zn-SOD and GSH-Px may be a consequence of the increased lipid peroxidation initiated by ADR. In {minus}Cu rats, ADR caused severe hemolytic anemia characterized by a 19% decrease in hematocrit and a 17-fold increase in splenic Fe. These data suggest that there are numerous interactions between ADR toxicity and Cu and Se status.

  7. Selective predisposition to bacterial infections in IRAK-4-deficient children : IRAK-4-dependent TLRs are otherwise redundant in protective immunity

    NARCIS (Netherlands)

    Ku, Cheng-Lung; von Bernuth, Horst; Picard, Capucine; Zhang, Shen-Ying; Chang, Huey-Hsuan; Yang, Kun; Chrabieh, Maya; Issekutz, Andrew C.; Cunningham, Coleen K.; Gallin, John; Holland, Steven M.; Roifman, Chaim; Ehl, Stephan; Smart, Joanne; Tang, Mimi; Barrat, Franck J.; Levy, Ofer; McDonald, Douglas; Day-Good, Noorbibi K.; Miller, Richard; Takada, Hidetoshi; Hara, Toshiro; Al-Hajjar, Sami; Al-Ghonaium, Abdulaziz; Speert, David; Sanlaville, Damien; Li, Xiaoxia; Geissmann, Frederic; Vivier, Eric; Marodi, Laszlo; Garty, Ben-Zion; Chapel, Helen; Rodriguez-Gallego, Carlos; Bossuyt, Xavier; Abel, Laurent; Puel, Anne; Casanova, Jean-Laurent

    2007-01-01

    Human interleukin ( IL) 1 receptor - associated kinase 4 ( IRAK- 4) deficiency is a recently discovered primary immunodefi ciency that impairs Toll/ IL- 1R immunity, except for the Toll- like receptor ( TLR) 3 - and TLR4 - interferon ( IFN)-alpha/beta pathways. The clinical and immunological

  8. Genetics Home Reference: adenosine deaminase 2 deficiency

    Science.gov (United States)

    ... Twitter Home Health Conditions Adenosine deaminase 2 deficiency Adenosine deaminase 2 deficiency Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description Adenosine deaminase 2 (ADA2) deficiency is a disorder characterized ...

  9. Genetics Home Reference: lactate dehydrogenase deficiency

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions Lactate dehydrogenase deficiency Lactate dehydrogenase deficiency Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Lactate dehydrogenase deficiency is a condition that affects how the ...

  10. Genetics Home Reference: carnitine palmitoyltransferase I deficiency

    Science.gov (United States)

    ... SL, Raff ML. Novel mutations in CPT 1A define molecular heterogeneity of hepatic carnitine palmitoyltransferase I deficiency. ... What is newborn screening? New Pages type 2 diabetes mitochondrial complex I deficiency mitochondrial complex V deficiency ...

  11. Facts about Vitamin K Deficiency Bleeding

    Science.gov (United States)

    ... label> Information For… Media Policy Makers Facts about Vitamin K Deficiency Bleeding Recommend on Facebook Tweet Share Compartir ... deficient ” or has a “ vitamin deficiency ”. What is vitamin K and why is it important? Vitamin K is ...

  12. Genetics Home Reference: corticosterone methyloxidase deficiency

    Science.gov (United States)

    ... deficiency corticosterone methyloxidase deficiency Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. ... methyloxidase deficiency can cause nausea, vomiting, dehydration, low blood pressure, extreme tiredness (fatigue), and muscle weakness. Affected infants ...

  13. Morbidity and GH deficiency

    DEFF Research Database (Denmark)

    Stochholm, Kirstine; Laursen, Torben; Green, Anders

    2008-01-01

    OBJECTIVE: To estimate morbidity in Denmark in all patients with GH deficiency (GHD). DESIGN: Morbidity was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in the GHD patients were studied and additional morbidity noted. Diagnoses and dates of admissions were...... identified in the National Patient Registry. Lag time until first admission was used as a measure of morbidity. Patients were divided into childhood onset (CO) and adult onset (AO), discriminated by an age cut-off of 18 years at onset of GHD. METHOD: Sex- and cause-specific hazard ratios (HRs) in CO and AO...... GHD compared with controls. RESULTS: Total morbidity was significantly increased in the GHD patients. HR for CO males: 3.1 (95% confidence interval (CI): 2.7-3.7), CO females: 3.2 (95% CI: 2.6-3.9), AO males: 2.9 (95% CI: 2.6-3.2), and AO females: 3.2 (95% CI: 2.8-3.6). In 18 out of 20 chapters from...

  14. Genetics Home Reference: phosphoglycerate kinase deficiency

    Science.gov (United States)

    ... Genetic Testing Registry: Phosphoglycerate kinase 1 deficiency Other Diagnosis and Management Resources (1 link) Children Living with Inherited Metabolic Diseases (CLIMB) (UK): Phosphoglycerate Kinase Deficiency (PDF) General Information ...

  15. Iron-Responsive Olfactory Uptake of Manganese Improves Motor Function Deficits Associated with Iron Deficiency

    Science.gov (United States)

    Kim, Jonghan; Li, Yuan; Buckett, Peter D.; Böhlke, Mark; Thompson, Khristy J.; Takahashi, Masaya; Maher, Timothy J.; Wessling-Resnick, Marianne

    2012-01-01

    Iron-responsive manganese uptake is increased in iron-deficient rats, suggesting that toxicity related to manganese exposure could be modified by iron status. To explore possible interactions, the distribution of intranasally-instilled manganese in control and iron-deficient rat brain was characterized by quantitative image analysis using T1-weighted magnetic resonance imaging (MRI). Manganese accumulation in the brain of iron-deficient rats was doubled after intranasal administration of MnCl2 for 1- or 3-week. Enhanced manganese level was observed in specific brain regions of iron-deficient rats, including the striatum, hippocampus, and prefrontal cortex. Iron-deficient rats spent reduced time on a standard accelerating rotarod bar before falling and with lower peak speed compared to controls; unexpectedly, these measures of motor function significantly improved in iron-deficient rats intranasally-instilled with MnCl2. Although tissue dopamine concentrations were similar in the striatum, dopamine transporter (DAT) and dopamine receptor D1 (D1R) levels were reduced and dopamine receptor D2 (D2R) levels were increased in manganese-instilled rats, suggesting that manganese-induced changes in post-synaptic dopaminergic signaling contribute to the compensatory effect. Enhanced olfactory manganese uptake during iron deficiency appears to be a programmed “rescue response” with beneficial influence on motor impairment due to low iron status. PMID:22479410

  16. 25-Hydroxyvitamin D3-deficiency enhances oxidative stress and corticosteroid resistance in severe asthma exacerbation.

    Directory of Open Access Journals (Sweden)

    Nan Lan

    Full Text Available Oxidative stress plays a significant role in exacerbation of asthma. The role of vitamin D in oxidative stress and asthma exacerbation remains unclear. We aimed to determine the relationship between vitamin D status and oxidative stress in asthma exacerbation. Severe asthma exacerbation patients with 25-hydroxyvitamin D3-deficiency (V-D deficiency or 25-hydroxyvitamin D-sufficiency (V-D sufficiency were enrolled. Severe asthma exacerbation with V-D-deficiency showed lower forced expiratory volume in one second (FEV1 compared to that with V-D-sufficiency. V-D-deficiency intensified ROS release and DNA damage and increased TNF-α, OGG1 and NFκB expression and NFκB phosphorylation in severe asthma exacerbation. Supplemental vitamin D3 significantly increased the rates of FEV1 change and decreased ROS and DNA damage in V-D-deficiency. Vitamin D3 inhibited LPS-induced ROS and DNA damage and were associated with a decline in TNF-α and NFκB in epithelial cells. H2O2 reduces nuclear translocation of glucocorticoid receptors in airway epithelial cell lines. V-D pretreatment enhanced the dexamethasone-induced nuclear translocation of glucocorticoid receptors in airway epithelial cell lines and monocytes from 25-hydroxyvitamin D3-deficiency asthma patients. These findings indicate that V-D deficiency aggravates oxidative stress and DNA damage, suggesting a possible mechanism for corticosteroid resistance in severe asthma exacerbation.

  17. Iron-responsive olfactory uptake of manganese improves motor function deficits associated with iron deficiency.

    Directory of Open Access Journals (Sweden)

    Jonghan Kim

    Full Text Available Iron-responsive manganese uptake is increased in iron-deficient rats, suggesting that toxicity related to manganese exposure could be modified by iron status. To explore possible interactions, the distribution of intranasally-instilled manganese in control and iron-deficient rat brain was characterized by quantitative image analysis using T1-weighted magnetic resonance imaging (MRI. Manganese accumulation in the brain of iron-deficient rats was doubled after intranasal administration of MnCl(2 for 1- or 3-week. Enhanced manganese level was observed in specific brain regions of iron-deficient rats, including the striatum, hippocampus, and prefrontal cortex. Iron-deficient rats spent reduced time on a standard accelerating rotarod bar before falling and with lower peak speed compared to controls; unexpectedly, these measures of motor function significantly improved in iron-deficient rats intranasally-instilled with MnCl(2. Although tissue dopamine concentrations were similar in the striatum, dopamine transporter (DAT and dopamine receptor D(1 (D1R levels were reduced and dopamine receptor D(2 (D2R levels were increased in manganese-instilled rats, suggesting that manganese-induced changes in post-synaptic dopaminergic signaling contribute to the compensatory effect. Enhanced olfactory manganese uptake during iron deficiency appears to be a programmed "rescue response" with beneficial influence on motor impairment due to low iron status.

  18. of iron deficiency in adolescent female athletes

    Directory of Open Access Journals (Sweden)

    J Malczewska-Lenczowska

    2017-04-01

    Full Text Available The aim of this study was to analyse the effectiveness of new haematology parameters related to reticulocytes and mature red blood cells to differentiate pre latent and latent iron deficiency. The study included 219 female athletes (aged 15-20 years representing volleyball, handball, cycling, canoeing, cross-country skiing, swimming and judo. To assess iron status the concentration of ferritin, soluble transferrin receptor (sTfR, iron and total iron binding capacity (TIBC were determined in serum. In addition to blood morphology, the mean cellular haemoglobin content in erythrocytes (CH and reticulocytes (CHr, mean cellular haemoglobin concentration in reticulocytes (CHCMr, the percentage of erythrocytes (HYPOm and reticulocytes (HYPOr with decreased cellular haemoglobin concentration, the percentage of erythrocytes (LowCHm and reticulocytes (LowCHr with decreased cellular haemoglobin content, and percentage of erythrocytes with decreased volume (MICROm were determined. Subjects with ferritin <30 ng/ml were classified as having stage I (pre-latent iron deficiency (ID. The second stage (latent ID was diagnosed when low ferritin was accompanied by elevated sTfR and/or elevated TIBC values. The frequency of ID (without anaemia symptoms was high, amounting to 60% (stage I in 45%, stage II in 15% of subjects. In subjects with stage I ID significant changes in haematological variables concerned mainly reticulocytes: CHCMr (p<.001, CHr (p<.05, LowCHr (p<.05, HYPOr (p<.001 in comparison to normal iron stores. In athletes with latent ID, there were also significant changes (p<.001 in many indices of mature red blood cells, i.e. haemoglobin concentration (Hb, mean corpuscular haemoglobin (MCH, mean corpuscular haemoglobin concentration (MCHC, CH, %LowCHm, as well as %MICROm (p<.01 in relation to the group without iron deficiency. The main finding of this study was that the diminished or exhausted iron stores had already caused changes in reticulocytes

  19. Genetics Home Reference: CLPB deficiency

    Science.gov (United States)

    ... or severe CLPB deficiency have clouding of the lenses of the eyes ( cataracts ) from birth (congenital) or ... Lung Cancer Awareness Month Celebrating National Family Health History Day All Bulletins Features What are genome editing ...

  20. Reconstructive surgery for fibular deficiency.

    Science.gov (United States)

    Shatilov, O E; Rozkov, A V; Cheminova, T V

    1991-08-01

    Three types of fibular deficiency are described which determine the nature of the surgery and prosthesis required. The surgical management of 50 patients who had a total of 103 operations is described.

  1. Iron deficiency among blood donors

    DEFF Research Database (Denmark)

    Rigas, A. S.; Pedersen, O. B.; Magnussen, K.

    2017-01-01

    and menopausal status are the strongest predictors of iron deficiency. Only little information on the health effects of iron deficiency in blood donors exits. Possibly, after a standard full blood donation, a temporarily reduced physical performance for women is observed. However, iron deficiency among blood...... donors is not reflected in a reduced self-perceived mental and physical health. In general, the high proportion of iron-deficient donors can be alleviated either by extending the inter-donation intervals or by guided iron supplementation. The experience from Copenhagen, the Capital Region of Denmark......, is that routine ferritin measurements and iron supplementation are feasible and effective ways of reducing the proportion of donors with low haemoglobin levels....

  2. Iron deficiency and cognitive functions

    OpenAIRE

    Jáuregui-Lobera, Ignacio

    2014-01-01

    Ignacio Jáuregui-Lobera Department of Nutrition and Bromatology, Pablo de Olavide University, Seville, Spain Abstract: Micronutrient deficiencies, especially those related to iodine and iron, are linked to different cognitive impairments, as well as to potential long-term behavioral changes. Among the cognitive impairments caused by iron deficiency, those referring to attention span, intelligence, and sensory perception functions are mainly cited, as well as those associated with...

  3. Epithelial CaSR Deficiency Alters Intestinal Integrity and Promotes Proinflammatory Immune Responses

    OpenAIRE

    Cheng, Sam X.; Lightfoot, Yaíma L.; Yang, Tao; Zadeh, Mojgan; Tang, Lieqi; Sahay, Bikash; Wang, Gary P.; Owen, Jennifer L.; Mohamadzadeh, Mansour

    2014-01-01

    The intestinal epithelium is equipped with sensing receptor mechanisms that interact with luminal microorganisms and nutrients to regulate barrier function and gut immune responses, thereby maintaining intestinal homeostasis. Herein, we clarify the role of the extracellular calcium-sensing receptor (CaSR) using intestinal epithelium-specific Casr−/− mice. Epithelial CaSR deficiency diminished intestinal barrier function, altered microbiota composition, and skewed immune responses towards proi...

  4. Adenosine Kinase Deficiency in the Brain Results in Maladaptive Synaptic Plasticity.

    Science.gov (United States)

    Sandau, Ursula S; Colino-Oliveira, Mariana; Jones, Abbie; Saleumvong, Bounmy; Coffman, Shayla Q; Liu, Long; Miranda-Lourenço, Catarina; Palminha, Cátia; Batalha, Vânia L; Xu, Yiming; Huo, Yuqing; Diógenes, Maria J; Sebastião, Ana M; Boison, Detlev

    2016-11-30

    Adenosine kinase (ADK) deficiency in human patients (OMIM:614300) disrupts the methionine cycle and triggers hypermethioninemia, hepatic encephalopathy, cognitive impairment, and seizures. To identify whether this neurological phenotype is intrinsically based on ADK deficiency in the brain or if it is secondary to liver dysfunction, we generated a mouse model with a brain-wide deletion of ADK by introducing a Nestin-Cre transgene into a line of conditional ADK deficient Adk(fl/fl) mice. These Adk(Δbrain) mice developed a progressive stress-induced seizure phenotype associated with spontaneous convulsive seizures and profound deficits in hippocampus-dependent learning and memory. Pharmacological, biochemical, and electrophysiological studies suggest enhanced adenosine levels around synapses resulting in an enhanced adenosine A1 receptor (A1R)-dependent protective tone despite lower expression levels of the receptor. Theta-burst-induced LTP was enhanced in the mutants and this was dependent on adenosine A2A receptor (A2AR) and tropomyosin-related kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A2A receptor activity in Adk(Δbrain) mice restored normal associative learning and contextual memory and attenuated seizure risk. We conclude that ADK deficiency in the brain triggers neuronal adaptation processes that lead to dysregulated synaptic plasticity, cognitive deficits, and increased seizure risk. Therefore, ADK mutations have an intrinsic effect on brain physiology and may present a genetic risk factor for the development of seizures and learning impairments. Furthermore, our data show that blocking A2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency. A novel human genetic condition (OMIM #614300) that is based on mutations in the adenosine kinase (Adk) gene has been discovered recently. Affected patients develop hepatic encephalopathy, seizures

  5. Autophagy induction by tetrahydrobiopterin deficiency

    Science.gov (United States)

    Kwak, Sang Su; Suk, Jinkyu; Choi, Ji Hye; Yang, Seungkyung; Kim, Jin Woo; Sohn, Seonghyang; Chung, Jae Hoon; Hong, Yong Hee; Lee, Dong Hwan; Ahn, Jeong Keun; Min, Hyesun; Fu, Ya-Min; Meadows, Gary G

    2011-01-01

    Tetrahydrobiopterin (BH4) deficiency is a genetic disorder associated with a variety of metabolic syndromes such as phenylketonuria (PKU). In this article, the signaling pathway by which BH4 deficiency inactivates mTORC1 leading to the activation of the autophagic pathway was studied utilizing BH4-deficient Spr-/- mice generated by the knockout of the gene encoding sepiapterin reductase (SR) catalyzing BH4 synthesis. We found that mTORC1 signaling was inactivated and autophagic pathway was activated in tissues from Spr-/- mice. This study demonstrates that tyrosine deficiency causes mTORC1 inactivation and subsequent activation of autophagic pathway in Spr-/- mice. Therapeutic tyrosine diet completely rescued dwarfism and mTORC1 inhibition but inactivated autophagic pathway in Spr-/- mice. Tyrosine-dependent inactivation of mTORC1 was further supported by mTORC1 inactivation in Pahenu2 mouse model lacking phenylalanine hydroxylase (Pah). NIH3T3 cells grown under the condition of tyrosine restriction exhibited autophagy induction. However, mTORC1 activation by RhebQ64L, a positive regulator of mTORC1, inactivated autophagic pathway in NIH3T3 cells under tyrosine-deficient conditions. In addition, this study first documents mTORC1 inactivation and autophagy induction in PKU patients with BH4 deficiency. PMID:21795851

  6. Omega-3 fatty acid deficiency during brain maturation reduces neuronal and behavioral plasticity in adulthood.

    Directory of Open Access Journals (Sweden)

    Harsharan Singh Bhatia

    Full Text Available Omega-3-fatty acid DHA is a structural component of brain plasma membranes, thereby crucial for neuronal signaling; however, the brain is inefficient at synthesizing DHA. We have asked how levels of dietary n-3 fatty acids during brain growth would affect brain function and plasticity during adult life. Pregnant rats and their male offspring were fed an n-3 adequate diet or n-3 deficient diets for 15 weeks. Results showed that the n-3 deficiency increased parameters of anxiety-like behavior using open field and elevated plus maze tests in the male offspring. Behavioral changes were accompanied by a level reduction in the anxiolytic-related neuropeptide Y-1 receptor, and an increase in the anxiogenic-related glucocorticoid receptor in the cognitive related frontal cortex, hypothalamus and hippocampus. The n-3 deficiency reduced brain levels of docosahexaenoic acid (DHA and increased the ratio n-6/n-3 assessed by gas chromatography. The n-3 deficiency reduced the levels of BDNF and signaling through the BDNF receptor TrkB, in proportion to brain DHA levels, and reduced the activation of the BDNF-related signaling molecule CREB in selected brain regions. The n-3 deficiency also disrupted the insulin signaling pathways as evidenced by changes in insulin receptor (IR and insulin receptor substrate (IRS. DHA deficiency during brain maturation reduces plasticity and compromises brain function in adulthood. Adequate levels of dietary DHA seem crucial for building long-term neuronal resilience for optimal brain performance and aiding in the battle against neurological disorders.

  7. PD123319 augments angiotensin II-induced abdominal aortic aneurysms through an AT2 receptor-independent mechanism.

    Directory of Open Access Journals (Sweden)

    Alan Daugherty

    Full Text Available AT2 receptors have an unclear function on development of abdominal aortic aneurysms (AAAs, although a pharmacological approach using the AT2 receptor antagonist PD123319 has implicated a role. The purpose of the present study was to determine the role of AT2 receptors in AngII-induced AAAs using a combination of genetic and pharmacological approaches. We also defined effects of AT2 receptors in AngII-induced atherosclerosis and thoracic aortic aneurysms.Male AT2 receptor wild type (AT2 +/y and deficient (AT2 -/y mice in an LDL receptor -/- background were fed a saturated-fat enriched diet, and infused with either saline or AngII (500 ng/kg/min. AT2 receptor deficiency had no significant effect on systolic blood pressure during AngII-infusion. While AngII infusion induced AAAs, AT2 receptor deficiency did not significantly affect either maximal width of the suprarenal aorta or incidence of AAAs. The AT2 receptor antagonist PD123319 (3 mg/kg/day and AngII were co-infused into male LDL receptor -/- mice that were either AT2 +/y or -/y. PD123319 had no significant effect on systolic blood pressure in either wild type or AT2 receptor deficient mice. Consistent with our previous findings, PD123319 increased AngII-induced AAAs. However, this effect of PD123319 occurred irrespective of AT2 receptor genotype. Neither AT2 receptor deficiency nor PD123319 had any significant effect on AngII-induced thoracic aortic aneurysms or atherosclerosis.AT2 receptor deficiency does not affect AngII-induced AAAs, thoracic aortic aneurysms and atherosclerosis. PD123319 augments AngII-induced AAAs through an AT2 receptor-independent mechanism.

  8. Generation of an ASGR1 homozygous mutant human embryonic stem cell line WAe001-A-6 using CRISPR/Cas9

    Directory of Open Access Journals (Sweden)

    Yingying Xu

    2017-07-01

    Full Text Available The gene asialoglycoprotein receptor 1 (ASGR1 encodes a subunit of the asialoglycoprotein receptor. Here we report the generation of a human embryonic stem cell line WAe001-A-6 harbouring homozygous ASGR1 mutations using CRISPR/Cas9. The mutation involves a 37 bp deletion, resulting in a frame shift. The homozygous knockout WA01 cell line maintains a normal karyotype, typical stem cell morphology, pluripotency and differentiation potential in vitro.

  9. Implications of vitamin D deficiency in lithiasic patient and in general population.

    Science.gov (United States)

    Millán-Rodríguez, F; Gavrilov, P; Gracia-García, S; Angerri-Feu, O; Sánchez-Martín, F M; Villavicencio-Mavrich, H

    2015-05-01

    Vitamin D deficiency causes problems in mineral metabolism but also overall health. In first place a review of the topic was carried out. Then, in order to contextualize it in lithiasic patient, a study on Vitamin D deficiency and its possible relationship with impaired PTH levels is performed. A review of topics such as metabolism, epidemiology and the relationship of vitamin D deficiency with several pathologies was performed. Besides a multivariate analysis and a correlation study between vitamin D and PTH levels was conducted in 100 lithiasic patients. We present a review of Vitamin D metabolism, receptors and functions, as well as about its valuation methodology and the treatment of its deficiency. Lithiasic patients show a higher vitamin D deficiency than general population. Vitamin D deficiency has been significantly associated with increased PTH levels. In addition, there is enough literature showing a relationship between vitamin D deficiency not only with bone disease, but also with multiple diseases. vitamin D levels should be measured in all lithiasic patients, and those with vitamin D deficiency should be treated. Copyright © 2014 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

  10. Heat Shock Factor 1 Deficiency Affects Systemic Body Temperature Regulation.

    Science.gov (United States)

    Ingenwerth, Marc; Noichl, Erik; Stahr, Anna; Korf, Horst-Werner; Reinke, Hans; von Gall, Charlotte

    2016-01-01

    Heat shock factor 1 (HSF1) is a ubiquitous heat-sensitive transcription factor that mediates heat shock protein transcription in response to cellular stress, such as increased temperature, in order to protect the organism against misfolded proteins. In this study, we analysed the effect of HSF1 deficiency on core body temperature regulation. Body temperature, locomotor activity, and food consumption of wild-type mice and HSF1-deficient mice were recorded. Prolactin and thyroid-stimulating hormone levels were measured by ELISA. Gene expression in brown adipose tissue was analysed by quantitative real-time PCR. Hypothalamic HSF1 and its co-localisation with tyrosine hydroxylase was analysed using confocal laser scanning microscopy. HSF1-deficient mice showed an increase in core body temperature (hyperthermia), decreased overall locomotor activity, and decreased levels of prolactin in pituitary and blood plasma reminiscent of cold adaptation. HSF1 could be detected in various hypothalamic regions involved in temperature regulation, suggesting a potential role of HSF1 in hypothalamic thermoregulation. Moreover, HSF1 co-localises with tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, suggesting a potential role of HSF1 in the hypothalamic control of prolactin release. In brown adipose tissue, levels of prolactin receptor and uncoupled protein 1 were increased in HSF1-deficient mice, consistent with an up-regulation of heat production. Our data suggest a role of HSF1 in systemic thermoregulation. © 2015 S. Karger AG, Basel.

  11. [Xanthine oxidase deficiency (hereditary xanthinuria), molybdenum cofactor deficiency].

    Science.gov (United States)

    Sumi, S; Wada, Y

    1996-12-01

    Hereditary xanthinuria is a rare autosomal recessive disorder, with xanthine oxidase deficiency. Patients often display renal symptoms because they excrete a large amounts of xanthine in urine. An high-fluid-intake, alow-purine-food, and alkalinization of urine are effective in the patients. Molybdenum cofactor is essential for xanthine oxidase, sulfite oxidase and aldehyde oxidase. Patients with molybdenum cofactor deficiency display severe neurological symptoms, such as severe convulsions. The patients increase urinary excretions of xanthine and sulfite. Treatments are ineffective for neurological symptoms.

  12. Iron deficiency and bariatric surgery.

    Science.gov (United States)

    Jáuregui-Lobera, Ignacio

    2013-05-15

    It is estimated that the prevalence of anaemia in patients scheduled for bariatric surgery is higher than in the general population and the prevalence of iron deficiencies (with or without anaemia) may be higher as well. After surgery, iron deficiencies and anaemia may occur in a higher percentage of patients, mainly as a consequence of nutrient deficiencies. In addition, perioperative anaemia has been related with increased postoperative morbidity and mortality and poorer quality of life after bariatric surgery. The treatment of perioperative anaemia and nutrient deficiencies has been shown to improve patients' outcomes and quality of life. All patients should undergo an appropriate nutritional evaluation, including selective micronutrient measurements (e.g., iron), before any bariatric surgical procedure. In comparison with purely restrictive procedures, more extensive perioperative nutritional evaluations are required for malabsorptive procedures due to their nutritional consequences. The aim of this study was to review the current knowledge of nutritional deficits in obese patients and those that commonly appear after bariatric surgery, specifically iron deficiencies and their consequences. As a result, some recommendations for screening and supplementation are presented.

  13. Leaf Senescence by Magnesium Deficiency

    Directory of Open Access Journals (Sweden)

    Keitaro Tanoi

    2015-12-01

    Full Text Available Magnesium ions (Mg2+ are the second most abundant cations in living plant cells, and they are involved in various functions, including photosynthesis, enzyme catalysis, and nucleic acid synthesis. Low availability of Mg2+ in an agricultural field leads to a decrease in yield, which follows the appearance of Mg-deficient symptoms such as chlorosis, necrotic spots on the leaves, and droop. During the last decade, a variety of physiological and molecular responses to Mg2+ deficiency that potentially link to leaf senescence have been recognized, allowing us to reconsider the mechanisms of Mg2+ deficiency. This review focuses on the current knowledge about the physiological responses to Mg2+ deficiency including a decline in transpiration, accumulation of sugars and starch in source leaves, change in redox states, increased oxidative stress, metabolite alterations, and a decline in photosynthetic activity. In addition, we refer to the molecular responses that are thought to be related to leaf senescence. With these current data, we give an overview of leaf senescence induced by Mg deficiency.

  14. Iron Deficiency and Bariatric Surgery

    Directory of Open Access Journals (Sweden)

    Ignacio Jáuregui-Lobera

    2013-05-01

    Full Text Available It is estimated that the prevalence of anaemia in patients scheduled for bariatric surgery is higher than in the general population and the prevalence of iron deficiencies (with or without anaemia may be higher as well. After surgery, iron deficiencies and anaemia may occur in a higher percentage of patients, mainly as a consequence of nutrient deficiencies. In addition, perioperative anaemia has been related with increased postoperative morbidity and mortality and poorer quality of life after bariatric surgery. The treatment of perioperative anaemia and nutrient deficiencies has been shown to improve patients’ outcomes and quality of life. All patients should undergo an appropriate nutritional evaluation, including selective micronutrient measurements (e.g., iron, before any bariatric surgical procedure. In comparison with purely restrictive procedures, more extensive perioperative nutritional evaluations are required for malabsorptive procedures due to their nutritional consequences. The aim of this study was to review the current knowledge of nutritional deficits in obese patients and those that commonly appear after bariatric surgery, specifically iron deficiencies and their consequences. As a result, some recommendations for screening and supplementation are presented.

  15. Transient impairment of the adaptive response to fasting in FXR-deficient mice

    NARCIS (Netherlands)

    Cariou, B; van Harmelen, K; Duran-Sandoval, D; van Dijk, T; Grefhorst, A; Bouchaert, E; Fruchart, JC; Gonzalez, FJ; Kuipers, F; Staels, B

    2005-01-01

    The farnesoid X receptor (FXR) has been suggested to play a role in gluconeogenesis. To determine whether FXR modulates the response to fasting in vivo, FXR-deficient (FXR-/-) and wild-type mice were submitted to fasting for 48 h. Our results demonstrate that FXR modulates the kinetics of

  16. Infection-derived lipids elicit a novel immune deficiency circuitry in arthropods

    Science.gov (United States)

    The insect Immune Deficiency (IMD) pathway resembles the tumor necrosis factor receptor network in mammals and senses diaminopimelic-type peptidoglycans present in Gram-negative bacteria. Whether unidentified chemical moieties elicit the IMD signaling cascade remains unknown. Here, we disclose thoug...

  17. Muscarinic M3 receptors on structural cells regulate cigarette smoke-induced neutrophilic airway inflammation in mice

    NARCIS (Netherlands)

    Kistemaker, Loes E.M.; van Os, Ronald P.; Dethmers-Ausema, Albertina; Bos, I. Sophie T.; Hylkema, Machteld N.; van den Berge, Maarten; Hiemstra, Pieter S; Wess, Jürgen; Meurs, Herman; Kerstjens, Huib A.M.; Gosens, Reinoud

    2015-01-01

    Anticholinergics, blocking the muscarinic M-3 receptor, are effective bronchodilators for patients with chronic obstructive pulmonary disease. Recent evidence from M-3 receptor-deficient mice (M3R-/-) indicates that M-3 receptors also regulate neutrophilic inflammation in response to cigarette smoke

  18. Human Coenzyme Q10 Deficiency

    Science.gov (United States)

    Quinzii, Catarina M.; DiMauro, Salvatore

    2006-01-01

    Ubiquinone (coenzyme Q10 or CoQ10) is a lipid-soluble component of virtually all cell membranes and has multiple metabolic functions. Deficiency of CoQ10 (MIM 607426) has been associated with five different clinical presentations that suggest genetic heterogeneity, which may be related to the multiple steps in CoQ10 biosynthesis. Patients with all forms of CoQ10 deficiency have shown clinical improvements after initiating oral CoQ10 supplementation. Thus, early diagnosis is of critical importance in the management of these patients. This year, the first molecular defect causing the infantile form of primary human CoQ10 deficiency has been reported. The availability of genetic testing will allow for a better understanding of the pathogenesis of this disease and early initiation of therapy (even presymptomatically in siblings of patients) in this otherwise life-threatening infantile encephalomyopathy. PMID:17094036

  19. Differential diagnosis of iron deficiency

    OpenAIRE

    Vicari, Perla [UNIFESP; Figueiredo, Maria Stella [UNIFESP

    2010-01-01

    A deficiência de ferro é considerada a patologia hematológica mais prevalente no homem. Assim, é fundamental a adequada identificação de suas causas, bem como a diferenciação com outras patologias distintas para adequada abordagem da deficiência de ferro. Neste artigo são brevemente descritas outras condições que podem cursar com anemia microcítica, tais como: talassemias, anemia de doença crônica, anemia sideroblástica e envenenamento por chumbo, patologias estas que devem ser afastadas dura...

  20. Newborn screening for MCAD deficiency

    DEFF Research Database (Denmark)

    Horvath, Gabriella A; Davidson, A G F; Stockler-Ipsiroglu, Sylvia G

    2008-01-01

    BACKGROUND: Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency is an autosomal recessive disorder of fatty acid oxidation, with potential fatal outcome. MCAD deficiency is diagnosed by acylcarnitine analysis on newborn screening blood spot cards by tandem mass spectrometry. Early diagnosis...... length acylcarnitines, octanoylcarnitine (C8) and decanoylcarnitine (C10), were measured on newborn screening blood spot cards. Out of 121,000 live births, 17 newborns had C8 values above the screening cut-off of 0.38 umol/L. Ten newborns had elevated C8 on repeat cards and were investigated further...