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Sample records for asialoglycoprotein receptor deficiency

  1. Susceptibility to T cell-mediated liver injury is enhanced in asialoglycoprotein receptor-deficient mice.

    Science.gov (United States)

    McVicker, Benita L; Thiele, Geoffrey M; Casey, Carol A; Osna, Natalia A; Tuma, Dean J

    2013-05-01

    T cell activation and associated pro-inflammatory cytokine production is a pathological feature of inflammatory liver disease. It is also known that liver injury is associated with marked impairments in the function of many hepatic proteins including a hepatocyte-specific binding protein, the asialoglycoprotein receptor (ASGPR). Recently, it has been suggested that hepatic ASGPRs may play an important role in the physiological regulation of T lymphocytes, leading to our hypothesis that ASGPR defects correlate with inflammatory-mediated events in liver diseases. Therefore, in this study we investigated whether changes in hepatocellular ASGPR expression were related to the dysregulation of intrahepatic T lymphocytes and correlate with the development of T-cell mediated hepatitis. Mice lacking functional ASGPRs (receptor-deficient, RD), and wild-type (WT) controls were intravenously injected with T-cell mitogens, Concanavalin A (Con A) or anti-CD3 antibody. As a result of T cell mitogen treatment, RD mice lacking hepatic ASGPRs displayed enhancements in liver pathology, transaminase activities, proinflammatory cytokine expression, and caspase activation compared to that observed in normal WT mice. Furthermore, FACS analysis demonstrated that T-cell mitogen administration resulted in a significant rise in the percentage of CD8+ lymphocytes present in the livers of RD animals versus WT mice. Since these two mouse strains differ only in whether they express the hepatic ASGPR, it can be concluded that proper ASGPR function exerts a protective effect against T cell mediated hepatitis and that impairments to this hepatic receptor could be related to the accumulation of cytotoxic T cells that are observed in inflammatory liver diseases.

  2. Cellular distribution of {sup 111}In-LDTPA galactose BSA in normal and asialoglycoprotein receptor-deficient mouse liver

    Energy Technology Data Exchange (ETDEWEB)

    Deal, Kim A.; Cristel, Michael E.; Welch, Michael J

    1998-05-01

    {sup 111}In-LDTPA galactose BSA (bovine serum albumin) was used to evaluate the asialoglycoprotein receptor (ASGPR) system in both normal and ASGPR-deficient mice. The radiolabeled glycoprotein had complete liver uptake in both normal and ASGPR-deficient mice. Metabolism and hepatic cell-type distribution studies were performed. The normal mouse excreted greater than 60% of the hepatic activity, while the ASGPR-deficient mouse excreted less than 40% of the hepatic activity. {sup 111}In-LDTPA galactose BSA was metabolized to {sup 111}In-LDTPA-L-lysine in both mouse types. Normal mice showed 70% of the radioactivity in the hepatocyte, whereas the homozygous ASGPR-deficient mouse had equal activity in the hepatocyte and the hepatic endothelial cell.

  3. Impact of asialoglycoprotein receptor deficiency on the development of liver injury

    Institute of Scientific and Technical Information of China (English)

    Serene ML Lee; Carol A Casey; Benita L McVicker

    2009-01-01

    The asialoglycoprotein (ASGP) receptor is a wellcharacterized hepatic receptor that is recycled via the common cellular process of receptor-mediated endocytosis (RME). The RME process plays an integral part in the proper trafficking and routing of receptors and ligands in the healthy cell. Thus, the missorting or altered transport of proteins during RME is thought to play a role in several diseases associated with hepatocyte and liver dysfunction. Previously,we examined in detail alterations that occur in hepatocellular RME and associated receptor functions as a result of one particular liver injury, alcoholic liver disease (ALD). The studies revealed profound ethanolmediated impairments to the ASGP receptor and the RME process, indicating the importance of this receptor and the maintenance of proper endocytic events in normal tissue. To further clarify these observations,studies were performed utilizing knockout mice (lacking a functional ASGP receptor) to which were administered several liver toxicants. In addition to alcohol, we examined the effects following administration of anti-Fas (CD95) antibody, carbon tetrachloride (CCl4) and lipopolysaccharide (LPS)/galactosamine. The results of these studies demonstrated that the knockout mice sustained enhanced liver injury in response to all of the treatments, as shown by increased indices of liver damage, such as enhancement of serum enzyme levels,histopathological scores, as well as hepatocellular death.Overall, the work completed to date suggests a possible link between hepatic receptors and liver injury. In particular, adequate function and content of the ASGP receptor may provide protection against various toxinmediated liver diseases.

  4. Glycomimetic ligands for the human asialoglycoprotein receptor.

    Science.gov (United States)

    Mamidyala, Sreeman K; Dutta, Sanjay; Chrunyk, Boris A; Préville, Cathy; Wang, Hong; Withka, Jane M; McColl, Alexander; Subashi, Timothy A; Hawrylik, Steven J; Griffor, Matthew C; Kim, Sung; Pfefferkorn, Jeffrey A; Price, David A; Menhaji-Klotz, Elnaz; Mascitti, Vincent; Finn, M G

    2012-02-01

    The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding receptor expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery of therapeutic agents. We report several classes of galactosyl analogues with varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted for several trifluoromethylacetamide derivatives without covalent attachment to the protein. A variety of new ligands were obtained with affinity for ASGPR as good as or better than that of the parent N-acetylgalactosamine, showing that modification on either side of the key C3,C4-diol moiety is well tolerated, consistent with previous models of a shallow binding pocket. The galactosyl pyranose motif therefore offers many opportunities for the attachment of other functional units or payloads while retaining low-micromolar or better affinity for the ASGPR.

  5. Asialoglycoprotein receptor mediated hepatocyte targeting - strategies and applications.

    Science.gov (United States)

    D'Souza, Anisha A; Devarajan, Padma V

    2015-04-10

    Hepatocyte resident afflictions continue to affect the human population unabated. The asialoglycoprotein receptor (ASGPR) is primarily expressed on hepatocytes and minimally on extra-hepatic cells. This makes it specifically attractive for receptor-mediated drug delivery with minimum concerns of toxicity. ASGPR facilitates internalization by clathrin-mediated endocytosis and exhibits high affinity for carbohydrates specifically galactose, N-acetylgalactosamine and glucose. Isomeric forms of sugar, galactose density and branching, spatial geometry and galactose linkages are key factors influencing ligand-receptor binding. Popular ligands for ASGPR mediated targeting are carbohydrate polymers, arabinogalactan and pullulan. Other ligands include galactose-bearing glycoproteins, glycopeptides and galactose modified polymers and lipids. Drug-ligand conjugates provide a viable strategy; nevertheless ligand-anchored nanocarriers provide an attractive option for ASGPR targeted delivery and are widely explored. The present review details various ligands and nanocarriers exploited for ASGPR mediated delivery of drugs to hepatocytes. Nanocarrier properties affecting ASGPR mediated uptake are discussed at length. The review also highlights the clinical relevance of ASGPR mediated targeting and applications in diagnostics. ASGPR mediated hepatocyte targeting provides great promise for improved therapy of hepatic afflictions.

  6. Formation of functional asialoglycoprotein receptor after transfection with cDNAs encoding the receptor proteins.

    OpenAIRE

    McPhaul, M; Berg, P.

    1986-01-01

    The rat asialoglycoprotein receptor (ASGP-R) has been expressed in cultured rat hepatoma cells (HTC cells) after transfection with cloned cDNAs. Fluorescence-activated cell sorting of transfected cells was used to identify the functional cDNA clones and to isolate cells expressing the ASGP-R. Simultaneous or sequential transfections with two cloned cDNAs that encode related but distinctive polypeptide chains were needed to obtain ASGP-R activity; transfection with either cDNA alone failed to ...

  7. Three-Dimensional Models of the Oligomeric Human Asialoglycoprotein Receptor (ASGP-R)

    OpenAIRE

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

    2010-01-01

    The work presented here is aimed at suggesting plausible hypotheses for functional oligomeric forms of the human asialoglycoprotein receptor (ASGP-R), by applying a combination of different computational techniques. The functional ASGP-R is a hetero-oligomer, that comprises of several subunits of two different kinds (H1 and H2), which are highly homologous. Its stoichiometry is still unknown. An articulated step-wise modeling protocol was used in order to build the receptor model in a minimal...

  8. Asialoglycoprotein receptor (ASGPR): a peculiar target of liver-specific autoimmunity

    OpenAIRE

    Roggenbuck, Dirk; Mytilinaiou, Maria G.; Lapin, Sergey V.; Reinhold, Dirk; Conrad, Karsten

    2012-01-01

    Asialoglycoprotein receptor (ASGPR) autoantibodies have been considered specific markers of autoimmune hepatitis (AIH). The exact mechanisms responsible for the development of these autoantibodies and leading to autoimmunity to this peculiar liver receptor remain elusive. Furthermore, loss of T cell tolerance to ASGPR has been demonstrated in patients with AIH, but it is poorly understood whether such liver-specific T cell responses bear a pathogenic potential and/or participate in the precip...

  9. Galactosylated manganese ferrite nanoparticles for targeted MR imaging of asialoglycoprotein receptor.

    Science.gov (United States)

    Yang, Seung-Hyun; Heo, Dan; Lee, Eugene; Kim, Eunjung; Lim, Eun-Kyung; Lee, Young Han; Haam, Seungjoo; Suh, Jin-Suck; Huh, Yong-Min; Yang, Jaemoon; Park, Sahng Wook

    2013-11-29

    Cancer cells can express specific biomarkers, such as cell membrane proteins and signaling factors. Thus, finding biomarkers and delivering diagnostic agents are important in the diagnosis of cancer. In this study, we investigated a biomarker imaging agent for the diagnosis of hepatic cancers. The asialoglycoprotein receptor (ASGPr) was selected as a biomarker for hepatoma cells and the ASGPr-targetable imaging agent bearing a galactosyl group was prepared using manganese ferrite nanoparticles (MFNP) and galactosylgluconic acid. The utility of the ASGPr-targetable imaging agent, galactosylated MFNP (G-MFNP) was assessed by several methods in ASGPr-expressing HepG2 cells as target cells and ASGPr-deficient MCF7 cells. Physical and chemical properties of G-MFNP were examined using Fourier-transform infrared spectroscopy, dynamic light scattering, zeta potential analysis, and transmission electron microscopy. No significant cytotoxicity was observed in either cell line. Targeting ability was assessed using flow cytometry, magnetic resonance imaging, inductively coupled plasma atomic emission spectroscopy, absorbance analysis, dark-field microscopy, Prussian blue staining, and transmission electron microscopy. We demonstrated that G-MFNP target successfully and bind to ASGPr-expressing HepG2 cells specifically. We suggest that these results will be useful in strategies for cancer diagnoses based on magnetic resonance imaging.

  10. (18)F-FBHGal for asialoglycoprotein receptor imaging in a hepatic fibrosis mouse model.

    Science.gov (United States)

    Kao, Hao-Wen; Chen, Chuan-Lin; Chang, Wen-Yi; Chen, Jenn-Tzong; Lin, Wuu-Jyh; Liu, Ren-Shyan; Wang, Hsin-Ell

    2013-02-15

    Quantification of the expression of asialoglycoprotein receptor (ASGPR), which is located on the hepatocyte membrane with high-affinity for galactose residues, can help assess ASGPR-related liver diseases. A hepatic fibrosis mouse model with lower asialoglycoprotein receptor expression was established by dimethylnitrosamine (DMN) administration. This study developed and demonstrated that 4-(18)F-fluoro-N-(6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexyl)benzamide ((18)F-FBHGal), a new (18)F-labeled monovalent galactose derivative, is an asialoglycoprotein receptor (ASGPR)-specific PET probe in a normal and a hepatic fibrosis mouse models. Immunoassay exhibited a linear correlation between the accumulation of GalH-FITC, a fluorescent surrogate of FBHGal, and the amount of ASGPR. A significant reduction in HepG2 cellular uptake (P ASGPR blocking agent. Animal studies showed the accumulation of (18)F-FBHGal in fibrosis liver (14.84±1.10 %ID/g) was appreciably decreased compared with that in normal liver (20.50±1.51 %ID/g, P ASGPR-related liver dysfunction.

  11. Three-Dimensional Models of the Oligomeric Human Asialoglycoprotein Receptor (ASGP-R

    Directory of Open Access Journals (Sweden)

    Anna Maria Bianucci

    2010-10-01

    Full Text Available The work presented here is aimed at suggesting plausible hypotheses for functional oligomeric forms of the human asialoglycoprotein receptor (ASGP-R, by applying a combination of different computational techniques. The functional ASGP-R is a hetero-oligomer, that comprises of several subunits of two different kinds (H1 and H2, which are highly homologous. Its stoichiometry is still unknown. An articulated step-wise modeling protocol was used in order to build the receptor model in a minimal oligomeric form, necessary for it to bind multi-antennary carbohydrate ligands. The ultimate target of the study is to contribute to increasing the knowledge of interactions between the human ASGP-R and carbohydrate ligands, at the molecular level, pertinent to applications in the field of hepatic tissue engineering.

  12. Asialoglycoprotein receptor (ASGPR): a peculiar target of liver-specific autoimmunity.

    Science.gov (United States)

    Roggenbuck, Dirk; Mytilinaiou, Maria G; Lapin, Sergey V; Reinhold, Dirk; Conrad, Karsten

    2012-12-01

    Asialoglycoprotein receptor (ASGPR) autoantibodies have been considered specific markers of autoimmune hepatitis (AIH). The exact mechanisms responsible for the development of these autoantibodies and leading to autoimmunity to this peculiar liver receptor remain elusive. Furthermore, loss of T cell tolerance to ASGPR has been demonstrated in patients with AIH, but it is poorly understood whether such liver-specific T cell responses bear a pathogenic potential and/or participate in the precipitation of AIH. Newly developed enzyme-linked immunosorbent assays have led to the investigation of the sensitivity and specificity of anti-ASGPR antibodies for AIH. The present review provides an overview of the diagnostic and clinical relevance of anti-ASGPR antibodies. A thorough investigation of the autoreactivity against ASGPR may assist efforts to understand liver autoimmunity in susceptible individuals.

  13. Asialoglycoprotein receptor (ASGPR) as target autoantigen in liver autoimmunity: lost and found.

    Science.gov (United States)

    Rigopoulou, Eirini I; Roggenbuck, Dirk; Smyk, Daniel S; Liaskos, Christos; Mytilinaiou, Maria G; Feist, Eugen; Conrad, Karsten; Bogdanos, Dimitrios P

    2012-12-01

    Asialoglycoprotein receptor (ASGPR) has attracted the attention of liver immunologists for many years. This liver-specific lectin was found to be a major B and T cell autoantigenic target in patients with autoimmune liver diseases, and in particular in autoimmune hepatitis (AIH). This review discusses the biological significance of ASGPR and its relevance to the pathogenesis of autoimmune and virus-triggered liver diseases. We also discuss emerging data on the diagnostic and clinical relevance of anti-ASGPR antibodies in light of recent reports based on commercially available anti-ASGPR enzyme-linked immunosorbent assays. Finally, we critically revisit the data reporting on disease-specific cellular immune responses against ASGPR and their relevance in relation to the pathogenesis of AIH.

  14. Asialoglycoprotein receptor and liposome synergistically mediate the gene transfer into primary rat hepatocytes

    Institute of Scientific and Technical Information of China (English)

    李崇辉; 温守明; 翟海峰; 孙曼霁

    1999-01-01

    Gene transfer into primary rat hepatocytes was performed by employing cationic liposome as DNA carrier and the specific ligand of hepatic asialoglycoprotein receptor (ASGPR), asialofetuin, as liver-targeting ligand. The resuits showed that asialofetuin, when added to the gene transfer complexes, could significantly increase the hepatocyte transfeetion efficiency, and alleviate the cellular toxicity of Lipofectin. Several synthetic ligands of ASGPR (galactosyl albumin) could also increase the transfection efficiency of hepatocyte like asialofetuin. It was proved that ASGPR and cationic liposome could synergistically mediate the gene transfer into primary rat hepatoeytes. This novel gene delivery system provided a safer, more simple and efficient gene transfer method for primary hepatocytes, and showed prospecting application in hepatic gene therapy.

  15. Ga-68-labeled neolactosylated human serum albumin (LSA) for PET imaging of hepatic asialoglycoprotein receptor

    International Nuclear Information System (INIS)

    Introduction: The purpose of this study was the development of 68Ga-labeled neolactosylated human serum albumin (LSA) for imaging asialoglycoprotein receptors in the liver by using positron emission tomography (PET), which would enable functional imaging with higher resolution than single-photon emission computed tomography (SPECT). Methods: LSA was synthesized by conjugating α-lactose to human serum albumin (HSA) by reductive amination. LSA was conjugated with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-NOTA) and the resultant NOTA-LSA was labeled with 68Ga at room temperature. The labeling efficiency of NOTA-LSA was evaluated as a function of pH and time. The stability of 68Ga-NOTA-LSA in phosphate buffered saline (PBS) and human serum at 37 °C was determined. Biodistribution and PET studies of 68Ga-NOTA-LSA were performed in mice following tail vein injection of radiotracer. Results: The numbers of lactose and NOTA units per HSA were determined to be 31.7 and 4.6, respectively. When the reaction was done at room temperature, the labeling efficiency of NOTA-LSA was higher than 99% at pH 4.8 and 96% at pH 6. More than 95% of the detected radioactivity was associated with the intact molecule for at least the 4 h following synthesis when incubated in PBS or human serum at 37 °C. Biodistribution and animal PET studies showed specific retention of 68Ga-NOTA-LSA in liver following intravenous administration. Conclusion: 68Ga-NOTA-LSA was successfully developed for imaging asialoglycoprotein receptors in the liver with a simple labeling method, high labeling efficiency, and high stability

  16. Has asialoglycoprotein receptor (ASGP-R) a role to play in binding and processing of different parasites?

    OpenAIRE

    2002-01-01

    Liver asialoglycoprotein receptor (ASGP-R), which specifically recognizes and binds galactose and N-acetyl galactosamine, has been implicated in binding and endocytosis of glycoproteins. Therefore, the possibility that it may have a role in contacting and processing pathogenic organisms was investigated. The interaction in vitro between ASGP-R and surface oligosaccharide structures of Echinococcus granulosus and Trichinella spiralis was studied by immunohistochemical methods. Specific binding...

  17. Development of syngeneic monoclonal anti-idiotype antibodies to mouse monoclonal anti-asialoglycoprotein receptor antibody.

    Directory of Open Access Journals (Sweden)

    Hirai M

    2002-06-01

    Full Text Available Anti-idiotype antibodies (Ab2 play an important role in the homeostasis of immune responses and are related to the development and the disease activity of certain autoimmune diseases. The asialoglycoprotein receptor (ASGPR is considered one of the target antigens in the pathogenesis of autoimmune chronic active hepatitis (AIH. We previously developed a mouse monoclonal antibody (clone 8D7 which recognizes rat and human ASGPR. In this study, to help investigate the anti-ASGPR antibody-anti-idiotype antibody network in patients with AIH, we developed a syngeneic mouse monoclonal Ab2 to the 8D7 anti-ASGPR antibody (Ab1. One clone, designated as 3C8, tested positive for specific reactivity to 8D7-Ab1 and did not bind to other irrelevant immunoglobulins. By competitive inhibition assays, the binding of 8D7-Ab1 to liver membrane extracts, i.e., the crude antigen preparation, was inhibited by 3C8-Ab2 in a dose-dependent manner, and the binding of 8D7-Ab1 to 3C8-Ab2 was inhibited by the liver membrane extracts. In the immunohistochemical analysis, 3C8-Ab2 blocked the specific staining of sinusoidal margins of rat hepatocytes by 8D7-Ab1. These results suggest that 3C8 anti-idiotype antibody recognizes the specific idiotypic determinants within the antigen-binding site of 8D7-Ab1.

  18. Tailored Presentation of Carbohydrates on a Coiled Coil-Based Scaffold for Asialoglycoprotein Receptor Targeting.

    Science.gov (United States)

    Zacco, Elsa; Hütter, Julia; Heier, Jason L; Mortier, Jérémie; Seeberger, Peter H; Lepenies, Bernd; Koksch, Beate

    2015-09-18

    The coiled-coil folding motif represents an ideal scaffold for the defined presentation of ligands due to the possibility of positioning them at specific distances along the axis. We created a coiled-coil glycopeptide library to characterize the distances between the carbohydrate-binding sites of the asialoglycoprotein receptors (ASGPR) on hepatocytes. The components of the glycopeptide library vary for the number of displayed ligands (galactose), their position on the peptide sequence, and the space between peptide backbone and carbohydrate. We determined the binding of the glycopeptides to the hepatocytes, and we established the optimal distance and orientation of the galactose moieties for interaction with the ASGPR using flow cytometry. We confirmed that the binding occurs through endocytosis mediated by ASGPR via inhibition studies with cytochalasin D; fluorescence microscopy studies display the uptake of the carrier peptides inside the cell. Thus, this study demonstrates that the coiled-coil motif can be used as reliable scaffold for the rational presentation of ligands.

  19. Asialoglycoprotein Receptor-Mediated Gene Delivery to Hepatocytes Using Galactosylated Polymers.

    Science.gov (United States)

    Thapa, Bindu; Kumar, Piyush; Zeng, Hongbo; Narain, Ravin

    2015-09-14

    Highly efficient, specific, and nontoxic gene delivery vector is required for gene therapy to the liver. Hepatocytes exclusively express asialoglycoprotein receptor (ASGPR), which can recognize and bind to galactose or N-acetylgalactosamine. Galactosylated polymers are therefore explored for targeted gene delivery to the liver. A library of safe and stable galactose-based glycopolymers that can specifically deliver genes to hepatocytes were synthesized having different architectures, compositions, and molecular weights via the reversible addition-fragmentation chain transfer process. The physical and chemical properties of these polymers have a great impact on gene delivery efficacy into hepatocytes, as such block copolymers are found to form more stable complexes with plasmid and have high gene delivery efficiency into ASGPR expressing hepatocytes. Transfection efficiency and uptake of polyplexes with these polymers decreased significantly by preincubation of hepatocytes with free asialofetuin or by adding free asialofetuin together with polyplexes into hepatocytes. The results confirmed that polyplexes with these polymers were taken up specifically by hepatocytes via ASGPR-mediated endocytosis. The results from transfection efficiency and uptake of these polymers in cells without ASGPR, such as SK Hep1 and HeLa cells, further support this mechanism. Since in vitro cytotoxicity assays prove these glycopolymers to be nontoxic, they may be useful for delivery of clinically important genes specifically to the liver.

  20. Constant serum levels of secreted asialoglycoprotein receptor sH2a and decrease with cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Ron Benyair; Maria Kondratyev; Elena Veselki; Sandra Tolchinsky; Marina Shenkman; Yoav Lurie; Gerardo Z Lederkremer

    2011-01-01

    AIM: To investigate the existence and levels of sH2a, a soluble secreted form of the asialoglycoprotein receptor in human serum.METHODS: Production of recombinant sH2a and development of a monoclonal antibody and an enzyme-linked immunosorbent assay (ELISA).This assay was used to determine the presence and concentration of sH2a in human sera of individuals of both sexes and a wide range of ages.RESULTS: The recombinant protein was produced successfully and a specific ELISA assay was developed. The levels of sH2a in sera from 62 healthy individuals varied minimally (147 ± 19 ng/mL).In contrast, 5 hepatitis C patients with cirrhosis showed much decreased sH2a levels (50 ± 9 ng/mL).CONCLUSION: Constant sH2a levels suggest constitutive secretion from hepatocytes in healthy individuals.This constant level and the decrease with cirrhosis suggest a diagnostic potential.

  1. Cloning, Expression and Polyclonal Antibody Preparation of the Asialoglycoprotein Receptor of Marmota Himalayan

    Institute of Scientific and Technical Information of China (English)

    YANG Yan; HUANG Huang; ZHANG Zhenghua; WANG Baoju; TIAN Yongjun; LU Mengji; YANG Dongliang

    2007-01-01

    The objective of this study is to express the carbohydrate recognition domain (CRD) of the asialoglycoprotein receptor (ASGPR) H1 and H2 subunits of Marmota himalayan in vitro, and develop polyclonal antibodies against the recombinant proteins. RT-PCR was used to amplify ASGPR CRDH1 and CRDH2 from the liver tissue of Marmota himalayan. The products of amplification were subcloned into prokaryotic expression vector pRSET-B, and expressed in E. coli BL21(DE3)plysS. The recombinant proteins were purified using Ni-NTA spin column. The purified proteins were inoculated into BALB/c mice to develop polyclonal antibodies. The sensitivity and specificity of antibodies were evaluated by enzyme-linked immunosorbent assay (ELISA), Western blotting and immunohistochemical staining (IHC). The polyclonal antibodies showed high sensitivity and specificity against both denaturated and native ASGPR proteins. We successfully amplified and expressed the ASGPR CRDs of Marmota himalayan. The nucleic sequences of ASGPR CRDH1 and CRDH2 of Marmota himalayan have been submitted to Genbank and the sequence ID are DQ 845465 and DQ845466, respectively. The proteins and antibodies prepared can be used for targeting gene therapy in a new animal model-Marmota himalayan-for the research of infectious diseases of hepatitis viruses and liver cancer treatment.

  2. A New Splice Variant of the Major Subunit of Human Asialoglycoprotein Receptor Encodes a Secreted Form in Hepatocytes

    OpenAIRE

    Jia Liu; Bin Hu; Yan Yang; Zhiyong Ma; Yuan Yu; Shenpei Liu; Baoju Wang; Xiping Zhao; Mengji Lu; Dongliang Yang

    2010-01-01

    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 geno...

  3. Cholesterol anchored arabinogalactan for asialoglycoprotein receptor targeting: synthesis, characterization, and proof of concept of hepatospecific delivery.

    Science.gov (United States)

    Pathak, Pankaj Omprakash; Nagarsenker, Mangal Shailesh; Barhate, Chandrashekhar Rishikant; Padhye, Sameer Govind; Dhawan, Vivek Vijay; Bhattacharyya, Dibyendu; Viswanathan, C L; Steiniger, Frank; Fahr, Alfred

    2015-05-18

    Asialoglycoprotein receptors (ASGPR) are hepatocyte bound receptors, which exhibit receptor mediated endocytosis (RME) for galactose specific moieties. Arabinogalactan (AG), a liver specific high galactose containing branched polysaccharide was hydrophobized using cholesterol (CHOL) as a lipid anchor via a two step reaction process to yield the novel polysaccharide lipid conjugated ligand (CHOL-AL-AG). CHOL-AL-AG was characterized by Fourier transform infra red (FTIR) spectroscopy, (1)H and (13)C nuclear magnetic spectroscopy (NMR), size exclusion chromatography (SEC) and differential scanning calorimetry (DSC). Conventional liposomes (CL) and surface modified liposomes (SML) containing CHOL-AL-AG were prepared using reverse phase evaporation technique. Effect of CHOL-AL-AG concentration on particle size and zeta potential of SML was evaluated. Surface morphology of CL and SML was studied using cryo-transmission electron microscopy (cryo-TEM). In vitro binding affinity of SML and CL was evaluated using Ricinus communis agglutinin (RCA) assay. Cellular uptake of SML and CL was determined on ASGPR expressing HepG2 cell lines by confocal laser scanning microscopy technique (CLSM). FTIR spectra revealed bands at 1736 cm(-1) and 1664 cm(-1) corresponding to ester and carbamate functional groups, respectively. Signals at δ 0.5-2.5 corresponding to the cholestene ring and δ 3-5.5 corresponding to the carbohydrate backbone were observed in (1)H NMR spectrum of the product. CHOL-AL-AG possessed a mean average molecular weight of 27 KDa as determined by size exclusion chromatography. An endothermic peak at 207 °C was observed in the DSC thermogram of CHOL-AL-AG, which was not observed in thermograms of reactants and intermediate product. Synthesized CHOL-AL-AG was successfully incorporated in liposomes to yield SML. Both CL and SML possessed a mean particle size of ∼ 200 nm with polydispersity index of ∼ 0.25. The zeta potential of CLs was observed to be -17 m

  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. A new liver function test using the asialoglycoprotein-receptor system on the liver cell membrane, 1

    International Nuclear Information System (INIS)

    We evaluated the validity of a new radionuclide liver imaging method using an asialoglycoprotein (ASGP) receptor system on the cell membrane. Neoglycoprotein was labeled with 99mTc using SnCl2 as a reductant and administered into normal rats and those with 3'-metyl-4-dimethylaminoazobenzene induced liver cancer. This protein is physiologically equivalent to ASGP and thus binds to ASGP receptors, and is taken up by the liver. In the normal rats, liver images obtained with this new method were as clear as those obtained with 99mTc-Sn colloid. In the rats with liver cancer, lesions (10 mm in diameter) were visualized as accumulated defects showing a distinct contrast to the surrounding tissues. These defects were consistent with the macroscopic observations, and also were supported by the absence of ASGP receptor activity in lesions confirmed by measurements in cancerous and non-cancerous areas. The results indicate the usefulness of labeled neoglycoprotein as radiopharmaceutical for liver RI imaging. (author)

  6. Physiological roles of asialoglycoprotein receptors (ASGPRs) variants and recent advances in hepatic-targeted delivery of therapeutic molecules via ASGPRs.

    Science.gov (United States)

    Hu, Jing; Liu, Jia; Yang, Dongliang; Lu, Mengji; Yin, Jian

    2014-01-01

    The asialoglycoprotein receptor (ASGPR) is a high-capacity C-type lectin receptor mainly expressed on mammalian hepatic cells. The physiological function of ASGPR has not been completely clarified and is thought to be specific binding and internalization of galactose (Gal) or N-acetylgalactosamine (GalNAc)-terminating glycoproteins by hepatocytes. The human ASGPR is comprised of two homologous polypeptides, H1 and H2. ASGPR H1 has two splice variants (H1a and H1b) and ASGPR H2 has three splice variants (H2a, H2b, and H2c). These variants have been discovered to exist both in human liver tissues and in human hepatoma cells. Variant H1b, which has an in-frame deletion of exon 2 resulting in the loss of the transmembrane domain and is secreted as a soluble protein, encodes functional soluble ASGPR (s- ASGPR). Based on our previous results, we proposed the possible physiological function of s-ASGPR, which is well interpreted in the Galactosyl Homeostasis Hypothesis proposed by Weigel. ASGPR is one of the most promising targets for hepatic delivery. In this review, the recent progresses of cationic polysomes and liposomes as effective non-viral delivery system via ASGPR are also presented.

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  8. Targeted delivery of macromolecular drugs: asialoglycoprotein receptor (ASGPR) expression by selected hepatoma cell lines used in antiviral drug development.

    Science.gov (United States)

    Li, Yan; Huang, Guifang; Diakur, James; Wiebe, Leonard I

    2008-10-01

    The asialoglycoprotein receptor (ASGPR), an endocytotic cell surface receptor expressed by hepatocytes, is triggered by triantennary binding to galactose residues of macromolecules such as asialoorosomucoid (ASOR). The capacity of this receptor to import large molecules across the cellular plasma membrane makes it an enticing target for receptor-mediated drug delivery to hepatocytes and hepatoma cells via ASGPR-mediated endocytosis. This study describes the preparation and characterization of (125)I-ASOR, and its utility in the assessment of ASGPR expression by HepG2, HepAD38 and Huh5-2 human hepatoma cell lines. ASOR was prepared from human orosomucoid, using acid hydrolysis to remove sialic acid residues, then radioiodinated using iodogen. (125)I-ASOR was purified by gel column chromatography and characterized by SDS-PAGE electrophoresis. The ASOR yield by acid hydrolysis was 75%, with approximately 87 % of the sialic acid residues removed. Electrophoresis and gel chromatography demonstrated substantial differences in (125)I-ASOR quality depending on the method of radioiodination. ASGPR densities per cell were estimated at 76,000 (HepG2), 17,000 (HepAD38) and 3,000 (Huh-5-2). (125)I-ASOR binding to ASGPR on HepG2 cells was confirmed through galactose- and EDTA- challenge studies. It is concluded that (125)I-ASOR is a facilely-prepared, stable assay reagent for ASGPR expression if appropriately prepared, and that HepG2 cells, but not HepAD38 or Huh-5-2 cells, are suitable for studies exploiting the endocytotic ASGPR.

  9. The unsialylated subpopulation of recombinant activated factor VII binds to the asialo-glycoprotein receptor (ASGPR) on primary rat hepatocytes.

    Science.gov (United States)

    Seested, Torben; Nielsen, Hanne M; Christensen, Erik I; Appa, Rupa S

    2010-12-01

    Recombinant activated factor VII (rFVIIa; NovoSeven®) is a heterogeneously glycosylated serine protease used for treatment of haemophiliacs with inhibitors. The drug substance contains a subpopulation consisting of ~20% of rFVIIa molecules which are unsialylated and consists of carbohydrate moieties with terminally exposed galactose and N-acetyl-D-galactosamine (GalNAc). Recently, data from an in situ perfused liver model showed that a subpopulation of rFVIIa, appearing to be unsialylated rFVIIa, was cleared by the liver, thus suggesting a carbohydrate-moiety mediated mechanism. The parenchymal cells of the liver, hepatocytes, are known to abundantly express functional carbohydrate-specific receptors and in this study we therefore used primary rat hepatocytes to study binding and intracellular fate of rFVIIa at a cellular level. Immunofluorescence microscopy showed that rFVIIa was distributed into distinct intracellular vesicles and electron microscopic autoradiography revealed that radioiodinated rFVIIa distributed only into cytoplasmic free vesicles resembling endosomes and lysosomes. These findings suggest that endocytosis of rFVIIa in hepatocytes could be partly mediated via initial membrane binding to a receptor. Quantitative binding studies showed that the presence of excess unlabelled asialo-orosomucoid, asialo-rFVIIa and GalNAc significantly decreased binding of 125I-rFVIIa. An antibody which specifically binds to the carbohydrate recognition domain of the asialoglycoprotein receptor (ASGPR) significantly decreased binding of asialo-rFVIIa by ~36% and rFVIIa by ~19%. Together our data showed that a receptor-mediated mechanism involving the ASGPR is able to bind a subpopulation of unsialylated rFVIIa, while a hepatic mechanism for binding and clearing sialylated rFVIIa is still unknown.

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

    Energy Technology Data Exchange (ETDEWEB)

    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. Anti-asialoglycoprotein receptor autoantibodies, detected by a capture-immunoassay, are associated with autoimmune liver diseases.

    Directory of Open Access Journals (Sweden)

    Yoshioka M

    2002-04-01

    Full Text Available In autoimmune chronic active hepatitis (AIH and primary biliary cirrhosis (PBC, various autoantibodies including anti-asialoglycoprotein receptor (ASGPR antibodies have been found in patients' sera. We have previously developed a mouse monoclonal antibody against rat and human ASGPR. In this study, we developed a capture enzyme-linked immunosorbent assay (ELISA for detection of anti-ASGPR antibodies using this monoclonal antibody and investigated the occurrence of anti-ASGPR antibodies in the sera of patients with various liver diseases. Serum samples were obtained from 123 patients with various liver diseases, including 21 patients with AIH and 40 patients with PBC. In this capture ELISA, the target antigen in the crude rat liver membrane extracts was captured on the ELISA wells by the ASGPR-specific mouse monoclonal antibody. Thus, the cumbersome process of antigen purification was rendered unnecessary. Using this capture ELISA, we detected the anti-ASGPR antibody in 67% of the patients with AIH, in 100% of the patients with PBC, and in 57% of the patients with acute hepatitis type A. However, the anti-ASGPR antibody was rarely detected in patients with other liver diseases such as primary sclerosing cholangitis and obstructive jaundice. Our findings suggest that this capture ELISA would be useful for the detection of anti-ASGPR antibodies in autoimmune liver diseases.

  12. Synthesis and biological evaluation of 18F-FB-NGA as a hepatic asialoglycoprotein receptor PET imaging agent

    International Nuclear Information System (INIS)

    Asialoglycoprotein receptor (ASGP-R) is a hepatic membrane receptor that uniquely exists on the surface of mammalian hepatocytes, and has been used as target of liver functional imaging agents for many years. We labeled the Galactosyl-neoglycoalbumin (NGA) with 18F to get a PET molecular probe 18F-FB-NGA and evaluated its ability as a liver functional PET imaging agent. The 18F-FB-NGA was prepared with NGA by conjugation with N- succinimidyl-4-18F-fluorobenzoate (18F-SFB) and purified with PD-10 desalting column. The radiolabeling yield and radiochemical purity of 18F-FB-NGA were determined by radio-HPLC. Starting with 18F-F-, the total time for '18F-FB -NGA was about 120±310 min. The decay-corrected radiochemical yield is about 25-30%. The radiochemical purity of purified 18F-FB-NGA was more than 98%. Labeled with 185-1850 MBq 18F-SFB, the specific activity of 18F-FB- NGA was estimated to be 7.83-78.3 TBq/mmol. Biodistribution of 18F-FB-NGA in normal mice was investigated after injection through the tail vein. The results showed that the liver accumulated 39.4 7±3.42 and 12.12±6.11% ID/g at 10 and 30 min after injection, respectively. Dynamic MicroPET images in mice were acquired with and without block after injection of the radiotracer, respectively. High liver activity accumulation was observed at 5 min after injection in normal group. On the contrary, the liver accumulation was significantly lower after block, indicating the specific binding to ASGP-R. 18F-FB-NGA is probably a potential PET liver imaging agent. (authors)

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

    Science.gov (United States)

    Vasanthan, Kirthanashri S; Sethuraman, Swaminathan; Parthasarathy, Meera

    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.

  14. 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.

  15. Genetics Home Reference: leptin receptor deficiency

    Science.gov (United States)

    ... Understand Genetics Home Health Conditions leptin receptor deficiency leptin receptor deficiency Enable Javascript to view the expand/ ... boxes. Print All Open All Close All Description Leptin receptor deficiency is a condition that causes severe ...

  16. Clinical significance of anti-asialoglycoprotein receptor autoantibodies, detected by a capture-immunoassay, in autoimmune liver diseases

    OpenAIRE

    森末, 佳子

    2002-01-01

    In the development of autoimmune chronic acive hepatitis (AIH), the pathogenic relevance of antimmune responses against asialoglycoprotein recepter (ASGPR) has been implicated. We have previously developed a capture enzyme-linked immunsorbent assay (ELISA) for detection of anti-ASGPR antibodies and found a high prevalence of anti-ASGPR antibodies in AIH and primary biliary cirrhosis (PBC). IN this study, to clarify the clinical singnifi-cance of the measurement of anti-ASGPR antibodies in aut...

  17. 肝脏去唾液酸糖蛋白受体的研究进展%Research progress of the asialoglycoprotein receptor in liver

    Institute of Scientific and Technical Information of China (English)

    石红; 刘健; 余进洪

    2014-01-01

    肝脏去唾液酸糖蛋白受体(ASGPR)与肝脏疾病的发生发展密切相关,去唾液酸糖蛋白受体用于临床,对于肝脏疾病的早期诊断以及指导治疗和评价预后有重要的临床意义。本文介绍了去唾液酸糖蛋白受体的发生发展过程及国内外的研究进展,并对其未来的发展方向做了展望。%The asialoglycoprotein receptor (ASGPR), which is closely related to the development of liver diseases, has important clinical significance in the early diagnosis of liver diseases and guiding treatment and evaluating prognosis. This paper introduced the progress of ASGPR both at home and abroad, and made the outlook for its future development direction.

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

    Directory of Open Access Journals (Sweden)

    Emo Chiellini

    2007-01-01

    Full Text Available A practical approach for addressing the computer simulation of protein-carbohydrate interactions is described here. An articulated computational protocol was setup and validated by checking its ability to predict experimental data, available in theliterature, and concerning the selectivity shown by the Carbohydrate Recognition Domain(CRD of the human asialoglycoprotein receptor (ASGP-R toward Gal-type ligands. Somerequired features responsible for the interactions were identified. Subsequently the sameprotocol was applied to monomer sugar molecules that constitute the building blocks foralginates and ulvans. Such sugar polymers may supply a low-cost source of rare sugars witha potential impact on several industrial applications, from pharmaceutical to fine chemicalindustry. An example of their applicative exploitation could be given by their use indeveloping biomaterial with adhesion properties toward hepatocytes, through interactionwith the ASGP-R. Such a receptor has been already proposed as a target for exogenousmolecules, specifically in the case of hepatocytes, for diagnostic and therapeutic purposes.The DOCK5.2 program was used to search optimal locations of the above ligands of interestinto CRD binding site and to roughly estimate interaction energies. Finally, the binding ∆G oftheoretical protein-ligand complexes was estimated by using the DelPhi program in which thesolvation free energy is accounted for with a continuum solvent model, by solving the Poisson-Boltzmann equation. The structure analysis of the obtained complexes and their ∆G values suggest that one of the sugar monomers of interest shows the desired characteristics.

  19. Simplified quantification method for in vivo SPECT/CT imaging of asialoglycoprotein receptor with 99mTc-p(VLA-co-VNI) to assess and stage hepatic fibrosis in mice

    OpenAIRE

    Zhang, Deliang; Guo, Zhide; Zhang, Pu; Li, Yesen; Su, Xinhui; You, Linyi; Gao, Mengna; Liu, Chang; Wu, Hua; Zhang, Xianzhong

    2016-01-01

    The goal of this study is to develop a noninvasive method of SPECT imaging to quantify and stage liver fibrosis with an Asialoglycoprotein receptor (ASGP-R) targeting tracer—99mTc-p(VLA-co-VNI). ASGP-Rs are well known to specifically express in the mammalian liver. Here, we demonstrated ASGP-R expression decreased in carbon tetrachloride (CCl4)-induced mouse model. ASGP-R expression correlated with liver fibrosis progression. ASGP-R could be a useful marker in the stage of liver fibrosis. Liv...

  20. Detection of circulating tumor cells in hepatocellular carcinoma using antibodies against asialoglycoprotein receptor, carbamoyl phosphate synthetase 1 and pan-cytokeratin.

    Directory of Open Access Journals (Sweden)

    Jun Li

    Full Text Available BACKGROUND: Asialoglycoprotein receptor (ASGPR-ligand-based separation combined with identification with Hep Par 1 or pan-cytokeratin (P-CK antibody have been demonstrated to detect circulating tumor cells (CTCs in hepatocellular carcinoma (HCC. The aim of this study was to develop an improved enrichment and identification system that allows the detection of all types of HCC CTCs. METHODS: The specificity of the prepared anti-ASGPR monoclonal antibody was characterized. HCC cells were bound by ASGPR antibody and subsequently magnetically isolated by second antibody-coated magnetic beads. Isolated HCC cells were identified by immunofluorescence staining using a combination of anti-P-CK and anti-carbamoyl phosphate synthetase 1 (CPS1 antibodies. Blood samples spiked with HepG2 cells were used to determine recovery and sensitivity. CTCs were detected in blood samples from HCC patients and other patients. RESULTS: ASGPR was exclusively expressed in human hepatoma cell line, normal hepatocytes and HCC cells in tissue specimens detected by the ASGPR antibody staining. More HCC cells could be identified by the antibody cocktail for CPS1 and P-CK compared with a single antibody. The current approach obtained a higher recovery rate of HepG2 cells and more CTC detection from HCC patients than the previous method. Using the current method CTCs were detected in 89% of HCC patients and no CTCs were found in the other test subjects. CONCLUSIONS: Our anti-ASGPR antibody could be used for specific and efficient HCC CTC enrichment, and anti-P-CK combined with anti-CPS1 antibodies is superior to identification with one antibody alone in the sensitivity for HCC CTC detection.

  1. Effect of size and conformation of the ligand on asialoglycoprotein receptor-mediated ligand internalization and degradation in rat hepatocytes

    International Nuclear Information System (INIS)

    The rates of internalization and degradation of 125-I-labeled desialylated cyanogen bromide fragment I of orosomucoid (AS-CNBr-I) and its reduced and carboxymethylated derivative (AS-RC-CNBr-I) were compared with those of 125I-labeled asialoorosomucoid (ASOR) in rat hepatocytes. At 30 nM the rates of internalization and degradation of 125I-AS-CNBr-I were greater than those of 125I-ASOR. 125I-AS-RC-CNBr-I also had a lower rate of internalization and degradation. In contrast to 125I-ASOR, when degradation was inhibited by 5 μM colchicine there was a significant intracellular accumulation of the smaller ligands. At 40C the hepatocytes were found to bind the fragmented ligands more than 125I-ASOR. Incubation of the cells with bound ligand at 370 indicated that diacytosis of 125I-ASOR was greater than the smaller ligands. Colchincine markedly enhanced diacytosis of 125I-ASOR. On the other hand, there were marked accumulation of the smaller ligands by colchicine. These results suggest that the rates of internalization, degradation and diacytosis of the ligand are affected by the size and conformation of the ligand through different rates of receptor binding and intracellular transport

  2. 去唾液酸糖蛋白受体介导的肝脏靶向性研究进展%Study on asialoglycoprotein receptor-mediated liver targeting:current progress

    Institute of Scientific and Technical Information of China (English)

    徐文; 殷正丰

    2006-01-01

    去唾液酸糖蛋白受体(asialoglycoprotein receptor,ASGPR)又称半乳糖受体,主要表达于哺乳动物肝窦状隙的肝实质细胞表面,参与多种生理功能.多年来ASGPR一直被用于介导药物和基因的肝靶向递送以及肝脏成像等方面的研究,目前已取得许多进展.ASGPR介导的药物肝靶向递送研究主要集中在抗肿瘤药物、降胆固醇药物等.基因肝靶向递送多见于反义药物.肝脏成像研究包括评价肝脏功能、鉴别肝细胞肝癌和肿瘤肝转移灶等.近年来ASGPR的靶向性应用研究还进一步扩展到肝细胞立体培养、肝细胞筛选及肝细胞移植等领域.本文就这些内容作一综述.

  3. Selection and Identification of RNA Aptamer Specific for Hepatic Asialoglycoprotein Receptor by SELEX%肝脏去唾液酸糖蛋白受体特异性RNA适配子的SELEX筛选与鉴定

    Institute of Scientific and Technical Information of China (English)

    刘嘉; 杨东亮; 杨燕; 胡斌; 马智勇; 余源; 黄红平; 陆蒙吉; 冯新华; 郭培宣

    2009-01-01

    目的 获得能够特异性高亲和力结合肝脏特异性去唾液酸糖蛋白受体(asialoglycoprotein receptor, ASGPR)的RNA适配子,为开发诊断和治疗肝脏疾病的靶向性试剂和药物奠定基础.方法 合成一个长度为115 nt含有25个随机序列的单链DNA随机文库,通过体外转录构建出单链RNA适配子随机文库,以肝脏ASGPR大亚基为靶蛋白,采用SELEX(systematic evolution of ligands by exponential enrichment)技术筛选具有高亲和力的ASGPR特异性RNA适配子;通过膜结合测定实验、凝胶阻滞实验鉴定筛选适配子对靶蛋白的特异性和亲和力.结果 经过12轮筛选获得了具有高亲和力的肝脏ASGPR特异性RNA适配子.结论 成功地筛选出了具有高亲和力的肝脏ASGPR特异性RNA适配子库.

  4. Simplified quantification method for in vivo SPECT/CT imaging of asialoglycoprotein receptor with 99mTc-p(VLA-co-VNI) to assess and stage hepatic fibrosis in mice

    Science.gov (United States)

    Zhang, Deliang; Guo, Zhide; Zhang, Pu; Li, Yesen; Su, Xinhui; You, Linyi; Gao, Mengna; Liu, Chang; Wu, Hua; Zhang, Xianzhong

    2016-01-01

    The goal of this study is to develop a noninvasive method of SPECT imaging to quantify and stage liver fibrosis with an Asialoglycoprotein receptor (ASGP-R) targeting tracer—99mTc-p(VLA-co-VNI). ASGP-Rs are well known to specifically express in the mammalian liver. Here, we demonstrated ASGP-R expression decreased in carbon tetrachloride (CCl4)-induced mouse model. ASGP-R expression correlated with liver fibrosis progression. ASGP-R could be a useful marker in the stage of liver fibrosis. Liver uptake value (LUV) derived by SPECT imaging was used to assess liver fibrosis in the CCl4-induced mouse model. LUV = [radioactivity (liver uptake)/radioactivity (injected)] × 100/liver volume. The LUV decreased along with the disease progression. The relationships between LUV and liver hydroxyproline (i.e. collagen), as well as Sirius Red were established and verified. A strong negative linear correlation was found between LUV and hydroxyproline levels (r = −0.83) as well as LUV and Sirius Red quantification (r = −0.83). In conclusion, SPECT imaging with 99mTc-p(VLA-co-VNI) is useful in evaluating and staging liver fibrosis in vivo. PMID:27150943

  5. Simplified quantification method for in vivo SPECT/CT imaging of asialoglycoprotein receptor with (99m)Tc-p(VLA-co-VNI) to assess and stage hepatic fibrosis in mice.

    Science.gov (United States)

    Zhang, Deliang; Guo, Zhide; Zhang, Pu; Li, Yesen; Su, Xinhui; You, Linyi; Gao, Mengna; Liu, Chang; Wu, Hua; Zhang, Xianzhong

    2016-01-01

    The goal of this study is to develop a noninvasive method of SPECT imaging to quantify and stage liver fibrosis with an Asialoglycoprotein receptor (ASGP-R) targeting tracer-(99m)Tc-p(VLA-co-VNI). ASGP-Rs are well known to specifically express in the mammalian liver. Here, we demonstrated ASGP-R expression decreased in carbon tetrachloride (CCl4)-induced mouse model. ASGP-R expression correlated with liver fibrosis progression. ASGP-R could be a useful marker in the stage of liver fibrosis. Liver uptake value (LUV) derived by SPECT imaging was used to assess liver fibrosis in the CCl4-induced mouse model. LUV = [radioactivity (liver uptake)/radioactivity (injected)] × 100/liver volume. The LUV decreased along with the disease progression. The relationships between LUV and liver hydroxyproline (i.e. collagen), as well as Sirius Red were established and verified. A strong negative linear correlation was found between LUV and hydroxyproline levels (r = -0.83) as well as LUV and Sirius Red quantification (r = -0.83). In conclusion, SPECT imaging with (99m)Tc-p(VLA-co-VNI) is useful in evaluating and staging liver fibrosis in vivo. PMID:27150943

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

    OpenAIRE

    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.

  7. 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.

  8. α5GABAA receptor deficiency causes autism-like behaviors.

    Science.gov (United States)

    Zurek, Agnieszka A; Kemp, Stephen W P; Aga, Zeenia; Walker, Susan; Milenkovic, Marija; Ramsey, Amy J; Sibille, Etienne; Scherer, Stephen W; Orser, Beverley A

    2016-05-01

    The prevalence of autism spectrum disorders (ASDs), which affect over 1% of the population, has increased twofold in recent years. Reduced expression of GABAA receptors has been observed in postmortem brain tissue and neuroimaging of individuals with ASDs. We found that deletion of the gene for the α5 subunit of the GABAA receptor caused robust autism-like behaviors in mice, including reduced social contacts and vocalizations. Screening of human exome sequencing data from 396 ASD subjects revealed potential missense mutations in GABRA5 and in RDX, the gene for the α5GABAA receptor-anchoring protein radixin, further supporting a α5GABAA receptor deficiency in ASDs. PMID:27231709

  9. Study on the preparation of ligand of hepatic asialoglycoprotein receptor%肝脏去唾液酸糖蛋白受体的配体制备研究

    Institute of Scientific and Technical Information of China (English)

    石红; 余进洪; 刘健

    2015-01-01

    目的:优化制备出具有高效性的肝脏去唾液酸糖蛋白受体(ASGPR)的配体半乳糖化多聚赖氨酸(Gal-PLL),为后期肝靶向性纳米液态氟碳微球超声造影剂的制备以及肝脏靶向分子成像提供依据。方法采用还原胺化法,根据各反应组分的比例不同总体分为实验组(A、B组)和对照组(C组),A、B组又分别细分成3组。 A组将3种不同摩尔比的D-半乳糖和多聚赖氨酸分别与等量的足量还原剂硼氢化钠(NaBH4)进行反应,B组将相同摩尔比的D-半乳糖和多聚赖氨酸分别与3种不同量的还原剂进行反应。各组产物均经葡聚糖凝胶柱分离纯化,得到不同化合物分子质量的达峰曲线并进行分析。结果当还原剂等量时,适量减少D-半乳糖的量,分离纯化的化合物分子质量的达峰曲线提前;当D-半乳糖与多聚赖氨酸摩尔比相等时,适当减少还原剂的量,分离纯化的化合物分子质量的达峰曲线亦出现提前;当D-半乳糖与还原剂的摩尔比为1∶1时,反应合成的半乳糖化多聚赖氨酸化合物与游离组分的曲线分离最为明显,且化合物的量达到最大值。结论当还原剂等量时,适量减少D-半乳糖可增强D-半乳糖与多聚赖氨酸的偶联效果;而当D-半乳糖与多聚赖氨酸摩尔比相等时,适量减少还原剂,D-半乳糖与多聚赖氨酸的偶联效果更佳;当D-半乳糖与还原剂的摩尔比为1∶1时,D-半乳糖与多聚赖氨酸的偶联效果最好。D-半乳糖与多聚赖氨酸的偶联效果不仅与2者的配比相关,也与D-半乳糖与还原剂的配比相关。%Objective To optimize the preparation of high-efficiency galactocylated poly-L-lysine (Gal-PLL) ligand of the asialoglycoprotein receptor in liver, providing premise and foundation for upper preparation of ultrasound contrast agent of liver targeted nanoscale perfluorocarbon microballoon and the liver

  10. The Experimental Research on vp3 Gene Targeting Therapy for Hepatoma by Asialoglycoprotein Receptor In Vivo%脱唾液酸糖蛋白受体介导的vp3基因靶向性治疗肝癌的实验研究

    Institute of Scientific and Technical Information of China (English)

    孙军; 王宇哲; 屈伸; 彭冬君; 宗义强

    2004-01-01

    目的利用肝细胞表面存在特异的脱唾液酸糖蛋白受体(asialoglycoprotein receptor,ASGPR),探索ASGPR介导的vp3基因肝细胞靶向性治疗肝癌的方法.方法将携带vp3基因的质粒通过多聚左旋赖氨酸(poly-L-lysine,PLL)与该受体的天然配体脱唾液酸粘蛋白(asialoorosomucoid,Asor)结合,获得Asor-PLL-vp3复合物;通过体外转染、放射性同位素标记检测和动物实验鉴定该复合物的肝细胞靶向性.结果成功制备了较纯的可溶性的蛋白-核酸复合物;体内外实验结果表明Asor-PLL-vp3复合物具有良好的肝细胞靶向性.结论通过制备Asor-PLL-vp3复合物,利用ASGPR介导实现了vp3的肝细胞靶向性基因转移,证实了该复合物具有体内靶向性治疗肝癌的可行性.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Engelund, Anna; Fahrenkrug, Jan; Harrison, Adrian; Luuk, Hendrik; Hannibal, Jens

    2012-05-01

    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, and by in situ hybridization histochemistry, we demonstrated the presence of PAC1R mRNA. Mice lacking PAC1R exhibited a significantly attenuated PLR compared to wild type mice upon light stimulation, and the difference became more pronounced as light intensity was increased. Our findings accord well with observations of the PLR in the melanopsin-deficient mouse. We conclude that PACAP/PAC1R signaling is involved in the sustained phase of the PLR at high irradiances.

  13. Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice

    OpenAIRE

    Seiji Hayashizaki; Shinobu Hirai; Yumi Ito; Yoshiko Honda; Yosefu Arime; Ichiro Sora; Haruo Okado; Tohru Kodama; Masahiko Takada

    2013-01-01

    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 behaviora...

  14. 去唾液酸糖蛋白受体抗体阳性的Ⅰ型自身免疫性肝炎生物学性状及其意义%Biological significance of autoantibodies to asialoglycoprotein receptor in patients with type Ⅰautoimmune hepatitis

    Institute of Scientific and Technical Information of China (English)

    吴虹杰; 徐芸

    2011-01-01

    AIM: To investigate the differences in clinical, biochemical, immunoserologic, genetic, histolog-ical features and response to treatment between patients with type 1 autoimmune hepatitis (AIH-Ⅰ) who were positive for autoantibodies to asialoglycoprotein receptor (ASGPR) and those negative for anti-ASGPR.METHODS: A total of 79 patients with AIH-Ⅰ were screened for the presence of anti-ASGPR by ELISA and were divided into anti-ASGPR-positive group and anti-ASGPR-negative group.RESULTS: There were 59 patients in the anti-ASGPR-positive group and 20 patients in the anti-ASGPR-positive group. No significant differences were found between anti-ASGPR-positive and-negative patients in age, gender,alanine transaminase (ALT) activity, aspar-tate aminotransferase (AST) activity, alkaline phosphatase (ALP) activity, gamma glutanmic transpeptidase (y-GT) activity, antinuclear autoantibodies (ANA), smooth muscle auto-antibodies (SMA), DR3, and DR4. The levels of immunoglobulin G, C3, histological inflammatory activity and fibrosis, and response to treatment differed significantly between the two groups.CONCLUSION: The presence of anti-ASGPR is correlated, to a certain extent, with inflammatory activity, pathological changes, and response to treatment in patients with AIH- Ⅰ.%目的:探讨去唾液酸糖蛋白受体抗体(Autoantibodies to asialoglycoprotein receptor,antiASGPR)阳性和阴性Ⅰ型自身免疫性肝炎(type Iauto-immune hepatitis AIH-I)在临床、生化、免疫学、遗传学、组织学特点及其治疗应答反应的差异.方法:应用酶联免疫分析法(ELISA)检测79例确诊的AIH-Ⅰ患者血清中anti-ASGPR,将其分为anti-ASGPR阳性组及阴性组.结果:患者中anti-ASGPR阳性的百分比为75%,阳性患者(n=59)中,男性(n=7),女性(n =52),平均年龄(49.1±8.6)岁;阴性患者(n=20)中,男性(n=2),女性(n=18),平均年龄(47.1±7.9)岁,阳性患者与阴性患者在年龄、性别、ALT、AST、ALP、GGT、ANA、SMA、DR3、DR4

  15. 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)...

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Cloning and expression of the human asialoglycoprotein receptor H1 subunit and preliminary application%去唾液酸糖蛋白受体H1亚单位基因片段的克隆表达及其检测自身免疫性肝炎的价值

    Institute of Scientific and Technical Information of China (English)

    张妍; 李永哲; 吴琳; 刘国振; 张蜀澜; 胡朝军; 佟大伟

    2009-01-01

    Objective To clone and express the human asialoglycoprotein receptor(ASGPR) H1 subunit, purify and identify the immunoreactivity of the recombinant protein, and establish the enzyme linked immunosorbent assay (ELISA) to detect anti-ASGPR antibodies in diagnosis of autoimmune hepatitis. Methods The CRDHI cDNA (435 bp) was subcloned into eukaryotic vector PEGH, and the recombinant protein expression was induced by D (+)-Galactose. The recombinant CRDH1 was purified with Glutathione Sepharose 4B, and its immunoreactivity was identified by SDS-PAGE and western blot as well as MALDI-TOF. ELISA was established to detect the anti-ASGPR antibodies in serum samples of 45 patients with AIH, 30 patients with SLE, 30 patients with RA, 10 patients with SS and 30 normal controls. Results The sequencing of recombinant plasmid showed the CRDH1 gene was successfully inserted to the eukaryotic expression vector with correct sequence and open reading frame. The fusion protein showed a molecular weight of 42 500 Da on SDS-PAGE gel and confirmed to be the human ASGPR by MALDI-MS through peptide mass fingerprint analysis with Mascot in human protein database. It shared 98. 34% homology with ASGPR H1 subunit. Western blot analysis showed that the fusion protein had the same immunoreactivity as human ASGPR. The results of ELISA indicated that the positive rate of anti-ASGPR was 35.6% ( 16/45 ), but the ELISA was negative in other control. There was significant difference of positivity of the autoantibodies between AIH and non-AIH controls (χ2 = 31.85,P < 0. 01 ). Conclusions The human plasmid containing ASGPR is successfully clone into Saccharomyces cerevisiae Y258. The recombinant autoantigen owns good antigenicity and specificity. ELISA established with the purified protein shows good specificity for diagnosis of AIH.%目的 克隆去唾液酸糖蛋白受体(asialoglycoprotein reeeptor,ASGPR)H1亚单位显性表位435 bp基因片段,构建表达重组质粒,进行表达、纯化,以

  18. 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,...

  19. Neuromedin U Receptor 2-Deficient Mice Display Differential Responses in Sensory Perception, Stress, and Feeding▿

    OpenAIRE

    Zeng, Hongkui; Gragerov, Alexander; Hohmann, John G.; Pavlova, Maria N.; Schimpf, Brian A.; Xu, Hui; Wu, Long-Jun; Toyoda, Hiroki; Zhao, Ming-Gao; Rohde, Alex D.; Gragerova, Galina; Onrust, Rene; Bergmann, John E.; Zhuo, Min; Gaitanaris, George A.

    2006-01-01

    Neuromedin U (NMU) is a highly conserved neuropeptide with a variety of physiological functions mediated by two receptors, peripheral NMUR1 and central nervous system NMUR2. Here we report the generation and phenotypic characterization of mice deficient in the central nervous system receptor NMUR2. We show that behavioral effects, such as suppression of food intake, enhanced pain response, and excessive grooming induced by intracerebroventricular NMU administration were abolished in the NMUR2...

  20. 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

  1. 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...

  2. 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...

  3. 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…

  4. 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...

  5. An unusual case of iron deficiency anemia is associated with extremely low level of transferrin receptor.

    Science.gov (United States)

    Hao, Shuangying; Li, Huihui; Sun, Xiaoyan; Li, Juan; Li, Kuanyu

    2015-01-01

    A case study of a female patient, diagnosed with iron deficiency anemia, was unresponsive to oral iron treatment and only partially responsive to parenteral iron therapy, a clinical profile resembling the iron-refractory iron deficiency anemia (IRIDA) disorder. However, the patient failed to exhibit microcytic phenotype, one of the IRIDA hallmarks. Biochemical assays revealed that serum iron, hepcidin, interluekin 6, and transferrin saturation were within the normal range of references or were comparable to her non-anemic offspring. Iron contents in serum and red blood cells and hemoglobin levels were measured, which confirmed the partial improvement of anemia after parenteral iron therapy. Strikingly, serum transferrin receptor in patient was almost undetectable, reflecting the very low activity of bone-marrow erythropoiesis. Our data demonstrate that this is not a case of systemic iron deficiency, but rather cellular iron deficit due to the low level of transferrin receptor, particularly in erythroid tissue.

  6. Prokaryotic expression of asialoglycoprotein receptor H1 subunit and its application in the diagnosis of autoimmune hepatitis%去唾液酸糖蛋白受体H1亚单位表达及用于自身免疫性肝炎诊断的研究

    Institute of Scientific and Technical Information of China (English)

    乔健; 姜东林; 薛育政; 龚芳; 李成万

    2014-01-01

    去唾液酸糖蛋白受体(asialoglycoprotein receptor,ASGPR)是肝细胞膜表面特有的一种内吞性受体,H1是参与内吞功能的主要亚基.自身免疫性肝炎(autoimmune-hepatitis,AIH)患者存在抗-ASGPR的自身抗体.本研究以去唾液酸糖蛋白受体H1亚基在大肠杆菌中诱导表达,用纯化的重组去唾液酸糖蛋白受体H1亚单位rH1作为检测抗原,建立间接法rH1-IgG-ELISA,检测抗去唾液酸糖蛋白受体IgG抗体,观察其阳性和阴性符合率,并对rH1-IgG-ELISA检测的精确度、灵敏度和特异性进行评价.结果显示制备的rH1重组蛋白纯度在90%以上;以该重组抗原建立的rH1-IgG-ELISA的最佳检测条件为:重组抗原rH1的包被浓度为6 μg/ml,血清稀释度1 ∶ 100,酶标记的羊抗人IgG 1∶3000稀释;用rH1-IgG-ELISA对混合ASGPR阳性和阴性血清的重复检测表明:IgG阳性血清的检测值的变异系数(CV值)为9.9%,IgG阴性血清的CV值为9.7%;灵敏度检测表明血清稀释度在1∶50~1∶200均可检出阳性;特异性试验的抑制率为63.5%; rH1-IgG-ELISA与总符合率为87.36%,其中阳性和阴性符合率分别为82%(41/50)和93.33%(42/45).故建立的rH1-IgG-ELISA具有较好的灵敏性和特异性,与提供的ASGPR阳性血清有较高的符合率,表明该法具有较好的AIH诊断价值,可进一步推广应用.

  7. Study on the role of asialoglycoprotein receptor for human bone marrow mesenchymal stem cells against hepatitis B virus infection%骨髓间充质干细胞对乙型肝炎病毒的易感性及与无涎糖蛋白受体的关系

    Institute of Scientific and Technical Information of China (English)

    谢婵; 谢仕斌; 张绍全; 谢俊强; 林炳亮; 高志良

    2010-01-01

    Objective To investigate the susceptibility of bone marrow mesenchymal stem cell (BMSC) to hepatitis B virus (HBV) infection during induction toward hepatocyte and the role of asialoglycoprotein receptor (ASGPR) in BMSC HBV infection. Methods BMSC obtained from hepatitis B patients were tested for HBV infection and then cultured with HBV infectious serum in vitro and induced to differentiate into hepatocyte through exposure to hepatocyte growth factor (HGF), fibroblast growth factor-4(FGF-4), and epidermal growth factor(EGF). Subsequently these cells were determined for the presence of hepatitis B virus e antigen( HBeAg), hepatitis B virus surface antigen(HBsAg) and ASGPR. All experiments were repeated for 3 times in 5 different samples. The results were analyzed by non-parametric test. Results After 6 days of exposure, BMSC-derived hepatocyte-like cells expressed hepatic special genes and proteins, including alpha fetoprotein(AFP),cytokeratin18 (CK18), albumin (Alb), and manifested hepatocyte functions, including glycogen synthesis, urea secretion and albumin synthesis. Expressions of CK18 and Alb were increased, and AFP was decreased with time of induction. The BMSC were resistant to HBV infection both in vitro and in vivo or after induction toward hepatocyte. ASGPR expression level was low in BMSC, which was increased in the induced BMSC but still lower than that of the control HepG2 cells. Conclusions BMSC are resistant to HBV infection both in vitro and in vivo. The low level expression of ASGPR may be a reason for this.%目的 评价骨髓间充质干细胞(BMSC)向肝细胞诱导过程中对HBV的易感性及无涎糖蛋白受体(ASGPR)对BMSC感染HBV的作用.方法 体外使用肝细胞生长因子、成纤维细胞生长因子-4和表皮生长因子,将BMSC诱导分化为肝细胞.检测乙型肝炎患者BMSC的HBV感染情况,并对原代及诱导培养后的BMSC进行体外HBV感染实验,检测BMSC感染后的HBsAg、HBcAg表达情况,并检测BMSC

  8. Assessment of hepatic functional reserve by converted asialoglycoprotein receptor values calculated from parameters of indocyanine green test and thromboelastograph%应用吲哚青绿试验与血栓弹力图替代去唾液酸糖蛋白受体分析定量评估肝储备功能

    Institute of Scientific and Technical Information of China (English)

    张珂; 郭立民; 穆毅; 蒋力; 贾哲; 李宝亮; 赫嵘; 黄容海; 鲁岩; 李勤涛; 丁振昊

    2014-01-01

    目的:应用吲哚青绿实验与血栓弹力图检测指标,替代肝细胞表面去唾液酸糖蛋白受体分析,建立肝储备功能定量评估系统,并与Child-Pugh评分进行比较,了解其在肝切除术患者肝储备功能评估中的临床应用价值。方法对2012年1月1日至12月31日于本科室行肝部分切除术肝占位病变的患者共55例,测量PHCASGPR+、ICGR15、EHBF、R值与K值,建立以PHCASGPR+为因变量(Y), ICGR15、EHBF、R值与K值为自变量(Xn)的肝储备功能定量评估系统,与Child-Pugh评分进行比较,了解两种方法预测术后肝功能代偿情况的准确率。结果 Child-Pugh预测术后肝功能代偿良好准确率为56.67%,Y值预测术后肝功能代偿良好准确率为84.62%(χ2=5.374,P =0.020);Child-Pugh预测术后肝功能代偿不全准确率为76.00%,Y值预测术后肝功能代偿不全准确率为96.55%(χ2=5.400,P =0.020)。结论建立的肝储备功能定量评估系统能够更全面评价肝切除患者围手术期肝储备功能。%Objective To verify the value of asialoglycoprotein receptors (ASGPR) analyzed by lfow cytometry (FCM) in assessing hepatic functional reserve, and establish a conversion formula for the ASGPR value with the parameters of indocyanine green (ICG) test and thromboelastography (TEG). This assessment method was compared with the Child-Pugh score to evaluate its predictive value for hepatic functional reserve in patients undergoing liver resection.Methods Total of 55 patients with liver tumors had partial hepatectomy in our department from January 1st to December 31st, 2012. The percentages of ASGPR+hepatocyte (PHCASGPR+), ICGR15, effective hepatic blood lfow (EHBF), R value and K value were examined to establish the quantitative assessment method for liver functional reserve. The PHCASGPR+ was defined as a dependent variable (Y) while the ICGR15, EHBF, R value and K value were defined as independent variables

  9. Diagnosis of Iron Deficiency in Inflammatory Bowel Disease by Transferrin Receptor-Ferritin Index.

    Science.gov (United States)

    Abitbol, Vered; Borderie, Didier; Polin, Vanessa; Maksimovic, Fanny; Sarfati, Gilles; Esch, Anouk; Tabouret, Tessa; Dhooge, Marion; Dreanic, Johann; Perkins, Geraldine; Coriat, Romain; Chaussade, Stanislas

    2015-07-01

    Iron deficiency is common in patients with inflammatory bowel disease (IBD), but can be difficult to diagnose in the presence of inflammation because ferritin is an acute phase reactant. The transferrin receptor-ferritin index (TfR-F) has a high sensitivity and specificity for iron deficiency diagnosis in chronic diseases. The diagnostic efficacy of TfR-F is little known in patients with IBD. The aim of the study was to assess the added value of TfR-F to iron deficiency diagnosis in a prospective cohort of patients with IBD.Consecutive IBD patients were prospectively enrolled. Patients were excluded in case of blood transfusion, iron supplementation, or lack of consent. IBD activity was assessed on markers of inflammation (C-reactive protein, endoscopy, fecal calprotectin). Hemoglobin, ferritin, vitamin B9 and B12, Lactate dehydrogenase, haptoglobin, and soluble transferrin receptor (sTfR) were assayed. TfR-F was calculated as the ratio sTfR/log ferritin. Iron deficiency was defined by ferritin 2 in the presence of inflammation.One-hundred fifty patients with median age 38 years (16-78) and Crohn disease (n = 105), ulcerative colitis (n = 43), or unclassified colitis (n = 2) were included. Active disease was identified in 45.3%. Anemia was diagnosed in 28%. Thirty-six patients (24%) had ferritin deficiency excluding TfR-F analysis, 13 of 30 (43.3%) had TfR-F >2. Overall, iron deficiency was diagnosed in 32.7% of the patients.TfR-F in addition to ferritin iron deficiency. TfR-F appeared as a useful biomarker that could help physicians to diagnose true iron deficiency in patients with active IBD.

  10. Vitamin D receptor deficiency impairs inner ear development in zebrafish.

    Science.gov (United States)

    Kwon, Hye-Joo

    2016-09-16

    The biological actions of vitamin D are largely mediated through binding to the vitamin D receptor (VDR), a member of the nuclear hormone receptor family, which regulates gene expression in a wide variety of tissues and cells. Mutations in VDR gene have been implicated in ear disorders (hearing loss and balance disorder) but the mechanisms are not well established. In this study, to investigate the role of VDR in inner ear development, morpholino-mediated gene knockdown approaches were used in zebrafish model system. Two paralogs for VDR, vdra and vdrb, have been identified in zebrafish. Knockdown of vdra had no effect on ear development, whereas knockdown of vdrb displayed morphological ear defects including smaller otic vesicles with malformed semicircular canals and abnormal otoliths. Loss-of-vdrb resulted in down-regulation of pre-otic markers, pax8 and pax2a, indicating impairment of otic induction. Furthermore, zebrafish embryos lacking vdrb produced fewer sensory hair cells in the ears and showed disruption of balance and motor coordination. These data reveal that VDR signaling plays an important role in ear development. PMID:27526995

  11. 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.

  12. Stromal endothelin B receptor-deficiency inhibits breast cancer growth and metastasis

    OpenAIRE

    Binder, Claudia; Hagemann, Thorsten; Sperling, Swetlana; Schulz, Matthias; Pukrop, Tobias; Grimshaw, Matthew J; Ehrenreich, Hannelore

    2009-01-01

    The endothelin (ET) axis, often deregulated in cancers, is a promising target for anticancer strategies. While previous investigations have focussed mostly on ET action in malignant cells, we chose a model, allowing separate assessment of the effects of ETs and their receptors ETAR and ETBR in the tumor cells and the stromal compartment, which is increasingly recognized as a key player in cancer progression. In homozygous spotting lethal rats (sl/sl), a model of constitutive ETBR-deficiency, ...

  13. Familial hypercholesterolemia in a rhesus monkey pedigree: molecular basis of low density lipoprotein receptor deficiency.

    OpenAIRE

    HUMMEL, M.; Li, Z G; Pfaffinger, D; Neven, L.; Scanu, A M

    1990-01-01

    We have recently identified a family of rhesus monkeys with members exhibiting a spontaneous hypercholesterolemia associated with a low density lipoprotein receptor (LDLR) deficiency. By using the polymerase chain reaction, we now show that the affected monkeys are heterozygous for a nonsense mutation in exon 6 of the LDLR gene. This mutation changes the sequence of the codon for amino acid 284 (tryptophan) from TGG to TAG, thereby generating a nonsense codon potentially resulting in a trunca...

  14. Citrullus lanatus `Sentinel' (Watermelon) Extract Reduces Atherosclerosis in LDL Receptor Deficient Mice

    OpenAIRE

    Poduri, Aruna; Rateri, Debra L.; Saha, Shubin K.; Saha, Sibu; Daugherty, Alan

    2012-01-01

    Watermelon (Citrullus lanatus or C. lanatus) has many potentially bioactive compounds including citrulline, which may influence atherosclerosis. In this study, we determined the effects of C. lanatus, provided as an extract of the cultivar `sentinel', on hypercholesterolemia-induced atherosclerosis in mice. Male LDL receptor deficient mice at 8 weeks old were given either C. lanatus `sentinel' extract (2% vol/vol; n=10) or a mixture of matching carbohydrates (2% vol/vol; n=8) as the control i...

  15. The Relationship Between Gene Polymorphism of Leptin and Leptin Receptor and Growth Hormone Deficiency

    OpenAIRE

    He, Jinshui; Fang, Yanling; Lin, Xinfu; Zhou, Huowang; ZHU, SHAOBO; Zhang, Yugui; Yang, Huicong; Ye, Xiaoling

    2016-01-01

    Backgrounds Growth hormone deficiency (GHD) is a major cause of congenital short stature. GHD patients have significantly decreased serum leptin levels, which are regulated by gene polymorphism of leptin and leptin receptor. This study thus investigated the relationship between gene polymorphism and susceptibility to GHD. Material/Methods A case-control study was performed using 180 GHD children in addition to 160 healthy controls. After the extraction of whole genomic DNA, the genotypes of l...

  16. CRF2 receptor-deficiency eliminates opiate withdrawal distress without impairing stress coping.

    Science.gov (United States)

    Ingallinesi, M; Rouibi, K; Le Moine, C; Papaleo, F; Contarino, A

    2012-12-01

    The opiate withdrawal syndrome is a severe stressor that powerfully triggers addictive drug intake. However, no treatment yet exists that effectively relieves opiate withdrawal distress and spares stress-coping abilities. The corticotropin-releasing factor (CRF) system mediates the stress response, but its role in opiate withdrawal distress and bodily strategies aimed to cope with is unknown. CRF-like signaling is transmitted by two receptor pathways, termed CRF(1) and CRF(2). Here, we report that CRF(2) receptor-deficient (CRF(2)(-/-)) mice lack the dysphoria-like and the anhedonia-like states of opiate withdrawal. Moreover, in CRF(2)(-/-) mice opiate withdrawal does not increase the activity of brain dynorphin, CRF and periaqueductal gray circuitry, which are major substrates of opiate withdrawal distress. Nevertheless, CRF(2) receptor-deficiency does not impair brain, neuroendocrine and autonomic stress-coping responses to opiate withdrawal. The present findings point to the CRF(2) receptor pathway as a unique target to relieve opiate withdrawal distress without impairing stress-coping abilities.

  17. Quantitative evaluation of liver functional reserve by asialoglycoprotein receptor and clinical test indexs%应用去唾液酸糖蛋白受体及临床指标建立肝储备功能定量评估系统

    Institute of Scientific and Technical Information of China (English)

    李勤涛; 丁振昊; 郭立民; 穆毅; 蒋力; 张珂; 黄容海; 李宝亮; 贾哲; 鲁岩; 赫嵘

    2014-01-01

    目的:探讨应用肝细胞表面ASGPR流式细胞分析及临床指标建立肝储备功能定量评估系统,并与Child-Pugh评分进行比较,了解其在患者术前肝储备功能评估中的临床应用价值。方法选择32例肝占位病变行肝部分切除术患者,术前检测ICGR15与EHBF、R值与K值以及临床生化指标、Child-Pugh评分,以此作为自变量(Xn),以肝组织标本PHCASGPR+为因变量(Y),通过多元线性回归分析,建立肝储备功能定量评估系统,并与Child-Pugh评分进行比较,了解两种方法预测术后肝功能代偿情况的准确率。按照回归方程计算46例肝占位病变接受肝部分切除术及肝硬化并门脉高压症接受断流术患者肝储备功能定量值,评估肝储备功能情况,预测术后肝功能恢复情况,比较术前不同Child-Pugh分级与Y值患者术后肝功能恢复情况。结果在预测术后肝功能代偿良好准确率方面,Y值优于Child-Pugh分级(P =0.030);而在预测术后肝功能代偿不良准确率方面,Y值与Child-Pugh分级无统计学差异(P =1.000)。结论新肝储备功能定量评估系统能一定程度提高肝切除或肝硬化患者术前肝储备功能评价准确度,具有临床应用价值。%Objective To investigate a quantitative assessment of hepatic functional reserve using flow cytometric analysis of asialoglycoprotein receptors (ASGPR) on the liver cell surface and regular clinical indexes. This assessment method was compared with the Child-Pugh score to evaluate its predictive value for hepatic functional reserve in patients undergoing liver resection or devascularization. Methods Total of 32 patients with liver tumors had partial hepatectomy. The percentage of the ASGPR+hepatocyte (PHCASGPR+), ICGR15, effective hepatic blood flow (EHBF), the R value, the K value and regular clinical parameters were examined to evaluate a quantitative assessment method for liver functional

  18. 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...... 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...... of the P2X7R KO mouse. Further experiments are needed to elucidate the exact role of the P2X7 receptors in bone cancer pain. Pain-related behaviours had an earlier onset in bone cancer-bearing, P2X7 receptor-deficient mice, and treatment with A-438079 failed to alleviate pain-related behaviours....

  19. Establishment and characterization of DB-1: a leptin receptor-deficient murine macrophage cell line.

    Science.gov (United States)

    Dib, Lea H; Ortega, M Teresa; Melgarejo, Tonatiuh; Chapes, Stephen K

    2016-08-01

    Metabolic and immune mediators activate many of the same signal transduction pathways. Therefore, molecules that regulate metabolism often affect immune responses. Leptin is an adipokine that exemplifies this interplay. Leptin is the body's major nutritional status sensor, but it also plays a key role in immune system regulation. To provide an in vitro tool to investigate the link between leptin and innate immunity, we immortalized and characterized a leptin receptor-deficient macrophage cell line, DB-1. The cell line was created using bone marrow cells from leptin receptor-deficient mice. Bone marrow cells were differentiated into macrophages by culturing them with recombinant mouse macrophage colony stimulating factor, and passaged when confluent for 6 months. The cells spontaneously immortalized at approximately passage 20. Cells were cloned twice by limiting dilution cloning prior to characterization. The macrophage cell line is diploid and grows at a linear rate for 4-5 days before reaching the growth plateau. The cells are MAC-2 and F4/80 positive and have phagocytic activity similar to primary macrophages from wild-type and leptin receptor-deficient mice. DB-1 cells were responsive to stimulation with interferon-γ as measured by increase in Nos2 transcript levels. In addition, DB-1 macrophages are not responsive to the chemotactic signaling of adipocyte conditioned media nor leptin when compared to primary WT macrophages. We believe that DB-1 cells provide a dependable tool to study the role of leptin or the leptin receptor in obesity-associated inflammation and immune system dysregulation. PMID:25599862

  20. 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...

  1. 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 diet-induc

  2. 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.

  3. Helicobacter hepaticus infection promotes hepatitis and preneoplastic foci in farnesoid X receptor (FXR deficient mice.

    Directory of Open Access Journals (Sweden)

    Alton G Swennes

    Full Text Available Farnesoid X receptor (FXR is a nuclear receptor that regulates bile acid metabolism and transport. Mice lacking expression of FXR (FXR KO have a high incidence of foci of cellular alterations (FCA and liver tumors. Here, we report that Helicobacter hepaticus infection is necessary for the development of increased hepatitis scores and FCA in previously Helicobacter-free FXR KO mice. FXR KO and wild-type (WT mice were sham-treated or orally inoculated with H. hepaticus. At 12 months post-infection, mice were euthanized and liver pathology, gene expression, and the cecal microbiome were analyzed. H. hepaticus induced significant increases hepatitis scores and FCA numbers in FXR KO mice (P<0.01 and P<0.05, respectively. H. hepaticus altered the beta diversity of cecal microbiome in both WT and FXR KO mice compared to uninfected mice (P<0.05. Significant upregulation of β-catenin, Rela, Slc10a1, Tlr2, Nos2, Vdr, and Cyp3a11 was observed in all FXR KO mice compared to controls (P<0.05. Importantly, H. hepaticus and FXR deficiency were necessary to significantly upregulate Cyp2b10 (P<0.01. FXR deficiency was also a potent modulator of the cecal microbiota, as observed by a strong decrease in alpha diversity. A significant decrease in Firmicutes, particularly members of the order Clostridiales, was observed in FXR KO mice (P<0.05 and FDR<5%, ANOVA. While FXR deficiency strongly affects expression of genes related to immunity and bile acid metabolism, as well as the composition of the microbiome; however, its deficiency was not able to produce significant histopathological changes in the absence of H. hepaticus infection.

  4. Emotional response in dopamine D2L receptor-deficient mice

    OpenAIRE

    Hranilovic, Dubravka; Bucan, Maja; Wang, Yanyan

    2008-01-01

    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 reflec...

  5. Toll-like receptor-2 deficiency enhances non-alcoholic steatohepatitis

    Directory of Open Access Journals (Sweden)

    Brady Kristen

    2010-05-01

    Full Text Available Abstract Background Previously we reported that mice deficient in toll-like receptor 4 (TLR-4 signalling were protected from diet-induced non-alcoholic steatohepatitis (NASH. Another member of the toll-like receptor family, TLR-2, has been shown to play a role in lipid trafficking via uptake of diacylated lipoproteins. However, a role for TLR-2 in NASH has not been elucidated. The objectives of the current study were to examine the influence of dietary fat quality and TLR-2 on NASH pathogenesis. Methods Steatohepatitis was induced in male Db, C57BL/6 and TLR-2-/- mice by feeding an L-amino acid-defined diet that was deficient in methionine and choline (MCDD. Mice fed the base diet supplemented with methionine and choline (control diet; CD were used as controls. To determine the role of fat quality, MCDD was enriched with polyunsaturated corn oil (PUFA or coconut oil that is comprised mostly of saturated fat (SAFA; the total amount of each fat was 112.9 g/kg of diet. After 8 weeks of feeding CD or MCDD, hepatic steatosis, inflammation and necrosis were evaluated in histological sections. Total RNA was extracted from frozen liver samples and mRNA expression of TNFα, collagen α1, IL-10, peroxisome proliferator-activated receptor-γ (PPAR-γ, TLR-4, and CD14, was analyzed via real-time PCR. Protein levels of TLR-2 were analyzed by western blot. Results Panlobular macrovessicular steatosis and diffuse leukocyte infiltration were noted in PUFA-fed Db mice. Histological scores demonstrated significantly less steatosis, inflammation and necrosis in SAFA-fed mice of all mouse strains. However, compared to wild type mice, hepatocellular damage was notably more severe in TLR-2-/- mice. Consistent with histological findings, mRNA expression of TNFα was elevated by approximately 3-fold in TLR-2-/- mice; PPAR-γ expression was blunted in this strain compared to wild type. Expression of the matrix protein collagen αI was also significantly higher in TLR-2

  6. Maternal profiling of corticotropin-releasing factor receptor 2 deficient mice in association with restraint stress

    OpenAIRE

    D’Anna, Kimberly L.; Sharon A Stevenson; Gammie, Stephen C.

    2008-01-01

    Mice deficient in corticotropin releasing factor receptor 2 (CRF2) (C57BL/6J:129Sv background) exhibit impaired maternal defense (protection of offspring) and are more reactive to stressors than wild-type mice. To further understand CRF2’s role in maternal behavior, we crossed the knockout mice with a line bred for high maternal defense that also has elevated maternal care relative to inbred lines. Maternal care was normal in knockout mice (relative to wild-type). Maternal defense was impaire...

  7. 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.

  8. 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.

  9. Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2.

    Science.gov (United States)

    Molina, H; Holers, V M; Li, B; Fung, Y; Mariathasan, S; Goellner, J; Strauss-Schoenberger, J; Karr, R W; Chaplin, D D

    1996-04-16

    Complement receptor 1 (CR1, CD35) and complement receptor 2 (CR2, CD21) have been implicated as regulators of B-cell activation. We explored the role of these receptors in the development of humoral immunity by generating CR1- and CR2-deficient mice using gene-targeting techniques. These mice have normal basal levels of IgM and of IgG isotypes. B- and T-cell development are overtly normal. Nevertheless, B-cell responses to low and high doses of a T-cell-dependent antigen are impaired with decreased titers of antigen-specific IgM and IgG isotypes. This defect is not complete because there is still partial activation of B lymphocytes during the primary immune response, with generation of splenic germinal centers and a detectable, although reduced, secondary antibody response. These data suggest that certain T-dependent antigens manifest an absolute dependence on complement receptors for the initiation of a normally robust immune response. PMID:8622941

  10. Genetic NMDA receptor deficiency disrupts acute and chronic effects of cocaine but not amphetamine.

    Science.gov (United States)

    Ramsey, Amy J; Laakso, Aki; Cyr, Michel; Sotnikova, Tatyana D; Salahpour, Ali; Medvedev, Ivan O; Dykstra, Linda A; Gainetdinov, Raul R; Caron, Marc G

    2008-10-01

    NMDA receptor-mediated glutamate transmission is required for several forms of neuronal plasticity. Its role in the neuronal responses to addictive drugs is an ongoing subject of investigation. We report here that the acute locomotor-stimulating effect of cocaine is absent in NMDA receptor-deficient mice (NR1-KD). In contrast, their acute responses to amphetamine and to direct dopamine receptor agonists are not significantly altered. The striking attenuation of cocaine's acute effects is not likely explained by alterations in the dopaminergic system of NR1-KD mice, since most parameters of pre- and postsynaptic dopamine function are unchanged. Consistent with the behavioral findings, cocaine induces less c-Fos expression in the striatum of these mice, while amphetamine-induced c-Fos expression is intact. Furthermore, chronic cocaine-induced sensitization and conditioned place preference are attenuated and develop more slowly in mutant animals, but amphetamine's effects are not altered significantly. Our results highlight the importance of NMDA receptor-mediated glutamatergic transmission specifically in cocaine actions, and support a hypothesis that cocaine and amphetamine elicit their effects through differential actions on signaling pathways. PMID:18185498

  11. Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2.

    Science.gov (United States)

    Molina, H; Holers, V M; Li, B; Fung, Y; Mariathasan, S; Goellner, J; Strauss-Schoenberger, J; Karr, R W; Chaplin, D D

    1996-04-16

    Complement receptor 1 (CR1, CD35) and complement receptor 2 (CR2, CD21) have been implicated as regulators of B-cell activation. We explored the role of these receptors in the development of humoral immunity by generating CR1- and CR2-deficient mice using gene-targeting techniques. These mice have normal basal levels of IgM and of IgG isotypes. B- and T-cell development are overtly normal. Nevertheless, B-cell responses to low and high doses of a T-cell-dependent antigen are impaired with decreased titers of antigen-specific IgM and IgG isotypes. This defect is not complete because there is still partial activation of B lymphocytes during the primary immune response, with generation of splenic germinal centers and a detectable, although reduced, secondary antibody response. These data suggest that certain T-dependent antigens manifest an absolute dependence on complement receptors for the initiation of a normally robust immune response.

  12. The Relationship Between Gene Polymorphism of Leptin and Leptin Receptor and Growth Hormone Deficiency.

    Science.gov (United States)

    He, Jinshui; Fang, Yanling; Lin, Xinfu; Zhou, Huowang; Zhu, Shaobo; Zhang, Yugui; Yang, Huicong; Ye, Xiaoling

    2016-01-01

    BACKGROUND Growth hormone deficiency (GHD) is a major cause of congenital short stature. GHD patients have significantly decreased serum leptin levels, which are regulated by gene polymorphism of leptin and leptin receptor. This study thus investigated the relationship between gene polymorphism and susceptibility to GHD. MATERIAL AND METHODS A case-control study was performed using 180 GHD children in addition to 160 healthy controls. After the extraction of whole genomic DNA, the genotypes of leptin and leptin receptor gene loci were analyzed by sequencing for single-nucleotide polymorphism. RESULTS The frequency distribution of all alleles identified in leptin gene (loci rs7799039) and leptin receptor gene (loci rs1137100 and rs1137101) fit Hardy-Weinberg equilibrium. There was a significant difference in allele frequency at loci rs7799039 or rs1137101, as individuals with heterozygous GA allele had lower (rs7799039) or higher (rs1137101) GHD risk. No significant difference in allele frequency was discovered at loci rs1137100 (p>0.05), which was unrelated to GHD susceptibility. CONCLUSIONS Gene polymorphism of leptin (loci rs7799039) and leptin receptor (loci rs1137101) are correlated with GHD susceptibility. PMID:26915772

  13. Antidepressant activity of fluoxetine in the zinc deficiency model in rats involves the NMDA receptor complex.

    Science.gov (United States)

    Doboszewska, Urszula; Szewczyk, Bernadeta; Sowa-Kućma, Magdalena; Młyniec, Katarzyna; Rafało, Anna; Ostachowicz, Beata; Lankosz, Marek; Nowak, Gabriel

    2015-01-01

    The zinc deficiency animal model of depression has been proposed; however, it has not been validated in a detailed manner. We have recently shown that depression-like behavior induced by dietary zinc restriction is associated with up-regulation of hippocampal N-methyl-d-aspartate receptor (NMDAR). Here we examined the effects of chronic administration of a selective serotonin reuptake inhibitor, fluoxetine (FLX), on behavioral and biochemical alterations (within NMDAR signaling pathway) induced by zinc deficiency. Male Sprague Dawley rats were fed a zinc adequate diet (ZnA, 50mg Zn/kg) or a zinc deficient diet (ZnD, 3mg Zn/kg) for 4 weeks. Then, FLX treatment (10mg/kg, i.p.) begun. Following 2 weeks of FLX administration the behavior of the rats was examined in the forced swim test (FST) and the spontaneous locomotor activity test. Twenty four hours later tissue was harvested. The proteins of NMDAR (GluN1, GluN2A and GluN2B) or AMPAR (GluA1) subunits, p-CREB and BDNF in the hippocampus (Western blot) and serum zinc level (TXRF) were examined. Depression-like behavior induced by ZnD in the FST was sensitive to chronic treatment with FLX. ZnD increased levels of GluN1, GluN2A, GluN2B and decreased pS485-GluA1, p-CREB and BDNF proteins. Administration of FLX counteracted the zinc restriction-induced changes in serum zinc level and hippocampal GluN1, GluN2A, GluN2B and p-CREB but not BDNF or pS845-GluA1 protein levels. This finding adds new evidence to the predictive validity of the proposed zinc deficiency model of depression. Antidepressant-like activity of FLX in the zinc deficiency model is associated with NMDAR complex. PMID:25845739

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

    OpenAIRE

    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 diet-induced obesity. Whether this phenotype of CB1-/- mice is related to altered fat metabolism in adipose tissue is unknown. Methods: We evaluated adipose tissue differentiation/proliferation markers and q...

  15. Altered hippocampal long-term synaptic plasticity in mice deficient in the PGE2 EP2 receptor

    OpenAIRE

    Yang, Hongwei; Zhang, Jian; Breyer, Richard M.; Chen, Chu

    2008-01-01

    Our laboratory demonstrated previously that PGE2-induced modulation of hippocampal synaptic transmission is via a presynaptic PGE2 EP2 receptor. However, little is known about whether the EP2 receptor is involved in hippocampal long-term synaptic plasticity and cognitive function. Here we show that long-term potentiation (LTP) at the hippocampal perforant path synapses was impaired in mice deficient in the EP2 (KO), while membrane excitability and passive properties in granule neurons were no...

  16. Reduced locomotor activity and exploratory behavior in CC chemokine receptor 4 deficient mice.

    Science.gov (United States)

    Ambrée, Oliver; Klassen, Irene; Förster, Irmgard; Arolt, Volker; Scheu, Stefanie; Alferink, Judith

    2016-11-01

    Chemokines and their receptors are key regulators of immune cell trafficking and activation. Recent findings suggest that they may also play pathophysiological roles in psychiatric diseases like depression and anxiety disorders. The CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are functionally involved in neuroinflammation as well as anti-infectious and autoimmune responses. However, their influence on behavior remains unknown. Here we characterized the functional role of the CCR4-CCL17 chemokine-receptor axis in the modulation of anxiety-related behavior, locomotor activity, and object exploration and recognition. Additionally, we investigated social exploration of CCR4 and CCL17 knockout mice and wild type (WT) controls. CCR4 knockout (CCR4(-/-)) mice exhibited fewer anxiety-related behaviors in the elevated plus-maze, diminished locomotor activity, exploratory behavior, and social exploration, while their recognition memory was not affected. In contrast, CCL17 deficient mice did not show an altered behavior compared to WT mice regarding locomotor activity, anxiety-related behavior, social exploration, and object recognition memory. In the dark-light and object recognition tests, CCL17(-/-) mice even covered longer distances than WT mice. These data demonstrate a mechanistic or developmental role of CCR4 in the regulation of locomotor and exploratory behaviors, whereas the ligand CCL17 appears not to be involved in the behaviors measured here. Thus, either CCL17 and the alternative ligand CCL22 may be redundant, or CCL22 is the main activator of CCR4 in these processes. Taken together, these findings contribute to the growing evidence regarding the involvement of chemokines and their receptors in the regulation of behavior. PMID:27469058

  17. [Treatment approach to congenital myasthenic syndrome in a patient with acetylcholine receptor deficiency].

    Science.gov (United States)

    Ishigaki, Keiko; Murakami, Terumi; Ito, Yasushi; Yanagisawa, Akiko; Kodaira, Kayano; Shishikura, Keiko; Suzuki, Haruko; Hirayama, Yoshito; Osawa, Makiko

    2009-01-01

    Congenital myasthenic syndromes (CMS) are rare heterogeneous disorders of neurotransmission caused by genetic defects of neuromuscular junction molecules. While CMS patients have been reported worldwide, in Japan there have been only a few descriptions of adult CMS patients with acetylcholinesterase (AChE) deficiency and slow channel syndrome. Herein, we report a Japanese CMS patient with acetylcholine receptor (AChR) deficiency, diagnosed during childhood, and our treatment approach to the patient. This 13-year-old Japanese boy had had severe myasthenic symptoms since infancy. Ptosis, his first symptom, appeared at 5 months and nasal voice was recognized at 2 years of age. AchR and anti-muscle-specific tyrosine kinase (Musk) antibody remained negative. A positive tensilon test and decremental response on electromyogram supported the diagnosis of sero-negative myasthenia gravis. Despite thymectomy and strong immunosuppressive therapy including steroid pulse and FK 506, he gradually deteriorated and became wheelchair bound. Genetic analyses for AchR, Rapsyn, Musk and AChE were negative. At age 11 years, a muscle biopsy was performed in the deltoid muscle for neuromuscular junction sampling. Electron microscopic and confocal microscopic analysis of endplates showed almost complete loss of AChR and the diagnosis of CMS with AChR deficiency was confirmed. All immunosuppressive therapies were discontinued. Instead, we started Ubretide and 3,4-diaminopyridine (DAP) after obtaining informed consent. Although not approved in Japan for this use, 3,4-DAP is reportedly effective in refractory cases of CMS. The patient experienced no side effects. Despite all of the objective data were improving, his subjective symptoms and ADL remained poor. There are still many challenges in the treatment of the patient. PMID:19172815

  18. 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.

  19. Effects of Melanocortin 3 and 4 Receptor Deficiency on Energy Homeostasis in Rats

    Science.gov (United States)

    You, Panpan; Hu, Handan; Chen, Yuting; Zhao, Yongliang; Yang, Yiqing; Wang, Tongtong; Xing, Roumei; Shao, Yanjiao; Zhang, Wen; Li, Dali; Chen, Huaqing; Liu, Mingyao

    2016-01-01

    Melanocortin-3 and 4 receptors (MC3R and MC4R) can regulate energy homeostasis, but their respective roles especially the functions of MC3R need more exploration. Here Mc3r and Mc4r single and double knockout (DKO) rats were generated using CRISPR-Cas9 system. Metabolic phenotypes were examined and data were compared systematically. Mc3r KO rats displayed hypophagia and decreased body weight, while Mc4r KO and DKO exhibited hyperphagia and increased body weight. All three mutants showed increased white adipose tissue mass and adipocyte size. Interestingly, although Mc3r KO did not show a significant elevation in lipids as seen in Mc4r KO, DKO displayed even higher lipid levels than Mc4r KO. DKO also showed more severe glucose intolerance and hyperglycaemia than Mc4r KO. These data demonstrated MC3R deficiency caused a reduction of food intake and body weight, whereas at the same time exhibited additive effects on top of MC4R deficiency on lipid and glucose metabolism. This is the first phenotypic analysis and systematic comparison of Mc3r KO, Mc4r KO and DKO rats on a homogenous genetic background. These mutant rats will be important in defining the complicated signalling pathways of MC3R and MC4R. Both Mc4r KO and DKO are good models for obesity and diabetes research. PMID:27713523

  20. Serum transferrin receptor, serum ferritin and serum transferrin receptor-ferritin index in adults with iron deficiency anaemia

    International Nuclear Information System (INIS)

    Bone marrow iron store has been considered the gold standard, but is invasive, painful and expensive and not suitable for everyone. serum transferrin receptor (stfr) which is the concentration of the soluble fragment of transferrin receptor in serum, is an important new haematological parameter. the ratio of stfr to log sf is known as stfr-sf index. this study was conducted to evaluate stfr, ferritin and stfr-f index in diagnosing and differentiating iron deficiency anaemia (ida) from anaemia of chronic disease (acd). methods: one hundred and sixteen (116) adult subjects (80 anaemic and 36 controls) who already had their bone marrow examination done for various reasons were included in the study. stfr, sf, and their index were measured and compared with bone marrow iron stores. absence of iron stores denoted ida whereas increased macrophage iron with decreased siderocytes and sideroblasts was diagnostic of acd. results: out of 80 anaemic patients, 47 were diagnosed as ida while 33 were diagnosed as acd. in case of ida the diagnostic accuracy of index was 91.57%, stfr had accuracy of 85.54% while sf had accuracy of 75.90%. in case of acd, the diagnostic accuracy of stfr was 91.30%, index 89.86%, while sf had accuracy of 79.71%. conclusion: stfr-sf index is a better parameter than stfr or ferritin alone but should only be used when the results of these parameters seem altered or a bone marrow aspiration is mandatory for diagnosis of acd. the estimation of stfr or index may offer a simple non invasive method that may enable more accurate assessments of iron status in such patients. (author)

  1. Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice.

    Science.gov (United States)

    Zhang, Xiaoyan; Huang, Shizheng; Gao, Min; Liu, Jia; Jia, Xiao; Han, Qifei; Zheng, Senfeng; Miao, Yifei; Li, Shuo; Weng, Haoyu; Xia, Xuan; Du, Shengnan; Wu, Wanfu; Gustafsson, Jan-Åke; Guan, Youfei

    2014-02-11

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is mainly expressed in liver and small intestine, where it plays an important role in bile acid, lipid, and glucose metabolism. The kidney also has a high FXR expression level, with its physiological function unknown. Here we demonstrate that FXR is ubiquitously distributed in renal tubules. FXR agonist treatment significantly lowered urine volume and increased urine osmolality, whereas FXR knockout mice exhibited an impaired urine concentrating ability, which led to a polyuria phenotype. We further found that treatment of C57BL/6 mice with chenodeoxycholic acid, an FXR endogenous ligand, significantly up-regulated renal aquaporin 2 (AQP2) expression, whereas FXR gene deficiency markedly reduced AQP2 expression levels in the kidney. In vitro studies showed that the AQP2 gene promoter contained a putative FXR response element site, which can be bound and activated by FXR, resulting in a significant increase of AQP2 transcription in cultured primary inner medullary collecting duct cells. In conclusion, the present study demonstrates that FXR plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up-regulating its target gene AQP2 expression in the collecting ducts. PMID:24464484

  2. 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.

  3. Anti-phospholipid antibodies restore mesenteric ischemia/reperfusion-induced injury in complement receptor 2/complement receptor 1-deficient mice.

    Science.gov (United States)

    Fleming, Sherry D; Egan, Ryan P; Chai, Chunyan; Girardi, Guillermina; Holers, V Michael; Salmon, Jane; Monestier, Marc; Tsokos, George C

    2004-12-01

    Complement receptor 2-deficient (Cr2(-/-)) mice are resistant to mesenteric ischemia/reperfusion (I/R) injury because they lack a component of the natural Ab repertoire. Neither the nature of the Abs that are involved in I/R injury nor the composition of the target Ag, to which recognition is lacking in Cr2(-/-) mice, is known. Because anti-phospholipid Abs have been shown to mediate fetal growth retardation and loss when injected into pregnant mice, we performed experiments to determine whether anti-phospholipid Abs can also reconstitute I/R injury and, therefore, represent members of the injury-inducing repertoire that is missing in Cr2(-/-) mice. We demonstrate that both murine and human monoclonal and polyclonal Abs against negatively charged phospholipids can reconstitute mesenteric I/R-induced intestinal and lung tissue damage in Cr2(-/-) mice. In addition, Abs against beta2 glycoprotein I restore local and remote tissue damage in the Cr2(-/-) mice. Unlike Cr2(-/-) mice, reconstitution of I/R tissue damage in the injury-resistant Rag-1(-/-) mouse required the infusion of both anti-beta2-glycoprotein I and anti-phospholipid Ab. We conclude that anti-phospholipid Abs can bind to tissues subjected to I/R insult and mediate tissue damage. PMID:15557203

  4. CB1 receptor deficiency decreases wheel-running activity: consequences on emotional behaviours and hippocampal neurogenesis.

    Science.gov (United States)

    Dubreucq, Sarah; Koehl, Muriel; Abrous, Djoher N; Marsicano, Giovanni; Chaouloff, Francis

    2010-07-01

    Chronic voluntary wheel-running activity has been reported to hypersensitise central CB1 receptors in mice. On the other hand, pharmacological findings suggest that the CB1 receptor could be involved in wheel-running behaviour and in running-induced neurogenesis in the hippocampus. We analysed wheel-running behaviour for 6 weeks and measured its consequences on hippocampal neurogenesis in CB1 knockout (CB1(-/-)) animals, compared to wild-type (CB1(+/+)) littermates. Because wheel running has been shown to affect locomotor reactivity in novel environments, memory for aversive events and depression-like behaviours, we also assessed these behaviours in control and running CB1(+/+) and CB1(-/-) mice. When compared with running CB1(+/+) mice, the distance covered weekly by CB1(-/-) mice was decreased by 30-40%, an observation accounted for by decreased time spent and maximal velocity on the wheels. Analyses of running distances with respect to the light/dark cycle revealed that mutant covered less distance throughout both the inactive and the active phases of that cycle. Locomotion in an activity cage, exploration in an open field, and immobility time in the forced swim test proved insensitive to chronic wheel running in either genotype. Wheel running, per se, did not influence the expression and extinction of cued fear memory but counteracted in a time-dependent manner the deficiency of extinction measured in CB1(-/-) mice. Hippocampal neurogenesis, assessed by doublecortin labelling of immature neurons in the dentate gyrus, was lowered by 40% in control CB1(-/-) mice, compared to control CB1(+/+) mice. Although CB1(-/-) mice ran less than their wild-type littermates, the 6-week running protocol increased neurogenesis to similar extents (37-39%) in both genotypes. This study suggests that mouse CB1 receptors control wheel running but not its neurogenic consequences in the hippocampus.

  5. Deficiency of phospholipase A2 receptor exacerbates ovalbumin-induced lung inflammation.

    Science.gov (United States)

    Tamaru, Shun; Mishina, Hideto; Watanabe, Yosuke; Watanabe, Kazuhiro; Fujioka, Daisuke; Takahashi, Soichiro; Suzuki, Koji; Nakamura, Takamitsu; Obata, Jun-Ei; Kawabata, Kenichi; Yokota, Yasunori; Murakami, Makoto; Hanasaki, Kohji; Kugiyama, Kiyotaka

    2013-08-01

    Secretory phospholipase A2 (sPLA2) plays a critical role in the genesis of lung inflammation through proinflammatory eicosanoids. A previous in vitro experiment showed a possible role of cell surface receptor for sPLA2 (PLA2R) in the clearance of extracellular sPLA2. PLA2R and groups IB and X sPLA2 are expressed in the lung. This study examined a pathogenic role of PLA2R in airway inflammation using PLA2R-deficient (PLA2R(-/-)) mice. Airway inflammation was induced by immunosensitization with OVA. Compared with wild-type (PLA2R(+/+)) mice, PLA2R(-/-) mice had a significantly greater infiltration of inflammatory cells around the airways, higher levels of groups IB and X sPLA2, eicosanoids, and Th2 cytokines, and higher numbers of eosinophils and neutrophils in bronchoalveolar lavage fluid after OVA treatment. In PLA2R(-/-) mice, intratracheally instilled [(125)I]-labeled sPLA2-IB was cleared much more slowly from bronchoalveolar lavage fluid compared with PLA2R(+/+) mice. The degradation of the instilled [(125)I]-labeled sPLA2-IB, as assessed by trichloroacetic acid-soluble radioactivity in bronchoalveolar lavage fluid after instillation, was lower in PLA2R(-/-) mice than in PLA2R(+/+) mice. In conclusion, PLA2R deficiency increased sPLA2-IB and -X levels in the lung through their impaired clearance from the lung, leading to exaggeration of lung inflammation induced by OVA treatment in a murine model.

  6. 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; Burgio, Gaetan

    2015-11-01

    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, Tfrc(MRI24910), 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.

  7. Toll-like receptor 2 deficiency leads to delayed exacerbation of ischemic injury

    Directory of Open Access Journals (Sweden)

    Bohacek Ivan

    2012-08-01

    Full Text Available Abstract Background Using a live imaging approach, we have previously shown that microglia activation after stroke is characterized by marked and long-term induction of the Toll-like receptor (TLR 2 biophotonic signals. However, the role of TLR2 (and potentially other TLRs beyond the acute innate immune response and as early neuroprotection against ischemic injury is not well understood. Methods TLR2−/− mice were subjected to transient middle cerebral artery occlusion followed by different reperfusion times. Analyses assessing microglial activation profile/innate immune response were performed using in situ hybridization, immunohistochemistry analysis, flow cytometry and inflammatory cytokine array. The effects of the TLR2 deficiency on the evolution of ischemic brain injury were analyzed using a cresyl violet staining of brain sections with appropriate lesion size estimation. Results Here we report that TLR2 deficiency markedly affects post-stroke immune response resulting in delayed exacerbation of the ischemic injury. The temporal analysis of the microglia/macrophage activation profiles in TLR2−/− mice and age-matched controls revealed reduced microglia/macrophage activation after stroke, reduced capacity of resident microglia to proliferate as well as decreased levels of monocyte chemotactic protein-1 (MCP-1 and consequently lower levels of CD45high/CD11b+ expressing cells as shown by flow cytometry analysis. Importantly, although acute ischemic lesions (24 to 72 h were smaller in TLR2−/− mice, the observed alterations in innate immune response were more pronounced at later time points (at day 7 after initial stroke, which finally resulted in delayed exacerbation of ischemic lesion leading to larger chronic infarctions as compared with wild-type mice. Moreover, our results revealed that TLR2 deficiency is associated with significant decrease in the levels of neurotrophic/anti-apoptotic factor Insulin-like growth factor-1 (IGF-1

  8. 4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice.

    Science.gov (United States)

    Patti, M E; Sun, X J; Bruening, J C; Araki, E; Lipes, M A; White, M F; Kahn, C R

    1995-10-20

    Insulin receptor substrate-1 (IRS-1) is the major cytoplasmic substrate of the insulin and insulin-like growth factor (IGF)-1 receptors. Transgenic mice lacking IRS-1 are resistant to insulin and IGF-1, but exhibit significant residual insulin action which corresponds to the presence of an alternative high molecular weight substrate in liver and muscle. Recently, Sun et al. (Sun, X.-J., Wang, L.-M., Zhang, Y., Yenush, L. P., Myers, M. G., Jr., Glasheen, E., Lane, W.S., Pierce, J. H., and White, M. F. (1995) Nature 377, 173-177) purified and cloned 4PS, the major substrate of the IL-4 receptor-associated tyrosine kinase in myeloid cells, which has significant structural similarity to IRS-1. To determine if 4PS is the alternative substrate of the insulin receptor in IRS-1-deficient mice, we performed immunoprecipitation, immunoblotting, and phosphatidylinositol (PI) 3-kinase assays using specific antibodies to 4PS. Following insulin stimulation, 4PS is rapidly phosphorylated in liver and muscle, binds to the p85 subunit of PI 3-kinase, and activates the enzyme. Insulin stimulation also results in the association of 4PS with Grb 2 in both liver and muscle. In IRS-1-deficient mice, both the phosphorylation of 4PS and associated PI 3-kinase activity are enhanced, without an increase in protein expression. Immunodepletion of 4PS from liver and muscle homogenates removes most of the phosphotyrosine-associated PI 3-kinase activity in IRS-1-deficient mice. Thus, 4PS is the primary alternative substrate, i.e. IRS-2, which plays a major role in physiologic insulin signal transduction via both PI 3-kinase activation and Grb 2/Sos association. In IRS-1-deficient mice, 4PS/IRS-2 provides signal transduction to these two major pathways of insulin signaling.

  9. Deficiency of Angiotensin Type 1a Receptors in Adipocytes Reduces Differentiation and Promotes Hypertrophy of Adipocytes in Lean Mice

    OpenAIRE

    Putnam, Kelly; Batifoulier-Yiannikouris, Frederique; Bharadwaj, Kalyani G.; Lewis, Eboni; Karounos, Michael; Daugherty, Alan; Cassis, Lisa A.

    2012-01-01

    Adipocytes express angiotensin receptors, but the direct effects of angiotensin II (AngII) stimulating this cell type are undefined. Adipocytes express angiotensin type 1a receptor (AT1aR) and AT2R, both of which have been implicated in obesity. In this study, we determined the effects of adipocyte AT1aR deficiency on adipocyte differentiation and the development of obesity in mice fed low-fat (LF) or high-fat (HF) diets. Mice expressing Cre recombinase under the control of the aP2 promoter w...

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

    Directory of Open Access Journals (Sweden)

    Hui Li

    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.

  11. Intracellular receptor sorting during endocytosis: Comparative immunoelectron microscopy of multiple receptors in rat liver

    NARCIS (Netherlands)

    Slot, J.W.; Geuze, H.J.; Strous, G.J.A.M.; Peppard, J.; Figura, K. von; Hasilik, A.; Schwartz, A.L.

    1984-01-01

    Using double-label quantitative immunoelectron microscopy on ultrathin cryosections of rat liver, we have compared the endocytotic pathways of the receptors for asialoglycoprotein (ASGP-R), mannose-6-phosphate ligands (MP-R), and polymeric IgA (IgA-R). All three were found within the Golgi complex,

  12. Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+ Macrophage Function during Viral Infection

    OpenAIRE

    Xu, Haifeng C.; Huang, Jun; Khairnar, Vishal; Duhan, Vikas; Pandyra, Aleksandra A; Grusdat, Melanie; Shinde, Prashant; McIlwain, David R.; Maney, Sathish Kumar; Gommerman, Jennifer; Löhning, Max; Ohashi, Pamela S.; Mak, Tak W; Pieper, Kathrin; Sic, Heiko

    2015-01-01

    The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the gener...

  13. The transcobalamin receptor knockout mouse: a model for vitamin B12 deficiency in the central nervous system

    OpenAIRE

    Lai, Shao-Chiang; Nakayama, Yasumi; Sequeira, Jeffrey M.; Wlodarczyk, Bogdan J.; Cabrera, Robert M.; Finnell, Richard H.; Bottiglieri, Teodoro; Quadros, Edward V.

    2013-01-01

    The membrane receptor (TCblR/CD320) for transcobalamin (TC)-bound cobalamin (Cbl) facilitates the cellular uptake of Cbl. A genetically modified mouse model involving ablation of the CD320 gene was generated to study the effects on cobalamin homeostasis. The nonlethal nature of this knockout and the lack of systemic cobalamin deficiency point to other mechanisms for cellular Cbl uptake in the mouse. However, severe cobalamin depletion in the central nervous system (CNS) after birth (P

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    Directory of Open Access Journals (Sweden)

    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

  16. EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

    Science.gov (United States)

    Lu, Ankang; Zuo, Caojian; He, Yuhu; Chen, Guilin; Piao, Lingjuan; Zhang, Jian; Xiao, Bing; Shen, Yujun; Tang, Juan; Kong, Deping; Alberti, Sara; Chen, Di; Zuo, Shenkai; Zhang, Qianqian; Yan, Shuai; Fei, Xiaochun; Yuan, Fei; Zhou, Bin; Duan, Shengzhong; Yu, Yu; Lazarus, Michael; Su, Yunchao; Breyer, Richard M.; Funk, Colin D.; Yu, Ying

    2015-01-01

    Pulmonary arterial hypertension (PAH) is commonly associated with chronic hypoxemia in disorders such as chronic obstructive pulmonary disease (COPD). Prostacyclin analogs are widely used in the management of PAH patients; however, clinical efficacy and long-term tolerability of some prostacyclin analogs may be compromised by concomitant activation of the E-prostanoid 3 (EP3) receptor. Here, we found that EP3 expression is upregulated in pulmonary arterial smooth muscle cells (PASMCs) and human distal pulmonary arteries (PAs) in response to hypoxia. Either pharmacological inhibition of EP3 or Ep3 deletion attenuated both hypoxia and monocrotaline-induced pulmonary hypertension and restrained extracellular matrix accumulation in PAs in rodent models. In a murine PAH model, Ep3 deletion in SMCs, but not endothelial cells, retarded PA medial thickness. Knockdown of EP3α and EP3β, but not EP3γ, isoforms diminished hypoxia-induced TGF-β1 activation. Expression of either EP3α or EP3β in EP3-deficient PASMCs restored TGF-β1 activation in response to hypoxia. EP3α/β activation in PASMCs increased RhoA-dependent membrane type 1 extracellular matrix metalloproteinase (MMP) translocation to the cell surface, subsequently activating pro–MMP-2 and promoting TGF-β1 signaling. Activation or disruption of EP3 did not influence PASMC proliferation. Together, our results indicate that EP3 activation facilitates hypoxia-induced vascular remodeling and pulmonary hypertension in mice and suggest EP3 inhibition as a potential therapeutic strategy for pulmonary hypertension. PMID:25664856

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

    Directory of Open Access Journals (Sweden)

    Christian Roy

    Full Text Available OBJECTIVE: To investigate the impact of whole body C5a receptor (C5aR deficiency on energy metabolism and fat storage. DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

  18. Citrullus lanatus 'sentinel' (watermelon) extract reduces atherosclerosis in LDL receptor-deficient mice.

    Science.gov (United States)

    Poduri, Aruna; Rateri, Debra L; Saha, Shubin K; Saha, Sibu; Daugherty, Alan

    2013-05-01

    Watermelon (Citrullus lanatus or C. lanatus) has many potentially bioactive compounds including citrulline, which may influence atherosclerosis. In this study, we determined the effects of C. lanatus, provided as an extract of the cultivar 'sentinel,' on hypercholesterolemia-induced atherosclerosis in mice. Male low-density lipoprotein receptor-deficient mice at 8 weeks old were given either C. lanatus 'sentinel' extract (2% vol/vol; n=10) or a mixture of matching carbohydrates (2% vol/vol; n=8) as the control in drinking water while being fed a saturated fat-enriched diet for 12 weeks ad libitum. Mice consuming C. lanatus 'sentinel' extract had significantly increased plasma citrulline concentrations. Systolic blood pressure was comparable between the two groups. Consumption of C. lanatus 'sentinel' extract led to lower body weight and fat mass without influencing lean mass. There were no differences in food and water intake and in urine output between the two groups. C. lanatus 'sentinel' extract administration decreased plasma cholesterol concentrations that were attributed to reductions of intermediate-/low-density lipoprotein cholesterol. Plasma concentrations of monocyte chemoattractant protein-1 and interferon-gamma were decreased and those of interleukin-10 were increased in mice consuming C. lanatus 'sentinel' extract. Intake of C. lanatus 'sentinel' extract resulted in reductions of atherosclerosis in both aortic arch and thoracic regions. In conclusion, consumption of C. lanatus 'sentinel' extract led to reduced body weight gain, decreased plasma cholesterol concentrations, improved homeostasis of pro- and anti-inflammatory cytokines, and attenuated development of atherosclerosis without affecting systolic blood pressure in hypercholesterolemic mice. PMID:22902326

  19. 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. PMID:27144096

  20. Up-regulation of striatal adenosine A(2A) receptors with iron deficiency in rats: effects on locomotion and cortico-striatal neurotransmission.

    Science.gov (United States)

    Quiroz, César; Pearson, Virginia; Gulyani, Seema; Allen, Richard; Earley, Christopher; Ferré, Sergi

    2010-07-01

    Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A(2A) receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A(2A) receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A(2A) receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A(2A) receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A(2A) receptors was found in rats fed during 3 weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A(2A) receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A(2A) receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A(2A) receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A(2A) receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  2. OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice

    DEFF Research Database (Denmark)

    Barrow, Alexander David; Raynal, Nicolas; Levin Andersen, Thomas;

    2011-01-01

    Osteoclasts are terminally differentiated leukocytes that erode the mineralized bone matrix. Osteoclastogenesis requires costimulatory receptor signaling through adaptors containing immunoreceptor tyrosine-based activation motifs (ITAMs), such as Fc receptor common γ (FcRγ) and DNAX-activating pr...

  3. Altered hippocampal long-term synaptic plasticity in mice deficient in the PGE2 EP2 receptor

    Science.gov (United States)

    Yang, Hongwei; Zhang, Jian; Breyer, Richard M.; Chen, Chu

    2008-01-01

    Our laboratory demonstrated previously that PGE2-induced modulation of hippocampal synaptic transmission is via a presynaptic PGE2 EP2 receptor. However, little is known about whether the EP2 receptor is involved in hippocampal long-term synaptic plasticity and cognitive function. Here we show that long-term potentiation (LTP) at the hippocampal perforant path synapses was impaired in mice deficient in the EP2 (KO), while membrane excitability and passive properties in granule neurons were normal. Importantly, escape latency in the water maze in EP2 KO was longer than that in age-matched EP2 wild-type littermates (WT). We also observed that LTP was potentiated in EP2 WT animals that received lipopolysaccharide (LPS, i.p.), but not in EP2 KO. Bath application of PGE2 or butaprost, an EP2 receptor agonist, increased synaptic transmission and decreased paired-pulses ratio (PPR) in EP2 WT mice, but failed to induce the changes in EP2 KO mice. Meanwhile, synaptic transmission was elevated by application of forskolin, an adenylyl cyclase activator, both in EP2 KO and WT animals. In addition, the PGE2-enhanced synaptic transmission was significantly attenuated by application of PKA, IP3 or MAPK inhibitors in EP2 WT animals. Our results show that hippocampal long-term synaptic plasticity is impaired in mice deficient in the EP2, suggesting that PGE2-EP2 signaling is important for hippocampal long-term synaptic plasticity and cognitive function. PMID:19012750

  4. 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.

  5. Compared with saturated fatty acids, dietary monounsaturated fatty acids and carbohydrates increase atherosclerosis and VLDL cholesterol levels in LDL receptor-deficient, but not apolipoprotein E-deficient, mice

    OpenAIRE

    Merkel, Martin; Velez-Carrasco, Wanda; Hudgins, Lisa C.; Breslow, Jan L.

    2001-01-01

    Heart-healthy dietary recommendations include decreasing the intake of saturated fatty acids (SFA). However, the relative benefit of replacing SFA with monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), or carbohydrates (CARB) is still being debated. We have used two mouse models of atherosclerosis, low density lipoprotein receptor-deficient (LDLRKO) and apolipoprotein E-deficient (apoEKO) mice to measure the effects of four isocaloric diets enriched with either SFA, MUFA...

  6. The transcobalamin receptor knockout mouse: a model for vitamin B12 deficiency in the central nervous system.

    Science.gov (United States)

    Lai, Shao-Chiang; Nakayama, Yasumi; Sequeira, Jeffrey M; Wlodarczyk, Bogdan J; Cabrera, Robert M; Finnell, Richard H; Bottiglieri, Teodoro; Quadros, Edward V

    2013-06-01

    The membrane receptor (TCblR/CD320) for transcobalamin (TC)-bound cobalamin (Cbl) facilitates the cellular uptake of Cbl. A genetically modified mouse model involving ablation of the CD320 gene was generated to study the effects on cobalamin homeostasis. The nonlethal nature of this knockout and the lack of systemic cobalamin deficiency point to other mechanisms for cellular Cbl uptake in the mouse. However, severe cobalamin depletion in the central nervous system (CNS) after birth (Pmouse model; however, it does provide a model with which to evaluate metabolic pathways and genes affected. PMID:23430977

  7. Galanin 3 receptor-deficient mice show no alteration in the oxazolone-induced contact dermatitis phenotype.

    Science.gov (United States)

    Botz, Bálint; Brunner, Susanne M; Kemény, Ágnes; Pintér, Erika; McDougall, Jason J; Kofler, Barbara; Helyes, Zsuzsanna

    2016-09-01

    Allergic contact dermatitis (ACD) is an inflammatory skin disease induced by allergen exposure and characterized by erythema, oedema and immune cell infiltration. The sensory peptide galanin (GAL) and its three receptors (GAL1-3 ) are involved in regulating inflammation. As GAL and its receptors are expressed in human and murine skin and GAL expression is increased in oxazolone-induced contact allergy, it could play a role in dermatitis. As GAL reduces neurogenic plasma extravasation in the mouse skin via GAL3 activation, the role of GAL3 in the oxazolone-induced dermatitis model was explored. Following topical challenge with oxazolone, GAL3 gene-deficient mice showed a trend towards reduced ear thickness. Plasma extravasation and neutrophil infiltration increased considerably upon oxazolone challenge in both GAL3 knockout animals and wild-type controls without any observable effect of the gene deletion. We conclude that a lack of GAL3 does not influence oxazolone-induced ACD. PMID:27121264

  8. 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

    2011-01-01

    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 o

  9. Congenital myasthenic syndromes in two kinships with end-plate acetylcholine receptor and utrophin deficiency

    DEFF Research Database (Denmark)

    Sieb, J P; Dörfler, P; Tzartos, S;

    1998-01-01

    markedly reduced. In Patient 1, but not in Patient 2, the envelopment of the nerve terminal by Schwann cell was increased. Acetylcholine-receptor (AChR) density was reduced as judged by the reduced immunoreactivity to antibodies against different receptor subunits. Immunohistochemical analysis of proteins...

  10. A lipidomics study reveals hepatic lipid signatures associating with deficiency of the LDL receptor in a rat model.

    Science.gov (United States)

    Wang, Hong Yu; Quan, Chao; Hu, Chunxiu; Xie, Bingxian; Du, Yinan; Chen, Liang; Yang, Wei; Yang, Liu; Chen, Qiaoli; Shen, Bin; Hu, Bian; Zheng, Zhihong; Zhu, Haibo; Huang, Xingxu; Xu, Guowang; Chen, Shuai

    2016-01-01

    The low-density lipoprotein receptor (LDLR) plays a critical role in the liver for the clearance of plasma low-density lipoprotein (LDL). Its deficiency causes hypercholesterolemia in many models. To facilitate the usage of rats as animal models for the discovery of cholesterol-lowering drugs, we took a genetic approach to delete the LDLR in rats aiming to increase plasma LDL cholesterol (LDL-C). An LDLR knockout rat was generated via zinc-finger nuclease technology, which harbors a 19-basepair deletion in the seventh exon of the ldlr gene. As expected, deletion of the LDLR elevated total cholesterol and total triglyceride in the plasma, and caused a tenfold increase of plasma LDL-C and a fourfold increase of plasma very low-density lipoprotein (VLDL-C). A lipidomics analysis revealed that deletion of the LDLR affected hepatic lipid metabolism, particularly lysophosphatidylcholines, free fatty acids and sphingolipids in the liver. Cholesterol ester (CE) 20:4 also displayed a significant increase in the LDLR knockout rats. Taken together, the LDLR knockout rat offers a new model of hypercholesterolemia, and the lipidomics analysis reveals hepatic lipid signatures associating with deficiency of the LDL receptor. PMID:27378433

  11. Peroxisome proliferator-activated receptor gamma B cell-specific deficient mice have an impaired antibody response1

    Science.gov (United States)

    Ramon, Sesquile; Bancos, Simona; Thatcher, Thomas H.; Murant, Thomas I.; Moshkani, Safiehkhatoon; Sahler, Julie M.; Bottaro, Andrea; Sime, Patricia J.; Phipps, Richard P.

    2012-01-01

    Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ, a ligand activated transcription factor, has important anti-inflammatory and anti-proliferative functions and it has been associated with diseases including diabetes, scarring and atherosclerosis among others. PPARγ is expressed in most bone marrow derived cells and influences their function. PPARγ ligands can stimulate human B cell differentiation and promote antibody production. A knowledge gap is that the role of PPARγ in B cells under physiological conditions is not known. We developed a new B cell-specific PPARγ (B-PPARγ) knockout mouse and explored the role of PPARγ during both the primary and secondary immune response. Here, we show that PPARγ deficiency in B cells decreases germinal center B cells and plasma cell development as well as the levels of circulating antigen-specific antibodies during a primary challenge. Inability to generate germinal center B cells and plasma cells is correlated to decreased MHC class II expression and decreased Bcl-6 and Blimp-1 levels. Furthermore, B-PPARγ-deficient mice have an impaired memory response, characterized by low titers of antigen-specific antibodies and low numbers of antigen-experienced antibody-secreting cells. However, B-PPARγ-deficient mice have no differences in B cell population distribution within neither primary nor secondary lymphoid organs during development. This is the first report to show under physiological conditions that PPARγ expression in B cells is required for an efficient B cell-mediated immune response as it regulates B cell differentiation and antibody production. PMID:23041568

  12. Peroxisome proliferator-activated receptor γ B cell-specific-deficient mice have an impaired antibody response.

    Science.gov (United States)

    Ramon, Sesquile; Bancos, Simona; Thatcher, Thomas H; Murant, Thomas I; Moshkani, Safiehkhatoon; Sahler, Julie M; Bottaro, Andrea; Sime, Patricia J; Phipps, Richard P

    2012-11-15

    Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ, a ligand-activated transcription factor, has important anti-inflammatory and antiproliferative functions, and it has been associated with diseases including diabetes, scarring, and atherosclerosis, among others. PPARγ is expressed in most bone marrow-derived cells and influences their function. PPARγ ligands can stimulate human B cell differentiation and promote Ab production. A knowledge gap is that the role of PPARγ in B cells under physiological conditions is not known. We developed a new B cell-specific PPARγ (B-PPARγ) knockout mouse and explored the role of PPARγ during both the primary and secondary immune response. In this article, we show that PPARγ deficiency in B cells decreases germinal center B cells and plasma cell development, as well as the levels of circulating Ag-specific Abs during a primary challenge. Inability to generate germinal center B cells and plasma cells is correlated to decreased MHC class II expression and decreased Bcl-6 and Blimp-1 levels. Furthermore, B-PPARγ-deficient mice have an impaired memory response, characterized by low titers of Ag-specific Abs and low numbers of Ag-experienced, Ab-secreting cells. However, B-PPARγ-deficient mice have no differences in B cell population distribution within primary or secondary lymphoid organs during development. This is the first report, to our knowledge, to show that, under physiological conditions, PPARγ expression in B cells is required for an efficient B cell-mediated immune response as it regulates B cell differentiation and Ab production.

  13. Expression and regulation of neuromedin B in pituitary corticotrophs of male melanocortin 2 receptor-deficient mice.

    Science.gov (United States)

    Kameda, Hiraku; Miyoshi, Hideaki; Shimizu, Chikara; Nagai, So; Nakamura, Akinobu; Kondo, Takuma; Chida, Dai; Atsumi, Tatsuya

    2014-07-01

    The hypothalamic-pituitary-adrenal (HPA) axis is a major part of the neuroendocrine system that controls responses to stress, and has an important function in the regulation of various body processes. We previously created a mouse line deficient in the melanocortin 2 receptor (MC2R). MC2R-deficient mice (MC2R(-/-) mice) have high adrenocorticotropic hormone (ACTH) levels because of undetectable corticosterone levels. Increased neuromedin B (NMB) expression was recently reported in the pituitary gland of adrenalectomized mice, a model for acute adrenal insufficiency. To investigate gene expression in the pituitary gland under chronic adrenal deficiency, we examined the pituitary gland of MC2R(-/-) mice, a model of chronic adrenal insufficiency. To understand the molecular background of pituitary cells under chronic adrenal deficiency, we first performed DNA microarray analyses using the pituitary glands of the MC2R(-/-) mice. The DNA microarray analysis and real-time polymerase chain reaction showed that NMB expression was higher in the MC2R(-/-) than in the wild-type (WT) mice. We detected NMB expression in the MC2R(-/-) pituitary corticotrophs by immunohistochemistry using the specific antibodies for ACTH and NMB. In addition, the plasma NMB concentration was significantly higher in the MC2R(-/-) mice than in the WT mice. Subcutaneous implantation of a sustained-release corticosterone pellet decreased the expression of NMB mRNA as well as pituitary proopiomelanocortin mRNA. In isolated anterior pituitary cells, NMB mRNA expression was increased by the administration of corticotropin-releasing hormone (CRH) and was suppressed by dexamethasone treatment. In this study, we first demonstrate NMB expression in corticotrophs and its regulation by CRH and glucocorticoids. Furthermore, corticotrophs seemed to secrete NMB into the systemic circulation. PMID:24742195

  14. Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism).

    OpenAIRE

    Daughaday, W H; Trivedi, B

    1987-01-01

    It has recently been recognized that human serum contains a protein that specifically binds human growth hormone (hGH). This protein has the same restricted specificity for hGH as the membrane-bound GH receptor. To determine whether the GH-binding protein is a derivative of, or otherwise related to, the GH receptor, we have examined the serum of three patients with Laron-type dwarfism, a condition in which GH refractoriness has been attributed to a defect in the GH receptor. The binding of 12...

  15. 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.

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

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    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

  17. 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

    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...... chemoattractant protein-1, MIP-1beta, MIP-2, lymphotactin and T cell activation gene-3 during the course of the disease. CCR5-deficient mice were also susceptible to disease induction by MOG. The dispensability of MIP-1alpha and CCR5 for MOG-induced EAE in C57BL / 6 mice supports the idea that differential...

  18. G protein-coupled receptor 39 deficiency is associated with pancreatic islet dysfunction

    DEFF Research Database (Denmark)

    Holst, Birgitte; Egerod, Kristoffer L; Jin, Chunyu;

    2009-01-01

    G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn(++) sensor signaling mainly through the G(q) and G(12/13) pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1alpha and HNF-4a...... insulin in response to glucose stimulation than islets from wild-type littermates. It is concluded that GPR39 is involved in the control of endocrine pancreatic function, and it is suggested that this receptor could be a novel potential target for the treatment of diabetes.......G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn(++) sensor signaling mainly through the G(q) and G(12/13) pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1alpha and HNF-4......alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(-/-) mice were studied in vivo, especially in respect of...

  19. 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...

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

    Directory of Open Access Journals (Sweden)

    Oosterveer Maaike H

    2011-12-01

    Full Text Available Abstract 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 diet-induced obesity. Whether this phenotype of CB1-/- mice is related to altered fat metabolism in adipose tissue is unknown. Methods We evaluated adipose tissue differentiation/proliferation markers and quantified lipogenic and lipolytic activities in fat tissues of CB1-/- and CB1+/+ mice fed a high-fat (HF or a high-fat/fish oil (HF/FO diet as compared to animals receiving a low-fat chow diet. Comparison between HF diet and HF/FO diet allowed to investigate the influence of dietary fat quality on adipose tissue biology in relation to CB1 functioning. Results The adiposity-resistant phenotype of the CB1-/- mice was characterized by reduced fat mass and adipocyte size in HF and HF/FO-fed CB1-/- mice in parallel to a significant increase in energy expenditure as compared to CB1+/+ mice. The expression levels of adipocyte differentiation and proliferation markers were however maintained in these animals. Consistent with unaltered lipogenic gene expression, the fatty acid synthesis rates in adipose tissues from CB1-/- and CB1+/+ mice were unchanged. Whole-body and adipose-specific lipoprotein lipase (LPL activities were also not altered in CB1-/- mice. Conclusions These findings indicate that protection against diet-induced adiposity in CB1-deficient mice is not related to changes in adipocyte function per se, but rather results from increased energy dissipation by oxidative and non-oxidative pathways.

  1. Novel mechanism by which probucol lowers low density lipoprotein levels demonstrated in the LDL receptor-deficient rabbit

    Energy Technology Data Exchange (ETDEWEB)

    Naruszewicz, M.; Carew, T.E.; Pittman, R.C.; Witztum, J.L.; Steinberg, D.

    1984-11-01

    Treatment of low density lipoprotein (LDL) receptor-deficient rabbits (WHHL rabbits) with probucol (1% w/w in a chow diet) lowered their LDL-cholesterol levels by 36%, consonant with the reported effectiveness of the drug in patients deficient in the LDL receptor. Initial studies of LDL fractional catabolic rate (FCR) using /sup 125/I-labeled LDL prepared from the serum of untreated WHHL rabbits showed no difference between probucol-treated WHHL rabbits and untreated WHHL rabbits. When, however, /sup 125/I-labeled LDL was prepared from donor WHHL rabbits under treatment with probucol and injected back into them, the FCR was found to be increased by about 50% above that measured simultaneously using /sup 131/I-labeled LDL prepared from untreated WHHL donors. The labeled LDL from probucol-treated donors was also metabolized more rapidly than that from untreated donors when injected into untreated WHHL rabbits or into untreated wild-type New Zealand White rabbits. Finally, it was shown that rabbit skin fibroblasts in culture degraded labeled LDL prepared from probucol-treated WHHL rabbits more rapidly than that prepared from untreated WHHL donors. This was true both for normal rabbit fibroblasts and also for WHHL skin fibroblasts, although the absolute degradation rates in the latter were, of course, much lower for both forms of LDL. The data indicate that a major mechanism by which probucol lowers LDL levels relates not to changes in the cellular mechanisms for LDL uptake or to changes in LDL production but rather to intrinsic changes in the structure and metabolism of the plasma LDL of the probucol-treated animal.

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

    Science.gov (United States)

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

    2011-03-01

    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) cycle. The neuropeptide vasoactive intestinal polypetide (VIP) and its receptor (VPAC2) are highly expressed in the SCN. Recent studies indicate that VIPergic signaling plays an essential role in the maintenance of ongoing circadian rhythmicity by synchronizing SCN cells and by maintaining rhythmicity within individual neurons. To further increase the understanding of the role of VPAC2 signaling in circadian regulation, we implanted telemetric devices and simultaneously measured core body temperature, spontaneous activity, and heart rate in a strain of VPAC2-deficient mice and compared 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 to that of wild-type mice. The use of telemetric devices to measure circadian locomotor activity, temperature, and heart rate, together with the classical determination of circadian rhythms of wheel-running activity, raises questions about how representative wheel-running activity may be of other behavioral parameters, especially when animals have altered circadian phenotype.

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

    NARCIS (Netherlands)

    A.M. Friel (Anne M.); L. Zhang (Ling); C.A. Pru (Cindy A.); N.C. Clark (Nicole C.); M.L. McCallum (Melissa L.); L.J. Blok (Leen); T. Shioda (Toshi); J.J. Peluso (John J.); B.R. Rueda (Bo R.); J.K. Pru (James K.)

    2015-01-01

    textabstractEndometrial 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

  4. 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

  5. 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.

  6. 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.

  7. 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

    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

  8. 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.

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

    Science.gov (United States)

    Willecke, Florian; Yuan, Chujun; Oka, Kazuhiro; Chan, Lawrence; Hu, Yunying; Barnhart, Shelley; Bornfeldt, Karin E.; Goldberg, Ira J.; Fisher, Edward A.

    2015-01-01

    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. PMID:26046657

  10. Hyaluronan Accumulation Is Elevated in Cultures of Low Density Lipoprotein Receptor-deficient Cells and Is Altered by Manipulation of Cell Cholesterol Content*

    OpenAIRE

    Sakr, Sana W.; Potter-Perigo, Susan; Kinsella, Michael G.; Johnson, Pamela Y.; Braun, Kathleen R.; Goueffic, Yann; Rosenfeld, Michael E.; Wight, Thomas N.

    2008-01-01

    The extracellular matrix molecule hyaluronan (HA) accumulates in human atherosclerotic lesions. Yet the reasons for this accumulation have not been adequately addressed. Because abnormalities in lipid metabolism promote atherosclerosis, we have asked whether disrupted cholesterol homeostasis alters HA accumulation in low density lipoprotein receptor-deficient cell cultures. Cultured aortic smooth muscle cells (ASMC) from Watanabe heritable hyperlipidemic (WHHL) rabbits...

  11. 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.

  12. 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

    a 24-h rhythmic expression in the adrenal of WT mice under L/D and dark conditions. During a L/D cycle, the adrenal clock gene rhythm in VPAC2-KO mice was phase-advanced by approximately 6 h compared to WT mice and became arrhythmic in constant darkness. A significant 24-h rhythmic variation...... oscillator based on a group of clock genes and their protein products. Mice lacking the VPAC2 receptor display disrupted circadian rhythm of physiology and behaviour, and therefore, we using real-time RT-PCR quantified (1) the mRNAs for the clock genes Per1 and Bmal1 in the adrenal gland and SCN, (2......) 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...

  13. 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.

  14. Estrogen-related receptor-α (ERRα) deficiency in skeletal muscle impairs regeneration in response to injury.

    Science.gov (United States)

    LaBarge, Samuel; McDonald, Marisa; Smith-Powell, Leslie; Auwerx, Johan; Huss, Janice M

    2014-03-01

    The estrogen-related receptor-α (ERRα) regulates mitochondrial biogenesis and glucose and fatty acid oxidation during differentiation in skeletal myocytes. However, whether ERRα controls metabolic remodeling during skeletal muscle regeneration in vivo is unknown. We characterized the time course of skeletal muscle regeneration in wild-type (M-ERRαWT) and muscle-specific ERRα(-/-) (M-ERRα(-/-)) mice after injury by intramuscular cardiotoxin injection. M-ERRα(-/-) mice exhibited impaired regeneration characterized by smaller myofibers with increased centrally localized nuclei and reduced mitochondrial density and cytochrome oxidase and citrate synthase activities relative to M-ERRαWT. Transcript levels of mitochondrial transcription factor A, nuclear respiratory factor-2a, and peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1β, were downregulated in the M-ERRα(-/-) muscles at the onset of myogenesis. Furthermore, coincident with delayed myofiber recovery, we observed reduced muscle ATP content (-45% vs. M-ERRαWT) and enhanced AMP-activated protein kinase (AMPK) activation in M-ERRα(-/-) muscle. We subsequently demonstrated that pharmacologic postinjury AMPK activation was sufficient to delay muscle regeneration in WT mice. AMPK activation induced ERRα transcript expression in M-ERRαWT muscle and in C2C12 myotubes through induction of the Esrra promoter, indicating that ERRα may control gene regulation downstream of the AMPK pathway. Collectively, these results suggest that ERRα deficiency during muscle regeneration impairs recovery of mitochondrial energetic capacity and perturbs AMPK activity, resulting in delayed myofiber repair.

  15. Human androgen deficiency: insights gained from androgen receptor knockout mouse models

    OpenAIRE

    Kesha Rana; Davey, Rachel A; Zajac, Jeffrey D

    2014-01-01

    The mechanism of androgen action is complex. Recently, significant advances have been made into our understanding of how androgens act via the androgen receptor (AR) through the use of genetically modified mouse models. A number of global and tissue-specific AR knockout (ARKO) models have been generated using the Cre-loxP system which allows tissue- and/or cell-specific deletion. These ARKO models have examined a number of sites of androgen action including the cardiovascular system, the immu...

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

    OpenAIRE

    Yousif Nasser; Al-amran Fadhil G

    2011-01-01

    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.)...

  17. NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice

    OpenAIRE

    Langbein, Heike; Brunssen, Coy; Hofmann, Anja; Cimalla, Peter; Brux, Melanie; Bornstein, Stefan R; Deussen, Andreas; Koch, Edmund; Morawietz, Henning

    2015-01-01

    Aims Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation of superoxide anions by NADPH oxidase Nox1, 2, and 5 reduces nitric oxide availability and can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role of H2O2 produced by main endothelial isoform Nox4. Therefore, we analysed the impact of genetic deletion of Nox4 on endothelial dysfunction and atherosclerosis in the low-density lipoprotein receptor (Ldl...

  18. Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor (SR-BI)–deficient mice

    OpenAIRE

    Miettinen, Helena E.; Rayburn, Helen; Krieger, Monty

    2001-01-01

    Mammalian female fertility depends on complex interactions between the ovary and the extraovarian environment (e.g., the hypothalamic-hypophyseal ovarian axis). The role of plasma lipoproteins in fertility was examined using HDL-receptor SR-BI knockout (KO) mice. SR-BI KO females have abnormal HDLs, ovulate dysfunctional oocytes, and are infertile. Fertility was restored when the structure and/or quantity of abnormal HDL was altered by inactivating the apoAI gene or administering the choleste...

  19. Estrogen receptor β-deficient female mice develop a bladder phenotype resembling human interstitial cystitis

    OpenAIRE

    Imamov, Otabek; Yakimchuk, Konstantin; Morani, Andrea; Schwend, Thomas; Wada-Hiraike, Osamu; Razumov, Sergei; Warner, Margaret; Gustafsson, Jan-Åke

    2007-01-01

    Interstitial cystitis/painful bladder syndrome is a disease seen mostly in women, and symptoms tend to be worse premenopausally or during ovulation. The four cardinal symptoms of interstitial cystitis/painful bladder syndrome are bladder pain, urgency, frequency, and nocturia. Estrogen has been implicated in the etiology of this disease, but the role of the two estrogen receptors (ER), ERα and ERβ, has not been investigated. We found that, in the bladders of WT mice, ERβ is expressed in the b...

  20. 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

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

    Science.gov (United States)

    García-López, Roberto; de la Morena-Barrio, María Eugenia; Alsina, Laia; Pérez-Dueñas, Belén; Jaeken, Jaak; Serrano, Mercedes; Casado, Mercedes; Hernández-Caselles, Trinidad

    2016-01-01

    Background 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. Objective To evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors. Methods 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. Results 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. Conclusions 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

  2. 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.

  3. Association of Transcobalamin II (TCN2) and Transcobalamin II-Receptor (TCblR) Genetic Variations With Cobalamin Deficiency Parameters in Elderly Women.

    Science.gov (United States)

    Kurnat-Thoma, Emma L; Pangilinan, Faith; Matteini, Amy M; Wong, Bob; Pepper, Ginette A; Stabler, Sally P; Guralnik, Jack M; Brody, Lawrence C

    2015-07-01

    Cobalamin (vitamin B12) deficiency is a subtle progressive clinical disorder, affecting nearly 1 in 5 individuals > 60 years old. This deficiency is produced by age-related decreases in nutrient absorption, medications that interfere with vitamin B12 absorption, and other comorbidities. Clinical heterogeneity confounds symptom detection for elderly adults, as deficiency sequelae range from mild fatigue and weakness to debilitating megaloblastic anemia and permanent neuropathic injury. A better understanding of genetic factors that contribute to cobalamin deficiency in the elderly would allow for targeted nursing care and preventive interventions. We tested for associations of common variants in genes involved in cobalamin transport and homeostasis with metabolic indicators of cobalamin deficiency (homocysteine and methylmalonic acid) as well as hematologic, neurologic, and functional performance features of cobalamin deficiency in 789 participants of the Women's Health and Aging Studies. Although not significant when corrected for multiple testing, eight single nucleotide polymorphisms (SNPs) in two genes, transcobalamin II (TCN2) and the transcobalamin II-receptor (TCblR), were found to influence several clinical traits of cobalamin deficiency. The three most significant findings were the identified associations involving missense coding SNPs, namely, TCblR G220R (rs2336573) with serum cobalamin, TCN2 S348F (rs9621049) with homocysteine, and TCN2 P259R (rs1801198) with red blood cell mean corpuscular volume. These SNPs may modify the phenotype in older adults who are more likely to develop symptoms of vitamin B12 malabsorption. PMID:25657319

  4. Association of Transcobalamin II (TCN2) and Transcobalamin II-Receptor (TCblR) Genetic Variations With Cobalamin Deficiency Parameters in Elderly Women.

    Science.gov (United States)

    Kurnat-Thoma, Emma L; Pangilinan, Faith; Matteini, Amy M; Wong, Bob; Pepper, Ginette A; Stabler, Sally P; Guralnik, Jack M; Brody, Lawrence C

    2015-07-01

    Cobalamin (vitamin B12) deficiency is a subtle progressive clinical disorder, affecting nearly 1 in 5 individuals > 60 years old. This deficiency is produced by age-related decreases in nutrient absorption, medications that interfere with vitamin B12 absorption, and other comorbidities. Clinical heterogeneity confounds symptom detection for elderly adults, as deficiency sequelae range from mild fatigue and weakness to debilitating megaloblastic anemia and permanent neuropathic injury. A better understanding of genetic factors that contribute to cobalamin deficiency in the elderly would allow for targeted nursing care and preventive interventions. We tested for associations of common variants in genes involved in cobalamin transport and homeostasis with metabolic indicators of cobalamin deficiency (homocysteine and methylmalonic acid) as well as hematologic, neurologic, and functional performance features of cobalamin deficiency in 789 participants of the Women's Health and Aging Studies. Although not significant when corrected for multiple testing, eight single nucleotide polymorphisms (SNPs) in two genes, transcobalamin II (TCN2) and the transcobalamin II-receptor (TCblR), were found to influence several clinical traits of cobalamin deficiency. The three most significant findings were the identified associations involving missense coding SNPs, namely, TCblR G220R (rs2336573) with serum cobalamin, TCN2 S348F (rs9621049) with homocysteine, and TCN2 P259R (rs1801198) with red blood cell mean corpuscular volume. These SNPs may modify the phenotype in older adults who are more likely to develop symptoms of vitamin B12 malabsorption.

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

    Science.gov (United States)

    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 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.

  6. 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.

  7. Kit formulated asialoglycoprotein receptor targeting tracer based on copolymer for liver SPECT imaging

    International Nuclear Information System (INIS)

    Introduction: Specific targeting of galactose-carrying molecule to ASGP-R in normal hepatocytes has been demonstrated before. In this study, galactosyl polystyrene was synthesized from controllable ratio of functional monomers and radio-labelled with 99mTc by formulated kit for SPECT imaging of hepatic function. Methods: p(VLA-co-VNI)(46:54) was synthesized by free-radical copolymerization initiated by AIBN, purified by dialysis, lyophilized to kit with Tricine and TPPTS as co-ligands for 99mTc labeling. Radiotracer 99mTc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was prepared and evaluated by in vitro stability, in vivo metabolism, ex vivo biodistribution and microSPECT/CT imaging in normal KM mice. MicroSPECT/CT and microMRI imaging were also performed in C57BL/b6 mice with xenograft hepatic carcinoma for hepatic function evaluation. Results: 99mTc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was obtained in high radio chemical purity (RCP) (> 99%) by using instant kit without further purification and excellent in vitro and in vivo stability. The result of biodistribution showed that liver had high uptake (90.49 ± 10.68 ID%/g) at 30 min after injection and was blocked significantly by cold copolymer. MicroSPECT imaging in normal KM mice at 1 h and 4 h after injection showed good liver retention and targeting properties. Significant defect of activity was observed in the tumor site which was confirmed by MRI imaging. Conclusion: 99mTc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) with lower ratio of targeting moiety has no observable effect on the specific binding affinity and liver uptake. This makes it possible to introduce more imaging units for multi-modality imaging. Furthermore, the instant kit preparation of 99mTc-labeling provides great potential for the evaluation of hepatocyte function in clinical application

  8. Asialoglycoprotein receptor-magnetic dual targeting nanoparticles for delivery of RASSF1A to hepatocellular carcinoma

    OpenAIRE

    Wan-Jiang Xue; Ying Feng; Fei Wang; Yi-Bing Guo; Peng Li; Lei Wang; Yi-Fei Liu; Zhi-Wei Wang; Yu-Min Yang; Qin-Sheng Mao

    2016-01-01

    We developed a nanovector with double targeting properties for efficiently delivering the tumor suppressor gene RASSF1A specifically into hepatocellular carcinoma (HCC) cells by preparing galactosylated-carboxymethyl chitosan-magnetic iron oxide nanoparticles (Gal-CMCS-Fe3O4-NPs). After conjugating galactose and CMCS to the surface of Fe3O4-NPs, we observed that Gal-CMCS-Fe3O4-NPs were round with a relatively stable zeta potential of +6.5 mV and an mean hydrodynamic size of 40.1 ± 5.3 nm. Gal...

  9. Asialoglycoprotein receptor-magnetic dual targeting nanoparticles for delivery of RASSF1A to hepatocellular carcinoma

    Science.gov (United States)

    Xue, Wan-Jiang; Feng, Ying; Wang, Fei; Guo, Yi-Bing; Li, Peng; Wang, Lei; Liu, Yi-Fei; Wang, Zhi-Wei; Yang, Yu-Min; Mao, Qin-Sheng

    2016-02-01

    We developed a nanovector with double targeting properties for efficiently delivering the tumor suppressor gene RASSF1A specifically into hepatocellular carcinoma (HCC) cells by preparing galactosylated-carboxymethyl chitosan-magnetic iron oxide nanoparticles (Gal-CMCS-Fe3O4-NPs). After conjugating galactose and CMCS to the surface of Fe3O4-NPs, we observed that Gal-CMCS-Fe3O4-NPs were round with a relatively stable zeta potential of +6.5 mV and an mean hydrodynamic size of 40.1 ± 5.3 nm. Gal-CMCS-Fe3O4-NPs had strong DNA condensing power in pH 7 solution and were largely nontoxic. In vitro experiments demonstrated that Gal-CMCS-Fe3O4-NPs were highly selective for HCC cells and liver cells. In vivo experiments showed the specific accumulation of Gal-CMCS-Fe3O4-NPs in HCC tissue, especially with the aid of an external magnetic field. Nude mice with orthotopically transplanted HCC received an intravenous injection of the Gal-CMCS-Fe3O4-NPs/pcDNA3.1(+)RASSF1A compound and intraperitoneal injection of mitomycin and had an external magnetic field applied to the tumor area. These mice had the smallest tumors, largest percentage of TUNEL-positive cells, and highest caspase-3 expression levels in tumor tissue compared to other groups of treated mice. These results suggest the potential application of Gal-CMCS-Fe3O4-NPs for RASSF1A gene delivery for the treatment of HCC.

  10. 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 <1% were at risk for deficiency. Hemoglobin was higher in white 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.

  11. Melanocortin 1 receptor-signaling deficiency results in an articular cartilage phenotype and accelerates pathogenesis of surgically induced murine osteoarthritis.

    Directory of Open Access Journals (Sweden)

    Julia Lorenz

    Full Text Available Proopiomelanocortin-derived peptides exert pleiotropic effects via binding to melanocortin receptors (MCR. MCR-subtypes have been detected in cartilage and bone and mediate an increasing number of effects in diathrodial joints. This study aims to determine the role of MC1-receptors (MC1 in joint physiology and pathogenesis of osteoarthritis (OA using MC1-signaling deficient mice (Mc1re/e. OA was surgically induced in Mc1re/e and wild-type (WT mice by transection of the medial meniscotibial ligament. Histomorphometry of Safranin O stained articular cartilage was performed with non-operated controls (11 weeks and 6 months and 4/8 weeks past surgery. µCT-analysis for assessing epiphyseal bone architecture was performed as a longitudinal study at 4/8 weeks after OA-induction. Collagen II, ICAM-1 and MC1 expression was analysed by immunohistochemistry. Mc1re/e mice display less Safranin O and collagen II stained articular cartilage area compared to WT prior to OA-induction without signs of spontaneous cartilage surface erosion. This MC1-signaling deficiency related cartilage phenotype persisted in 6 month animals. At 4/8 weeks after OA-induction cartilage erosions were increased in Mc1re/e knees paralleled by weaker collagen II staining. Prior to OA-induction, Mc1re/e mice do not differ from WT with respect to bone parameters. During OA, Mc1re/e mice developed more osteophytes and had higher epiphyseal bone density and mass. Trabecular thickness was increased while concomitantly trabecular separation was decreased in Mc1re/e mice. Numbers of ICAM-positive chondrocytes were equal in non-operated 11 weeks Mc1re/e and WT whereas number of positive chondrocytes decreased during OA-progression. Unchallenged Mc1re/e mice display smaller articular cartilage covered area without OA-related surface erosions indicating that MC1-signaling is critical for proper cartilage matrix integrity and formation. When challenged with OA, Mc1re/e mice develop a more

  12. Immunization with cationized BSA inhibits progression of disease in ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis.

    Science.gov (United States)

    Kolbus, Daniel; Wigren, Maria; Ljungcrantz, Irena; Söderberg, Ingrid; Alm, Ragnar; Björkbacka, Harry; Nilsson, Jan; Fredrikson, Gunilla N

    2011-06-01

    Immune responses against modified self-antigens generated by hypercholesterolemia play an important role in atherosclerosis identifying the immune system as a possible novel target for prevention and treatment of cardiovascular disease. It has recently been shown that these immune responses can be modulated by subcutaneous injection of adjuvant. In the present study we immunized 25-week old ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis with adjuvant and two different concentrations of the carrier molecule cationized BSA (cBSA). Plasma levels of Th2-induced apolipoprotein B (apoB)/IgG1 immune complexes were increased in the cBSA immunized groups verifying induction of immunity against a self-antigen. Mice were sacrificed at 36 weeks of age and atherosclerosis was monitored by en face Oil red O staining of the aorta. Immunization with 100 μg cBSA inhibited plaque progression, whereas the lower dose (50 μg) did not. In addition, the higher dose induced a more stable plaque phenotype, indicated by a higher content of collagen and less macrophages and T cells in the plaques. Moreover, there was an increased ratio of Foxp3+/Foxp3⁻ T cells in the circulation suggesting activation of a regulatory T cell response. In conclusion, we show that immunization with cBSA induces an immune response against apoB as well as an activation of Treg cells. This was associated with development of a more stable plaque phenotype and reduced atherosclerosis progression.

  13. 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.

  14. Adipose tissue deficiency results in severe hyperlipidemia and atherosclerosis in the low-density lipoprotein receptor knockout mice.

    Science.gov (United States)

    Wang, Mengyu; Gao, Mingming; Liao, Jiawei; Qi, Yanfei; Du, Ximing; Wang, Yuhui; Li, Ling; Liu, George; Yang, Hongyuan

    2016-05-01

    Adipose tissue can store over 50% of whole-body cholesterol; however, the physiological role of adipose tissue in cholesterol metabolism and atherogenesis has not been directly assessed. Here, we examined lipoprotein metabolism and atherogenesis in a unique mouse model of severe lipodystrophy: the Seipin(-/-) mice, and also in mice deficient in both low-density lipoprotein receptor (Ldlr) and Seipin: the Ldlr(-/-)Seipin(-/-) mice. Plasma cholesterol was moderately increased in the Seipin(-/-) mice when fed an atherogenic diet. Strikingly, plasma cholesterol reached ~6000 mg/dl in the Seipin(-/-)Ldlr(-/-) mice on an atherogenic diet, as compared to ~1000 mg/dl in the Ldlr(-/-) mice on the same diet. The Seipin(-/-)Ldlr(-/-) mice also developed spontaneous atherosclerosis on chow diet and severe atherosclerosis on an atherogenic diet. Rosiglitazone treatment significantly reduced the hypercholesterolemia of the Seipin(-/-)Ldlr(-/-) mice, and also alleviated the severity of atherosclerosis. Our results provide direct evidence, for the first time, that the adipose tissue plays a critical role in the clearance of plasma cholesterol. Our results also reveal a previously unappreciated strong link between adipose tissue and LDLR in plasma cholesterol metabolism.

  15. Site-specific influence of polyunsaturated fatty acids on atherosclerosis in immune incompetent LDL receptor deficient mice.

    Science.gov (United States)

    Reardon, Catherine A; Blachowicz, Lydia; Gupta, Gaorav; Lukens, John; Nissenbaum, Michael; Getz, Godfrey S

    2006-08-01

    Polyunsaturated fatty acids (PUFA) are thought to influence plasma lipid levels, atherosclerosis, and the immune system. In this study, we fed male LDL receptor deficient (LDLR(-/-)) mice and immune incompetent LDLR(-/-) RAG2(-/-) mice diets containing predominantly saturated fats (milk fat) or PUFA (safflower oil) to determine if the response to diet was influenced by immune status. Relative to milk fat diet, plasma lipid and VLDL levels in both the LDLR(-/-) and LDLR(-/-) RAG2(-/-) mice fed safflower oil diet were lower, suggesting that the primary effect of PUFA on plasma lipids was not due to its inhibition of the immune system. Neither diet nor immune status influenced hepatic triglyceride production and post-heparin lipase activity, suggesting that the differences in triglyceride levels are due to differences in rates of catabolism of triglyceride-rich lipoproteins. While both diets promoted atherogenesis, both aortic root and innominate artery atherosclerosis in LDLR(-/-) mice was less in safflower oil fed animals. In contrast, a site-specific effect of PUFA was observed in the immune incompetent LDLR(-/-) RAG2(-/-). In these mice, aortic root atherosclerosis, but not innominate artery atherosclerosis, was less in PUFA fed animal. These results suggest that PUFA and the immune system may influence innominate artery atherosclerosis by some overlapping mechanisms.

  16. 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.

  17. Constitutive androstane receptor agonist, TCPOBOP, attenuates steatohepatitis in the methionine choline-deficient diet-fed mouse

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To ascertain whether constitutive androstane receptor (CAR) activation by 1,4-bis-[2-(3,5,dichloropyridyloxy)] benzene (TCPOBOP) modulates steatohepatitis in the methionine choline-deficient (MCD) diet-fed animal. METHODS: C57/BL6 wild-type mice were fed the MCD or standard diet for 2 wk and were treated with either the CAR agonist, TCPOBOP, or the CAR inverse agonist, androstanol. RESULTS: Expression of CYP2B10 and CYP3A11, known CAR target genes, increased 30-fold and 45-fold, respectively, in TCPOBOP-treated mice fed the MCD diet. TCPOBOP treatment reduced hepatic steatosis (44.6 ± 5.4% vs 30.4 ± 4.5%, P < 0.05) and serum triglyceride levels (48 ± 8 vs 20 ± 1 mg/Dl, P < 0.05) in MCD dietfed mice as compared with the standard diet-fed mice. This reduction in hepatic steatosis was accompanied by an increase in enzymes involved in fatty acid microsomal ω-oxidation and peroxisomal β-oxidation, namely CYP4A10, LPBE, and 3-ketoacyl-CoA thiolase. The reduction in steatosis was also accompanied by a reduction in liver cell apoptosis and inflammation. In contrast, androstanol was without effect on any of the above parameters. CONCLUSION: CAR activation stimulates induction of genes involved in fatty acid oxidation, and ameliorates hepatic steatosis, apoptosis and inflammation.

  18. Receptor for Advanced Glycation End Products (RAGE) Deficiency Attenuates the Development of Atherosclerosis in Diabetes

    Science.gov (United States)

    Soro-Paavonen, Aino; Watson, Anna M.D.; Li, Jiaze; Paavonen, Karri; Koitka, Audrey; Calkin, Anna C.; Barit, David; Coughlan, Melinda T.; Drew, Brian G.; Lancaster, Graeme I.; Thomas, Merlin; Forbes, Josephine M.; Nawroth, Peter P.; Bierhaus, Angelika; Cooper, Mark E.; Jandeleit-Dahm, Karin A.

    2008-01-01

    OBJECTIVE—Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE−/− model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS—ApoE−/− and RAGE−/−/apoE−/− double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS—Although diabetic apoE−/− mice showed increased plaque accumulation (14.9 ± 1.7%), diabetic RAGE−/−/apoE−/− mice had significantly reduced atherosclerotic plaque area (4.9 ± 0.4%) to levels not significantly different from control apoE−/− mice (4.3 ± 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-κB subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE−/− mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE−/−/apoE−/− mice. CONCLUSIONS—This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications. PMID:18511846

  19. Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice.

    Science.gov (United States)

    Inagaki-Ohara, K; Mayuzumi, H; Kato, S; Minokoshi, Y; Otsubo, T; Kawamura, Y I; Dohi, T; Matsuzaki, G; Yoshimura, A

    2014-01-01

    Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.

  20. Estrogen receptor 2b deficiency impairs the antiviral response of zebrafish.

    Science.gov (United States)

    López-Muñoz, Azucena; Liarte, Sergio; Gómez-González, Nuria E; Cabas, Isabel; Meseguer, José; García-Ayala, Alfonsa; Mulero, Victoriano

    2015-11-01

    Although several studies have demonstrated the ability of some endocrine disruptive chemicals (EDCs) to alter the physiology of zebrafish, the immune-reproductive interaction has received little attention in this species. In this study, we used a homozygous line carrying an insertion of 8 amino acids in the ligand-binding domain of the estrogen receptor 2b gene (esr2b) to further understand the role of estrogen signaling on innate immunity. Adult mutant fish showed distorted sexual ratios related with alterations in testicular morphology and supraphysiological testosterone and 17β-estradiol (E2) levels. Immunity-wise, although esr2b mutant fish showed unaltered antibacterial responses, they were unable to mount an effective antiviral response upon viral challenge. RT-qPCR analysis demonstrated that mutant fish were able to induce the genes encoding major antiviral molecules, including Ifnphi1, Ifnphi2, Infphi3, Mxb and Mxc, and the negative feedback regulator of cytokine signaling Socs1. Notably, although esr2b mutant larvae showed a similar resistance to SVCV infection to their wild type siblings, waterborne E2 increased their viral susceptibility. Similarly, the exposure of adult wild type zebrafish to E2 also resulted in increased susceptibility to SVCV infection. Finally, the administration of recombinant Ifnphi1 hardly reversed the higher viral susceptibility of esr2b mutant zebrafish, suggesting that elevated socs1 levels impair Ifn signaling. All together, these results uncover an important role for E2 and Esr signaling in the fine-tuning of sexual hormone balance and the antiviral response of vertebrates.

  1. Guipi decoction effects on brain somatostatin levels and receptor mRNA expression in rats with spleen deficiency

    Institute of Scientific and Technical Information of China (English)

    Huinan Qian; Le Wang; Libo Shen; Xueqin Hu

    2008-01-01

    BACKGROUND:Somatostatin is abundant in the hypothalamus,cerebral cortex,limbic system,and mesencephalon.Somatostatin mRNA expression in the brain of rats with spleen deficiency is noticeably reduced,as well as attenuation of cognitive function. OBJECTIVE:To observe the interventional effect of Guipi decoction on somatostatin level and somatostatin receptor 1(SSTRI)mRNA expression in different encephalic regions of rats with spleen deficiency,and to compare the interventional effects of Guipi decoction,Chaihu Shugan powder,and Tianwang Buxin pellet. DESIGN:A randomized controlled observation. SETTING:Basic Medical College,Beijing University of Traditional Chinese Medicine.MATERIALS:Fifty adult Wistar male rats,of clean grade,weighing(160 ± 10)g,were provided by Beijing Weitong Lihua Laboratory Animal Technology Co.,Ltd.The protocol was performed in accordance with ethical guidelines for the use and care of animals.Somatostatin 1 polyclonal anti-rabbit antibody and SSTR1 in situ hybridization kit were provided by Department of Neuroanatomy,Shanghai Second Military Medical University of Chinese PLA.The drug for developing rat models of spleen deficiency was composed of Dahuang,Houpu and Zhishi,and prepared at 2:1:1.Guipi decoction,Chaihu Shugan powder,and Tianwang Buxin pellet recipes were made according to previous studies.METHODS:This study was performed at the Basic Medical College,Beijing University of Traditional Chinese Medicine from March 2002 to March 2005.The rats were randomly divided into 5 groups,with 10 rats in each group:normal,model,Guipi decoction,Chaihu Shugan powder,and Tianwang Buxin pelletgroups.Rat models of the latter 4 groups were developed by methods of purgation with bitter and cold nature drugs,improper diet,and overstrain.The rats received 7.5 g/kg of the drugs each morning and were fasted every other day,but were allowed free access to water at all times,The rats were forced to swim in 25℃ water until fatigued.Rats in the normal group

  2. Genomic dissection and prioritizing of candidate genes of QTL for regulating spontaneous arthritis on chromosome 1 in mice deficient for interleukin-1 receptor antagonist

    Indian Academy of Sciences (India)

    Yanhong Cao; Jifei Zhang; Yan Jiao; Jian Yan; Feng Jiao; Xiaoyun Liu; Robert W. Williams; Karen A. Hasty; John M. Stuart; Weikuan Gu

    2012-08-01

    Rheumatoid arthritis is a heterogeneous disease with clinical and biological polymorphisms. IL-1RN is a protein that binds to interleukin-1 (IL-1) receptors and inhibits the binding of IL-1-alpha and IL-1-beta. IL-1RN levels are elevated in the blood of patients with a variety of infectious, immune, and traumatic conditions. Balb/c mice deficient in IL-1ra (mouse gene of IL-1RN) develop spontaneous autoimmune arthritis while DBA/1 mice deficient in IL-1ra do not. Previously, we identified a major QTL that regulates the susceptibility to arthritis in Balb/c mice with IL-1ra deficiency. In this study, we found that the QTL may contain two peaks that are regulated by two sets of candidate genes. By haplotype analysis, the total genomic regions of candidate genes were reduced from about 19 Mbp to approximately 9 Mbp. The total number of candidate genes was reduced from 208 to 21.

  3. Augmented atherogenesis in LDL receptor deficient mice lacking both macrophage ABCA1 and ApoE.

    Directory of Open Access Journals (Sweden)

    Bart Lammers

    Full Text Available AIM: ABCA1 protects against atherosclerosis by facilitating cholesterol efflux from macrophage foam cells in the arterial wall to extracellular apolipoprotein (apo A-I. In contrast to apoA-I, apoE is secreted by macrophages and can, like apoA-I, induce ABCA1-mediated cholesterol efflux. Yet, the combined effect of macrophage ABCA1 and apoE on lesion development is unexplored. METHODS AND RESULTS: LDL receptor knockout (KO mice were transplanted with bone marrow from ABCA1/apoE double KO (dKO mice, their respective single KO's, and wild-type (WT controls and were challenged with a high-fat/high-cholesterol diet for 9 weeks. In vitro cholesterol efflux experiments showed no differences between ABCA1 KO and dKO macrophages. The serum non-HDL/HDL ratio in dKO transplanted mice was 1.7-fold and 2.4-fold (p<0.01 increased compared to WT and ABCA1 KO transplanted mice, respectively. The atherosclerotic lesion area in dKO transplanted animals (650±94×10(3 µm(2, however, was 1.9-fold (p<0.01 and 1.6-fold (p<0.01 increased compared to single knockouts (ABCA1 KO: 341±20×10(3 µm(2; apoE KO: 402±78×10(3 µm(2, respectively and 3.1-fold increased (p<0.001 compared to WT (211±20×10(3 µm(2. When normalized for serum cholesterol exposure, macrophage ABCA1 and apoE independently protected against atherosclerotic lesion development (p<0.001. Moreover, hepatic expression levels of TNFα and IL-6 were highly induced in dKO transplanted animals (3.0-fold; p<0.05, and 4.3-fold; p<0.001, respectively. In agreement, serum IL-6 levels were also enhanced in ABCA1 KO transplanted mice (p<0.05 and even further enhanced in dKO transplanted animals (3.1-fold as compared to ABCA1 KO transplanted animals; p<0.05. CONCLUSIONS: Combined deletion of macrophage ABCA1 and apoE results in a defect in cholesterol efflux and, compared to ABCA1 KO transplanted mice, elevated serum total cholesterol levels. Importantly, these mice also suffer from enhanced systemic and hepatic

  4. 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. PMID:27169626

  5. Deficiency of Nuclear Receptor Nur77 Aggravates Mouse Experimental Colitis by Increased NFκB Activity in Macrophages.

    Directory of Open Access Journals (Sweden)

    Anouk A J Hamers

    Full Text Available Nuclear receptor Nur77, also referred to as NR4A1 or TR3, plays an important role in innate and adaptive immunity. Nur77 is crucial in regulating the T helper 1/regulatory T-cell balance, is expressed in macrophages and drives M2 macrophage polarization. In this study we aimed to define the function of Nur77 in inflammatory bowel disease. In wild-type and Nur77-/- mice, colitis development was studied in dextran sodium sulphate (DSS- and 2,4,6-trinitrobenzene sulfonic acid (TNBS-induced models. To understand the underlying mechanism, Nur77 was overexpressed in macrophages and gut epithelial cells. Nur77 protein is expressed in colon tissues from Crohn's disease and Ulcerative colitis patients and colons from colitic mice in inflammatory cells and epithelium. In both mouse colitis models inflammation was increased in Nur77-/- mice. A higher neutrophil influx and enhanced IL-6, MCP-1 and KC production was observed in Nur77-deficient colons after DSS-treatment. TNBS-induced influx of T-cells and inflammatory monocytes into the colon was higher in Nur77-/- mice, along with increased expression of MCP-1, TNFα and IL-6, and decreased Foxp3 RNA expression, compared to wild-type mice. Overexpression of Nur77 in lipopolysaccharide activated RAW macrophages resulted in up-regulated IL-10 and downregulated TNFα, MIF-1 and MCP-1 mRNA expression through NFκB repression. Nur77 also strongly decreased expression of MCP-1, CXCL1, IL-8, MIP-1α and TNFα in gut epithelial Caco-2 cells. Nur77 overexpression suppresses the inflammatory status of both macrophages and gut epithelial cells and together with the in vivo mouse data this supports that Nur77 has a protective function in experimental colitis. These findings may have implications for development of novel targeted treatment strategies regarding inflammatory bowel disease and other inflammatory diseases.

  6. Orp8 deficiency in bone marrow-derived cells reduces atherosclerotic lesion progression in LDL receptor knockout mice.

    Directory of Open Access Journals (Sweden)

    Erik van Kampen

    Full Text Available INTRODUCTION: Oxysterol binding protein Related Proteins (ORPs mediate intracellular lipid transport and homeostatic regulation. ORP8 downregulates ABCA1 expression in macrophages and cellular cholesterol efflux to apolipoprotein A-I. In line, ORP8 knockout mice display increased amounts of HDL cholesterol in blood. However, the role of macrophage ORP8 in atherosclerotic lesion development is unknown. METHODS AND RESULTS: LDL receptor knockout (KO mice were transplanted with bone marrow (BM from ORP8 KO mice and C57Bl/6 wild type mice. Subsequently, the animals were challenged with a high fat/high cholesterol Western-type diet to induce atherosclerosis. After 9 weeks of Western-Type diet feeding, serum levels of VLDL cholesterol were increased by 50% in ORP8 KO BM recipients compared to the wild-type recipients. However, no differences were observed in HDL cholesterol. Despite the increase in VLDL cholesterol, lesions in mice transplanted with ORP8 KO bone marrow were 20% smaller compared to WT transplanted controls. In addition, ORP8 KO transplanted mice displayed a modest increase in the percentage of macrophages in the lesion as compared to the wild-type transplanted group. ORP8 deficient macrophages displayed decreased production of pro-inflammatory factors IL-6 and TNFα, decreased expression of differentiation markers and showed a reduced capacity to form foam cells in the peritoneal cavity. CONCLUSIONS: Deletion of ORP8 in bone marrow-derived cells, including macrophages, reduces lesion progression after 9 weeks of WTD challenge, despite increased amounts of circulating pro-atherogenic VLDL. Reduced macrophage foam cell formation and lower macrophage inflammatory potential are plausible mechanisms contributing to the observed reduction in atherosclerosis.

  7. Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice.

    Directory of Open Access Journals (Sweden)

    Kuniha Konuma

    Full Text Available Many attempts have been made to find novel therapeutic strategies for non-alcoholic steatohepatitis (NASH, while their clinical efficacy is unclear. We have recently reported a novel rodent model of NASH using melanocortin 4 receptor-deficient (MC4R-KO mice, which exhibit the sequence of events that comprise hepatic steatosis, liver fibrosis, and hepatocellular carcinoma with obesity-related phenotypes. In the liver of MC4R-KO mice, there is a unique histological feature termed hepatic crown-like structures (hCLS, where macrophages interact with dead hepatocytes and fibrogenic cells, thereby accelerating inflammation and fibrosis. In this study, we employed MC4R-KO mice to examine the effect of highly purified eicosapentaenoic acid (EPA, a clinically available n-3 polyunsaturated fatty acid, on the development of NASH. EPA treatment markedly prevented the development of hepatocyte injury, hCLS formation and liver fibrosis along with lipid accumulation. EPA treatment was also effective even after MC4R-KO mice developed NASH. Intriguingly, improvement of liver fibrosis was accompanied by the reduction of hCLS formation and plasma kallikrein-mediated transforming growth factor-β activation. Moreover, EPA treatment increased the otherwise reduced serum concentrations of adiponectin, an adipocytokine with anti-inflammatory and anti-fibrotic properties. Collectively, EPA treatment effectively prevents the development and progression of NASH in MC4R-KO mice along with amelioration of hepatic steatosis. This study unravels a novel anti-fibrotic mechanism of EPA, thereby suggesting a clinical implication for the treatment of NASH.

  8. 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.

  9. 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. PMID:26800321

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

    Directory of Open Access Journals (Sweden)

    Florent M Martin

    Full Text Available 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.

  11. 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.

  12. CD8+ T Cell Response to Gammaherpesvirus Infection Mediates Inflammation and Fibrosis in Interferon Gamma Receptor-Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Brigid M O'Flaherty

    Full Text Available Idiopathic pulmonary fibrosis (IPF, one of the most severe interstitial lung diseases, is a progressive fibrotic disorder of unknown etiology. However, there is growing appreciation for the role of viral infection in disease induction and/or progression. A small animal model of multi-organ fibrosis, which involves murine gammaherpesvirus (MHV68 infection of interferon gamma receptor deficient (IFNγR-/- mice, has been utilized to model the association of gammaherpesvirus infections and lung fibrosis. Notably, several MHV68 mutants which fail to induce fibrosis have been identified. Our current study aimed to better define the role of the unique MHV68 gene, M1, in development of pulmonary fibrosis. We have previously shown that the M1 gene encodes a secreted protein which possesses superantigen-like function to drive the expansion and activation of Vβ4+ CD8+ T cells. Here we show that M1-dependent fibrosis is correlated with heightened levels of inflammation in the lung. We observe an M1-dependent cellular infiltrate of innate immune cells with most striking differences at 28 days-post infection. Furthermore, in the absence of M1 protein expression we observed reduced CD8+ T cells and MHV68 epitope specific CD8+ T cells to the lungs-despite equivalent levels of viral replication between M1 null and wild type MHV68. Notably, backcrossing the IFNγR-/- onto the Balb/c background, which has previously been shown to exhibit weak MHV68-driven Vβ4+ CD8+ T cell expansion, eliminated MHV68-induced fibrosis-further implicating the activated Vβ4+ CD8+ T cell population in the induction of fibrosis. We further addressed the role that CD8+ T cells play in the induction of fibrosis by depleting CD8+ T cells, which protected the mice from fibrotic disease. Taken together these findings are consistent with the hypothesized role of Vβ4+ CD8+ T cells as mediators of fibrotic disease in IFNγR-/- mice.

  13. Endocytosis of the ASGP receptor H1 is reduced by mutation of tyrosine-5 but still occurs via coated pits

    OpenAIRE

    Fuhrer, C; Geffen, I; Spiess, M.

    1991-01-01

    The clustering of plasma membrane receptors in clathrin-coated pits depends on determinants within their cytoplasmic domains. In several cases, individual tyrosine residues were shown to be necessary for rapid internalization. We have mutated the single tyrosine at position 5 in the cytoplasmic domain of the major subunit H1 of the asialoglycoprotein receptor to alanine. Expressed in fibroblasts cells, the mutant protein was accumulated in the plasma membrane, and its rate of internalization ...

  14. NK cells infiltrating a MHC class I-deficient lung adenocarcinoma display impaired cytotoxic activity toward autologous tumor cells associated with altered NK cell-triggering receptors.

    Science.gov (United States)

    Le Maux Chansac, Béatrice; Moretta, Alessandro; Vergnon, Isabelle; Opolon, Paule; Lécluse, Yann; Grunenwald, Dominique; Kubin, Marek; Soria, Jean-Charles; Chouaib, Salem; Mami-Chouaib, Fathia

    2005-11-01

    NK cells are able to discriminate between normal cells and cells that have lost MHC class I (MHC-I) molecule expression as a result of tumor transformation. This function is the outcome of the capacity of inhibitory NK receptors to block cytotoxicity upon interaction with their MHC-I ligands expressed on target cells. To investigate the role of human NK cells and their various receptors in the control of MHC-I-deficient tumors, we have isolated several NK cell clones from lymphocytes infiltrating an adenocarcinoma lacking beta2-microglobulin expression. Unexpectedly, although these clones expressed NKG2D and mediated a strong cytolytic activity toward K562, Daudi and allogeneic MHC-class I+ carcinoma cells, they were unable to lyse the autologous MHC-I- tumor cell line. This defect was associated with alterations in the expression of natural cytotoxicity receptor (NCR) by NK cells and the NKG2D ligands, MHC-I-related chain A, MHC-I-related chain B, and UL16 binding protein 1, and the ICAM-1 by tumor cells. In contrast, the carcinoma cell line was partially sensitive to allogeneic healthy donor NK cells expressing high levels of NCR. Indeed, this lysis was inhibited by anti-NCR and anti-NKG2D mAbs, suggesting that both receptors are required for the induced killing. The present study indicates that the MHC-I-deficient lung adenocarcinoma had developed mechanisms of escape from the innate immune response based on down-regulation of NCR and ligands required for target cell recognition.

  15. 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....

  16. Inverse regulation of interleukin-6 (IL-6) and IL-6 receptor in histamine deficient histidine decarboxylase-knock-out mice

    NARCIS (Netherlands)

    Horváth, B V; Falus, A; Tóth, S; Szalai, Cs; Lázár-Molnár, E; Holub, M Cs; Buzás, E; Nagy, A; Fulop, A K

    2002-01-01

    Interleukin-6, a multifunctional cytokine upon binding to its receptor on hepatocytes regulates production of acute phase proteins involved in local and systemic inflammation. Gene expression and biosynthesis of IL-6 and its receptor (IL-6 R/gp130) is under complex regulation. Histamine, in addition

  17. 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.

  18. Compared with saturated fatty acids, dietary monounsaturated fatty acids and carbohydrates increase atherosclerosis and VLDL cholesterol levels in LDL receptor-deficient, but not apolipoprotein E-deficient, mice.

    Science.gov (United States)

    Merkel, M; Velez-Carrasco, W; Hudgins, L C; Breslow, J L

    2001-11-01

    Heart-healthy dietary recommendations include decreasing the intake of saturated fatty acids (SFA). However, the relative benefit of replacing SFA with monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), or carbohydrates (CARB) is still being debated. We have used two mouse models of atherosclerosis, low density lipoprotein receptor-deficient (LDLRKO) and apolipoprotein E-deficient (apoEKO) mice to measure the effects of four isocaloric diets enriched with either SFA, MUFA, PUFA, or CARB on atherosclerotic lesion area and lipoprotein levels. In LDLRKO mice, compared with the SFA diet, the MUFA and CARB diets significantly increased atherosclerosis in both sexes, but the PUFA diet had no effect. The MUFA and CARB diets also increased very low density lipoprotein-cholesterol (VLDL-C) and LDL-cholesterol (LDL-C) in males and VLDL-C levels in females. Analysis of data from LDLRKO mice on all diets showed that atherosclerotic lesion area correlated positively with VLDL-C levels (males: r = 0.47, P diet, the CARB diet significantly decreased VLDL-C in males and the MUFA, PUFA, and CARB diets decreased VLDL-C and the CARB diet decreased LDL-C in females. In summary, in LDLRKO mice the replacement of dietary SFA by either MUFA or CARB causes a proportionate increase in both atherosclerotic lesion area and VLDL-C. There were no significant dietary effects on atherosclerotic lesion area in apoEKO mice. These results are surprising and suggest that, depending on the underlying genotype, dietary MUFA and CARB can actually increase atherosclerosis susceptibility, probably by raising VLDL-C levels through a non-LDL receptor, apoE-dependent pathway. PMID:11606787

  19. Relation between increased anxiety and reduced expression of alpha1 and alpha2 subunits of GABA(A) receptors in Wfs1-deficient mice.

    Science.gov (United States)

    Raud, Sirli; Sütt, Silva; Luuk, Hendrik; Plaas, Mario; Innos, Jürgen; Kõks, Sulev; Vasar, Eero

    2009-08-28

    Mutations in the coding region of the WFS1 gene cause Wolfram syndrome, a rare multisystem neurodegenerative disorder of autosomal recessive inheritance. In clinical studies a relation between mutations in the Wfs1 gene and increased susceptibility for mood disorders has been established. According to our previous studies, mice lacking Wfs1 gene displayed increased anxiety in stressful environment. As the GABA-ergic system plays a significant role in the regulation of anxiety, we analyzed the expression of GABA-related genes in the forebrain structures of wild-type and Wfs1-deficient mice. Experimentally naïve Wfs1-deficient animals displayed a significant down-regulation of alpha1 (Gabra1) and alpha2 (Gabra2) subunits of GABA(A) receptors in the temporal lobe and frontal cortex. Exposure of wild-type mice to the elevated plus-maze decreased levels of Gabra1 and Gabra2 genes in the temporal lobe. A similar tendency was also established in the frontal cortex of wild-type animals exposed to behavioral test. In Wfs1-deficient mice the elevated plus-maze exposure did not induce further changes in the expression of Gabra1 and Gabra2 genes. By contrast, the expression of Gad1 and Gad2 genes, enzymes responsible for the synthesis of GABA, was not significantly affected by the exposure of mice to the elevated plus-maze or by the invalidation of Wfs1 gene. Altogether, the present study demonstrates that increased anxiety of Wfs1-deficient mice is probably linked to reduced expression of Gabra1 and Gabra2 genes in the frontal cortex and temporal lobe. PMID:19477223

  20. N-methyl-D-aspartate receptor - nitric oxide synthase pathway in the cortex of Nogo-A-deficient rats in relation to brain laterality and schizophrenia

    Directory of Open Access Journals (Sweden)

    Zdena eKristofikova

    2013-08-01

    Full Text Available It has been suggested that Nogo-A, a myelin-associated protein, could play a role in the pathogenesis of schizophrenia and that Nogo-A-deficient rodents could serve as an animal model for schizophrenic symptoms. Since changes in brain laterality are typical of schizophrenia, we investigated whether Nogo-A-deficient rats showed any signs of disturbed asymmetry in cortical N-methyl-D-aspartate (NMDA receptor–nitric oxide synthase (NOS pathway, which is reported as dysfunctional in schizophrenia. In particular, we measured separately in the right and left hemisphere of young and old Nogo-A-deficient male rats the expression of NMDA receptor subunits (NR1, NR2A and NR2B in the frontal cortex and activities of NOS isoforms (neuronal (nNOS, endothelial (eNOS and inducible (iNOS in the parietal cortex. In young controls, we observed right/left asymmetry of iNOS activity and three positive correlations (between NR1 in the left and NR2B laterality, between NR2B in the right and left sides, and between NR1 in the right side and nNOS laterality. In old controls, we found bilateral decreases in NR1, an increase in NR2B in the right side and two changes in correlations in the NR1–nNOS pathway. In young Nogo-A-deficient rats, we observed an increase in iNOS activity in the left hemisphere and two changes in correlations in NR1–nNOS and NR2A–eNOS, compared to young controls. Finally, we revealed in old Nogo-A-deficient animals, bilateral decreases in NR1 and one change in correlation between eNOS–iNOS, compared to old controls. Although some findings from schizophrenic brains did not manifest in Nogo-A-deficient rats (e.g., no alterations in NR2B, others did (e.g., alterations demonstrating accelerated ageing in young but not old animals, those occurring exclusively in the right hemisphere in young and old animals and those suggesting abnormal frontoparietal cortical interactions in young animals.

  1. 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

  2. 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 brain-specifi

  3. Diabetic Nephropathy Is Accelerated by Farnesoid X Receptor Deficiency and Inhibited by Farnesoid X Receptor Activation in a Type 1 Diabetes Model

    OpenAIRE

    Wang, Xiaoxin X.; Jiang, Tao; Shen, Yan; Caldas, Yupanqui; Miyazaki-Anzai, Shinobu; Santamaria, Hannah; Urbanek, Cydney; Solis, Nathaniel; Scherzer, Pnina; Lewis, Linda; Gonzalez, Frank J.; Adorini, Luciano; Pruzanski, Mark; Jeffrey B Kopp; Verlander, Jill W.

    2010-01-01

    OBJECTIVE The pathogenesis of diabetic nephropathy is complex and involves activation of multiple pathways leading to kidney damage. An important role for altered lipid metabolism via sterol regulatory element binding proteins (SREBPs) has been recently recognized in diabetic kidney disease. Our previous studies have shown that the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, modulates renal SREBP-1 expression. The purpose of the present study was then to determ...

  4. [1N,12N]Bis(Ethyl)-cis-6,7-Dehydrospermine: a New Drug for Treatment and Prevention of Cryptosporidium parvum Infection of Mice Deficient in T-Cell Receptor Alpha

    OpenAIRE

    Waters, W. R.; Frydman, B.; Marton, L J; Valasinas, A.; Reddy, V. K.; Harp, J A; Wannemuehler, M J; Yarlett, N

    2000-01-01

    Cryptosporidium parvum infection of T-cell receptor alpha (TCR-α)-deficient mice results in a persistent infection. In this study, treatment with a polyamine analogue (SL-11047) prevented C. parvum infection in suckling TCR-α-deficient mice and cleared an existing infection in older mice. Treatment with putrescine, while capable of preventing infection, did not clear C. parvum from previously infected mice. These findings provide further evidence that polyamine metabolic pathways are targets ...

  5. Peroxisome proliferator–activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor–deficient mice

    OpenAIRE

    Li, Andrew C.; Kathleen K Brown; Silvestre, Mercedes J.; Willson, Timothy M; Palinski, Wulf; Glass, Christopher K.

    2000-01-01

    The peroxisome proliferator–activated receptor γ (PPARγ) is a nuclear receptor that regulates fat-cell development and glucose homeostasis and is the molecular target of a class of insulin-sensitizing agents used for the management of type 2 diabetes mellitus. PPARγ is highly expressed in macrophage foam cells of atherosclerotic lesions and has been demonstrated in cultured macrophages to both positively and negatively regulate genes implicated in the development of atherosclerosis. We report...

  6. The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells

    OpenAIRE

    Burek, C. J.; Roth, J.; Koch, H. G.; Harzer, K.; Los, Marek Jan; Schulze-Osthoff, Klaus

    2001-01-01

    The activation of sphingomyelinases leading to the generation of ceramide has been implicated in various apoptotic pathways. However, the role of ceramide as an essential death mediator remains highly controversial. In the present study, we investigated the functional relevance of ceramide in a genetic model by using primary cells from a Farber disease patient. These cells accumulate ceramide as the result of an inherited deficiency of acidic ceramidase. We demonstrate that Farber disease lym...

  7. Peroxisome proliferator-activated receptor gamma agonism reduces the insulin-stimulated increase in circulating interleukin-6 in growth hormone (GH) replaced GH-deficient adults

    DEFF Research Database (Denmark)

    Krag, Morten B; Rasmussen, Lars M; Hansen, Troels K;

    2008-01-01

    SUMMARY Context: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists modify cardiovascular risk factors and inflammatory markers in patients with type 2 diabetes. Growth hormone (GH) treatment in GH-deficient (GHD) patients may cause insulin resistance and exerts ambiguous effects...... on inflammatory markers. Objective: To investigate circulating markers of inflammation and endothelial function in GH replaced GHD patients before and after 12 weeks administration of either pioglitazone 30 mg/day (N=10) or placebo (N=10) in a randomized double-blind parallel design. Methods...... significantly abrogated this insulin-stimulated increment in IL-6 levels compared to placebo (P = 0.01). Furthermore PPARgamma agonist treatment significantly lowered basal IL-4 levels (P<0.05). Conclusions: 1) IL-6 levels increase during a hyperinsulinemic clamp in GH replaced patients, 2) This increase in IL...

  8. Clinical significance of complement deficiencies.

    Science.gov (United States)

    Pettigrew, H David; Teuber, Suzanne S; Gershwin, M Eric

    2009-09-01

    The complement system is composed of more than 30 serum and membrane-bound proteins, all of which are needed for normal function of complement in innate and adaptive immunity. Historically, deficiencies within the complement system have been suspected when young children have had recurrent and difficult-to-control infections. As our understanding of the complement system has increased, many other diseases have been attributed to deficiencies within the complement system. Generally, complement deficiencies within the classical pathway lead to increased susceptibility to encapsulated bacterial infections as well as a syndrome resembling systemic lupus erythematosus. Complement deficiencies within the mannose-binding lectin pathway generally lead to increased bacterial infections, and deficiencies within the alternative pathway usually lead to an increased frequency of Neisseria infections. However, factor H deficiency can lead to membranoproliferative glomerulonephritis and hemolytic uremic syndrome. Finally, deficiencies within the terminal complement pathway lead to an increased incidence of Neisseria infections. Two other notable complement-associated deficiencies are complement receptor 3 and 4 deficiency, which result from a deficiency of CD18, a disease known as leukocyte adhesion deficiency type 1, and CD59 deficiency, which causes paroxysmal nocturnal hemoglobinuria. Most inherited deficiencies of the complement system are autosomal recessive, but properidin deficiency is X-linked recessive, deficiency of C1 inhibitor is autosomal dominant, and mannose-binding lectin and factor I deficiencies are autosomal co-dominant. The diversity of clinical manifestations of complement deficiencies reflects the complexity of the complement system. PMID:19758139

  9. Dual Effects of IL-1 Overactivity on the Immune System in a Mouse Model of Arthritis due to Deficiency of IL-1 Receptor Antagonist

    Institute of Scientific and Technical Information of China (English)

    Jian Yan; Yan Jiao; Hong Chen; Feng Jiao; Karen A.Hasty; John M.Stuart; Weikuan Gu

    2013-01-01

    Previous studies have revealed the significance of cytokine interleukin 1 (IL-1) in the onset and progression of meumatoid arthritis (RA).The precise molecular mechanisms related to IL-1 underlying RA is still elusive.We conducted a whole genome-wide transcriptomal comparison of wild-type (WT) and arthritis-prone IL-1 receptor antagonist (IL-Irn) deficient BALB/c mice to address this issue.To refine our search efforts,gene expression profiling was also performed on paired wild-type and arthritis-resis nt IL-1m deficient DBA/1 mice as internal controls when identifying causative arthritis candidate genes.Two hundred and fifteen trans dpts were found to be dysregulated greater than or equal to 2-fold in the diseased mice.The altered transcriptome in BALB/c mice revealed increased myeloid cell activities and impaired lymphocyte functionality,suggesting dual regulatory effects of IL-1 hyperactivil on immunological changes associated with arthritis development.Phase-specific gene expression changes were identified,such as early increase and late decrease of heat shock protein coding genes.Moreover,common gene expression changes were also observed,especially the upregulation of paired Ig-like receptor A (Pira) in both early and late phases of arthritis.Real-time PCR was performed to validate the expression of Pira and an intervention experiment with a major histocompatibility complex (MHC) class I inhibitor (brefeldin A) was carried out to investigate the role of suppressing Pira activity.We conclude that global pattern changes of common and distinct gene expressions may represent novel opportunities for better control of RA through early diagnosis and development of alternative therapeutic strategies.

  10. Utrophin abundance is reduced at neuromuscular junctions of patients with both inherited and acquired acetylcholine receptor deficiencies

    NARCIS (Netherlands)

    Slater, CR; Young, C; Wood, SJ; Bewick, GS; Anderson, LVB; Baxter, P; Fawcett, PRW; Roberts, M; Jacobson, L; Kuks, J; Vincent, A; NewsomDavis, J

    1997-01-01

    Congenital myasthenic syndromes are a heterogenous group of conditions in which muscle weakness resulting from impaired neuromuscular transmission is often present from infancy. One form of congenital myasthenic syndrome is due to a reduction of the number of acetylcholine receptors (AChRs) at the n

  11. Melatonin receptor deficiency decreases and temporally shifts ecto-5'-nucleotidase mRNA levels in mouse prosencephalon.

    Science.gov (United States)

    Homola, Moran; Pfeffer, Martina; Robson, Simon C; Fischer, Claudia; Zimmermann, Herbert; Korf, Horst-Werner

    2016-07-01

    Ecto-5'-nucleotidase (eN) is the major extracellular adenosine-producing ecto-enzyme in mouse brain. Via the production of adenosine, eN participates in many physiological and pathological processes, such as wakefulness, inflammation, nociception and neuroprotection. The mechanisms regulating the expression of eN are therefore of considerable neurobiological and clinical interest. Having previously described a modulatory effect of melatonin in the regulation of eN mRNA levels, we decided to analyze the melatonin receptor subtype involved in the regulation of eN mRNA levels by comparing eN mRNA patterns in melatonin-proficient transgenic mice lacking either the melatonin receptor subtype 1 (MT1 KO) or both melatonin receptor subtypes (MT1 and MT2; MT1/2 KO) with the corresponding melatonin-proficient wild-type (WT) controls. By means of radioactive in situ hybridization, eN mRNA levels were found to be diminished in both MT1 and MT1/2 KO mice compared with WT controls suggesting stimulatory impacts of melatonin receptors on eN mRNA levels. Whereas eN mRNA levels increased during the day and peaked at night in WT and MT1 KO mice, eN mRNA levels at night were reduced and the peak was shifted toward day-time in double MT1/2 KO mice. These data suggest that the MT2 receptor subtype may play a role in the temporal regulation of eN mRNA availability. Notably, day-time locomotor activity was significantly higher in MT1/2 KO compared with WT mice. Our results suggest melatoninergic signaling as an interface between the purinergic system and the circadian system. PMID:26917036

  12. The Use of an IL-1 Receptor Antagonist Peptide to Control Inflammation in the Treatment of Corneal Limbal Epithelial Stem Cell Deficiency

    Directory of Open Access Journals (Sweden)

    E. Fok

    2015-01-01

    Full Text Available Corneal limbal stem cell deficiency (LSCD may be treated using ex vivo limbal epithelial stem cells (LESCs derived from cadaveric donor tissue. However, continuing challenges exist around tissue availability, inflammation, and transplant rejection. Lipopolysaccharide (LPS or recombinant human IL-1β stimulated primary human keratocyte and LESC models were used to investigate the anti-inflammatory properties of a short chain, IL-1 receptor antagonist peptide for use in LESC sheet growth to control inflammation. The peptide was characterized using mass spectroscopy and high performance liquid chromatography. Peptide cytotoxicity, patterns of cell cytokine expression in response to LPS or IL-1β stimulation, and peptide suppression of this response were investigated by MTS/LDH assays, ELISA, and q-PCR. Cell differences in LPS stimulated toll-like receptor 4 expression were investigated using immunocytochemistry. A significant reduction in rIL-1β stimulated inflammatory cytokine production occurred following LESC and keratocyte incubation with anti-inflammatory peptide and in LPS stimulated IL-6 and IL-8 production following keratocyte incubation with peptide (1 mg/mL P<0.05. LESCs produced no cytokine response to LPS stimulation and showed no TLR4 expression. The peptide supported LESC growth when adhered to a silicone hydrogel contact lens indicating potential use in improved LESC grafting through suppression of inflammation.

  13. Gamma Interferon (IFN-γ) Receptor Restricts Systemic Dengue Virus Replication and Prevents Paralysis in IFN-α/β Receptor-Deficient Mice

    OpenAIRE

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

    2012-01-01

    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 ...

  14. Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis

    International Nuclear Information System (INIS)

    The metabolism of infused 111In-labeled phospholipid liposomes was examined in Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack low density lipoprotein (LDL) receptors, and in normal control rabbits. The half-times (t/sub 1/2/) for clearance of 111In and excess phospholipid from plasma were 20.8 +/- 0.9 hr and 20.3 +/- 4.6 hr in WHHL and 20.0 +/- 0.8 hr and 19.6 +/- 2.2 hr in the normal rabbits. By 6 hr postinfusion, the plasma concentration of unesterified cholesterol increased by 2.2 +/- 0.23 mmol/liter in WHHL and 2.1 +/- 0.04 mmol/liter in normal rabbits, presumably reflecting mobilization of tissue sores. Disappearance of excess plasma cholesterol was > 90% complete in both groups of rabbits by 70 hr postinfusion. By quantitative γ camera imaging, hepatic trapping of 111In-labeled liposomes over time was indistinguishable between the two groups. At autopsy, the liver was the major organ of clearance. Aortic uptake of 111In was < 0.02%. Thus, mobilization of cholesterol and hepatic uptake of phospholipid liposomes do not require LDL receptors. Because phospholipid infusions produce rapid substantial regression of atherosclerosis in genetically normal animals, the results suggest that phospholipid liposomes or triglyceride phospholipid emulsions (e.g., Intralipid) might reduce atherosclerosis in WHHL rabbits and in humans with familial hypercholesterolemia

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

    OpenAIRE

    Ahamed, Karmene; Epaud, Ralph; Holzenberger, Martin; Bonora, Monique; Flejou, Jean-François; Puard, Julien; Clément, Annick; Henrion-Caude, Alexandra

    2005-01-01

    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 comp...

  16. Mannose receptor-mediated delivery of moss-made α-galactosidase A efficiently corrects enzyme deficiency in Fabry mice.

    Science.gov (United States)

    Shen, Jin-Song; Busch, Andreas; Day, Taniqua S; Meng, Xing-Li; Yu, Chun I; Dabrowska-Schlepp, Paulina; Fode, Benjamin; Niederkrüger, Holger; Forni, Sabrina; Chen, Shuyuan; Schiffmann, Raphael; Frischmuth, Thomas; Schaaf, Andreas

    2016-03-01

    Enzyme replacement therapy (ERT) is an effective treatment for several lysosomal storage disorders (LSDs). Intravenously infused enzymes are taken up by tissues through either the mannose 6-phosphate receptor (M6PR) or the mannose receptor (MR). It is generally believed that M6PR-mediated endocytosis is a key mechanism for ERT in treating LSDs that affect the non-macrophage cells of visceral organs. However, the therapeutic efficacy of MR-mediated delivery of mannose-terminated enzymes in these diseases has not been fully evaluated. We tested the effectiveness of a non-phosphorylated α-galactosidase A produced from moss (referred to as moss-aGal) in vitro and in a mouse model of Fabry disease. Endocytosis of moss-aGal was MR-dependent. Compared to agalsidase alfa, a phosphorylated form of α-galactosidase A, moss-aGal was more preferentially targeted to the kidney. Cellular localization of moss-aGal and agalsidase alfa in the heart and kidney was essentially identical. A single injection of moss-aGal led to clearance of accumulated substrate in the heart and kidney to an extent comparable to that achieved by agalsidase alfa. This study suggested that mannose-terminated enzymes may be sufficiently effective for some LSDs in which non-macrophage cells are affected, and that M6P residues may not always be a prerequisite for ERT as previously considered. PMID:26310963

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Angiotensin type 2-receptor (AT2R) activation induces hypotension in apolipoprotein E-deficient mice by activating peroxisome proliferator-activated receptor

    Science.gov (United States)

    Li, Ming; Tejada, Thor; Lambert, Jonathan P; Nicholson, Chad K; Yahiro, Eiji; Ambai, Vats T; Ali, Syeda F; Bradley, Eddie W; Graham, Robert M; Dell’Italia, Louis J; Calvert, John W; Naqvi, Nawazish

    2016-01-01

    Angiotensin II (Ang II) modulates blood pressure and atherosclerosis development through its vascular type-1 (AT1R) and type-2 (AT2R) receptors, which have opposing effects. AT2R activation produces hypotension, and is anti-atherogenic. Targeted overexpression of AT2Rs in vascular smooth muscle cells (VSMCs) indicates that these effects are due to increased nitric oxide (NO) generation. However, the role of endogenous VSMC AT2Rs in these events is unknown. Effect of 7-day low-dose Ang II-infusion (12 µg/kg/hr) on blood pressure was tested in 9-week-old apoE(-/-) mice fed a low or high cholesterol diet (LCD or HCD, respectively). Cardiac output was measured by echocardiography. Immunohistochemistry was performed to localize and quantify AT2Rs and p-Ser1177-endothelial nitric oxide synthase (eNOS) levels in the aortic arch. PD123319 and GW-9662 were used to selectively block the AT2R and peroxisome proliferator-activated receptor-γ (PPAR-γ), respectively. Ang II infusion decreased blood pressure by 12 mmHg (P LCD/apoE(-/-) mice without altering cardiac output; a response blocked by PD123319. Although, AT2R stimulation neither activated eNOS (p-Ser1177-eNOS) nor changed plasma NO metabolites, it caused an ~6-fold increase in VSMC PPAR-γ levels (P < 0.001) and the AT2R-mediated hypotension was abolished by GW-9662. AT2R-mediated hypotension was also inhibited by HCD, which selectively decreased VSMC AT2R expression by ~6-fold (P < 0.01). These findings suggest a novel pathway for the Ang II/AT2R-mediated hypotensive response that involves PPAR-γ, and is down regulated by a HCD. PMID:27679746

  19. Angiotensin type 2-receptor (AT2R) activation induces hypotension in apolipoprotein E-deficient mice by activating peroxisome proliferator-activated receptor-γ.

    Science.gov (United States)

    Li, Ming; Tejada, Thor; Lambert, Jonathan P; Nicholson, Chad K; Yahiro, Eiji; Ambai, Vats T; Ali, Syeda F; Bradley, Eddie W; Graham, Robert M; Dell'Italia, Louis J; Calvert, John W; Naqvi, Nawazish

    2016-01-01

    Angiotensin II (Ang II) modulates blood pressure and atherosclerosis development through its vascular type-1 (AT1R) and type-2 (AT2R) receptors, which have opposing effects. AT2R activation produces hypotension, and is anti-atherogenic. Targeted overexpression of AT2Rs in vascular smooth muscle cells (VSMCs) indicates that these effects are due to increased nitric oxide (NO) generation. However, the role of endogenous VSMC AT2Rs in these events is unknown. Effect of 7-day low-dose Ang II-infusion (12 µg/kg/hr) on blood pressure was tested in 9-week-old apoE((-/-)) mice fed a low or high cholesterol diet (LCD or HCD, respectively). Cardiac output was measured by echocardiography. Immunohistochemistry was performed to localize and quantify AT2Rs and p-Ser(1177)-endothelial nitric oxide synthase (eNOS) levels in the aortic arch. PD123319 and GW-9662 were used to selectively block the AT2R and peroxisome proliferator-activated receptor-γ (PPAR-γ), respectively. Ang II infusion decreased blood pressure by 12 mmHg (P < 0.001) in LCD/apoE((-/-)) mice without altering cardiac output; a response blocked by PD123319. Although, AT2R stimulation neither activated eNOS (p-Ser(1177)-eNOS) nor changed plasma NO metabolites, it caused an ~6-fold increase in VSMC PPAR-γ levels (P < 0.001) and the AT2R-mediated hypotension was abolished by GW-9662. AT2R-mediated hypotension was also inhibited by HCD, which selectively decreased VSMC AT2R expression by ~6-fold (P < 0.01). These findings suggest a novel pathway for the Ang II/AT2R-mediated hypotensive response that involves PPAR-γ, and is down regulated by a HCD. PMID:27679746

  20. An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy.

    Science.gov (United States)

    Ohsawa, Yutaka; Okada, Tadashi; Nishimatsu, Shin-Ichiro; Ishizaki, Masatoshi; Suga, Tomohiro; Fujino, Masahiro; Murakami, Tatsufumi; Uchino, Makoto; Tsuchida, Kunihiro; Noji, Sumihare; Hinohara, Atsushi; Shimizu, Toshiyuki; Shimizu, Kiyoshi; Sunada, Yoshihide

    2012-08-01

    Skeletal muscle expressing Pro104Leu mutant caveolin 3 (CAV3(P104L)) in mouse becomes atrophied and serves as a model of autosomal dominant limb-girdle muscular dystrophy 1C. We previously found that caveolin 3-deficient muscles showed activated intramuscular transforming growth factor beta (TGF-β) signals. However, the cellular mechanism by which loss of caveolin 3 leads to muscle atrophy is unknown. Recently, several small-molecule inhibitors of TGF-β type I receptor (TβRI) kinase have been developed as molecular-targeting drugs for cancer therapy by suppressing intracellular TGF-β1, -β2, and -β3 signaling. Here, we show that a TβRI kinase inhibitor, Ki26894, restores impaired myoblast differentiation in vitro caused by activin, myostatin, and TGF-β1, as well as CAV3(P104L). Oral administration of Ki26894 increased muscle mass and strength in vivo in wild-type mice, and improved muscle atrophy and weakness in the CAV3(P104L) mice. The inhibitor restored the number of satellite cells, the resident stem cells of adult skeletal muscle, with suppression of the increased phosphorylation of Smad2, an effector, and the upregulation of p21 (also known as Cdkn1a), a target gene of the TGF-β family members in muscle. These data indicate that both TGF-β-dependent reduction in satellite cells and impairment of myoblast differentiation contribute to the cellular mechanism underlying caveolin 3-deficient muscle atrophy. TβRI kinase inhibitors could antagonize the activation of intramuscular anti-myogenic TGF-β signals, thereby providing a novel therapeutic rationale for the alternative use of this type of anticancer drug in reversing muscle atrophy in various clinical settings. PMID:22584670

  1. Generation and characterization of a pseudotyped gene transfer system with selectivity for the hepatocyte-specific asialoglycoprotein receptor

    OpenAIRE

    Spiegel, Martin

    2000-01-01

    Ansätze zum therapeutischen in vivo Lebergentransfer erfordern leberrestringierte Gentransfersysteme. Die derzeit verwendeten amphotropen Moloney Murine Leukemia Virus (MoMLV)- Vektoren sind aufgrund ihres breiten Transduktionsspektrums für in vivo Applikationen nicht geeignet. In diesem Zusammenhang wurde die Möglichkeit der Pseudotypbildung zwischen ecotropem MoMLV und Sendai Virus (SeV), einem Parainfluenzavirus, untersucht. Der Einbau beider SeV- Hüllproteine (HN und F) ...

  2. Targeting the liver via the asialoglycoprotein-receptor : synthesis of directed small molecule libraries for the H1-CRD

    OpenAIRE

    Riva, Claudia

    2007-01-01

    The ASGP-R, exclusively located on the cell surfaces of hepatocytes, is well known for removing desialylated glycoproteins with terminal galactose or N - acetylgalactosamine residues from circulation. However, small high affinity ligands with more drug-like properties than the natural glycoproteins, that can be used for specific targeting of the liver, were not yet investigated for the human H1-CRD. Various small-directed libraries of galactose derivatives and mimics thereof we...

  3. 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. PMID:22973027

  4. Even in pneumococcal sepsis CD62L shedding on granulocytes proves to be a reliable functional test for the diagnosis of interleukin-1 receptor-associated kinase-4 deficiency.

    Science.gov (United States)

    Andres, Oliver; Strehl, Karoline; Kölsch, Uwe; Kunzmann, Steffen; Lebrun, Anne-Hélène; Stroh, Thorsten; Schwarz, Klaus; Morbach, Henner; von Bernuth, Horst; Liese, Johannes; Liefse, Johannes

    2013-09-01

    A 9-month-old infant presented with fatal pneumococcal sepsis and attenuated inflammation indices. Even in septic conditions, flow cytometry-based CD62L shedding test on granulocytes proved to be a fast and reliable diagnostic tool for the detection of a defect in the innate immunity. Confirmatory immunologic and genetic assays identified an autosomal-recessive interleukin-1 receptor-associated kinase-4 deficiency due to compound heterozygous mutations.

  5. 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.

  6. A polymorphism in the leptin receptor gene at position 223 is associated with growth hormone replacement therapy responsiveness in idiopathic short stature and growth hormone deficiency patients.

    Science.gov (United States)

    Su, Pen-Hua; Yang, Shun-Fa; Yu, Ju-Shan; Chen, Suh-Jen; Chen, Jia-Yuh

    2012-12-01

    We hypothesized that responses to growth hormone (GH) therapy by idiopathic short stature (ISS) and growth hormone deficiency (GHD) patients were associated with single nucleotide polymorphisms (SNPs) in the leptin (LEP) and leptin receptor (LEPR) genes. We retrospectively enrolled ISS (n = 32) and GHD (n = 38) patients and forty healthy age-and gender-matched children. They were genotyped for the LEP promoter at nt.-2548, and LEPR K109R and LEPR Q223R polymorphisms. Clinical and laboratory variables were determined before and after 2 years of GH treatment. ISS patients with G/A or A/A genotypes of the LEPR Q223R SNP had a significantly higher height velocity (cm/y) than ISS patients with the G/G genotype at 2 years after GH treatment. For GHD patients, G/A or A/A genotype of the LEPR K109R SNP was associated with higher body weight, higher BMI, and higher weight velocity than patients with the G/G genotype before GH treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher body weight, higher height velocity before treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher weight velocity before treatment, but a significantly lower weight velocity was found at 2 years after GH treatment. These results suggest LEPR Q223R SNP (rs1137101) is associated with outcomes of GH replacement therapy in ISS and GHD patients. PMID:23009903

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

    Science.gov (United States)

    Rieger, Toni; Merkler, Doron; Günther, Stephan

    2013-01-01

    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.

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

    Directory of Open Access Journals (Sweden)

    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. 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

    In humans at least two GH receptors are significantly expressed. One is the full-length receptor (GHR); the other is a truncated form (GHRtr), that lacks most of the intracellular domain. This receptor may inhibit the action of the full-length receptor. Circulating GH-binding protein (GHBP) is a ...

  10. Iron deficiency anaemia.

    Science.gov (United States)

    Lopez, Anthony; Cacoub, Patrice; Macdougall, Iain C; Peyrin-Biroulet, Laurent

    2016-02-27

    Anaemia affects roughly a third of the world's population; half the cases are due to iron deficiency. It is a major and global public health problem that affects maternal and child mortality, physical performance, and referral to health-care professionals. Children aged 0-5 years, women of childbearing age, and pregnant women are particularly at risk. Several chronic diseases are frequently associated with iron deficiency anaemia--notably chronic kidney disease, chronic heart failure, cancer, and inflammatory bowel disease. Measurement of serum ferritin, transferrin saturation, serum soluble transferrin receptors, and the serum soluble transferrin receptors-ferritin index are more accurate than classic red cell indices in the diagnosis of iron deficiency anaemia. In addition to the search for and treatment of the cause of iron deficiency, treatment strategies encompass prevention, including food fortification and iron supplementation. Oral iron is usually recommended as first-line therapy, but the most recent intravenous iron formulations, which have been available for nearly a decade, seem to replenish iron stores safely and effectively. Hepcidin has a key role in iron homoeostasis and could be a future diagnostic and therapeutic target. In this Seminar, we discuss the clinical presentation, epidemiology, pathophysiology, diagnosis, and acute management of iron deficiency anaemia, and outstanding research questions for treatment.

  11. Relationship between autophagy and the intracellular degradation of asialoglycoproteins in cultured rat hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Kindberg, G.M.; Refsnes, M.; Christoffersen, T.; Norum, K.R.; Berg, T.

    1987-05-25

    The relationship between autophagy and the intracellular distribution of endocytosed asialoorosomucoid was studied in cultured rat hepatocytes. Overt autophagy was induced by shifting the cells to a minimal salt medium. Incubation in minimal salt medium led to the formation of buoyant lysosomes at the expense of denser lysosomes manifested as a dual distribution of these organelles in Nycodenz gradients. Asialoorosomucoid was labeled with /sup 125/I-tyramine cellobiose. The labeled degradation products formed from this ligand are trapped at the site of degradation and may therefore serve as markers for the subgroup of lysosomes involved in the degradation. In control cells the degradation of the ligand was initiated in a light prelysosomal compartment and continued in denser lysosomes. In cells with high autophagic activity, the degradation of labeled asialoorosomucoid took place exclusively in a buoyant group of lysosomes. These results suggest that degradation of endocytosed ligand takes place in the same secondary lysosomes as substrate sequestered by autophagic mechanisms. These light lysosomes represent a subgroup of active lysosomes which are gradually recruited from dense bodies. Data are also presented that indicate that insulin may prevent the change in buoyant density brought about by incubation in deficient medium.

  12. Relationship between autophagy and the intracellular degradation of asialoglycoproteins in cultured rat hepatocytes

    International Nuclear Information System (INIS)

    The relationship between autophagy and the intracellular distribution of endocytosed asialoorosomucoid was studied in cultured rat hepatocytes. Overt autophagy was induced by shifting the cells to a minimal salt medium. Incubation in minimal salt medium led to the formation of buoyant lysosomes at the expense of denser lysosomes manifested as a dual distribution of these organelles in Nycodenz gradients. Asialoorosomucoid was labeled with 125I-tyramine cellobiose. The labeled degradation products formed from this ligand are trapped at the site of degradation and may therefore serve as markers for the subgroup of lysosomes involved in the degradation. In control cells the degradation of the ligand was initiated in a light prelysosomal compartment and continued in denser lysosomes. In cells with high autophagic activity, the degradation of labeled asialoorosomucoid took place exclusively in a buoyant group of lysosomes. These results suggest that degradation of endocytosed ligand takes place in the same secondary lysosomes as substrate sequestered by autophagic mechanisms. These light lysosomes represent a subgroup of active lysosomes which are gradually recruited from dense bodies. Data are also presented that indicate that insulin may prevent the change in buoyant density brought about by incubation in deficient medium

  13. 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

  14. 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”.

  15. 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. Howeve

  16. Systemic administration of the neurotensin NTS1 receptor agonist PD149163 improves performance on a memory task in naturally deficient male Brown Norway rats

    OpenAIRE

    Keiser, Ashley A.; Matazel, Katelin S.; Esser, Melissa K.; Feifel, David; Prus, Adam J.

    2014-01-01

    Agonists for neurotensin NTS1 receptor consistently exhibit antipsychotic effects in animal models without producing catalepsy, suggesting that NTS1 receptor agonists may be a novel class of drugs to treat schizophrenia. Moreover, studies utilizing NTS1 agonists have reported improvements in some aspects of cognitive functioning, including prepulse inhibition and learning procedures, that suggest an ability of NTS1 receptor agonists to diminish neurocognitive deficits. The present study sough...

  17. NMDA Receptors and Oxidative Stress Induced by the Major Metabolites Accumulating in HMG Lyase Deficiency Mediate Hypophosphorylation of Cytoskeletal Proteins in Brain From Adolescent Rats: Potential Mechanisms Contributing to the Neuropathology of This Disease.

    Science.gov (United States)

    Fernandes, Carolina Gonçalves; Pierozan, Paula; Soares, Gilberto Machado; Ferreira, Fernanda; Zanatta, Ângela; Amaral, Alexandre Umpierrez; Borges, Clarissa Günther; Wajner, Moacir; Pessoa-Pureur, Regina

    2015-10-01

    Neurological symptoms and cerebral abnormalities are commonly observed in patients with 3-hydroxy-3-methylglutaryl-CoA lyase (HMG lyase) deficiency, which is biochemically characterized by predominant tissue accumulation of 3-hydroxy-3-methylglutaric (HMG), 3-methylglutaric (MGA), and 3-methylglutaconic (MGT) acids. Since the pathogenesis of this disease is poorly known, the present study evaluated the effects of these compounds on the cytoskeleton phosphorylating system in rat brain. HMG, MGA, and MGT caused hypophosphorylation of glial fibrillary acidic protein (GFAP) and of the neurofilament subunits NFL, NFM, and NFH. HMG-induced hypophosphorylation was mediated by inhibiting the cAMP-dependent protein kinase (PKA) on Ser55 residue of NFL and c-Jun kinase (JNK) by acting on KSP repeats of NFM and NFH subunits. We also evidenced that the subunit NR2B of NMDA receptor and Ca(2+) was involved in HMG-elicited hypophosphorylation of cytoskeletal proteins. Furthermore, the antioxidants L-NAME and TROLOX fully prevented both the hypophosphorylation and the inhibition of PKA and JNK caused by HMG, suggesting that oxidative damage may underlie these effects. These findings indicate that the main metabolites accumulating in HMG lyase deficiency provoke hypophosphorylation of cytoskeleton neural proteins with the involvement of NMDA receptors, Ca(2+), and reactive species. It is presumed that these alterations may contribute to the neuropathology of this disease. PMID:26174040

  18. Wiskott-Aldrich Syndrome Interacting Protein Deficiency Uncovers the Role of the Co-receptor CD19 as a Generic Hub for PI3 Kinase Signaling in B Cells.

    Science.gov (United States)

    Keppler, Selina Jessica; Gasparrini, Francesca; Burbage, Marianne; Aggarwal, Shweta; Frederico, Bruno; Geha, Raif S; Way, Michael; Bruckbauer, Andreas; Batista, Facundo D

    2015-10-20

    Humans with Wiskott-Aldrich syndrome display a progressive immunological disorder associated with compromised Wiskott-Aldrich Syndrome Interacting Protein (WIP) function. Mice deficient in WIP recapitulate such an immunodeficiency that has been attributed to T cell dysfunction; however, any contribution of B cells is as yet undefined. Here we have shown that WIP deficiency resulted in defects in B cell homing, chemotaxis, survival, and differentiation, ultimately leading to diminished germinal center formation and antibody production. Furthermore, in the absence of WIP, several receptors, namely the BCR, BAFFR, CXCR4, CXCR5, CD40, and TLR4, were impaired in promoting CD19 co-receptor activation and subsequent PI3 kinase (PI3K) signaling. The underlying mechanism was due to a distortion in the actin and tetraspanin networks that lead to altered CD19 cell surface dynamics. In conclusion, our findings suggest that, by regulating the cortical actin cytoskeleton, WIP influences the function of CD19 as a general hub for PI3K signaling.

  19. Using Soluble Transferrin Receptor and Taking Inflammation into Account When Defining Serum Ferritin Cutoffs Improved the Diagnosis of Iron Deficiency in a Group of Canadian Preschool Inuit Children from Nunavik

    Science.gov (United States)

    Turgeon O'Brien, Huguette; Blanchet, Rosanne; Gagné, Doris; Vézina, Carole

    2016-01-01

    The prevalence of iron depletion, iron deficient erythropoiesis (IDE), and iron deficiency anemia (IDA) was assessed in preschool Inuit children using soluble transferrin receptor (sTfR) and traditional indicators of iron status while disregarding or taking inflammation into account when defining SF cutoffs. Iron depletion was defined as follows: (1) SF 5 mg/L, respectively. IDE corresponded to iron depletion combined with total iron binding capacity > 72 μmol/L and/or transferrin saturation < 16%. Iron depletion and IDE affected almost half of the children when accounting for inflammation, compared to one-third when the SF cutoff was defined regardless of CRP level (P < 0.0001). The prevalence of IDE adjusted for inflammation (45.1%) was very similar to the prevalence observed when sTfR was used as a sole marker of IDE (47.4%). The prevalence of anemia was 15%. The prevalence of IDA (IDE + hemoglobin < 110 g/L) was higher when accounting for than when disregarding inflammation (8.0% versus 6.2%, P = 0.083). Using sTfR and different SF cutoffs for children with versus without inflammation improved the diagnosis of iron depletion and IDE. Our results confirm that Inuit children are at particularly high risk for iron deficiency. PMID:27382488

  20. New competition assay for the solubilized hepatic galactosyl receptor

    Energy Technology Data Exchange (ETDEWEB)

    Ray, D.A.; Weigel, P.H.

    1985-02-15

    The present method of quantitating soluble asialoglycoprotein (galactosyl) receptor activity relies on the selective precipitation of receptor-ligand complexes to allow separation from free ligand. To provide an alternative to selective precipitation procedures, a simple and rapid method to assay for detergent-solubilized galactosyl receptor activity has been developed which uses permeabilized, fixed cells as a source of immobilized solid-phase receptors. Isolated rat hepatocytes were treated with digitonin to make available the internal as well as the external receptors. The permeable cells were also treated with glutaraldehyde to prevent further protein loss during subsequent exposure to detergents such as Triton X-100. The permeable/fixed cells, which retained about 70% of their total /sup 125/I-asialo-orosomucoid (/sup 125/I-ASOR)-binding activity, with 89% specific binding, were insoluble even in 0.5% Triton X-100 and were easily pelleted. The permeable/fixed cells can be prepared in advance and stored frozen for months. A detergent extract of receptor is mixed with a constant amount of both /sup 125/I-ASOR and permeable/fixed cells. Soluble active receptors compete with immobilized receptors on the treated cell for binding of the /sup 125/I-ASOR. The assay is reproducible, linear over a broad range of soluble receptor concentration, and can quantitate receptor activity from as few as 10(5) hepatocytes. A modified purification procedure for the rat hepatic galactosyl receptor using this competition assay is also described.

  1. Cutting Edge: IL-23 Receptor Deficiency Prevents the Development of Lupus Nephritis in C57BL/6–lpr/lpr Mice

    OpenAIRE

    Kyttaris, Vasileios C.; Zhang, Zheng; Kuchroo, Vijay K.; Oukka, Mohamed; Tsokos, George C.

    2010-01-01

    IL-17–producing T cells infiltrate kidneys of patients with lupus nephritis, and IL-23–treated lymph node cells from lupus-prone mice may transfer disease to Rag1-deficient mice. In this study, we show that IL-23R–deficient lupus-prone C57BL/6–lpr/lpr mice display decreased numbers of CD3+CD4−CD8− cells and IL-17A–producing cells in the lymph nodes and produce less anti-DNA Abs. In addition, clinical and pathology measures of lupus nephritis are abrogated. The presented experiments document t...

  2. Iron deficiency.

    Science.gov (United States)

    Scrimshaw, N S

    1991-10-01

    The world's leading nutritional problem is iron deficiency. 66% of children and women aged 15-44 years in developing countries have it. Further, 10-20% of women of childbearing age in developed countries are anemic. Iron deficiency is identified with often irreversible impairment of a child's learning ability. It is also associated with low capacity for adults to work which reduces productivity. In addition, it impairs the immune system which reduces the body's ability to fight infection. Iron deficiency also lowers the metabolic rate and the body temperature when exposed to cold. Hemoglobin contains nearly 73% of the body's iron. This iron is always being recycled as more red blood cells are made. The rest of the needed iron does important tasks for the body, such as binds to molecules that are reservoirs of oxygen for muscle cells. This iron comes from our diet, especially meat. Even though some plants, such as spinach, are high in iron, the body can only absorb 1.4-7% of the iron in plants whereas it can absorb 20% of the iron in red meat. In many developing countries, the common vegetarian diets contribute to high rates of iron deficiency. Parasitic diseases and abnormal uterine bleeding also promote iron deficiency. Iron therapy in anemic children can often, but not always, improve behavior and cognitive performance. Iron deficiency during pregnancy often contributes to maternal and perinatal mortality. Yet treatment, if given to a child in time, can lead to normal growth and hinder infections. However, excess iron can be damaging. Too much supplemental iron in a malnourished child promotes fatal infections since the excess iron is available for the pathogens use. Many countries do not have an effective system for diagnosing, treating, and preventing iron deficiency. Therefore a concerted international effort is needed to eliminate iron deficiency in the world.

  3. Quantitiative evaluation of liver function with hepatic receptor scintigraphy using Tc-99m galactosylated serum albumin (GSA)

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae Tae [College of Medicine, Kyungpook National Univ., Taegu (Korea, Republic of)

    1998-08-01

    The reduction in the amount of asialoglycoprotein (ASGP) receptor, which resides exclusively on the plasma membrane of functioning mammalian hepatocytes, as a consequence of hepatocellular damage has been demonstrated in various pathologic conditions of the liver. Galactosylated human serum albumin (GSA) is a newly developed receptor-binding agent, specific for the ASGP receptor. Tc-99m GSA binds quantitatively to liver ASGP receptors and the rate of accumulation in the liver is dependent on hepatic function represented as the amount of receptor, as well as the amount of ligand injected, its affinity to the receptor and the hepatic blood flow. The findings of Tc-99m GSA scintigraphy were reported to reflect the hepatic function of the patients with large hepatic tumors, obstructive jaundice, acute and chronic liver disease. Tc-99m GSA scintigraphy is an easy and reliable test and has the clinical potentials to evaluate the liver function in the patients with hepatic disorders.

  4. Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands

    International Nuclear Information System (INIS)

    The peroxisome proliferator activated receptor (PPAR) subgroup of the nuclear hormone receptor superfamily is activated by a variety of natural and synthetic ligands. PPARs can heterodimerize with retinoid X receptors, which have homology to other members of the nuclear receptor superfamily. Ligand binding to PPAR/RXRs results in recruitment of transcriptional coactivator proteins such as steroid receptor coactivator 1 (SRC-1) and CREB binding protein (CBP). Both SRC-1 and CBP are histone acetyltransferases, which by modifying nucleosomal histones, produce more open chromatin structure and increase transcriptional activity. Nuclear hormone receptors can recruit limiting amounts of coactivators from other transcription factor binding sites such as AP-1, thereby inhibiting the activity of AP-1 target genes. PPAR and RXR ligands have been used in experimental breast cancer therapy. The role of coactivator expression in mammary tumorigenesis and response to drug therapy has been the subject of recent studies. We examined the effects of loss of SRC-1 on MMTV-neu mediated mammary tumorigenesis. SRC-1 null mutation in mammary tumor prone mice increased the tumor latency period, reduced tumor proliferation index and metastasis, inhibited response to PPAR and RXR ligands, and induced genes involved in mammary gland differentiation. We also examined human breast cancer cell lines overexpressing SRC-1 or CBP. Coactivator overexpression increased cellular proliferation with resistance to PPAR and RXR ligands and remodeled chromatin of the proximal epidermal growth factor receptor promoter. These results indicate that histone acetyltransferases play key roles in mammary tumorigenesis and response to anti-proliferative therapies

  5. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice

    OpenAIRE

    Kumar, K. Ganesh; Sutton, Gregory M.; Dong, Jesse Z.; Roubert, Pierre; Plas, Pascale; Halem, Heather A.; Culler, Michael D.; Yang, Hyunwon; Dixit, Vishwa D.; Butler, Andrew A

    2009-01-01

    Melanocortin receptor agonists act in the brain to regulate food intake and body weight and, independently of these actions, affect insulin sensitivity. These experiments investigated the function of novel non-selective melanocortin receptor agonists (BIM-22493, BIM-22511) that cross the blood-brain barrier when administered peripherally. Treatment of diet-induced obese C57BL/6J (B6) mice with melanocortin agonists administered peripherally improved obesity, hyperinsulinemia (∼50%) and fatty ...

  6. Adenosine A2A receptor deficiency up-regulates cystatin F expression in white matter lesions induced by chronic cerebral hypoperfusion.

    Science.gov (United States)

    Duan, Wei; Ran, Hong; Zhou, Zhujuan; He, Qifen; Zheng, Jian

    2012-01-01

    In previous studies, we have shown that the inactivation of the adenosine A2A receptor exacerbates chronic cerebral hypoperfusion-induced white matter lesions (WMLs) by enhancing neuroinflammatory responses. However, the molecular mechanism underlying the effect of the adenosine A2A receptor remains unknown. Recent studies have demonstrated that cystatin F, a potent endogenous cysteine protease inhibitor, is selectively expressed in immune cells in association with inflammatory demyelination in central nervous system diseases. To understand the expression of cystatin F and its potential role in the effect of A2A receptor on WMLs induced through chronic cerebral hypoperfusion, we investigated cystatin F expression in the WMLs of A2A receptor gene knockout mice, the littermate wild-type mice and wild-type mice treated daily with the A2A receptor agonist CGS21680 or both CGS21680 and A2A receptor antagonist SCH58261 after chronic cerebral hypoperfusion. The results of quantitative-PCR and western blot analysis revealed that cystatin F mRNA and protein expression were significantly up-regulated in the WMLs after chronic cerebral hypoperfusion. In addition, cystatin F expression in the corpus callosum was significantly increased in A2A receptor gene knockout mice and markedly decreased in mice treated with CGS21680 on both the mRNA and protein levels. Additionally, SCH58261 counteracted the attenuation of cystatin F expression produced by CGS21680 after chronic cerebral hypoperfusion. Moreover, double immunofluorescence staining revealed that cystatin F was co-localized with the activated microglia marker CD11b. In conclusion, the cystatin F expression in the activated microglia is closely associated with the effect of the A2A receptors, which may be related to the neuroinflammatory responses occurring during the pathological process.

  7. Adenosine A2A receptor deficiency up-regulates cystatin F expression in white matter lesions induced by chronic cerebral hypoperfusion.

    Directory of Open Access Journals (Sweden)

    Wei Duan

    Full Text Available In previous studies, we have shown that the inactivation of the adenosine A2A receptor exacerbates chronic cerebral hypoperfusion-induced white matter lesions (WMLs by enhancing neuroinflammatory responses. However, the molecular mechanism underlying the effect of the adenosine A2A receptor remains unknown. Recent studies have demonstrated that cystatin F, a potent endogenous cysteine protease inhibitor, is selectively expressed in immune cells in association with inflammatory demyelination in central nervous system diseases. To understand the expression of cystatin F and its potential role in the effect of A2A receptor on WMLs induced through chronic cerebral hypoperfusion, we investigated cystatin F expression in the WMLs of A2A receptor gene knockout mice, the littermate wild-type mice and wild-type mice treated daily with the A2A receptor agonist CGS21680 or both CGS21680 and A2A receptor antagonist SCH58261 after chronic cerebral hypoperfusion. The results of quantitative-PCR and western blot analysis revealed that cystatin F mRNA and protein expression were significantly up-regulated in the WMLs after chronic cerebral hypoperfusion. In addition, cystatin F expression in the corpus callosum was significantly increased in A2A receptor gene knockout mice and markedly decreased in mice treated with CGS21680 on both the mRNA and protein levels. Additionally, SCH58261 counteracted the attenuation of cystatin F expression produced by CGS21680 after chronic cerebral hypoperfusion. Moreover, double immunofluorescence staining revealed that cystatin F was co-localized with the activated microglia marker CD11b. In conclusion, the cystatin F expression in the activated microglia is closely associated with the effect of the A2A receptors, which may be related to the neuroinflammatory responses occurring during the pathological process.

  8. Systemic administration of the neurotensin NTS₁-receptor agonist PD149163 improves performance on a memory task in naturally deficient male brown Norway rats.

    Science.gov (United States)

    Keiser, Ashley A; Matazel, Katelin S; Esser, Melissa K; Feifel, David; Prus, Adam J

    2014-12-01

    Agonists for the neurotensin NTS₁ receptor consistently exhibit antipsychotic effects in animal models without producing catalepsy, suggesting that NTS₁-receptor agonists may be a novel class of drugs to treat schizophrenia. Moreover, studies utilizing NTS₁ agonists have reported improvements in some aspects of cognitive functioning, including prepulse inhibition and learning procedures, which suggest an ability of NTS₁-receptor agonists to diminish neurocognitive deficits. The present study sought to assess both baseline delay-induced memory performance and the effects of NTS₁-receptor activation on learning and memory consolidation in male Long-Evans and Brown Norway rats using a delayed nonmatch-to-position task radial arm-maze task. In the absence of drugs, Brown Norway rats displayed a significant increase in spatial memory errors following 3-, 7-, and 24-hr delay, whereas Long-Evans rats exhibited an increase in spatial memory errors following only a 7-, and 24-hr delay. With Brown Norway rats, administration of PD149163 before or after an information trial significantly reduced errors during a retention trial after a 24 hr delay. Administration of the NTS(1/2)-receptor antagonist SR142948 prior to the information trial did not affect retention-trial errors. These data are consistent with previous findings that Brown Norway rats have natural cognitive deficits and that they may be useful for assessing putative antipsychotic drugs for cognitive efficacy. Moreover, the results of this study support previous findings suggesting that NTS₁-receptor agonists may improve some aspects of cognitive functioning.

  9. Hepatitis B virus (HBV) receptors: Deficiency in tumor results in scant HBV infection and overexpression in peritumor leads to higher recurrence risk

    Science.gov (United States)

    Ye, Fei; Fan, Qing-Min; Yu, Guo-Feng; Yu, Dan-Dan; Gao, Lu; Sun, Kai; Han, Zhi-Peng; Li, Rong; Yang, Yang; Zhao, Qiu-Dong; Wu, Meng-Chao; Wang, Hong-Yang; Wei, Li-Xin

    2015-01-01

    Hepatitis B virus (HBV) infection is a risk factor for hepatocarcinogenesis and recurrence. Here, we sought to characterize intratumoral and peritumoral expression of HBsAg and its specific receptors in HBsAg-positive hepatocellular carcinoma (HCC) patients and further examined their correlation with the recurrence-free survival (RFS). HCC tissue and adjacent normal tissue specimens were acquired from HBsAg-positive patients. The presence of HBsAg and receptors, as well as hepatic progenitor cells (HPCs) were detected by tissue microassay and immunohistochemistry. Necroinflammatory activity was evaluated by HE staining. The mean IOD of HBsAg and HBV DNA in the intratumoral tissues was markedly lower than that in the peritumoral tissues (P ASGPR (r = 0.506, P < 0.001) in peritumoral tissues. And the peritumoral HBsAg and receptors presented a positive association with necroinflammatory activity (P < 0.05). Inflammation induced by HBV infection presented a positive association with HPCs activation (P < 0.05). Additionally, due to lack of HBV receptors, HPCs was not preferentially infected with HBV, but activated HPCs had a significant correlation with HBsAg expression in peritumoral tissues, and the peritumoral HPCs activation was associated with RFS of HCC patients, therefore, the overexpression of HBsAg and receptors in peritumor were also with higher recurrence risk (P < 0.05). In conclusion, lack of HBV receptors resulted in scant HBV infection in tumor cells, and overexpression of HBsAg and receptors in peritumor was strongly associated with higher recurrence risk in HCC patients. PMID:26515593

  10. Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands

    Directory of Open Access Journals (Sweden)

    Crowe David L

    2010-11-01

    Full Text Available Abstract Background The peroxisome proliferator activated receptor (PPAR subgroup of the nuclear hormone receptor superfamily is activated by a variety of natural and synthetic ligands. PPARs can heterodimerize with retinoid X receptors, which have homology to other members of the nuclear receptor superfamily. Ligand binding to PPAR/RXRs results in recruitment of transcriptional coactivator proteins such as steroid receptor coactivator 1 (SRC-1 and CREB binding protein (CBP. Both SRC-1 and CBP are histone acetyltransferases, which by modifying nucleosomal histones, produce more open chromatin structure and increase transcriptional activity. Nuclear hormone receptors can recruit limiting amounts of coactivators from other transcription factor binding sites such as AP-1, thereby inhibiting the activity of AP-1 target genes. PPAR and RXR ligands have been used in experimental breast cancer therapy. The role of coactivator expression in mammary tumorigenesis and response to drug therapy has been the subject of recent studies. Methods We examined the effects of loss of SRC-1 on MMTV-neu mediated mammary tumorigenesis. Results SRC-1 null mutation in mammary tumor prone mice increased the tumor latency period, reduced tumor proliferation index and metastasis, inhibited response to PPAR and RXR ligands, and induced genes involved in mammary gland differentiation. We also examined human breast cancer cell lines overexpressing SRC-1 or CBP. Coactivator overexpression increased cellular proliferation with resistance to PPAR and RXR ligands and remodeled chromatin of the proximal epidermal growth factor receptor promoter. Conclusions These results indicate that histone acetyltransferases play key roles in mammary tumorigenesis and response to anti-proliferative therapies.

  11. 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.

  12. Active radar guides missile to its target: receptor-based targeted treatment of hepatocellular carcinoma by nanoparticulate systems.

    Science.gov (United States)

    Yan, Jing-Jun; Liao, Jia-Zhi; Lin, Ju-Sheng; He, Xing-Xing

    2015-01-01

    Patients with hepatocellular carcinoma (HCC) usually present at advanced stages and do not benefit from surgical resection, so drug therapy should deserve a prominent place in unresectable HCC treatment. But chemotherapy agents, such as doxorubicin, cisplatin, and paclitaxel, frequently encounter important problems such as low specificity and non-selective biodistribution. Recently, the development of nanotechnology led to significant breakthroughs to overcome these problems. Decorating the surfaces of nanoparticulate-based drug carriers with homing devices has demonstrated its potential in concentrating chemotherapy agents specifically to HCC cells. In this paper, we reviewed the current status of active targeting strategies for nanoparticulate systems based on various receptors such as asialoglycoprotein receptor, transferrin receptor, epidermal growth factor receptor, folate receptor, integrin, and CD44, which are abundantly expressed on the surfaces of hepatocytes or liver cancer cells. Furthermore, we pointed out their merits and defects and provided theoretical references for further research. PMID:25424700

  13. Deletion of glycerol channel aquaporin-9 (Aqp9) impairs long-term blood glucose control in C57BL/6 leptin receptor-deficient (db/db) obese mice

    DEFF Research Database (Denmark)

    Spegel, Peter; Chawade, Aakash; Nielsen, Søren;

    2015-01-01

    profiling did not detect differential gene expression between genotypes. Metabolite profiling revealed a sex independent increase in plasma glycerol (+55%) and glucose (+24%), and reduction in threonate (all at q < 0.1) in Aqp9(-/-) db/db mice compared to controls. Metabolite profiling thus confirms a role......Deletion of the glycerol channel aquaporin-9 (Aqp9) reduces postprandial blood glucose levels in leptin receptor-deficient (db/db) obese mice on a C57BL/6 × C57BLKS mixed genetic background. Furthermore, shRNA-mediated reduction of Aqp9 expression reduces liver triacylglycerol (TAG) accumulation in...... observed elevated plasma glucose in Aqp9(-/-) db/db mice (+1.1 mmol/L, life-time average), while plasma insulin concentration was reduced at the time of death. Glucose levels changed similarly in pentobarbital anesthetized, glucagon challenged Aqp9(wt) db/db and Aqp9(-/-) db/db mice. Liver transcriptional...

  14. [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. PMID:25765687

  15. 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 c...

  16. Absence of lactobacilli containing glycolipids with the α-galactose epitope and the enhanced fucosylation of a receptor glycolipid GA1 in the digestive tracts of immune-deficient scid mice.

    Science.gov (United States)

    Iwamori, Masao; Tanaka, Kyoko; Adachi, Shigeki; Aoki, Daisuke; Nomura, Taisei

    2015-07-01

    The Lactobacillus species in the digestive tracts of immune-deficient scid mice was distinct from that in control mice, i.e. Lactobacillus murinus in scid and L. johnsonii in control mice, according to their 16S-rRNA, indicating that a symbiotic relationship between lactobacilli and a host is established under pressure from the immune system. The caecal and colonal contents rich in L. murinus of scid mice were loose with a strong sour smell, resulting in diarrhoea, and those with L. johnsonii in control mice included abundant solid materials. Lactobacillus glycolipids were revealed to be recognized by the immune system, and by TLC-immunostaining, LacTetH-DG (Galα1-6Galα1-6Galα1-2Glcα1-3'DG) of L. johnsonii was detected in the stomach, caecum and colon of control mice, but not in those of scid ones, in which fucosylation of a receptor GA1 for L. johnsonii was enhanced more than 4-fold compared with in the control mice. Thus, structural modification of receptor glycolipids was revealed to occur in the process of establishment of a symbiotic relationship between lactobacilli and a host. LacTetH-DG was also immunogenic to human, because of the presence of natural antibodies against it, and the antibody binding to it was comparable to that of blood group- and species-related glycosphingolipids.

  17. Osteopontin deficiency enhances parathyroid hormone/ parathyroid hormone related peptide receptor (PPR) signaling-induced alteration in tooth formation and odontoblastic morphology

    OpenAIRE

    Morishita, Maki; Ono, Noriaki; Miyai, Kentano; Nakagawa, Tomomi; Hanyu, Ryo; Nagao, Masashi; Kamolratanakul, Paksinee; Notomi, Takuya; Rittling, Susan R; Denhardt, David T.; Kronenberg, Henry M.; Ezura, Yoichi; Hayata, Tadayoshi; Nakamoto, Tetsuya; Noda, Masaki

    2011-01-01

    Parathyroid hormone/parathyroid hormone-related protein receptor (PPR) signaling is known to be involved in tooth development. In bone, extracellular matrix protein osteopontin (OPN) is a negative regulator of PPR signaling in bone formation. However, the role of OPN in modulation of PPR action in tooth development is not understood. Therefore, we examined the tooth in double mutant mice. Constitutively active PPR was expressed specifically in the odontoblasts and osteoblasts (caPPR-tg) in th...

  18. Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor

    OpenAIRE

    Yamada, Yasuhiro; Kirillova, Irina; Peschon, Jacques J.; Fausto, Nelson

    1997-01-01

    The mechanisms that initiate liver regeneration after resection of liver tissue are not known. To determine whether cytokines are involved in the initiation of liver growth, we studied the regeneration of the liver after partial hepatectomy (PH) in mice lacking type I tumor necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely impaired in these animals, and the expected increases in the binding of the NF-κB and STAT3 transcription factors shortly after...

  19. Deficiency of complement receptors CR2/CR1 in Cr2 -/- mice reduces the extent of secondary brain damage after closed head injury

    OpenAIRE

    Neher, Miriam D.; Rich, Megan C; Keene, Chesleigh N; Weckbach, Sebastian; Bolden, Ashley L; Losacco, Justin T; Patane, Jenée; Flierl, Michael A; Kulik, Liudmila; Holers, V. Michael; Stahel, Philip F

    2014-01-01

    Complement activation at the C3 convertase level has been associated with acute neuroinflammation and secondary brain injury after severe head trauma. The present study was designed to test the hypothesis that Cr2 -/- mice, which lack the receptors CR2/CD21 and CR1/CD35 for complement C3-derived activation fragments, are protected from adverse sequelae of experimental closed head injury. Adult wild-type mice and Cr2 -/- mice on a C57BL/6 genetic background were subjected to focal closed head ...

  20. 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 ....05) in GHR KO. Relative left ventricular weight was 14% lower in GHR KO mice (P ... thickness was decreased in GHR KO (P KO mice, whereas the aorta of GHR KO mice showed an increased sensitivity...

  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. Evidence for a partial deficiency of the LDL (apo B,E) receptor within a family of rhesus monkeys with a spontaneous hypercholesterolemia

    International Nuclear Information System (INIS)

    Spontaneous hypercholesterolemia is rare among non-human primates. Through screening of a rhesus monkey colony they have identified a family in which 3 out of its 6 members have a persistent hypercholesterolemia on a cholesterol-free Purina Chow diet and are high responders to a dietary fat challenge. On a basal diet the 3 affected animals also exhibited high plasma levels of LDL and apoB. To shed light on the mechanism of the hypercholesterolemia they have grown in culture fibroblasts from skin biopsies obtained from all members of the rhesus monkey family and 12 control. Binding studies at 40C and ligand blotting experiments using 125I-LDL of either normolipidemic rhesus monkeys or human subjects have shown that the fibroblasts from the 3 monkeys with a spontaneous hypercholesterolemia have a significant reduction of the number of LDL receptor and to the same extent as fibroblasts derived from subjects with heterozygous FH studied at the same time. The data suggest that the spontaneous elevation of plasma cholesterol observed in the 3 family members is related, at least in part, to a defective uptake of LDL by the LDL receptor pathway

  3. Deficiency of complement receptors CR2/CR1 in Cr2⁻/⁻ mice reduces the extent of secondary brain damage after closed head injury.

    Science.gov (United States)

    Neher, Miriam D; Rich, Megan C; Keene, Chesleigh N; Weckbach, Sebastian; Bolden, Ashley L; Losacco, Justin T; Patane, Jenée; Flierl, Michael A; Kulik, Liudmila; Holers, V Michael; Stahel, Philip F

    2014-01-01

    Complement activation at the C3 convertase level has been associated with acute neuroinflammation and secondary brain injury after severe head trauma. The present study was designed to test the hypothesis that Cr2-/- mice, which lack the receptors CR2/CD21 and CR1/CD35 for complement C3-derived activation fragments, are protected from adverse sequelae of experimental closed head injury. Adult wild-type mice and Cr2-/- mice on a C57BL/6 genetic background were subjected to focal closed head injury using a standardized weight-drop device. Head-injured Cr2-/- mice showed significantly improved neurological outcomes for up to 72 hours after trauma and a significantly decreased post-injury mortality when compared to wild-type mice. In addition, the Cr2-/- genotype was associated with a decreased extent of neuronal cell death at seven days post-injury. Western blot analysis revealed that complement C3 levels were reduced in the injured brain hemispheres of Cr2-/- mice, whereas plasma C3 levels remained unchanged, compared to wild-type mice. Finally, head-injured Cr2-/- had an attenuated extent of post-injury C3 tissue deposition, decreased astrocytosis and microglial activation, and attenuated immunoglobulin M deposition in injured brains compared to wild-type mice. Targeting of these receptors for complement C3 fragments (CR2/CR1) may represent a promising future approach for therapeutic immunomodulation after traumatic brain injury. PMID:24885042

  4. Deficiency of complement receptors CR2/CR1 in Cr2⁻/⁻ mice reduces the extent of secondary brain damage after closed head injury.

    Science.gov (United States)

    Neher, Miriam D; Rich, Megan C; Keene, Chesleigh N; Weckbach, Sebastian; Bolden, Ashley L; Losacco, Justin T; Patane, Jenée; Flierl, Michael A; Kulik, Liudmila; Holers, V Michael; Stahel, Philip F

    2014-05-24

    Complement activation at the C3 convertase level has been associated with acute neuroinflammation and secondary brain injury after severe head trauma. The present study was designed to test the hypothesis that Cr2-/- mice, which lack the receptors CR2/CD21 and CR1/CD35 for complement C3-derived activation fragments, are protected from adverse sequelae of experimental closed head injury. Adult wild-type mice and Cr2-/- mice on a C57BL/6 genetic background were subjected to focal closed head injury using a standardized weight-drop device. Head-injured Cr2-/- mice showed significantly improved neurological outcomes for up to 72 hours after trauma and a significantly decreased post-injury mortality when compared to wild-type mice. In addition, the Cr2-/- genotype was associated with a decreased extent of neuronal cell death at seven days post-injury. Western blot analysis revealed that complement C3 levels were reduced in the injured brain hemispheres of Cr2-/- mice, whereas plasma C3 levels remained unchanged, compared to wild-type mice. Finally, head-injured Cr2-/- had an attenuated extent of post-injury C3 tissue deposition, decreased astrocytosis and microglial activation, and attenuated immunoglobulin M deposition in injured brains compared to wild-type mice. Targeting of these receptors for complement C3 fragments (CR2/CR1) may represent a promising future approach for therapeutic immunomodulation after traumatic brain injury.

  5. [Bacillus Calmette-Guérin (BCG) disease and interleukin 12 receptor β1 deficiency: clinical experience of two familial and one sporadic case].

    Science.gov (United States)

    Strickler, Alexis; Pérez, Amir; Risco, Migdy; Gallo, Silvanna

    2014-08-01

    BCG disease has been reported in primary and secondary immunodeficiency and as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). Investigation of this syndrome has led to the identifications of a series of genetic, inherited defects in the IL-12/IFN-γ axis. MSMD-causing mutations have been found in seven autosomal and two X-linked genes. In these patients, local or disseminated vaccine BCG infections are common. We report a clinical series including two infants with left axillary adenitis ipsilateral to the site of neonatal BCG immunization; one of them member of a family with two previously reported cases and a single sporadic case. All of them were diagnosed sequentially in Puerto Montt, Chile. The aim of this report is to notify the first Chilean disseminated BCG patients without previous immunodeficiency, in whom it was possible to identify an underlying immunodeficiency, although specific tests for IL-12/IFN-γ axis was no performed in our country. Clinical suspicion and international collaboration permitted to confirm IL12-Rβ1 deficiency in 2 of 3 familial cases and a sporadic case.

  6. Insulin-Like Growth Factor-Type 1 Receptor Inhibitor NVP-AEW541 Enhances Radiosensitivity of PTEN Wild-Type but Not PTEN-Deficient Human Prostate Cancer Cells

    International Nuclear Information System (INIS)

    Purpose: During the past decade, many clinical trials with both monoclonal antibodies and small molecules that target the insulin-like growth factor-type 1 receptor (IGF-1R) have been launched. Despite the important role of IGF-1R signaling in radioresistance, studies of such agents in combination with radiotherapy are lagging behind. Therefore, the aim of this study was to investigate the effect of the small molecule IGF-1R kinase inhibitor NVP-AEW541 on the intrinsic radioresistance of prostate cancer cells. Methods and Materials: The effect of NVP-AEW541 on cell proliferation, cell viability, IGF-1R signaling, radiosensitivity, cell cycle distribution, and double strand break repair was determined in three human prostate cancer cell lines (PC3, DU145, 22Rv1). Moreover, the importance of the PTEN pathway status was explored by means of transfection experiments with constitutively active Akt or inactive kinase-dead Akt. Results: NVP-AEW541 inhibited cell proliferation and decreased cell viability in a time-and dose-dependent manner in all three cell lines. Radiosensitization was observed in the PTEN wild-type cell lines DU145 and 22Rv1 but not in the PTEN-deficient PC3 cell line. NVP-AEW541-induced radiosensitization coincided with downregulation of phospho-Akt levels and high levels of residual double strand breaks. The importance of PTEN status in the radiosensitization effect was confirmed by transfection experiments with constitutively active Akt or inactive kinase-dead Akt. Conclusions: NVP-AEW541 enhances the effect of ionizing radiation in PTEN wild-type, but not in PTEN-deficient, prostate cancer cells. Proper patient selection based on the PTEN status of the tumor will be critical to the achievement of optimal results in clinical trials in which the combination of radiotherapy and this IGF-1R inhibitor is being explored.

  7. Divergent responses to thermogenic stimuli in BAT and subcutaneous adipose tissue from interleukin 18 and interleukin 18 receptor 1-deficient mice.

    Science.gov (United States)

    Pazos, Patricia; Lima, Luis; Tovar, Sulay; González-Touceda, David; Diéguez, Carlos; García, María C

    2015-12-10

    Brown and beige adipocytes recruitment in brown (BAT) or white adipose tissue, mainly in the inguinal fat pad (iWAT), meet the need for temperature adaptation in cold-exposure conditions and protect against obesity in face of hypercaloric diets. Using interleukin18 (Il18) and Il18 receptor 1- knockout (Il18r1-KO) mice, this study aimed to investigate the role of IL18 signaling in BAT and iWAT activation and thermogenesis under both stimuli. Il18-KO, extremely dietary obesity-prone as previously described, failed to develop diet-induced thermogenesis as assessed by BAT and iWAT Ucp1 mRNA levels. Overweight when fed standard chow but not HFD, HFD-fed Il18r1-KO mice exhibited increased iWAT Ucp1 gene expression. Energy expenditure was reduced in pre-obese Il18r1-KO mice and restored upon HFD-challenge. Cold exposure lead to similar results; Il18r1-KO mice were protected against acute body temperature drop, displaying a more brown-like structure, alternative macrophage activation and thermogenic gene expression in iWAT than WT controls. Opposite effects were observed in Il18-KO mice. Thus, Il18 and Il18r1 genetic ablation disparate effects on energy homeostasis are likely mediated by divergent BAT responses to thermogenic stimuli as well as iWAT browning. These results suggest that a more complex receptor-signaling system mediates the IL18 adipose-tissue specific effects in energy expenditure.

  8. Genetics Home Reference: isolated growth hormone deficiency

    Science.gov (United States)

    ... deficiency dwarfism, pituitary growth hormone deficiency dwarfism isolated GH deficiency isolated HGH deficiency isolated human growth hormone deficiency isolated somatotropin deficiency isolated somatotropin deficiency disorder ...

  9. VLCAD deficiency

    DEFF Research Database (Denmark)

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

    2006-01-01

    -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.......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...

  10. CX3 chemokine receptor 1 deficiency leads to reduced dendritic complexity and delayed maturation of newborn neurons in the adult mouse hippocampus

    Institute of Scientific and Technical Information of China (English)

    Feng Xiao; Jun-mei Xu; Xing-hua Jiang

    2015-01-01

    Previous studies have shown that microglia impact the proliferation and differentiation of neu-rons during hippocampal neurogenesisvia the fractalkine/CX3 chemokine receptor 1 (CX3CR1) signaling pathway. However, whether microglia can influence the maturation and dendritic growth of newborn neurons during hippocampal neurogenesis remains unclear. In the present study, we found that the number of doublecortin-positive cells in the hippocampus was decreased, and the dendritic length and number of intersections in newborn neurons in the hippocampus were reduced in transgenic adult mice with CX3CR1 deifciency (CX3CR1GFP/GFP). Furthermore, after experimental seizures were induced with kainic acid in these CX3CR1-deifcient mice, the expression of c-fos, a marker of neuronal activity, was reduced compared with wild-type mice. Collectively, the experimental ifndings indicate that the functional maturation of newborn neu-rons during hippocampal neurogenesis in adult mice is delayed by CX3CR1 deifciency.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Feeding long-chain n-3 polyunsaturated fatty acids to obese leptin receptor-deficient JCR:LA- cp rats modifies immune function and lipid-raft fatty acid composition.

    Science.gov (United States)

    Ruth, Megan R; Proctor, Spencer D; Field, Catherine J

    2009-05-01

    Dietary EPA and DHA modulate immunity and thereby may improve the aberrant immune function in obese states. To determine the effects of feeding fish oil (FO) containing EPA and DHA on splenocyte phospholipid (PL) and lipid-raft fatty acid composition, phenotypes and cytokine production, 14-week-old obese, leptin receptor-deficient JCR:LA-cp rats (cp/cp; n 10) were randomised to one of three nutritionally adequate diets for 3 weeks: control (Ctl, 0 % EPA+DHA); low FO (LFO, 0.8 % (w/w) EPA+DHA); high FO (HFO, 1.4 % (w/w) EPA+DHA). Lean JCR:LA-cp (+/ - or +/+) rats (n 5) were fed the Ctl diet. Obese Ctl rats had a higher proportion of n-3 PUFA in splenocyte PL than lean rats fed the same diet (P JCR:LA-cp rats. Feeding FO lowered the ex vivo inflammatory response, without altering IL-2 production from ConA-stimulated splenocytes which may occur independent of leptin signalling.

  13. 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.

  14. Glycine receptor deficiency and its effect on the horizontal vestibulo-ocular reflex: a study on the SPD1J mouse.

    Science.gov (United States)

    Hübner, Patrick P; Lim, Rebecca; Brichta, Alan M; Migliaccio, Americo A

    2013-04-01

    Inhibition is critical in the pathways controlling the vestibulo-ocular reflex (VOR) and plays a central role in the precision, accuracy and speed of this important vestibular-mediated compensatory eye movement. While γ-aminobutyric acid is the common fast inhibitory neurotransmitter in most of the VOR microcircuits, glycine is also found in key elements. For example, the omnidirectional pause neurons (OPNs) and inhibitory burst neurons in the horizontal VOR both use glycine as their preferred inhibitory neurotransmitter. Determining the precise contribution of glycine to the VOR pathway has been difficult due to the lack of selective tools; however, we used spasmodic mice that have a naturally occurring defect in the glycine receptor (GlyR) that reduces glycinergic transmission. Using this animal model, we compared the horizontal VOR in affected animals with unaffected controls. Our data showed that initial latency and initial peak velocity as well as slow-phase eye movements were unaffected by reduced glycinergic transmission. Importantly however, there were significant effects on quick-phase activity, substantially reducing their number (30-70 %), amplitude (~55 %) and peak velocity (~38 %). We suggest that the OPNs were primarily responsible for the reduced quick-phase properties, since they are part of an unmodifiable, or more 'hard-wired', microcircuit. In contrast, the effects of reduced glycinergic transmission on slow-phases were likely ameliorated by the intrinsically modifiable nature of this pathway. Our results also suggested there is a 'threshold' in GlyR-affected animals, below which the effects of reduced glycinergic transmission were undetected.

  15. 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

  16. The Presence of Clitoromegaly in the Nonclassical Form of 21-Hydroxylase Deficiency Could Be Partially Modulated by the CAG Polymorphic Tract of the Androgen Receptor Gene

    Science.gov (United States)

    Garcia Gomes, Larissa; Bugano Diniz Gomes, Diogo; Marcondes, José Antônio Miguel; Madureira, Guiomar; de Mendonca, Berenice Bilharinho; Bachega, Tânia A. Sartori Sanchez

    2016-01-01

    Background In the nonclassical form (NC), good correlation has been observed between genotypes and 17OH-progesterone (17-OHP) levels. However, this correlation was not identified with regard to the severity of hyperandrogenic manifestations, which could depend on interindividual variability in peripheral androgen sensitivity. Androgen action is modulated by the polymorphic CAG tract (nCAG) of the androgen receptor (AR) gene and by polymorphisms in 5α-reductase type 2 (SRD5A2) enzyme, both of which are involved in the severity of hyperandrogenic disorders. Objectives To analyze whether nCAG-AR and SRD5A2 polymorphisms influence the severity of the nonclassical phenotype. Patients NC patients (n = 114) diagnosed by stimulated-17OHP ≥10 ng/mL were divided into groups according to the beginning of hyperandrogenic manifestations (pediatric and adolescent/adult) and CYP21A2 genotypes (C/C: homozygosis for mild mutations; A/C: compound heterozygosis for severe/mild mutations). Methods CYP21A2 mutations were screened by allelic-specific PCR, MLPA and/or sequencing. HpaII-digested and HpaII-undigested DNA samples underwent GeneScan analysis to study nCAG, and the SRD5A2 polymorphisms were screened by RLFP. Results Mean nCAG did not differ among pediatric, adolescent/adult and asymptomatic subjects. In the C/C genotype, we observed a significantly lower frequency of longer CAG alleles in pediatric patients than in adolescent/adults (p = 0.01). In patients carrying the A/C genotype, the frequencies of shorter and longer CAG alleles did not differ between pediatric patients and adolescent/adults (p>0.05). Patients with clitoromegaly had significantly lower weighted CAG biallelic mean than those without it: 19.1±2.7 and 21.6±2.5, respectively (p = 0.007), independent of the CYP21A2 genotype's severity. The SRD5A2 polymorphisms were not associated with the variability of hyperandrogenic NC phenotypes. Conclusions In this series, we observed a modulatory effect of the CAG

  17. Omega-3 fatty acid deficient male rats exhibit abnormal behavioral activation in the forced swim test following chronic fluoxetine treatment: association with altered 5-HT1A and alpha2A adrenergic receptor expression.

    Science.gov (United States)

    Able, Jessica A; Liu, Yanhong; Jandacek, Ronald; Rider, Therese; Tso, Patrick; McNamara, Robert K

    2014-03-01

    Omega-3 fatty acid deficiency during development leads to enduing alterations in central monoamine neurotransmission in rat brain. Here we investigated the effects of omega-3 fatty acid deficiency on behavioral and neurochemical responses to chronic fluoxetine (FLX) treatment. Male rats were fed diets with (CON, n = 34) or without (DEF, n = 30) the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during peri-adolescent development (P21-P90). A subset of CON (n = 14) and DEF (n = 12) rats were administered FLX (10 mg/kg/d) through their drinking water for 30 d beginning on P60. The forced swimming test (FST) was initiated on P90, and regional brain mRNA markers of serotonin and noradrenaline neurotransmission were determined. Dietary ALA depletion led to significant reductions in frontal cortex docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (-26%, p = 0.0001) and DEF + FLX (-32%, p = 0.0001) rats. Plasma FLX and norfluoxetine concentrations did not different between FLX-treated DEF and CON rats. During the 15-min FST pretest, DEF + FLX rats exhibited significantly greater climbing behavior compared with CON + FLX rats. During the 5-min test trial, FLX treatment reduced immobility and increased swimming in CON and DEF rats, and only DEF + FLX rats exhibited significant elevations in climbing behavior. DEF + FLX rats exhibited greater midbrain, and lower frontal cortex, 5-HT1A mRNA expression compared with all groups including CON + FLX rats. DEF + FLX rats also exhibited greater midbrain alpha2A adrenergic receptor mRNA expression which was positively correlated with climbing behavior in the FST. These preclinical data demonstrate that low omega-3 fatty acid status leads to abnormal behavioral and neurochemical responses to chronic FLX treatment in male rats.

  18. Iron deficiency anemia: current strategies for the diagnosis and management

    OpenAIRE

    Zühre Kaya

    2013-01-01

    Iron deficiency is one of the commonest nutritional deficiencies in the world. It is multifactorial and may be caused by lack of intake, blood loss and intestinal causes. Clinical features are highly variable, and most patients are asymptomatic. Typical laboratory features of iron deficiency anemia (IDA) include a hypochromic microcytic anemia, low serum iron level, high total iron binding capacity, low serum ferritin level. Usefulness of monitoring serum transferrin receptor level (sTf...

  19. Effect of DP receptor deficiency on brain histamine contents in mice%前列腺素DP受体缺乏对小鼠脑内组胺含量的影响

    Institute of Scientific and Technical Information of China (English)

    洪宗元

    2005-01-01

    目的探讨前列腺素DP受体(DPR)缺乏对小鼠脑内组胺含量的影响.方法在乙醚麻醉下,分别于明时(8:AM)及暗时(8:00PM)断头处死野生型及DPR基因敲除型小鼠,迅速取出脑组织并分离出皮层、纹状体、海马、下丘脑、丘脑、中脑及脑干等脑区,制备匀浆并用HPLC荧光检测法测量其组胺含量.结果明时处死,DPR基因敲除型小鼠皮层、下丘脑及丘脑中的组胺含量明显低于野生型小鼠;暗时处死DPR小鼠,仅丘脑中组胺含量显著降低.结论DPR基因敲除型小鼠脑中组胺能神经活性显著降低,这一变化可能是该种小鼠尚能维持正常睡眠的代偿机制之一.%Objective To explore the effect of DP receptor (DPR) deficiency on brain histamine contents in mice. Methods Wild type (WT) and DPR knockout (KO) mice were killed by decapitation under anesthesia by diethyl ether at either light on phase (8:00 AM) or light off phase (8:00 PM). The brain tissues were quickly removed out and divided on ice into seven regions: the cortex, striatum, hippocampus, hypothalamus,thalamus, midbrain and medulla (brainstem). These brain regions were homogenized and histamine contents in the homogenates were determined by HPLC- fluorometry. Results At light on phase, histamine contents in hypothalamus, thalamus and cortex were significantly lower in DPR-KO mice than in WT mice (P = 0. 0384,0.0455 and 0. 0179, respectively). However, at light off phase the difference was only observed in the thalamus. Conclusion The activity of the histaminergic system decreased and the decrease might be one of the compensatory mechanisms for maintenance of the normal sleep in the null mice lacking DPR.

  20. Leukocyte Adhesion Deficiency (LAD)

    Science.gov (United States)

    ... Content Marketing Share this: Main Content Area Leukocyte Adhesion Deficiency (LAD) LAD is an immune deficiency in ... are slow to heal also may have LAD. Treatment and Research Doctors prescribe antibiotics to prevent and ...

  1. Factor VII deficiency

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/000548.htm Factor VII deficiency To use the sharing features on this page, please enable JavaScript. Factor VII (seven) deficiency is a disorder caused by a ...

  2. Folate-deficiency anemia

    Science.gov (United States)

    ... medlineplus.gov/ency/article/000551.htm Folate-deficiency anemia To use the sharing features on this page, please enable JavaScript. Folate-deficiency anemia is a decrease in red blood cells (anemia) ...

  3. 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 ...

  4. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... This Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video— ... treatment. For more information about living with and managing iron-deficiency anemia, go to the Health Topics ...

  5. Familial lipoprotein lipase deficiency

    Science.gov (United States)

    ... medlineplus.gov/ency/article/000408.htm Familial lipoprotein lipase deficiency To use the sharing features on this page, please enable JavaScript. Familial lipoprotein lipase deficiency is a group of rare genetic disorders ...

  6. Iron deficiency and cognition

    OpenAIRE

    Hulthén, Lena

    2003-01-01

    Iron deficiency is the most prevalent nutritional disorder in the world. One of the most worrying consequences of iron deficiency in children is the alteration of behaviour and cognitive performance. In iron-deficient children, striking behavioural changes are observed, such as reduced attention span, reduced emotional responsiveness and low scores on tests of intelligence. Animal studies on nutritional iron deficiency show effects on learning ability that parallel the human studies. Despite ...

  7. Iron-Deficiency Anemia

    Science.gov (United States)

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

  8. 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 ...

  9. 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.

  10. Lipoprotein lipase deficiency.

    OpenAIRE

    Shankar K; Bava H; Shetty J; Joshi M

    1997-01-01

    A rare case of a 3 month old child with lipoprotein lipase deficiency who presented with bronchopneumonia is reported. After noticing lipaemic serum and lipaemia retinalis, a diagnosis of hyperlipoproteinaemia was considered. Lipoprotein lipase deficiency was confirmed with post heparin lipoprotein lipase enzyme activity estimation.

  11. 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

  12. Iron deficiency in childhood

    NARCIS (Netherlands)

    L. Uijterschout

    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

  13. 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)....

  14. Vitamin deficiencies and excesses

    Science.gov (United States)

    Vitamins are essential nutrients that must be supplied exogenously either as part of a well balanced diet or as supplements. Deficiency states are uncommon in developed countries except, perhaps, among some food insecure families. In contrast, deficiency states are quite common in many developing ...

  15. 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 ...

  16. Deficiently Extremal Gorenstein Algebras

    Indian Academy of Sciences (India)

    Pavinder Singh

    2011-08-01

    The aim of this article is to study the homological properties of deficiently extremal Gorenstein algebras. We prove that if / is an odd deficiently extremal Gorenstein algebra with pure minimal free resolution, then the codimension of / must be odd. As an application, the structure of pure minimal free resolution of a nearly extremal Gorenstein algebra is obtained.

  17. Affinity labeling of the galactose/N-acetylgalactosamine-specific receptor of rat hepatocytes: preferential labeling of one of the subunits

    Energy Technology Data Exchange (ETDEWEB)

    Lee, R.T.; Lee, Y.C.

    1987-10-06

    The galactose/N-acetylgalactosamine-specific receptor (also known as asialoglycoprotein receptor) of rat hepatocytes consists of three subunits, one of which (43 kilodalton (kDa)) exists in a greater abundance (up to 70% of total protein) over the two minor species (52 and 60 kDa). When the receptor on the hepatocyte membranes was photoaffinity labeled with an /sup 125/I-labeled high-affinity reagent the labeling occurred mainly (51-80%) on one of the minor bands (52 kDa). Similarly, affinity-bound, N-acetylgalactosamine-modified lactoperoxidase radioiodinated the same 52-kDa band preferentially. In contrast, both the photoaffinity labeling and lactoperoxidase-catalyzed iodination of the purified, detergent-solubilized receptor resulted in a distribution of the label that is comparable to the Coomassie blue staining pattern of the three bands; i.e., the 43-kDa band was the major band labeled. These and other experimental results suggest that the preferential labeling of the minor band and inefficient labeling of the major band on the hepatocyte membrane resulted from a specific topological arrangement of these subunits on the membranes. The authors postulate that in the native, membrane-bound state of the receptor, the 52-kDa minor band is topologically prominent, while the major (43 kDa) band is partially masked. This partial masking may result from a tight packing of the receptor subunits on the membranes to form a lattice work.

  18. [Iron deficiency in the elderly].

    Science.gov (United States)

    Helsen, Tuur; Joosten, Etienne

    2016-06-01

    Anemia is a common diagnosis in the geriatric population, especially in institutionalized and hospitalized elderly. Most common etiologies for anemia in elderly people admitted to a geriatric ward are iron-deficiency anemia and anemia associated with chronic disease.Determination of serum ferritin is the most used assay in the differential diagnosis, despite low sensitivity and moderate specificity. New insights into iron homeostasis lead to new diagnostic assays such as serum hepcidin, serum transferrin receptor and reticulocyte hemoglobin equivalent.Importance of proper diagnosis and treatment for this population is large since there is a correlation between anemia and morbidity - mortality. Anemia is usually defined as hemoglobin less than 12 g/dl for women and less than 13 g/dl for men. There is no consensus for which hemoglobinvalue an investigation into underlying pathology is obligatory. This needs to be evaluated depending on functional condition of the patient. PMID:27106490

  19. Rescue of deficient amygdala tonic γ-aminobutyric acidergic currents in the Fmr(-/y) mouse model of fragile X syndrome by a novel γ-aminobutyric acid type A receptor-positive allosteric modulator.

    Science.gov (United States)

    Martin, Brandon S; Martinez-Botella, Gabriel; Loya, Carlos M; Salituro, Francesco G; Robichaud, Albert J; Huntsman, Molly M; Ackley, Mike A; Doherty, James J; Corbin, Joshua G

    2016-06-01

    Alterations in the ratio of excitatory to inhibitory transmission are emerging as a common component of many nervous system disorders, including autism spectrum disorders (ASDs). Tonic γ-aminobutyric acidergic (GABAergic) transmission provided by peri- and extrasynaptic GABA type A (GABAA ) receptors powerfully controls neuronal excitability and plasticity and, therefore, provides a rational therapeutic target for normalizing hyperexcitable networks across a variety of disorders, including ASDs. Our previous studies revealed tonic GABAergic deficits in principal excitatory neurons in the basolateral amygdala (BLA) in the Fmr1(-/y) knockout (KO) mouse model fragile X syndrome. To correct amygdala deficits in tonic GABAergic neurotransmission in Fmr1(-/y) KO mice, we developed a novel positive allosteric modulator of GABAA receptors, SGE-872, based on endogenously active neurosteroids. This study shows that SGE-872 is nearly as potent and twice as efficacious for positively modulating GABAA receptors as its parent molecule, allopregnanolone. Furthermore, at submicromolar concentrations (≤1 μM), SGE-872 is selective for tonic, extrasynaptic α4β3δ-containing GABAA receptors over typical synaptic α1β2γ2 receptors. We further find that SGE-872 strikingly rescues the tonic GABAergic transmission deficit in principal excitatory neurons in the Fmr1(-/y) KO BLA, a structure heavily implicated in the neuropathology of ASDs. Therefore, the potent and selective action of SGE-872 on tonic GABAA receptors containing α4 subunits may represent a novel and highly useful therapeutic avenue for ASDs and related disorders involving hyperexcitability of neuronal networks. © 2015 Wiley Periodicals, Inc. PMID:26308557

  20. 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 ...

  1. Iron-Deficiency Anemia

    Medline Plus

    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 ...

  2. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Entire Site Health Topics News & Resources Intramural Research Public Health Topics Education & Awareness Resources Contact The Health ... Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and development in children, ...

  3. Sleep Deprivation and Deficiency

    Science.gov (United States)

    ... page from the NHLBI on Twitter. What Are Sleep Deprivation and Deficiency? Sleep deprivation (DEP-rih-VA- ... Rate This Content: NEXT >> Updated: February 22, 2012 Sleep Infographic Sleep Disorders & Insufficient Sleep: Improving Health through ...

  4. Iron-Deficiency Anemia

    Medline Plus

    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, ...

  5. Manganese deficiency in plants

    DEFF Research Database (Denmark)

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

    2016-01-01

    Manganese (Mn) is an essential plant micronutrient with an indispensable function as a catalyst in the oxygen-evolving complex (OEC) of photosystem II (PSII). Even so, Mn deficiency frequently occurs without visual leaf symptoms, thereby masking the distribution and dimension of the problem...... 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....

  6. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Digg. Share this page from the NHLBI on Facebook. Add this link to the NHLBI to my ... such as tiredness, poor skin tone, dizziness, and depression. After her doctor diagnosed her with iron-deficiency ...

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... CAUSES WHO IS AT RISK SIGNS & SYMPTOMS DIAGNOSIS TREATMENTS PREVENTION LIVING WITH CLINICAL TRIALS LINKS Related Topics ... Doctors usually can successfully treat iron-deficiency anemia. Treatment will depend on the cause and severity of ...

  8. Iron-Deficiency Anemia

    Medline Plus

    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 ...

  9. Adult growth hormone deficiency

    OpenAIRE

    Vishal Gupta

    2011-01-01

    Adult growth hormone deficiency (AGHD) is being recognized increasingly and has been thought to be associated with premature mortality. Pituitary tumors are the commonest cause for AGHD. Growth hormone deficiency (GHD) has been associated with neuropsychiatric-cognitive, cardiovascular, neuromuscular, metabolic, and skeletal abnormalities. Most of these can be reversed with growth hormone therapy. The insulin tolerance test still remains the gold standard dynamic test to diagnose AGHD. Growth...

  10. Hepcidin expression in the liver of rats fed a magnesium-deficient diet.

    Science.gov (United States)

    Ishizaki, Natsumi; Kotani, Megumi; Funaba, Masayuki; Matsui, Tohru

    2011-10-01

    Mg deficiency accelerates Fe accumulation in the liver, which may induce various metabolic disturbances. In the present study, we examined the gene expression of Hepcidin, a peptide hormone produced in the liver to regulate intestinal Fe absorption negatively, in Mg-deficient rats. Although liver Fe concentration was significantly higher in rats fed an Mg-deficient diet for 4 weeks than in rats fed a control diet, Hepcidin expression in the liver was comparable between the dietary groups. Previous studies revealed that Fe overload up-regulated Hepcidin expression through transcriptional activation by Fe-induced bone morphogenetic protein (Bmp) 6, a growth/differentiation factor belonging to the transforming growth factor-β family, in the liver. Mg deficiency up-regulated the expression of Bmp6 but did not affect the expression of inhibition of DNA binding 1, a sensitive Bmp-responsive gene. In addition, the expression of Bmp receptors such as activin receptor-like kinase 2 (Alk2), activin receptor type IIA (Actr2a), activin receptor type IIB (Actr2b) and Bmp type II receptor (Bmpr2) was lower in the liver of Mg-deficient rats than in that of control rats. The present study indicates that accumulation of hepatic Fe by Mg deficiency is a stimulant inducing Bmp6 expression but not Hepcidin expression by blunting Bmp signalling possibly resulting from down-regulation of the receptor expression. Unresponsive Hepcidin expression may have a role in Mg deficiency-induced changes related to increased liver Fe.

  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. Icariin Rescues the Downregulated Testosterone and Testicle Androgen Receptor Expression in Kidney Yang Deficient Mice%淫羊藿苷可缓解肾阳虚小鼠睾酮及性腺雄激素受体基因的表达下调

    Institute of Scientific and Technical Information of China (English)

    包宇; 杨建雄; 孙润广

    2011-01-01

    本文主要研究肾阳虚(kidney yang deficiency)小鼠血清睾酮及性腺雄激素受体基因的表达,旨在揭示淫羊藿苷(icariin)对肾阳虚症状的影响.雄性小鼠随机分为6组,除正常组注射生理盐水外,其余组注射氢化可的松15 d;再分别给大、中、小剂量组淫羊藿苷,阳性组甲基睾酮,正常组和模型对照组蒸馏水,灌胃15 d.放射免疫法测血清中睾酮含量;RT-PCR和免疫组织化学方法检测雄激素受体基因在性腺组织中mRNA和蛋白质的表达情况.对照组小鼠平均体重最轻,与正常组比较差异显著(P0.05);性腺组织中,对照组雄激素受体和mRNA比正常组表达量低,差异显著(P0.05).结果表明,肾阳虚小鼠血清睾酮含量,性腺雄激素受体mRNA和蛋白质的表达与正常组相比均有所下降,淫羊藿苷能够抑制其下降,缓解肾阳虚症状.%To investigate the expression of testosterone and androgen receptor in the testicle tissue of kidney yang deficient mouse as well as the effects of icariin in kidney yang deficiency models, mice were injected with hydrocortisone intraperitoneally for 15 days, and then treated with three different doses of icariin for additional 15 days. Radioimmunoassay. Immunohistochemistry and real-time RT-PCR were used to measure serum testosterone, androgen receptor ( AR) proteins and mRNA levels in testicle tissue. Our results showed that model group was significant ( P 0.05). In the low dose icariin-treated group, the testosterone was lower than the normal group, but significantly higher than the model group. In the testicle, AR-immunostaining and AR mRNA were both reduced in the model group ( P 0. 05) , except the high dose icariin group which showed a higher AR and mRNA levels in the testicle tissue than the models (P < 0. 05 ). This study suggested that the reduced serum testosterone, androgen receptor mRNA and protein levels in the kidney yang deficient mice could be reversed with the icariin treatments.

  13. Antepartum ornithine transcarbamylase deficiency.

    Science.gov (United States)

    Nakajima, Hitoshi; Sasaki, Yosuke; Maeda, Tadashi; Takeda, Masako; Hara, Noriko; Nakanishi, Kazushige; Urita, Yoshihisa; Hattori, Risa; Miura, Ken; Taniguchi, Tomoko

    2014-01-01

    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. PMID:25759629

  14. Insomnia and sleep deficiency in pregnancy.

    Science.gov (United States)

    Reichner, Cristina A

    2015-12-01

    Insomnia and sleep deficiency in pregnancy are very common with most women reporting sleep disturbances during pregnancy. Insomnia and sleep deficiency are also more prevalent as pregnancy progresses, possibly related to pregnancy-related physical symptoms or discomfort. There is increasing evidence indicating that these sleep problems may be associated with adverse maternal and fetal outcomes such as depressive symptoms, increased pain during labor, more Caesarean sections, preterm birth, and low birth weight. Treatment of insomnia remains challenging as some of the more commonly used sleep inducing medications such as benzodiazepines and hypnotic benzodiazepine receptor agonists may be associated with adverse neonatal outcomes. Nonpharmacological treatments such as cognitive behavioral therapy are available but the data in pregnancy is often lacking. PMID:27512475

  15. Renal phenotypic investigations of megalin-deficient patients

    DEFF Research Database (Denmark)

    Storm, Tina; Tranebjærg, Lisbeth; Frykholm, Carina;

    2013-01-01

    The reabsorption of filtered plasma proteins, hormones and vitamins by the renal proximal tubules is vital for body homeostasis. Studies of megalin-deficient mice suggest that the large multi-ligand endocytic receptor megalin plays an essential role in this process. In humans, dysfunctional megal...

  16. The role of the endogenous opiates in zinc deficiency anorexia.

    Science.gov (United States)

    Essatara, M B; Morley, J E; Levine, A S; Elson, M K; Shafer, R B; McClain, C J

    1984-03-01

    Anorexia is a major symptom of zinc deficiency, but the mechanism(s) for this anorexia are poorly defined. Recent studies have suggested an integral role for endogenous opiate peptides in appetite regulation. Dynorphin, a leucine-enkephalin containing opiate peptide, is a potent inducer of spontaneous feeding. In this study we showed that zinc deficient animals were relatively resistant to dynorphin-induced feeding. Measurement of dynorphin levels using a highly sensitive radioimmunoassay showed that zinc deficient animals had lower levels of dynorphin in the hypothalamus than did ad lib fed animals, with weight restricted animals having intermediate values. [3H]-naloxone binding was significantly increased to isolated brain membranes from zinc deficient animals using 1 nM unlabeled naloxone when compared to ad lib fed controls with the weight restricted animals again having intermediate values. These data suggest that abnormalities in endogenous opiate regulation of appetite may well play a role in the anorexia of zinc deficiency. The effects of zinc deficiency on endogenous opiate action appear to include alterations in receptor affinity, a post-receptor defect and alterations in the synthesis and/or release of dynorphin. PMID:6146993

  17. 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.

  18. Prostaglandin Receptor Signaling in Disease

    Directory of Open Access Journals (Sweden)

    Toshiyuki Matsuoka

    2007-01-01

    Full Text Available Prostanoids, consisting of the prostaglandins (PGs and the thromboxanes (TXs, are a group of lipid mediators formed in response to various stimuli. They include PGD2, PGE2, PGF2α, PGI2, and TXA2. They are released outside of the cells immediately after synthesis, and exert their actions by binding to a G-protein coupled rhodopsin-type receptor on the surface of target cells. There are eight types of the prostanoid receptors conserved in mammals from mouse to human. They are the PGD receptor (DP, four subtypes of the PGE receptor (EP1, EP2, EP3, and EP4, the PGF receptor (FP, PGI receptor (IP, and TXA receptor (TP. Recently, mice deficient in each of these prostanoid receptors were generated and subjected to various experimental models of disease. These studies have revealed the roles of PG receptor signaling in various pathological conditions, and suggest that selective manipulation of the prostanoid receptors may be beneficial in treatment of the pathological conditions. Here we review these recent findings of roles of prostanoid receptor signaling and their therapeutic implications.

  19. Alpha1-antitrypsin deficiency

    DEFF Research Database (Denmark)

    Stolk, Jan; Seersholm, Niels; Kalsheker, Noor

    2006-01-01

    biennially to exchange views and research findings. The fourth biennial meeting was held in Copenhagen, Denmark, on 2-3 June 2005. This review covers the wide range of AAT deficiency-related topics that were addressed encompassing advances in genetic characterization, risk factor identification, clinical...... epidemiology, inflammatory and signalling processes, therapeutic advances, and lung imaging techniques....

  20. 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- ...

  1. 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 iodine-deficien

  2. 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 chil...

  3. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... body. Low iron levels 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 of anemia . The term "anemia" usually refers to ...

  4. THE EFFECTS OF ZINC DEFICIENCY ON THE CONCENTRATION OF BRAIN FREE AMINO ACIDS AND SYNAPTIC MEMBRANES N-METHYL-D-ASPARTATE RECEPTORS IN RATS%缺锌对大鼠脑组织游离氨基酸和突触膜 N-甲基-D-天冬氨酸受体含量的影响

    Institute of Scientific and Technical Information of China (English)

    刘燕强; 顾景范

    2003-01-01

    本研究进行了两系列实验以探讨缺锌对大鼠脑组织游离氨基酸和突触膜N-甲基-D-天冬氨酸受体含量的影响.在第一系列实验中,把生长大鼠随机分为三组即缺锌组(ZD)、对喂组(PF)和缺锌补锌组(ZS),分别饲喂低锌饲料(3.3mg/kg)、常锌饲料但给料量与缺锌组一致以及先饲喂缺锌饲料21d后再饲喂常锌饲料,持续饲喂35d.饲养实验结束后,采取脑组织样本以分析其中的游离氨基酸的含量.在第二系列实验中,第1和第2组的处理与实验1一致,而第3组则不限食地饲喂常锌饲料,持续饲喂28d.然后取海马组织以分析其中的NMDA受体的含量.结果表明,缺锌显著降低端脑中游离谷氨酸、牛磺酸、苏氨酸、丝氨酸、丙氨酸、半胱氨酸和精氨酸含量,同时使海马中NMDA受体的最大结合率降低.此结果可能与缺锌降低大鼠学习记忆功能有关.%Two experiments were used to evaluate the effects of zinc deficiency on the concentration of free amino acids and N-methyl-D-aspartate (NMDA) receptor. In Exp. 1, Growing rats respectively consumed a low zinc (3.3mg/kg) diet (ZD), the adequate zinc but restricted according to feed consumption of ZD group (PF) or an adequate zinc diet after a low zinc diet for 21d(ZS). The duration is 35d. The telencephalon tissues were used for free amino acid concentration analysis. In Exp. 2, The treatment of group 1 and 2 were similar to Exp.1, but the rats of group 3 consumed adequate zinc diet ad libitum. The duration is 28d. The hippocampus tissues were used for NMDA receptor concentration analysis. Zinc deficiency significantly reduced the concentration of glutamate, taurine, threonine, serine, alanine, cysteine and arginine in telencephalon tissues,and Bmax of NMDA receptors in hippocampus tissues. The results provides a good explanation for low learning and memory ability in zinc deficient rats.

  5. 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 ...

  6. Deficient T Cell Receptor Excision Circles (TRECs) in autosomal recessive hyper IgE syndrome caused by DOCK8 mutation: implications for pathogenesis and potential detection by newborn screening.

    Science.gov (United States)

    Dasouki, Majed; Okonkwo, Kingsley C; Ray, Abhishek; Folmsbeel, Caspian K; Gozales, Diana; Keles, Sevgi; Puck, Jennifer M; Chatila, Talal

    2011-11-01

    Loss of function of DOCK8 is the major cause of autosomal recessive hyper IgE syndrome, a primary immunodeficiency with adaptive and innate immune dysfunction. Patients affected with ARHIES have atopic dermatitis and recurrent, potentially life-threatening viral and bacterial infections. Three consanguineous Pakistani siblings presented with severe atopic dermatitis and superinfection. Direct sequencing of DOCK8 in all three affected siblings demonstrated homozygosity for a deleterious, novel exon 14 frame shift mutation. Current newborn screening for severe combined immunodeficiency syndrome (SCID) and related T cell disorders relies on the quantitation of T Cell Receptor Excision Cells (TRECs) in dried blood spots (DBS). Significantly, both older affected siblings had undetectable TRECs, and TREC copy number was reduced in the youngest sibling. These findings suggest that AR-HIES may be detected by TREC newborn screening, and this diagnosis should be considered in the evaluation of newborns with abnormal TRECs who do not have typical SCID. PMID:21763205

  7. Transient partial growth hormone deficiency due to zinc deficiency.

    Science.gov (United States)

    Nishi, Y; Hatano, S; Aihara, K; Fujie, A; Kihara, M

    1989-04-01

    We present here a 13-year-old boy with partial growth hormone deficiency due to chronic mild zinc deficiency. When zinc administration was started, his growth rate, growth hormone levels, and plasma zinc concentrations increased significantly. His poor dietary intake resulted in chronic mild zinc deficiency, which in turn could be the cause of a further loss of appetite and growth retardation. There was also a possibility of renal zinc wasting which may have contributed to zinc deficiency. Zinc deficiency should be carefully ruled out in patients with growth retardation. PMID:2708733

  8. 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

  9. Proximal Focal Femoral Deficiency

    Directory of Open Access Journals (Sweden)

    Vishal Kalia, Vibhuti

    2008-01-01

    Full Text Available Proximal focal femoral deficiency (PFFD is a developmental disorder of the proximal segment of thefemur and of acetabulum resulting in shortening of the affected limb and impairment of the function. It isa spectrum of congenital osseous anomalies characterized by a deficiency in the structure of the proximalfemur. The diagnosis is often made by radiological evaluation which includes identification and descriptionof PFFD and evaluation of associated limb anomalies by plain radiographs. Contrast arthrography orMagnetic Resonance Imaging is indicated when radiological features are questionable and to disclose thepresence and location of the femoral head and any cartilagenous anlage. The disorder is more commonlyunilateral and is apparent at birth. However, bilateral involvement is rarely seen. Therapy of the disorder isdirected towards satisfactory ambulation and specific treatment depending on the severity of dysplasia.

  10. Micronutrient deficiency in children.

    Science.gov (United States)

    Bhan, M K; Sommerfelt, H; Strand, T

    2001-05-01

    Malnutrition increases morbidity and mortality and affects physical growth and development, some of these effects resulting from specific micronutrient deficiencies. While public health efforts must be targeted to improve dietary intakes in children through breast feeding and appropriate complementary feeding, there is a need for additional measures to increase the intake of certain micronutrients. Food-based approaches are regarded as the long-term strategy for improving nutrition, but for certain micronutrients, supplementation, be it to the general population or to high risk groups or as an adjunct to treatment must also be considered. Our understanding of the prevalence and consequences of iron, vitamin A and iodine deficiency in children and pregnant women has advanced considerably while there is still a need to generate more knowledge pertaining to many other micronutrients, including zinc, selenium and many of the B-vitamins. For iron and vitamin A, the challenge is to improve the delivery to target populations. For disease prevention and growth promotion, the need to deliver safe but effective amounts of micronutrients such as zinc to children and women of fertile age can be determined only after data on deficiency prevalence becomes available and the studies on mortality reduction following supplementation are completed. Individual or multiple micronutrients must be used as an adjunct to treatment of common infectious diseases and malnutrition only if the gains are substantial and the safety window sufficiently wide. The available data for zinc are promising with regard to the prevention of diarrhea and pneumonia. It should be emphasized that there must be no displacement of important treatment such as ORS in acute diarrhea by adjunct therapy such as zinc. Credible policy making requires description of not only the clinical effects but also the underlying biological mechanisms. As findings of experimental studies are not always feasible to extrapolate to

  11. 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.

  12. Iron-Deficiency Anemia (For Parents)

    Science.gov (United States)

    ... Things to Know About Zika & Pregnancy Iron-Deficiency Anemia KidsHealth > For Parents > Iron-Deficiency Anemia Print A ... common nutritional deficiency in children. About Iron-Deficiency Anemia Every red blood cell in the body contains ...

  13. Potentiation of latent inhibition by haloperidol and clozapine is attenuated in Dopamine D2 receptor (Drd-2)-deficient mice: do antipsychotics influence learning to ignore irrelevant stimuli via both Drd-2 and non-Drd-2 mechanisms?

    Science.gov (United States)

    O'Callaghan, Matthew J; Bay-Richter, Cecilie; O'Tuathaigh, Colm Mp; Heery, David M; Waddington, John L; Moran, Paula M

    2014-10-01

    Whether the dopamine Drd-2 receptor is necessary for the behavioural action of antipsychotic drugs is an important question, as Drd-2 antagonism is responsible for their debilitating motor side effects. Using Drd-2 null mice (Drd2 -/-) it has previously been shown that Drd-2 is not necessary for antipsychotic drugs to reverse D-amphetamine disruption of latent inhibition (LI), a behavioural measure of learning to ignore irrelevant stimuli. Weiner's 'two-headed' model indicates that antipsychotics not only reverse LI disruption, 'disrupted LI', but also potentiate LI when low/absent in controls, 'persistent' LI. We investigated whether antipsychotic drugs haloperidol or clozapine potentiated LI in wild-type controls or Drd2 -/-. Both drugs potentiated LI in wild-type but not in Drd2 -/- mice, suggesting moderation of this effect of antipsychotics in the absence of Drd-2. Haloperidol potentiated LI similarly in both Drd1 -/- and wild-type mice, indicating no such moderation in Drd1 -/-. These data suggest that antipsychotic drugs can have either Drd-2 or non-Drd-2 effects on learning to ignore irrelevant stimuli, depending on how the abnormality is produced. Identification of the non-Drd-2 mechanism may help to identify novel non-Drd2 based therapeutic strategies for psychosis. PMID:25122042

  14. Vitamin D receptor gene polymorphisms and vitamin D deficiency rickets%维生素D受体基因多态性与维生素D缺乏性佝偻病的关系

    Institute of Scientific and Technical Information of China (English)

    郑敏; 罗建明

    2010-01-01

    维生素D缺乏性佝偻病(简称佝偻病)是由于儿童体内维生素D不足引起钙、磷代谢紊乱,使正在生长的骨骼在成骨过程中不能正常沉着钙盐而产生的一种以骨骼病变为特征的全身慢性营养性疾病.目前认为环境因素及营养因素等是主要致病原因,但遗传因素在其发生发展中的作用正逐渐受到重视.维生素D是人体内钙稳态和骨代谢的主要调节因子之一,其在体内的主要活性代谢产物是1,25-(OH)2D3.维生素D受体(vitamin D receptor,VDR)是介导1,25-(OH)2D3发挥生物学效应的核内生物大分子,VDR是由VDR基因编码,因此VDR基因是研究骨代谢性疾病遗传基础的候选基因之一.文章就VDR基因多态性与佝偻病遗传易感性之间的关系作一综述.

  15. Treatment of carnitine deficiency.

    Science.gov (United States)

    Winter, S C

    2003-01-01

    Carnitine deficiency is a secondary complication of many inborn errors of metabolism. Pharmacological treatment with carnitine not only corrects the deficiency, it facilitates removal of accumulating toxic acyl intermediates and the generation of mitochondrial free coenzyme A (CoA). The United States Food and Drug Administration (US FDA) approved the use of carnitine for the treatment of inborn errors of metabolism in 1992. This approval was based on retrospective chart analysis of 90 patients, with 18 in the untreated cohort and 72 in the treated cohort. Efficacy was evaluated on the basis of clinical and biochemical findings. Compelling data included increased excretion of disease-specific acylcarnitine derivatives in a dose-response relationship, decreased levels of metabolites in the blood, and improved clinical status with decreased hospitalization frequency, improved growth and significantly lower mortality rates as compared to historical controls. Complications of carnitine treatment were few, with gastrointestinal disturbances and odour being the most frequent. No laboratory or clinical safety issues were identified. Intravenous carnitine preparations were also approved for treatment of secondary carnitine deficiency. Since only 25% of enteral carnitine is absorbed and gastrointestinal tolerance of high doses is poor, parenteral carnitine treatment is an appealing alternative therapeutic approach. In 7 patients treated long term with high-dose weekly to daily venous boluses of parenteral carnitine through a subcutaneous venous port, benefits included decreased frequency of decompensations, improved growth, improved muscle strength and decreased reliance on medical foods with liberalization of protein intake. Port infections were the most troubling complication. Theoretical concerns continue to be voiced that carnitine might result in fatal arrhythmias in patients with long-chain fat metabolism defects. No published clinical studies substantiate these

  16. Melanocortin receptor accessory proteins in adrenal disease and obesity

    OpenAIRE

    Jackson, David S.; Ramachandrappa, Shwetha; Clark, Adrian J; Chan, Li F.

    2015-01-01

    Melanocortin receptor accessory proteins (MRAPs) are regulators of the melanocortin receptor family. MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency type 2. The role of its paralog melanocortin-2-receptor accessory protein 2 (MRAP2), which is predominantly expressed in the hypothalamus including the paraventricular nucle...

  17. 人去唾液酸糖蛋白受体单克隆抗体制备及其初步应用%Preparation of mouse anti-human asialoglycoprotein receptor monoclonal antibody and its preliminary application

    Institute of Scientific and Technical Information of China (English)

    李军; 陈磊; 孙斌; 张妤; 钱海华; 殷正丰

    2013-01-01

    目的 制备人去唾液酸糖蛋白受体(ASGPR)的小鼠单克隆抗体,并应用该抗体检测ASGPR在细胞系和组织中的表达.方法 对ASGPR H1大亚基进行序列分析,选取ASGPR1全长序列制备免疫原.通过RT PCR合成ASGPR1cDNA,构建ASGPR1表达重组载体,在E.coli BL21中表达后纯化,获得目的抗原.应用传统融合杂交瘤技术制备小鼠单克隆抗体,常规检测单抗亚类和效价,竞争抑制实验鉴定单抗特异性.用流式细胞术和免疫组织化学法分别检测ASGPR在多种肝源性与非肝源性细胞系以及多种肝组织中的表达.结果 制备的单克隆抗体亚型为IgG1,效价达1∶12 800.竞争抑制实验结果显示该单抗具有很好的ASGPR结合特异性,而且识别的肽段位于ASGPR胞外段.流式细胞术检测结果显示,ASGPR不同程度地表达于肝源性细胞系,但不表达于非肝源性细胞系.免疫组织化学检测结果显示,ASGPR专一性表达于正常肝组织和肝癌组织,在肝癌组织的表达与分化程度有关,高分化肝癌中的阳性率高于低分化肝癌(75.0% vs 28.6%,P<0.05).结论 成功制备高特异性人ASGPR小鼠单克隆抗体,适用于用流式细胞术和免疫组织化学法检测ASGPR表达,可用于临床病理鉴定原发性肝癌与转移性肝癌.

  18. 去唾液酸糖蛋白受体及其在药物肝靶向递送中的应用%Asialoglycoprotein Receptor and Its Application in Liver-targeted Drug Delivery

    Institute of Scientific and Technical Information of China (English)

    黄渊余; 梁子才

    2015-01-01

    去唾液酸糖蛋白受体(ASGPR)是肝细胞特异性表达的受体,且是一种高效的内吞型受体,去唾液酸糖蛋白、半乳糖、半乳糖胺、N-乙酰半乳糖胺等糖分子对其有高亲和性.该综述回顾了ASGPR的发现历程、结构特征、生物学功能、表达模式、胞吞特点.总结了影响ASGPR与其配体亲和、介导胞吞的影响因素(包括配体类型、触角数量、空间距离与颗粒粒径).概述了早期ASGPR与其特异性配体在药物递送中的应用.最后介绍了最近利用N-乙酰半乳糖胺的缀合或修饰来实现肝靶向核酸药物递送的研究进展.

  19. 非唾液酸糖蛋白受体显像在评估肝储备功能方面的应用价值%The clinical value of asialoglycoprotein receptor imaging for determining liver functional reserve.

    Institute of Scientific and Technical Information of China (English)

    张海山; 房学东; 何尔斯泰; 徐文贵; 郑泽霖

    2001-01-01

    目的探讨肝非唾液酸糖蛋自受体显像在评估肝储备功能方面的临床应用价值.方法静注T-新半乳糖白蛋白行肝非唾液酸糖蛋白受体显像,利用标准核医学设备和计算机软件获得肝非唾液酸糖蛋白受体浓度ASGPR,测定常用肝储备功能指标和吲哚绿15min滞留率.结果对照组和肝硬化肝功能Ⅰ级、Ⅱ级、Ⅲ级组[ASGPR]分别为0.780±0.163、0.576±0.150、0.512±0.124和0.265±0.158,除肝功能Ⅰ级和肝功能Ⅱ级组无显著性差异外(P>0.05),其余各组间均存在显著性差异(P<0.001);对照组和肝硬化组[ASGPR]与凝血酶原时间(%)、血清白蛋白血胆碱脂酶、吲哚青绿15min滞留率呈显著正相关(均P<0.001),与血总胆红素呈负相关(P=0.154).结论肝非唾液酸糖蛋白受体显像是一种有推广价值的评估肝储备功能的新方法,且可能较经典肝储备功能指标更敏感.

  20. 肝细胞表面去唾液酸糖蛋白受体的流式细胞分析%Flow Cytometric Evaluation of Asialoglycoprotein Receptor on the Surface of Hepatocytes

    Institute of Scientific and Technical Information of China (English)

    李文新; 张荣军; 谭成; 陶永辉; 金坚

    2000-01-01

    建立肝细胞表面去唾液酸糖蛋白受体(ASGPR)的流式细胞分析方法(FCM),对正常及损伤鼠肝细胞、肝癌细胞(BEL-7402)表面的ASGPR作同步比较分析.以异硫氰酸荧光素标记的新半乳糖白蛋白(FITC-NGA)为ASGPR的特异性配体,以培养的正常肝细胞(L-02)为靶细胞,建立肝细胞表面ASGPR的FCM.测定并计算正常及损伤鼠肝细胞,BEL-7402细胞与同一浓度的FITC-NGA同步反应后的平均荧光强度(MIF)值.FITC-NGA与L-02细胞表面ASGPR趋近饱和结合的浓度为0.4 mg/L,该浓度下正常及损伤鼠肝细胞,BEL-7402细胞的MIF值分别为228.7、5.81、1.13.该结合可以被至少50倍于FITC-NGA的NGA或10 mmol/L的EDTA完全抑制.FCM能够良好地揭示FITC-NGA同ASGPR之间的受配体结合特性.该方法证实BEL-7402细胞表面几乎没有ASGPR,损伤鼠肝细胞表面ASGPR的数量较正常鼠肝细胞显著减少.

  1. 组胺H1受体缺乏改变小鼠脑内组胺含量及昼夜节律%HISTAMINE H1 RECEPTOR DEFICIENCY ALTERS BRAIN HISTAMINE CONTENTS AND CIRCADIAN RHYTHM IN MICE

    Institute of Scientific and Technical Information of China (English)

    洪宗元

    2005-01-01

    在乙谜麻醉下,分别于明时(8:00 a.m.)及暗时(8:00 p.m.)断头处死野生型及组胺H1R基因敲除型小鼠,迅速取出脑组织并分离出皮层、纹状体、海马、下丘脑、丘脑、中脑及脑干等脑区.这些脑组织被制成匀浆并用HPLC荧光检测法测量其组胺含量.结果显示暗时处死时,H1R基因敲除型小鼠海马、丘脑、中脑及脑干中的组胺含量明显低于野生型小鼠.明时处死时,野生型小鼠各脑区组胺含量均较暗时处死显著降低,但这一变化在H1R基因敲除型小鼠中并未观察到.这些表明作为组胺的功能靶,H1R不仅介导组胺的功能,而且调节大脑中组胺含量与释放的昼夜节律.%Under anesthesia by diethyl ether, histamine H1 receptor (H1R) gene knockout (KO) and wild-type (WT) mice were killed by decapitation either at 8:00 p.m. or at 8:00 a.m. The brains were quickly removed out and divided on ice into seven regions: the cortex, striatum, hippocampus, hypothalamus, thalamus, midbrain and medulla. These brain regions were homogenized and the histamine content in the homogenate was determined by HPLC- fluorometry. The results showed that at 8:00 p.m. histamine contents in the hippocampus, thalamus, midbrain, and medulla of DPR-KO mice were significantly decreased compared with WT mice (P<0.05). In WT mice, histamine contents in almost all brain regions were markedly higher at 8:00 p.m. than at 8:00 a.m, whereas the difference was not observed in H1R KO mice. We conclude that as the function target of histamine, H1R not only modulates the function of histamine, but also regulates the histamine content and its synthesizing or releasing rhythm in the mouse brain.

  2. Phosphorus Deficiency in Ducklins

    Institute of Scientific and Technical Information of China (English)

    CuiHengmin; LuoLingping

    1995-01-01

    20 one-day-old Tianfu ducklings were fed on a natural diet deficient in phosphorus(Ca 0.80%,P 0.366%)for three weeks and examined for signs and lesions.Signs began to appear at the age of one week,and became serous at two weeks.13 ducklings died during the experiment.Morbidity was 100% and mortality was 65%.The affected ducklings mainly showed leg weakness,severe lamencess,deprssion,lack of appetite and stunted growth,The serum alkaline phosphatase activities increased markedly.The serum phosphorus concentration,tibial ash,ash calcium and phosphorus content decreased obviously.At necropsy,maxillae and ribe were soft,and the latter was crooked.Long ones were soft and broke easily.The hypertrophic zone of the growth-plate in the epiphysis of long ones was lengthened and osteoid tissue increased in the metaphyseal spongiosa histopathologically.The above mentioned symptoms and lesions could be prevented by adding phosphorus to the natural deficient diet(up to 0.65%),The relationship between lesions and signs,pathomorphological characterisation and pathogensis were also discussed in this paper.

  3. 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

  4. [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.

  5. Iatrogenic limbal stem cell deficiency.

    OpenAIRE

    Holland, E J; Schwartz, G S

    1997-01-01

    PURPOSE: To describe a group of patients with limbal stem cell (SC) deficiency without prior diagnosis of a specific disease entity known to be causative of SC deficiency. METHODS: We performed a retrospective review of the records of all patients with ocular surface disease presenting to the University of Minnesota between 1987 and 1996. Patients were categorized according to etiology of limbal deficiency. Patients who did not have a specific diagnosis previously described as being causative...

  6. Zinc deficiency and eating disorders.

    Science.gov (United States)

    Humphries, L; Vivian, B; Stuart, M; McClain, C J

    1989-12-01

    Decreased food intake, a cyclic pattern of eating, and weight loss are major manifestations of zinc deficiency. In this study, zinc status was evaluated in 62 patients with bulimia and 24 patients with anorexia nervosa. Forty percent of patients with bulimia and 54% of those with anorexia nervosa had biochemical evidence of zinc deficiency. The authors suggest that for a variety of reasons, such as lower dietary intake of zinc, impaired zinc absorption, vomiting, diarrhea, and binging on low-zinc foods, patients with eating disorders may develop zinc deficiency. This acquired zinc deficiency could then add to the chronicity of altered eating behavior in those patients. PMID:2600063

  7. 婴幼儿佝偻病VDR基因ApaI、BsmI位点多态性与连锁不平衡分析%Study on the association between vitamin D receptor gene polymorphism of ApaI and BsmI and vitamin D deficiency rickets

    Institute of Scientific and Technical Information of China (English)

    周丽; 石永生; 蒋成鹏; 王卫凯; 李宇宁

    2011-01-01

    Objective To study the distribution characters and linkage disequilibrium of vitamin D receptor(VDR) gene ApaI and BsmI polymorphism,and explore the genetic susceptibility of VDR and vitamin D deficiency rickets.Methods VDR gene ApaI and BsmI polymorphisms were determined by PCRRFLP technology in 56 cases of rickets and 76 cases of normal children.The frequencies of the VDR genotype and allele were compared between the two groups.The software SHEsis was used to make linkage disequilibrium analysis.Results No significant difference was found in either the frequency distribution of VDR gene ApaI and BsmI polymorphism or allele of them between two groups; Two polymorphisms didn't show linkage disequilibrium and D' and r2 were 0.23 and 0.01,respectively.Conclusions The ApaI and BsmI polymorphism of VDR gene might be not associated with vitamin D deficiency rickets.Two polymorphisms didn't show linkage disequilibrium.%目的 探讨婴幼儿佝偻病患者维生素D受体(VDR)基因ApaI、BsmI位点多态性分布特征及连锁不平衡关系及其与佝偻病的遗传易感因素.方法 应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法对56例佝偻病患儿和76例健康对照儿进行VDR基因ApaI、BsmI位点多态性的检测,分析两组VDR基因型和等位基因频率及两位点间连锁不平衡的关系.结果 两组VDR基因ApaI、BsmI位点基因型频率分布比较差异均无统计学意义(P>0.05).VDR基因ApaI、BsmI 位点等位基因频率在两组人群中的分布差异均无统计学意义(P>0.05).ApaI与BsmI二位点连锁不平衡系(D'=0.230,r2=0.01).结论 VDR基因ApaI、BsmI位点的多态性与维生素D缺乏性佝偻病无明显关系,且两位点不存在连锁不平衡关系.

  8. 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.

  9. IMMUNOGLOBULIN A (IgA AND ITS RECEPTORS

    Directory of Open Access Journals (Sweden)

    V. B. Klimovich

    2006-01-01

    Full Text Available Abstract. Daily IgA production in human organism comprises 3 to 5 g, thus exceeding total synthesis of other Ig classes. IgA in human body is presented by 9 structural variants. Its molecules belong to two subclasses, IgA1 and IgA2, the latter represented by two allotypes. In human serum, IgA1 monomers predominate, that are produced by the bone marrow cells. Mucosa-associated lymphoid tissues produce dimeric IgA1 and IgA2 molecules containing an accessory polypeptide J-chain. When transported across epithelial layer to the mucosal surface, an extracellular segment of polymeric IgA receptor (pIgAR is joining the dimeric IgA1, which becomes a ‘secretory’ component being a part cesretory IgA (sIgA molecule. The main function of sIgA is to bind bacteria and viruses at the mucosal surfaces, thus preventing pathogens to invade the internal spaces of the organism (immune exclusion. If transferred across epithelium, IgA may neutralize the viruses penetrating the cells, like as bind and deliver proteins and other antigens to the mucosal surface. The leukocyte IgA receptor (FcαRI, CD89 is expressed on the neutrophils, eosinophiles, monocytes/macrophages, as well as dendritic and Kupffer cells. The cytoplasmic domain FcαRI is devoid of an activation ITAM motif. To transduce signal, an FcαRI-associated chain of Fcγ receptor is used. Due to this mechanism, IgA binding leads to activation of phagocytosis, endocytosis, antigen presentation, synthesis of proinflammatory mediator and other immune functions. Fcα/μR receptor is a structural homologue of pIgR, and it is able to bind IgA and IgM, being, however, expressed only at the surface of mature B lymphocytes and macrophages. Interaction of IgA with asialoglycoprotein and transferrin (CD71 receptors, like as with some other molecules, that have yet undetermined role in immune defense and development of pathological events.

  10. Iron deficiency and iron deficiency anemia in women.

    Science.gov (United States)

    Coad, Jane; Pedley, Kevin

    2014-01-01

    Iron deficiency is one of the most common nutritional problems in the world and disproportionately affects women and children. Stages of iron deficiency can be characterized as mild deficiency where iron stores become depleted, marginal deficiency where the production of many iron-dependent proteins is compromised but hemoglobin levels are normal and iron deficiency anemia where synthesis of hemoglobin is decreased and oxygen transport to the tissues is reduced. Iron deficiency anemia is usually assessed by measuring hemoglobin levels but this approach lacks both specificity and sensitivity. Failure to identify and treat earlier stages of iron deficiency is concerning given the neurocognitive implications of iron deficiency without anemia. Most of the daily iron requirement is derived from recycling of senescent erythrocytes by macrophages; only 5-10 % comes from the diet. Iron absorption is affected by inhibitors and enhancers of iron absorption and by the physiological state. Inflammatory conditions, including obesity, can result in iron being retained in the enterocytes and macrophages causing hypoferremia as a strategic defense mechanism to restrict iron availability to pathogens. Premenopausal women usually have low iron status because of iron loss in menstrual blood. Conditions which further increase iron loss, compromise absorption or increase demand, such as frequent blood donation, gastrointestinal lesions, athletic activity and pregnancy, can exceed the capacity of the gastrointestinal tract to upregulate iron absorption. Women of reproductive age are at particularly high risk of iron deficiency and its consequences however there is a controversial argument that evolutionary pressures have resulted in an iron deficient phenotype which protects against infection.

  11. 肝肾不足型重型斑秃患者血皮质醇及糖皮质激素受体mRNA的表达状况%Serum cortisol and peripheral blood mononuclear cell glucocorticoid receptor mRNA expression in severe alopecia areata with liver-kidney deficiency syndrome

    Institute of Scientific and Technical Information of China (English)

    陈修漾; 陈达灿; 陈建宏; 危建安

    2012-01-01

    目的 探讨肝肾不足型重型斑秃患者血皮质醇、外周血单个核细胞(PBMC)中糖皮质激素受体mRNA(GRmRNA)表达状况与斑秃发病关系.方法 采用化学发光法检测23例肝肾不足型重型斑秃患者血皮质醇表达水平,并用逆转录-实时荧光定量聚合酶链反应分别检测该23例患者应用糖皮质激素(GC)治疗前后PBMC中GRmRNA表达水平,并与20例正常对照组相对比.结果 重型斑秃组与正常对照组两组血清皮质醇水平差异无统计学意义(P>0.05),重型斑秃组治疗前、后GRmRNA表达水平均低于正常对照组(P<0.05),并且治疗后GRmRNA表达水平比治疗前更低(P<0.01).结论 重型斑秃患者存在GC-GR紊乱,GRmRNA表达水平降低可能参与了重型斑秃的发病机制.肝肾不足型重型斑秃患者PBMC中GR mRNA表达水平显著低于正常对照组,这可能是重型斑秃肝肾不足证型在受体及基因水平上的病理变化,也可能是重型斑秃肝肾不足证型的微观本质之一.%Objective To investigate serum cortisol level and glucocorticoid receptors (GR) mRNA expression in peripheral blood mononuclear cells (PBMCs) in patients with severe alopecia areata and liver-kidney deficiency syndrome and their involvement in the pathogenesis of severe alopecia areata. Methods In 32 patients with severe alopecia areata, serum cortisol levels were measured by chemiluminescence assay and GR mRNA expression in the PBMCs was detected using reverse transcription real-time fluorescence quantitative PCR before and after treatment, with 20 normal subjects serving as the controls. Results Serum cortisol level showed no significant difference between the cases and the normal controls (P>0.05). The expression of GR mRNA in the PBMCs was significantly lower in the patients than in the normal controls (P<0.05). The expression of GR mRNA was even lower after treatments in patients with alopecia areata (P<0.01). Conclusion GC-GR disorder exists in

  12. 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 card

  13. 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. PMID:25636824

  14. Dopamine Receptors and Parkinson's Disease

    OpenAIRE

    Shin Hisahara; Shun Shimohama

    2011-01-01

    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 ...

  15. Outer membrane proteins induced by iron deficiency in Anabaena sp.PCC 7120

    Institute of Scientific and Technical Information of China (English)

    Yanling Dong; Xudong Xu

    2009-01-01

    Iron deficiency can induce cyanobacteria to synthesize siderophore receptor proteins on the outer membrane to enhance the uptake of iron. In this study, an outer membrane of high purity was prepared from Anabaena sp. PCC 7120 based on aqueous polymer two-phase partitioning and discontinuous sucrose density ultra-centrifugation, and the induction of outer membrane proteins by iron deficiency was investigated using 2-D gel electrophoresis. At least five outer membrane proteins were newly synthesized or significantly up-regulated in cells transferred to iron-deficient conditions, which were all identified to be siderophore receptor proteins according to MALDI-TOF-MS analyses. Bacterial luciferase reporter genes luxAB were employed to monitor the transcription of the encoding genes. The genes were induced by iron deficiency at the transcriptional level in different responsive modes. Luciferase activity expressed from an iron-regulated promoter may be used as a bioreporter for utilizable iron in natural water samples.

  16. Epileptogenesis after traumatic brain injury in Plau-deficient mice.

    Science.gov (United States)

    Bolkvadze, Tamuna; Rantala, Jukka; Puhakka, Noora; Andrade, Pedro; Pitkänen, Asla

    2015-10-01

    Several components of the urokinase-type plasminogen activator receptor (uPAR)-interactome, including uPAR and its ligand sushi-repeat protein 2, X-linked (SRPX2), are linked to susceptibility to epileptogenesis in animal models and/or humans. Recent evidence indicates that urokinase-type plasminogen activator (uPA), a uPAR ligand with focal proteinase activity in the extracellular matrix, contributes to recovery-enhancing brain plasticity after various epileptogenic insults such as traumatic brain injury (TBI) and status epilepticus. Here, we examined whether deficiency of the uPA-encoding gene Plau augments epileptogenesis after TBI. Traumatic brain injury was induced by controlled cortical impact in the somatosensory cortex of adult male wild-type and Plau-deficient mice. Development of epilepsy and seizure susceptibility were assessed with a 3-week continuous video-electroencephalography monitoring and a pentylenetetrazol test, respectively. Traumatic brain injury-induced cortical or hippocampal pathology did not differ between genotypes. The pentylenetetrazol test revealed increased seizure susceptibility after TBI (p<0.05) in injured mice. Epileptogenesis was not exacerbated, however, in Plau-deficient mice. Taken together, Plau deficiency did not worsen controlled cortical impact-induced brain pathology or epileptogenesis caused by TBI when assessed at chronic timepoints. These data expand previous observations on Plau deficiency in models of status epilepticus and suggest that inhibition of focal extracellular proteinase activity resulting from uPA-uPAR interactions does not modify epileptogenesis after TBI. PMID:26253597

  17. RNA-sequencing of WFS1-deficient pancreatic islets.

    Science.gov (United States)

    Ivask, Marilin; Hugill, Alison; Kõks, Sulev

    2016-04-01

    Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in theWFS1gene.WFS1encodes an endoplasmic reticulum resident transmembrane protein. TheWfs1-null mice exhibit progressive insulin deficiency and diabetes. The aim of this study was to describe the insulin secretion and transcriptome of pancreatic islets inWFS1-deficient mice.WFS1-deficient (Wfs1KO) mice had considerably less pancreatic islets than heterozygous (Wfs1HZ) or wild-type (WT) mice. Wfs1KOpancreatic islets secreted less insulin after incubation in 2 and 10 mmol/L glucose and with tolbutamide solution compared toWTand Wfs1HZislets, but not after stimulation with 20 mmol/L glucose. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KOhad an increased level of proinsulin. After incubation in 2 mmol/L glucose solution the proinsulin/insulin ratio in Wfs1KOwas significantly higher than that ofWTand Wfs1HZRNA-seq from pancreatic islets found melastatin-related transient receptor potential subfamily member 5 protein gene (Trpm5) to be downregulated inWFS1-deficient mice. Functional annotation ofRNAsequencing results showed thatWFS1 deficiency influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network. PMID:27053292

  18. 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.

  19. AHNAK deficiency promotes browning and lipolysis in mice via increased responsiveness to β-adrenergic signalling

    OpenAIRE

    Jae Hoon Shin; Seo Hyun Lee; Yo Na Kim; Il Yong Kim; Youn Ju Kim; Dong Soo Kyeong; Hee Jung Lim; Soo Young Cho; Junhee Choi; Young Jin Wi; Jae-Hoon Choi; Yeo Sung Yoon; Yun Soo Bae; Je Kyung Seong

    2016-01-01

    In adipose tissue, agonists of the β3-adrenergic receptor (ADRB3) regulate lipolysis, lipid oxidation, and thermogenesis. The deficiency in the thermogenesis induced by neuroblast differentiation-associated protein AHNAK in white adipose tissue (WAT) of mice fed a high-fat diet suggests that AHNAK may stimulate energy expenditure via development of beige fat. Here, we report that AHNAK deficiency promoted browning and thermogenic gene expression in WAT but not in brown adipose tissue of mice ...

  20. Glucose-6-Phosphate Dehydrogenase Deficiency Overview

    Science.gov (United States)

    ... Drugs GARD Information Navigator FAQs About Rare Diseases Glucose-6-phosphate dehydrogenase deficiency Title Other Names: G6PD ... G6PD deficiency Categories: Newborn Screening Summary Summary Listen Glucose 6 phosphate dehydrogenase (G6PD) deficiency is a hereditary ...

  1. Genetics Home Reference: factor V deficiency

    Science.gov (United States)

    ... Genetics Home Health Conditions factor V deficiency factor V deficiency Enable Javascript to view the expand/collapse ... Print All Open All Close All Description Factor V deficiency is a rare bleeding disorder. The signs ...

  2. Monocular Elevation Deficiency - Double Elevator Palsy

    Science.gov (United States)

    ... Español Condiciones Chinese Conditions Monocular Elevation Deficiency/ Double Elevator Palsy En Español Read in Chinese What is monocular elevation deficiency (Double Elevator Palsy)? Monocular Elevation Deficiency, also known by the ...

  3. Genetics Home Reference: congenital leptin deficiency

    Science.gov (United States)

    ... Genetics Home Health Conditions congenital leptin deficiency congenital leptin deficiency Enable Javascript to view the expand/collapse ... Print All Open All Close All Description Congenital leptin deficiency is a condition that causes severe obesity ...

  4. Genetics Home Reference: factor XIII deficiency

    Science.gov (United States)

    ... InfoSearch: Factor XIII deficiency Factor XIII Registry Database: Introduction to Factor XIII Deficiency MalaCards: factor xiii deficiency ... Library of Medicine Lister Hill National Center for Biomedical Communications 8600 Rockville Pike, Bethesda, MD 20894, USA ...

  5. Genetics Home Reference: combined pituitary hormone deficiency

    Science.gov (United States)

    ... Genetics Home Health Conditions combined pituitary hormone deficiency combined pituitary hormone deficiency Enable Javascript to view the ... boxes. Print All Open All Close All Description Combined pituitary hormone deficiency is a condition that causes ...

  6. [Iodine deficiency during pregnancy ].

    Science.gov (United States)

    de Luis, D A; Aller, R; Izaola, O

    2005-09-01

    Iodine is an essential micronutrient, it would be administered every day with our diet. The main role of this micronutrient is the synthesis of thyroid hormone. Thyroid hormones are related with brain development and metabolic regulation. Iodine deficit is related with goitre, and an important problem "diseases related with iodine deficiency", including high rate of neonatal mortality, decrease of intelligence, delayed of growth, high rate of aborts and congenital abnormalities.A risk group is pregnant women. Some authors have been demonstrated the utility of iodine supplementation during pregnancy. A systematic review of Cochrane group has shown that iodine supplementation during pregnancy decreased neonatal mortality RR 0.71 (0.56-0.9), and decrease the incidence of cretinism in children under 4 years RR 0.27 (0.12-0.6). As final recommendations, a program in pregnant women must be development to treat with iodine such as we make with folic acid. Pills with iron and iodine (1 mg iron and 25 ug iodine) have been demonstrated better results that pills with iodine. Tablets are the main presentation due to the role of the women in our Society and the work time. Programs of iodine enriched salt have been demonstrated a follow up of 50%. PMID:16386080

  7. Iodine deficiency disorders.

    Science.gov (United States)

    Elliott, T C

    1987-01-01

    Iodine deficiency disorder (IDD) affects 800 million people in the world, yet iodine supplementation is one of the most cost-effective nutritional interventions known. Iodine is incorporated into thyroid hormones, necessary for regulating metabolic rate, growth, and development of the brain and nervous system. IDD may appear as goiter in adults, usually not a serious problem, or in cretinism in children, which is marked by severe mental and physical retardation, with irreversible hearing and speech defects and either deaf-mutism, squint and paralysis, or stunting and edema. Children supplemented by age 1 or 2 can sometimes be helped. Foods contain variable amounts of iodine dependent on the soil where they are grown, hence mountainous and some inland regions have high goiter and IDD incidence. There are also goitrogenic foods, typically those of the cabbage family. Diagnosis is clinical or by blood tests for thyroid hormone levels and ratios. Finger-stick methods are available. Prevention of IDD is simple with either iodized salt or flour, iodinated central water supplies, injectable or oral iodine-containing oil. All cost about $.04 per person per year, except injections, which cost about $1 per person, but have the advantage that they could be combined with immunizations. Local problems with supplements are loss of iodine in salt with storage in tropics, and local production of cheaper uniodinated salt. Emphasis should be given to pregnant women and young children. There is no harm in giving pregnant women iodine injections in 2nd or 3rd trimester. PMID:12343033

  8. Differential diagnosis of tetrahydrobiopterin deficiency.

    Science.gov (United States)

    Niederwieser, A; Ponzone, A; Curtius, H C

    1985-01-01

    Six hundred and seventy-three children (483 newborns and 190 older selected children) were screened for tetrahydrobiopterin (BH4) deficiency by HPLC of urine pterins and BH4 load test. One patient with GTP cyclohydrolase I deficiency, 36 patients with dihydrobiopterin synthetase (DHBS) deficiency (of which six were in the newborn and 30 in the older children) and 14 with dihydropteridine reductase deficiency (DHPR) were found. All 37 patients with defective BH4 biosynthesis responded to a BH4 load by lowering of the elevated serum phenylalanine concentration but four of 14 patients with DHPR deficiency did not. Measurement of DHPR activity in blood spots on Guthrie cards is recommended. Since subvariants of patients with BH4 deficiency exist, homovanillic acid, 5-hydroxyindole acetic acid, pterins, phenylalanine, and tyrosine in cerebrospinal fluid should be measured for diagnosis and the control of therapy. The activity of the phosphate-eliminating enzyme (a key enzyme in BH4 biosynthesis and part of "DHBS") was measured in human liver and activities of approx. 1 n U (mg protein)-1 were found. In the liver biopsy of a patient with DHBS deficiency no activity (less than 3% of controls) was demonstrated. PMID:3930839

  9. Iron Deficiency Anemia in Pregnancy.

    Science.gov (United States)

    Breymann, Christian

    2015-10-01

    Anemia is a common problem in obstetrics and perinatal care. Any hemoglobin below 10.5 g/dL can be regarded as true anemia regardless of gestational age. Reasons for anemia in pregnancy are mainly nutritional deficiencies, parasitic and bacterial diseases, and inborn red blood cell disorders such as thalassemias. The main cause of anemia in obstetrics is iron deficiency, which has a worldwide prevalence between estimated 20%-80% and consists of a primarily female population. Stages of iron deficiency are depletion of iron stores, iron-deficient erythropoiesis without anemia, and iron deficiency anemia, the most pronounced form of iron deficiency. Pregnancy anemia can be aggravated by various conditions such as uterine or placental bleedings, gastrointestinal bleedings, and peripartum blood loss. In addition to the general consequences of anemia, there are specific risks during pregnancy for the mother and the fetus such as intrauterine growth retardation, prematurity, feto-placental miss ratio, and higher risk for peripartum blood transfusion. Besides the importance of prophylaxis of iron deficiency, the main therapy options for the treatment of pregnancy anemia are oral iron and intravenous iron preparations.

  10. Chemokines and their receptors in central nervous system disease

    NARCIS (Netherlands)

    Biber, K; de Jong, EK; van Weering, HRJ; Boddeke, HWGM

    2006-01-01

    Almost a decade ago, it was discovered that the human deficiency virus (HIV) makes use of chemokine receptors to infect blood cells. This appreciation of the clinical relevance of specific chemokine receptors has initiated a considerable boost in the field of chemokine research. It is clear today th

  11. Clinical manifestations of zinc deficiency.

    Science.gov (United States)

    Prasad, A S

    1985-01-01

    The essentiality of zinc for humans was recognized in the early 1960s. The causes of zinc deficiency include malnutrition, alcoholism, malabsorption, extensive burns, chronic debilitating disorders, chronic renal diseases, following uses of certain drugs such as penicillamine for Wilson's disease and diuretics in some cases, and genetic disorders such as acrodermatitis enteropathica and sickle cell disease. In pregnancy and during periods of growth the requirement of zinc is increased. The clinical manifestations in severe cases of zinc deficiency include bullous-pustular dermatitis, alopecia, diarrhea, emotional disorder, weight loss, intercurrent infections, hypogonadism in males; it is fatal if unrecognized and untreated. A moderate deficiency of zinc is characterized by growth retardation and delayed puberty in adolescents, hypogonadism in males, rough skin, poor appetite, mental lethargy, delayed wound healing, taste abnormalities, and abnormal dark adaptation. In mild cases of zinc deficiency in human subjects, we have observed oligospermia, slight weight loss, and hyperammonemia. Zinc is a growth factor. Its deficiency adversely affects growth in many animal species and humans. Inasmuch as zinc is needed for protein and DNA synthesis and for cell division, it is believed that the growth effect of zinc is related to its effect on protein synthesis. Whether or not zinc is required for the metabolism of somatomedin needs to be investigated in the future. Testicular functions are affected adversely as a result of zinc deficiency in both humans and experimental animals. This effect of zinc is at the end organ level; the hypothalamic-pituitary axis is intact in zinc-deficient subjects. Inasmuch as zinc is intimately involved in cell division, its deficiency may adversely affect testicular size and thus affect its functions. Zinc is required for the functions of several enzymes and whether or not it has an enzymatic role in steroidogenesis is not known at present

  12. Genetics Home Reference: adenosine monophosphate deaminase deficiency

    Science.gov (United States)

    ... links) CLIMB: Children Living with Inherited Metabolic Diseases Muscular Dystrophy Association: Myoadenylate Deaminase Deficiency Genetic Testing Registry (1 link) Muscle AMP deaminase deficiency ...

  13. Low Prevalence of Iron and Vitamin A Deficiency among Cambodian Women of Reproductive Age.

    Science.gov (United States)

    Wieringa, Frank T; Sophonneary, Prak; Whitney, Sophie; Mao, Bunsoth; Berger, Jacques; Conkle, Joel; Dijkhuizen, Marjoleine A; Laillou, Arnaud

    2016-04-01

    Nearly half of women of reproductive age (WRA) in Cambodia are anemic. To guide interventions, national data on nutritional causes of anemia, including iron deficiency and vitamin A deficiency, are needed. In 2012, a national household survey in WRA on antibodies to routine vaccine-preventable disease immunity was performed. We used serum samples from this survey to estimate the prevalence of iron and vitamin A deficiency in 2112 Cambodian WRA, aged 15 to 39 years. Iron deficiency was classified as low or marginal iron stores (ferritin concentrations corrected for inflammation iron deficient erythropoiesis (soluble transferrin receptor concentrations >8.3 mg/L; sTfR), or low total body iron (TBI) derived from Fer and sTfR concentrations (status was classified using retinol binding protein (RBP) concentrations corrected for inflammation as deficient (iron stores, low TBI and iron deficient erythropoiesis was 8.1%, 5.0% and 9.3% respectively. Almost 40% of the women had marginal iron stores. Iron status was better in women living in urban areas compared to rural areas (p deficiency was iron and vitamin A deficiency to the high prevalence of anemia in Cambodian WRA may be limited. The etiology of anemia in Cambodia needs to be elucidated further to guide current policies on anemia.

  14. 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...

  15. Evolutionary Processes and Mental Deficiency

    Science.gov (United States)

    Spitz, Herman H.

    1973-01-01

    The author hypothesizes that central nervous system damage of deficiency associated with mental retardation affects primarily those cortical processes which developed at a late stage in man's evolutionary history. (Author)

  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. 25-Hydroxyvitamin D3-deficiency enhances oxidative stress and corticosteroid resistance in severe asthma exacerbation.

    Science.gov (United States)

    Lan, Nan; Luo, Guangyan; Yang, Xiaoqiong; Cheng, Yuanyuan; Zhang, Yun; Wang, Xiaoyun; Wang, Xing; Xie, Tao; Li, Guoping; Liu, Zhigang; Zhong, Nanshan

    2014-01-01

    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.

  18. 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.

  19. Cutaneous findings of nutritional deficiencies in children.

    Science.gov (United States)

    Goskowicz, M; Eichenfield, L F

    1993-08-01

    Nutritional deficiencies may be associated with a variety of cutaneous findings in children. This review emphasizes new developments relating to cutaneous findings of nutritional deficiencies. Zinc deficiency, acrodermatitis enteropathica, and acrodermatitis enteropathica-like eruptions are seen with a variety of conditions including cystic fibrosis, anorexia nervosa, and breastfeeding. Similar cutaneous findings not related to zinc deficiency may also occur with such metabolic disorders as methylmalonic aciduria, multiple carboxylase deficiency, essential fatty acid deficiency and other amino acid deficiencies. Vitamin K deficiency is associated with hemorrhagic disease of the newborn and coagulopathy. Vitamin A deficiency presents with a variety of systemic findings and distinctive dermatologic findings. Acute vitamin A deficiency may be seen in children infected with measles and is associated with more severe disease. The systemic and cutaneous findings of vitamin C deficiency, scurvy, are discussed. PMID:8374671

  20. Zinc and its deficiency diseases.

    Science.gov (United States)

    Evans, G W

    1986-01-01

    The pervasive role of zinc in the metabolic function of the body results from its function as a cofactor of a multitude of enzymes. Zinc is found in every tissue in the body, and because zinc metalloenzymes are found in every known class of enzymes, the metal has a function in every conceivable type of biochemical pathway. Symptoms resulting from zinc deficiency are as diverse as the enzymes with which the metal is associated. If chronic, severe, and untreated, zinc deficiency can be fatal. Less drastic symptoms include infections, hypogonadism, weight loss, emotional disturbance, dermatitis, alopecia, impaired taste acuity, night blindness, poor appetite, delayed wound healing, and elevated blood ammonia levels. Many symptoms of zinc deficiency result from poor diet consumption, but often the most severe symptoms result from other factors including excessive alcohol use, liver diseases, malabsorption syndromes, renal disease, enteral or parenteral alimentation, administration of sulfhydryl-containing drugs, and sickle cell disease. The most severe symptoms of zinc deficiency occur in young children affected with the autosomal-recessive trait, acrodermatitis enteropathica. This disease results in decreased synthesis of picolinic acid which causes an impaired ability to utilize zinc from common food. Because simple laboratory analyses are often not reliable in determining zinc nutriture of a patient, those symptoms caused by suspected zinc deficiency are best verified by the oral administration of zinc dipicolinate. This zinc compound is efficacious and safe and would provide an accurate means of identifying symptoms that do result from zinc deficiency. PMID:3514057

  1. Adenosine receptor antagonists alter the stability of human epileptic GABAA receptors

    Science.gov (United States)

    Roseti, Cristina; Martinello, Katiuscia; Fucile, Sergio; Piccari, Vanessa; Mascia, Addolorata; Di Gennaro, Giancarlo; Quarato, Pier Paolo; Manfredi, Mario; Esposito, Vincenzo; Cantore, Gianpaolo; Arcella, Antonella; Simonato, Michele; Fredholm, Bertil B.; Limatola, Cristina; Miledi, Ricardo; Eusebi, Fabrizio

    2008-01-01

    We examined how the endogenous anticonvulsant adenosine might influence γ-aminobutyric acid type A (GABAA) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 μM), GABAA receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABAA-current (IGABA) run-down, which was consistently and significantly reduced by treatment with the nonselective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA) (1 units/ml), that inactivates adenosine. It was also found that selective antagonists of A2B (MRS1706, 10 nM) or A3 (MRS1334, 30 nM) receptors reduced IGABA run-down, whereas treatment with the specific A1 receptor antagonist DPCPX (10 nM) was ineffective. The selective A2A receptor antagonist SCH58261 (10 nM) reduced or potentiated IGABA run-down in ≈40% and ≈20% of tested oocytes, respectively. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 μM) potentiated IGABA run-down but only in ≈20% of tested oocytes. CGS15943 administration again decreased IGABA run-down in patch-clamped neurons from either human or rat neocortex slices. IGABA run-down in pyramidal neurons was equivalent in A1 receptor-deficient and wt neurons but much larger in neurons from A2A receptor-deficient mice, indicating that, in mouse cortex, GABAA-receptor stability is tonically influenced by A2A but not by A1 receptors. IGABA run-down from wt mice was not affected by 2-CA, suggesting maximal ARs activity by endogenous adenosine. Our findings strongly suggest that cortical A2–A3 receptors alter the stability of GABAA receptors, which could offer therapeutic opportunities. PMID:18809912

  2. PPARγ deficiency results in reduced lung elastic recoil and abnormalities in airspace distribution

    OpenAIRE

    Starcher Barry C; Ingenito Edward P; Tsai Larry W; Simon Dawn M; Mariani Thomas J

    2010-01-01

    Abstract Background Peroxisome proliferator-activated receptor (PPAR)-γ is a nuclear hormone receptor that regulates gene expression, cell proliferation and differentiation. We previously described airway epithelial cell PPARγ deficient mice that develop airspace enlargement with decreased tissue resistance and increased lung volumes. We sought to understand the impact of airspace enlargement in conditionally targeted mice upon the physio-mechanical properties of the lung. Methods We measured...

  3. 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.

  4. The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: role of endogenous TLR ligands.

    Science.gov (United States)

    Uaesoontrachoon, Kitipong; Cha, Hee-Jae; Ampong, Beryl; Sali, Arpana; Vandermeulen, Jack; Wei, Benjamin; Creeden, Brittany; Huynh, Tony; Quinn, James; Tatem, Kathleen; Rayavarapu, Sree; Hoffman, Eric P; Nagaraju, Kanneboyina

    2013-10-01

    An absence of dysferlin leads to activation of innate immune receptors such as Toll-like receptors (TLRs) and skeletal muscle inflammation. Myeloid differentiation primary response gene 88 (MyD88) is a key mediator of TLR-dependent innate immune signalling. We hypothesized that endogenous TLR ligands released from the leaking dysferlin-deficient muscle fibres engage TLRs on muscle and immune cells and contribute to disease progression. To test this hypothesis, we generated and characterized dysferlin and MyD88 double-deficient mice. Double-deficient mice exhibited improved body weight, grip strength, and maximum muscle contractile force at 6-8 months of age when compared to MyD88-sufficient, dysferlin-deficient A/J mice. Double-deficient mice also showed a decrease in total fibre number, which contributed to the observed increase in the number of central nuclei/fibres. These results indicate that there was less regeneration in the double-deficient mice. We next tested the hypothesis that endogenous ligands, such as single-stranded ribonucleic acids (ssRNAs), released from damaged muscle cells bind to TLR-7/8 and perpetuate the disease progression. We found that injection of ssRNA into the skeletal muscle of pre-symptomatic mice (2 months old) resulted in a significant increase in degenerative fibres, inflammation, and regenerating fibres in A/J mice. In contrast, characteristic histological features were significantly decreased in double-deficient mice. These data point to a clear role for the TLR pathway in the pathogenesis of dysferlin deficiency and suggest that TLR-7/8 antagonists may have therapeutic value in this disease. PMID:23857504

  5. [Iron deficiency and iron deficiency anemia are global health problems].

    Science.gov (United States)

    Dahlerup, Jens; Lindgren, Stefan; Moum, Björn

    2015-03-10

    Iron deficiency and iron deficiency anemia are global health problems leading to deterioration in patients' quality of life and more serious prognosis in patients with chronic diseases. The cause of iron deficiency and anemia is usually a combination of increased loss and decreased intestinal absorption and delivery from iron stores due to inflammation. Oral iron is first line treatment, but often hampered by intolerance. Intravenous iron is safe, and the preferred treatment in patients with chronic inflammation and bowel diseases. The goal of treatment is normalisation of hemoglobin concentration and recovery of iron stores. It is important to follow up treatment to ensure that these objectives are met and also long-term in patients with chronic iron loss and/or inflammation to avoid recurrence of anemia.

  6. Iron deficiency and cardiovascular disease.

    Science.gov (United States)

    von Haehling, Stephan; Jankowska, Ewa A; van Veldhuisen, Dirk J; Ponikowski, Piotr; Anker, Stefan D

    2015-11-01

    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 cardiovascular medicine. Data indicate that iron deficiency has detrimental effects in patients with coronary artery disease, heart failure (HF), and pulmonary hypertension, and possibly in patients undergoing cardiac surgery. Around one-third of all patients with HF, and more than one-half of patients with pulmonary hypertension, are affected by iron deficiency. Patients with HF and iron deficiency have shown symptomatic improvements from intravenous iron administration, and some evidence suggests that these improvements occur irrespective of the presence of anaemia. Improved exercise capacity has been demonstrated after iron administration in patients with pulmonary hypertension. However, to avoid iron overload and T-cell activation, it seems that recipients of cardiac transplantations should not be treated with intravenous iron preparations.

  7. STAT5B deficiency: Impacts on human growth and immunity.

    Science.gov (United States)

    Hwa, Vivian

    2016-06-01

    Growth hormone (GH) promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5B signaling cascade. The critical importance of STAT5B in human IGF-I production was confirmed with the identification of the first homozygous, autosomal recessive, STAT5B mutation in a young female patient who phenotypically resembled patients with classical growth hormone insensitivity (GHI) syndrome (Laron syndrome) due to mutations in the GHR gene, presenting with severe postnatal growth failure and marked IGF-I deficiency. Of note, the closely related STAT5A, which shares >95% amino acid identity with STAT5B, could not compensate for loss of functional STAT5B. To date, 7 homozygous, inactivating, STAT5B mutations in 10 patients have been reported. STAT5B deficient patients, unlike patients deficient in GHR, can also present with a novel, potentially fatal, primary immunodeficiency, which can manifest as chronic pulmonary disease. STAT5B deficiency may be underestimated in endocrine, immunology and pulmonary clinics. PMID:26703237

  8. Study on the association between vitamin D receptor gene polymorphism and vitamin D deficiency rickets in infants%维生素D受体基因多态性与婴幼儿佝偻病易感性的研究

    Institute of Scientific and Technical Information of China (English)

    周丽; 李宇宁; 张维华; 刘丽君; 安彩霞; 陶仲宾; 李湘津

    2009-01-01

    Objective To study the association of vitamin D receptor(VDR) gene BsmI polymorphism and the genetic susceptibility of vitamin D deficiency rickets in infants and to explore a new way of diagnosis and treat-ment. Methods Case-control study was adopted. 56 infants confirmed with rickets (case group) and 76 cases of normal infants (control group) were chosen as the subjects. PCR-RFLP was applied to examine VDR gene BsmI site polymorphism. The frequencies of the VDR genotype and allele were compared between the two groups. Results Frequencies of BB,Bb and bb genotypes were 3.6% (2/56),21.4% (12/56) and 75.0% (42/56) in the rickets group,and 1.3% (1/76),18.4% (14/76) and 80.3% (61/76) in the control group respectively(χ20.521,P> 0.05),frequencies of B,b alleles were 14.3% (16/112),85.7% (96/112) in the rickets group and 10.5% (16/152),89.5% (134/152) in the control group respectively(χ20.783,P>0.05). Multiple logistic regression analysis showed that VDR gene polymorphism Bsml had not higher risk of vitamin D deficiency rickets in Infants. Conclusion VDR gene polymorphism BsmI doesn't appear to pose risk on infants in developing vitamin D deficien-cy rickets.%目的 研究维生素D受体基因多态性与婴幼儿佝偻病易感性的相关性,为临床探索新的诊治途径提供理论依据.方法 采用病例对照研究,选择兰州大学第一医院儿内科确诊的佝倭病患儿56例(佝偻病组)和正常婴幼儿76例(正常对照组)作为研究对象.应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)分析检测VDR基因BsmI位点的多态性,比较2组之间的VDR基因型和等位基因频率.结果 佝偻病组和正常对照组VDR基因BsmI位点基因型分布频率分别为BB 3.6%(2/56)、Bb 21.4%(12/56)、bb 75.0%(42/56)和BB 1.3%(1/76)、Bb 18.4%(14/76)、bb 80.3%(61/76),2组之间的差异无统计学意义(χ20.521,P>0.05);佝偻病组和正常对照组的VDR基因BsmI位点等位基因分布频率分别为B 14.3%(16/112)、b 85

  9. 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

    Directory of Open Access Journals (Sweden)

    Anshula eSamarajeewa

    2014-11-01

    Full Text Available The serotonin (5-HT type 7 receptor is expressed throughout the CNS including cortical neurons. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA-induced toxicity. The tropomyosin-related kinase B (TrkB receptor is one of the receptors for brain-derived neurotrophic factor (BDNF and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins towards the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands.

  10. 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

    Science.gov (United States)

    Samarajeewa, Anshula; Goldemann, Lolita; Vasefi, Maryam S.; Ahmed, Nawaz; Gondora, Nyasha; Khanderia, Chandni; Mielke, John G.; Beazely, Michael A.

    2014-01-01

    The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the cortex and hippocampus. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF) receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA)-induced toxicity. The tropomyosin-related kinase B (TrkB) receptor is one of the receptors for brain-derived neurotrophic factor (BDNF) and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins toward the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands. PMID:25426041

  11. Folate Deficiency in Chronic Pancreatitis

    Directory of Open Access Journals (Sweden)

    Gopalakrishna Rajesh

    2010-07-01

    Full Text Available Dear Sir, While there has been a spurt of interest in genetic alterations associated with pancreatitis in the past few years, interest in the role of environmental factors has largely focused on alcoholism and smoking with insufficient attention being paid to the contributions of nutritional deficiency, and the role of environmental toxins in the pathogenesis of pancreatitis. Braganza and Dormandy [1] argue convincingly about the role played by cytochrome P450 monooxygenases (especially CYP1A enzyme induction by xenobiotics and the resultant oxidative stress, as also the now increasingly recognized reductive stress posed by the metabolites in initiating pancreatic injury. Their article underlines the important part played by the deficiency of methyl and thiol molecules in different stages of the progression of pancreatic damage. Furthermore, they attempt to establish a link between environmental and genetic factors and bring in a holistic view on the etiopathogenesis of chronic pancreatitis. We have recently demonstrated lower plasma methionine levels in two cohorts of chronic pancreatitis patients; one of tropical chronic pancreatitis and the other, of alcoholic chronic pancreatitis as compared to healthy controls [2] which suggests that deficiency of methyl groups may be a factor in various forms of pancreatitis. Similarly, we have shown lower red cell glutathione levels in chronic pancreatitis patients with tropical chronic pancreatitis and alcoholic chronic pancreatitis, indicating deficiency of thiol molecules. In addition, we have demonstrated significantly higher levels of plasma total homocysteine in chronic pancreatitis patients than in healthy controls. Moreover, our study has shown that there is a deficiency of red cell folate in the majority of chronic pancreatitis patients, more so in tropical chronic pancreatitis; and that folate deficiency appeared to be the key factor in hyperhomocysteinemia in chronic pancreatitis patients

  12. Iron deficiency in the tropics.

    Science.gov (United States)

    Fleming, A F

    1982-06-01

    Iron in food is classified as belonging to the haem pool, the nonhaem pool, and extraneous sources. Haem iron is derived from vegetable and animal sources with varying bioavailability. Hookworm infestation of the intestinal tract affects 450 million people in the tropics. Schistosoma mansoni caused blood loss in 7 Egyptian patients of 7.5- 25.9 ml/day which is equivalent to a daily loss of iron of .6-7.3 mg daily urinary loss of iron in 9 Egyptian patients. Trichuris trichiura infestation by whipworm is widespread in children with blood loss of 5 ml/day/worm. The etiology of anemia in children besides iron deficiency includes malaria, bacterial or viral infections, folate deficiency and sickle-cell disease. Severe infections cause profound iron-deficiency anemia in children in central American and Malaysia. Plasmodium falciparum malaria-induced anaemia in tropical Africa lowers the mean haemoglobin concentration in the population by 2 g/dI, causing profound anaemia in some. The increased risk of premature delivery, low birthweight, fetal abnormalities, and fetal death is directly related to the degree of maternal anemia. Perinatal mortality was reduced from 38 to 4% in treated anemic mothers. Mental performance was significantly lower in anemic school children and improved after they received iron. Supplements of iron, soy-protein, calcium, and vitamins given to villagers with widespread malnutrition, iron deficiency, and hookworm infestation in Colombia reduced enteric infections in children. Severe iron-deficiency anemia was treated in adults in northern Nigeria by daily in Ferastral 10 ml, which is equivalent to 500 mg of iron per day. Choloroquine, folic acid, rephenium hydroxynaphthoate, and tetrachlorethylene treat adults with severe iron deficiency from hookworm infestation in rural tropical Africa. Blood transfusion is indicated if the patient is dying of anaemia or is pregnant with a haemoglobin concentration 6 gm/dl. In South East Asia, mg per day

  13. [Phosphate metabolism and iron deficiency].

    Science.gov (United States)

    Yokoyama, Keitaro

    2016-02-01

    Autosomal dominant hypophosphatemic rickets(ADHR)is caused by gain-of-function mutations in FGF23 that prevent its proteolytic cleavage. Fibroblast growth factor 23(FGF23)is a hormone that inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D biosynthesis. Low iron status plays a role in the pathophysiology of ADHR. Iron deficiency is an environmental trigger that stimulates FGF23 expression and hypophosphatemia in ADHR. It was reported that FGF23 elevation in patients with CKD, who are often iron deficient. In patients with nondialysis-dependent CKD, treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and FGF23.

  14. Fetal effects of epidermal growth factor deficiency induced in rats by autoantibodies against epidermal growth factor

    DEFF Research Database (Denmark)

    Raaberg, Lasse; Nexø, Ebba; Jørgensen, P E;

    1995-01-01

    We have used rats with epidermal growth factor (EGF) autoantibodies to study the role of EGF deficiency during perinatal development. The study was focused on organs known to contain EGF or its receptor. Compared with controls, the offspring of autoimmune rats had a higher perinatal mortality and...

  15. Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency

    NARCIS (Netherlands)

    T. Turul (Tuba); I. Tezcan (Ilhan); S. de Bruin-Versteeg (Sandra); B.H. Barendregt (Barbara); I. Reisli (Ismail); O. Sanal (Ozden); J.J.M. van Dongen (Jacques); M. van der Burg (Mirjam)

    2009-01-01

    textabstractOne of the severe combined immunodeficiencies (SCIDs), which is caused by a genetic defect in the signal transduction pathways involved in T-cell activation, is the ZAP70 deficiency. Mutations in ZAP70 lead to both abnormal thymic development and defective T-cell receptor (TCR) signaling

  16. 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 alteration

  17. Pyogenic Bacterial Infections in Humans with MyD88 Deficiency

    Science.gov (United States)

    von Bernuth, Horst; Picard, Capucine; Jin, Zhongbo; Pankla, Rungnapa; Xiao, Hui; Ku, Cheng-Lung; Chrabieh, Maya; Mustapha, Imen Ben; Ghandil, Pegah; Camcioglu, Yildiz; Vasconcelos, Júlia; Sirvent, Nicolas; Guedes, Margarida; Vitor, Artur Bonito; Herrero-Mata, María José; Aróstegui, Juan Ignacio; Rodrigo, Carlos; Alsina, Laia; Ruiz-Ortiz, Estibaliz; Juan, Manel; Fortuny, Claudia; Yagüe, Jordi; Antón, Jordi; Pascal, Mariona; Chang, Huey-Hsuan; Janniere, Lucile; Rose, Yoann; Garty, Ben-Zion; Chapel, Helen; Issekutz, Andrew; Maródi, László; Rodriguez-Gallego, Carlos; Banchereau, Jacques; Abel, Laurent; Li, Xiaoxia; Chaussabel, Damien; Puel, Anne; Casanova1, Jean-Laurent

    2009-01-01

    MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in experimental settings of infection. We describe a distinct situation in a natural setting of human infection. Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease. However, these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age, but not due to any cellular leakiness in MyD88 deficiency. The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections. PMID:18669862

  18. Epigenetic Deficiencies and Replicative Stress

    DEFF Research Database (Denmark)

    Shoaib, Muhammad; Sørensen, Claus Storgaard

    2015-01-01

    Cancer cell-specific synthetic lethal interactions entail promising therapeutic possibilities. In this issue of Cancer Cell, Pfister et al. describe a synthetic lethal interaction where cancer cells deficient in H3K36me3 owing to SETD2 loss-of-function mutation are strongly sensitized to inhibiti...

  19. Dopamine beta-hydroxylase deficiency

    Directory of Open Access Journals (Sweden)

    Senard Jean-Michel

    2006-03-01

    Full Text Available Abstract Dopamine beta-hydroxylase (DβH deficiency is a very rare form of primary autonomic failure characterized by a complete absence of noradrenaline and adrenaline in plasma together with increased dopamine plasma levels. The prevalence of DβH deficiency is unknown. Only a limited number of cases with this disease have been reported. DβH deficiency is mainly characterized by cardiovascular disorders and severe orthostatic hypotension. First symptoms often start during a complicated perinatal period with hypotension, muscle hypotonia, hypothermia and hypoglycemia. Children with DβH deficiency exhibit reduced ability to exercise because of blood pressure inadaptation with exertion and syncope. Symptoms usually worsen progressively during late adolescence and early adulthood with severe orthostatic hypotension, eyelid ptosis, nasal stuffiness and sexual disorders. Limitation in standing tolerance, limited ability to exercise and traumatic morbidity related to falls and syncope may represent later evolution. The syndrome is caused by heterogeneous molecular alterations of the DBH gene and is inherited in an autosomal recessive manner. Restoration of plasma noradrenaline to the normal range can be achieved by therapy with the synthetic precursor of noradrenaline, L-threo-dihydroxyphenylserine (DOPS. Oral administration of 100 to 500 mg DOPS, twice or three times daily, increases blood pressure and reverses the orthostatic intolerance.

  20. Congenital β-lipoprotein deficiency

    NARCIS (Netherlands)

    Buchem, F.S.P. van; Pol, G.; Gier, J. de; Böttcher, C.J.F.; Pries, C.

    1966-01-01

    There are several degrees of β-lipoprotein deficiency. If there is no β-lipoprotein present, or if there are only traces of it, the Bassen-Kornzweig syndrome develops. A constant feature of this syndrome is disturbed fat absorption with accumulation of fat in the epithelium of intestinal mucosa and

  1. Lipoxin Receptors

    Directory of Open Access Journals (Sweden)

    Mario Romano

    2007-01-01

    Full Text Available Lipoxins (LXs represent a class of arachidonic acid (AA metabolites that carry potent immunoregulatory and anti-inflammatory properties, LXA4 and LXB4 being the main components of this series. LXs are generated by cooperation between 5-lipoxygenase (LO and 12- or 15-LO during cell-cell interactions or by single cell types. LX epimers at carbon 15, the 15-epi-LXs, are formed by aspirin-acetylated cyclooxygenase-2 (COX-2 in cooperation with 5-LO. 15-epi-LXA4 is also termed aspirin-triggered LX (ATL. In vivo studies with stable LX and ATL analogs have established that these eicosanoids possess potent anti-inflammatory activities. A LXA4 receptor has been cloned. It belongs to the family of chemotactic receptors and clusters with formyl peptide receptors on chromosome 19. Therefore, it was initially denominated formyl peptide receptor like 1 (FPRL1. This receptor binds with high affinity and stereoselectivity LXA4 and ATL. It also recognizes a variety of peptides, synthetic, endogenously generated, or disease associated, but with lower affinity compared to LXA4. For this reason, this receptor has been renamed ALX. This review summarizes the current knowledge on ALX expression, signaling, and potential pathophysiological role. The involvement of additional recognition sites in LX bioactions is also discussed.

  2. NCOA4 Deficiency Impairs Systemic Iron Homeostasis

    Directory of Open Access Journals (Sweden)

    Roberto Bellelli

    2016-01-01

    Full Text Available The cargo receptor NCOA4 mediates autophagic ferritin degradation. Here we show that NCOA4 deficiency in a knockout mouse model causes iron accumulation in the liver and spleen, increased levels of transferrin saturation, serum ferritin, and liver hepcidin, and decreased levels of duodenal ferroportin. Despite signs of iron overload, NCOA4-null mice had mild microcytic hypochromic anemia. Under an iron-deprived diet (2–3 mg/kg, mice failed to release iron from ferritin storage and developed severe microcytic hypochromic anemia and ineffective erythropoiesis associated with increased erythropoietin levels. When fed an iron-enriched diet (2 g/kg, mice died prematurely and showed signs of liver damage. Ferritin accumulated in primary embryonic fibroblasts from NCOA4-null mice consequent to impaired autophagic targeting. Adoptive expression of the NCOA4 COOH terminus (aa 239–614 restored this function. In conclusion, NCOA4 prevents iron accumulation and ensures efficient erythropoiesis, playing a central role in balancing iron levels in vivo.

  3. Cobalamin deficiency, hyperhomocysteinemia, and dementia

    Directory of Open Access Journals (Sweden)

    Steven F Werder

    2010-04-01

    Full Text Available Steven F Werder1,21Kansas University School of Medicine – Wichita, Wichita, KS, USA; 2Community Health Center of Southeast Kansas, Pittsburg, KS, USAIntroduction: Although consensus guidelines recommend checking serum B12 in patients with dementia, clinicians are often faced with various questions: (1 Which patients should be tested? (2 What test should be ordered? (3 How are inferences made from such testing? (4 In addition to serum B12, should other tests be ordered? (5 Is B12 deficiency compatible with dementia of the Alzheimer’s type? (6 What is to be expected from treatment? (7 How is B12 deficiency treated?Methods: On January 31st, 2009, a Medline search was performed revealing 1,627 citations related to cobalamin deficiency, hyperhomocysteinemia, and dementia. After limiting the search terms, all abstracts and/or articles and other references were categorized into six major groups (general, biochemistry, manifestations, associations and risks, evaluation, and treatment and then reviewed in answering the above questions.Results: The six major groups above are described in detail. Seventy-five key studies, series, and clinical trials were identified. Evidence-based suggestions for patient management were developed.Discussion: Evidence is convincing that hyperhomocysteinemia, with or without hypovitaminosis B12, is a risk factor for dementia. In the absence of hyperhomocysteinemia, evidence is less convincing that hypovitaminosis B12 is a risk factor for dementia. B12 deficiency manifestations are variable and include abnormal psychiatric, neurological, gastrointestinal, and hematological findings. Radiological images of individuals with hyperhomocysteinemia frequently demonstrate leukoaraiosis. Assessing serum B12 and treatment of B12 deficiency is crucial for those cases in which pernicious anemia is suspected and may be useful for mild cognitive impairment and mild to moderate dementia. The serum B12 level is the standard initial test

  4. Diagnosis of vitamin B12 deficiency.

    OpenAIRE

    HU, Rehman

    1984-01-01

    Vitamin B12 (cobalamin) deficiency occurs primarily as a result  of insufficient dietary intake or poor absorp-tion. There is widespread global prevalence of vitamin B12 deficiency, resulting in considerable morbidity.

  5. Genetics Home Reference: tyrosine hydroxylase deficiency

    Science.gov (United States)

    Skip to main content Your Guide to Understanding Genetic Conditions Enable Javascript for addthis links to activate. ... Conditions Genes Chromosomes & mtDNA Resources Help Me Understand Genetics Home Health Conditions TH deficiency tyrosine hydroxylase deficiency ...

  6. P-selectin deficiency exacerbates experimental glomerulonephritis: a protective role for endothelial P-selectin in inflammation

    OpenAIRE

    Rosenkranz, Alexander R.; Donna L. Mendrick; Cotran, Ramzi S.; Mayadas, Tanya N.

    1999-01-01

    P-selectin is a leukocyte adhesion receptor present in endothelial cells and platelets. We examined the role of P-selectin in the autologous phase of an accelerated model of anti-glomerular basement membrane (GBM) glomerulonephritis using P-selectin–deficient mice and chimeric mice expressing P-selectin only in platelets or endothelial cells. P-selectin–deficient mice exhibited more severe glomerular damage with increased interstitial mononuclear leukocytic infiltrates, and had significantly ...

  7. Cobalamin deficiency in children: A literature review

    OpenAIRE

    Moen, Synne Helland

    2013-01-01

    Objective: The aim of this review is to present cobalamin deficiency in children with a specific focus on infants. Background: Cobalamin deficiency is caused by inadequate intake, malabsorption or inborn errors of vitamin B12 metabolism. Cobalamin deficiency in infants is usually caused by deficiency in the mother. There is often a diagnostic delay among infants because the most frequent symptoms are unspecific, e.g., developmental delay, apathy, hypotonia, anorexia and failure to thrive. Chi...

  8. 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

  9. Iron Deficiency in Autism and Asperger Syndrome.

    Science.gov (United States)

    Latif, A.; Heinz, P.; Cook, R.

    2002-01-01

    Retrospective analysis of the full blood count and, when available, serum ferritin measurements of 96 children (52 with autism and 44 with Asperger syndrome) found six autistic children had iron deficiency and 12 of the 23 autistic children with serum ferritin measures were iron deficient. Far fewer Asperger children were iron deficient. Results…

  10. Vitamin D deficiency in Europe

    DEFF Research Database (Denmark)

    Cashman, Kevin D.; Dowling, Kirsten G; Škrabáková, Zuzana;

    2016-01-01

    BACKGROUND: Vitamin D deficiency has been described as being pandemic, but serum 25-hydroxyvitamin D [25(OH)D] distribution data for the European Union are of very variable quality. The NIH-led international Vitamin D Standardization Program (VDSP) has developed protocols for standardizing existing...... 25(OH)D values from national health/nutrition surveys. OBJECTIVE: This study applied VDSP protocols to serum 25(OH)D data from representative childhood/teenage and adult/older adult European populations, representing a sizable geographical footprint, to better quantify the prevalence of vitamin D...... sera. These data were combined with standardized serum 25(OH)D data from 4 previously standardized studies (for a total n = 55,844). Prevalence estimates of vitamin D deficiency [using various serum 25(OH)D thresholds] were generated on the basis of standardized 25(OH)D data. RESULTS: An overall pooled...

  11. DNA repair deficiency in neurodegeneration

    DEFF Research Database (Denmark)

    Jeppesen, Dennis Kjølhede; Bohr, Vilhelm A; Stevnsner, Tinna V.

    2011-01-01

    Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive...... neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative...... base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby...

  12. 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...... of MCAD and presymptomatic treatment can potentially reduce morbidity and mortality. OBJECTIVES: To evaluate incidence, clinical outcome, biochemical and molecular phenotype of MCAD cases detected in the first three years of newborn screening in British Columbia (BC). METHODS AND RESULTS: Medium chain...... is comparable to reports from other newborn screening programs. Persistence of elevated C8 levels and C8/C10 ratios in confirmed MCAD cases suggest that these are sensitive markers for newborn screening. Early detection and treatment have successfully prevented adverse health outcomes in patients with MCAD....

  13. Vitamin D deficiency in Fibromyalgia

    International Nuclear Information System (INIS)

    Objective: To check the Vitamin D levels in patients diagnosed as fibromyagia in our population. Methods: Study was done at Medical OPD of Civil Hospital Karachi, from January to March 2009. Female patients diagnosed as Fibromyalgia according to American College of Rheumatology (ACR) criteria and exclusion of systemic illness on examination, and normal reports of blood CP, ESR, serum calcium, phosphate and Alkaline Phosphatase, were asked to get Vitamin D levels in their serum. Vitamin D deficiency is defined as 30 ng/ml. Result: Forty female patients were included in the study. The mean age was 37.65 +- 11.5 years. Mean Vitamin D level was 17.41 +- 5.497 ng/ml. Thirty two (80%) of patients had Vitamin D deficiency, mean levels of 15.855 +- 4.918 ng/ml and 8(20%) had Vitamin D insufficiency, mean levels of 23.64 +- 2.39 ng/ml. Patients with vitamin D deficiency and age less than 45 years were 22 (68.75%), had mean vitamin D level 16.87 +- 4.48 ng/ml whereas in age ranging from 46-75 years were 10 (31.25%) had mean vitamin D level 16.09 +- 6.45 ng/ml. Conclusion: Vitamin D deficiency is frequently seen in patients diagnosed as fibromyalgia and nonspecific musculoskeletal pain in our population. Although the sample size of the study is small, but the figures are so alarming that it is an eye opener towards the need of a population based study, including normal population as well as those presenting with musculoskeletal pain. (author)

  14. [Iodine deficiency in cardiovascular diseases].

    Science.gov (United States)

    Molnár, I; Magyari, M; Stief, L

    1998-08-30

    The thyroid hormone deficiency on cardiovascular function can be characterized with decreased myocardial contractility and increased peripheral vascular resistance as well as with the changes in lipid metabolism. 42 patients with cardiovascular disease (mean age 65 +/- 13 yr, 16 males) were investigated if iodine insufficiency can play a role as a risk factor for the cardiovascular diseases. The patients were divided in 5 subgroups on the ground of the presence of hypertension, congestive heart failure, cardiomyopathy, coronary disfunction and arrhythmia. Urine iodine concentration (5.29 +/- 4.52 micrograms/dl) was detected with Sandell-Kolthoff colorimetric reaction. The most decreased urine iodine concentration was detected in the subgroups with arrhythmia and congestive heart failure (4.7 +/- 4.94 micrograms/dl and 4.9 +/- 4.81 micrograms/dl, respectively). An elevated TSH level was found by 3 patients (5.3 +/- 1.4 mlU/l). An elevation in lipid metabolism (cholesterol, triglyceride) associated with all subgroups without arrhythmia. In conclusion, the occurrence of iodine deficiency in cardiovascular disease is frequent. Iodine supplementation might prevent the worsing effect of iodine deficiency on cardiovascular disease.

  15. Stress regulates endocannabinoid-CB1 receptor signaling.

    Science.gov (United States)

    Hillard, Cecilia J

    2014-10-01

    The CB1 cannabinoid receptor is a G protein coupled receptor that is widely expressed throughout the brain. The endogenous ligands for the CB1 receptor (endocannabinoids) are N-arachidonylethanolamine and 2-arachidonoylglycerol; together the endocannabinoids and CB1R subserve activity dependent, retrograde inhibition of neurotransmitter release in the brain. Deficiency of CB1 receptor signaling is associated with anhedonia, anxiety, and persistence of negative memories. CB1 receptor-endocannabinoid signaling is activated by stress and functions to buffer or dampen the behavioral and endocrine effects of acute stress. Its role in regulation of neuronal responses is more complex. Chronic variable stress exposure reduces endocannabinoid-CB1 receptor signaling and it is hypothesized that the resultant deficiency in endocannabinoid signaling contributes to the negative consequences of chronic stress. On the other hand, repeated exposure to the same stress can sensitize CB1 receptor signaling, resulting in dampening of the stress response. Data are reviewed that support the hypothesis that CB1 receptor signaling is stress responsive and that maintaining robust endocannabinoid/CB1 receptor signaling provides resilience against the development of stress-related pathologies.

  16. Immune response against Sporothrix schenckii in TLR-4-deficient mice.

    Science.gov (United States)

    Sassá, Micheli Fernanda; Ferreira, Lucas Souza; Ribeiro, Livia Carolina de Abreu; Carlos, Iracilda Zeppone

    2012-07-01

    For many fungal diseases, macrophages are the major cell population implicated in host protection, primarily by their ability to eliminate the invading fungal pathogen through phagocytosis. In sporotrichosis, this remains true, because of macrophages’ ability to recognize Sporothrix schenckii through specific receptors for some of the fungus’ cellular surface constituents. Further confirmation for macrophages’ pivotal role in fungal diseases came with the identification of toll-like receptors, and the subsequent numerous associations found between TLR-4 deficiency and host susceptibility to diverse fungal pathogens. Involvement of TLR-4 in immune response against sporotrichosis has been conducted to investigate how TLR-4 signaling could affect inflammatory response development through evaluation of H2O2 production and IL-1β, IL-6 and TGF-β release during the course of S. schenckii infection on TLR-4-deficient mice. The results showed that macrophages are largely dependent on TLR-4 for inflammatory activation and that in the absence of TLR-4 signaling, increased TGF-β release may be one of the contributing factors for the abrogated inflammatory activation of peritoneal exudate cells during mice sporotrichosis.

  17. Zinc Deficiency in Humans and its Amelioration

    OpenAIRE

    Yashbir Singh Shivay

    2015-01-01

    Zinc (Zn) deficiency in humans has recently received considerable attention. Global mortality in children under 5 years of age in 2004 due to Zn deficiency was estimated at 4,53,207 as against 6,66,771 for vitamin A deficiency; 20,854 for iron deficiency and 3,619 for iodine deficiency. In humans 2800-3000 proteins contain Zn prosthetic group and Zn is an integral component of zinc finger prints that regulate DNA transcription. Zinc is a Type-2 nutrient, which means that its concentration in ...

  18. Iron deficiency anemia: current strategies for the diagnosis and management

    Directory of Open Access Journals (Sweden)

    Zühre Kaya

    2013-07-01

    Full Text Available Iron deficiency is one of the commonest nutritional deficiencies in the world. It is multifactorial and may be caused by lack of intake, blood loss and intestinal causes. Clinical features are highly variable, and most patients are asymptomatic. Typical laboratory features of iron deficiency anemia (IDA include a hypochromic microcytic anemia, low serum iron level, high total iron binding capacity, low serum ferritin level. Usefulness of monitoring serum transferrin receptor level (sTfR and hepcidin for identifying IDA have been examined in a few studies. Available data suggest that sTfR can potentially become a valuable tool for regular testing of patients in the future. Despite IDA is easily corrected with iron therapy, establishing the cause can be difficult, particularly in cases caused by disorders of iron transport. Education for clinician needs to focus on increasing awareness of the importance of failure respond to iron supplementation. The aim of this review was to outline the current strategies for the diagnosis and management of IDA in the light of the latest reports.http://dx.doi.org/10.7175/rhc.v4i3.480

  19. Glutamate receptors

    DEFF Research Database (Denmark)

    Kristensen, Anders S; Geballe, Matthew T; Snyder, James P;

    2006-01-01

    Fast excitatory synaptic transmission in the CNS relies almost entirely on the neurotransmitter glutamate and its family of ion channel receptors. An appreciation of the coupling between agonist binding and channel opening has advanced rapidly during the past five years, largely as a result of ne...

  20. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette;

    2003-01-01

    In 1972, Brazeau et al. isolated somatostatin (somatotropin release-inhibiting factor, SRIF), a cyclic polypeptide with two biologically active isoforms (SRIF-14 and SRIF-28). This event prompted the successful quest for SRIF receptors. Then, nearly a quarter of a century later, it was announced...

  1. Deficiencies in the Management of Iron Deficiency Anemia During Childhood.

    Science.gov (United States)

    Powers, Jacquelyn M; Daniel, Catherine L; McCavit, Timothy L; Buchanan, George R

    2016-04-01

    Limited high-quality evidence supports the management of iron deficiency anemia (IDA). To assess our institutional performance in this area, we retrospectively reviewed IDA treatment practices in 195 consecutive children referred to our center from 2006 to mid-2010. The majority of children were ≤4 years old (64%) and had nutritional IDA (74%). In 11- to 18-year-old patients (31%), the primary etiology was menorrhagia (42%). Many were referred directly to the emergency department and/or prescribed iron doses outside the recommended range. Poor medication adherence and being lost-to-follow-up were common. Substantial improvements are required in the management of IDA.

  2. Blood and hair lead in children with different extents of iron deficiency in Karachi

    Energy Technology Data Exchange (ETDEWEB)

    Ataur Rahman, Muhammad; Rahman, Bushra [Karachi Institute of Biotechnology and Genetic Engineering, University of Karachi, Karachi-75270 (Pakistan); Saeed Ahmad, Muhammad [School of Healthcare Science, Manchester Metropolitan University, Manchester M1 5GD (United Kingdom); Blann, Andrew [Department of Medicine, City Hospital, Birmingham B18 7QH, United Kingdom. (United Kingdom); Ahmed, Nessar, E-mail: N.Ahmed@mmu.ac.uk [School of Healthcare Science, Manchester Metropolitan University, Manchester M1 5GD (United Kingdom)

    2012-10-15

    Childhood iron deficiency has a high incidence in Pakistan. Some but not all studies have shown that dietary iron deficiency may cause increased absorption of lead as both compete for the same transporters in the small intestine. Therefore, children in Pakistan, residing in heavily polluted cities like Karachi may be prone to lead poisoning. This hypothesis was tested by investigating blood and hair lead concentrations in children from Karachi who were divided into four groups of iron status; normal, borderline iron deficiency, iron deficiency and iron deficiency anaemia. A prospective observational study was conducted where 269 children were categorized into four groups of iron status using the World Health Organization criteria and one based on soluble transferrin receptor measurements. Blood iron status was determined using a full blood count, serum iron, ferritin, transferrin saturation and soluble transferrin receptor measurements. Blood lead was determined by graphite atomic absorption spectroscopy, whereas hair lead was assessed using an inductively coupled plasma atomic emission spectroscopy technique. Blood lead concentrations were significantly higher in children with iron deficiency anaemia (mean [95% confidence intervals] were 24.9 [22.6-27.2] {mu}g/dL) compared to those with normal iron status (19.1 [16.8-21.4] {mu}g/dL) using WHO criteria. In contrast, hair lead content was not significantly different in children of different iron status. Our findings reinforce the importance of not only reducing environmental lead pollution but also the development of national health strategies to reduce childhood iron deficiency in Pakistan.

  3. Muscle phosphoglycerate mutase deficiency revisited

    DEFF Research Database (Denmark)

    Naini, Ali; Toscano, Antonio; Musumeci, Olimpia;

    2009-01-01

    storage disease type X and novel mutations in the gene encoding the muscle subunit of PGAM (PGAM2). DESIGN: Clinical, pathological, biochemical, and molecular analyses. SETTING: Tertiary care university hospitals and academic institutions. Patients A 37-year-old Danish man of Pakistani origin who had...... PGAM deficiency, and molecular studies revealed 2 novel homozygous mutations, a nonsense mutation and a single nucleotide deletion. Pathological studies of muscle showed mild glycogen accumulation but prominent tubular aggregates in both patients. CONCLUSIONS: We found that glycogen storage disease...

  4. Muscarinic Receptor Signaling in Colon Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rosenvinge, Erik C. von, E-mail: evonrose@medicine.umaryland.edu; Raufman, Jean-Pierre [University of Maryland School of Medicine, Division of Gastroenterology & Hepatology, 22 S. Greene Street, N3W62, Baltimore, MD 21201 (United States); Department of Veterans Affairs, VA Maryland Health Care System, 10 North Greene Street, Baltimore, MD 21201 (United States)

    2011-03-02

    According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal bile acids promote colon dysplasia. Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia. In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors. The present communication reviews muscarinic receptor expression in normal and neoplastic colon epithelium, the role of autocrine signaling following synthesis and release of acetylcholine from colon cancer cells, post-muscarinic receptor signaling including the role of transactivation of epidermal growth factor receptors and activation of the ERK and PI3K/AKT signaling pathways, the structural biology and metabolism of bile acids and evidence for functional interaction of bile acids with muscarinic receptors on human colon cancer cells. In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer.

  5. Muscarinic Receptor Signaling in Colon Cancer

    Directory of Open Access Journals (Sweden)

    Jean-Pierre Raufman

    2011-03-01

    Full Text Available According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal bile acids promote colon dysplasia. Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia. In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors. The present communication reviews muscarinic receptor expression in normal and neoplastic colon epithelium, the role of autocrine signaling following synthesis and release of acetylcholine from colon cancer cells, post-muscarinic receptor signaling including the role of transactivation of epidermal growth factor receptors and activation of the ERK and PI3K/AKT signaling pathways, the structural biology and metabolism of bile acids and evidence for functional interaction of bile acids with muscarinic receptors on human colon cancer cells. In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer.

  6. Dopamine and glucose, obesity and Reward Deficiency Syndrome

    Directory of Open Access Journals (Sweden)

    Kenneth eBlum

    2014-09-01

    Full Text Available Obesity and many well described eating disorders are accurately considered a global epidemic. The consequences of Reward Deficiency Syndrome, a genetic and epigenetic phenomena that involves the interactions of powerful neurotransmitters, are impairments of brain reward circuitry, hypodopaminergic function and abnormal craving behavior. Numerous sound neurochemical and genetic studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Important facts which could translate to potential therapeutic targets espoused in this review include: 1 brain dopamine (DA production and use is stimulated by consumption of alcohol in large quantities or carbohydrates bingeing; 2 in the mesolimbic system the enkephalinergic neurons are in close proximity, to glucose receptors; 3 highly concentrated glucose activates the calcium channel to stimulate dopamine release from P12 cells; 4 blood glucose and cerebrospinal fluid concentrations of homovanillic acid, the dopamine metabolite, are significantly correlated and 5 2-deoxyglucose the glucose analogue, in pharmacological doses associates with enhanced dopamine turnover and causes acute glucoprivation. Evidence from animal studies and human fMRI support the hypothesis that multiple, but similar brain circuits are disrupted in obesity and drug dependence and DA-modulated reward circuits are involved in pathologic eating behaviors. Treatment for addiction to glucose and drugs alike, based on a consensus of neuroscience research, should incorporate dopamine agonist therapy, in contrast to current theories and practices that use dopamine antagonists. Until now, powerful dopamine-D2 agonists have failed clinically, due to chronic down regulation of D2 receptors instead, consideration of novel less powerful D2 agonists that up-regulate D2 receptors seems prudent. We encourage new strategies targeted at improving DA function in the treatment and prevention of obesity a subtype of

  7. Role for M5 muscarinic acetylcholine receptors in cocaine addiction.

    Science.gov (United States)

    Fink-Jensen, Anders; Fedorova, Irina; Wörtwein, Gitta; Woldbye, David P D; Rasmussen, Thøger; Thomsen, Morgane; Bolwig, Tom G; Knitowski, Karen M; McKinzie, David L; Yamada, Masahisa; Wess, Jürgen; Basile, Anthony

    2003-10-01

    Muscarinic cholinergic receptors of the M5 subtype are expressed by dopamine-containing neurons of the ventral tegmentum. These M5 receptors modulate the activity of midbrain dopaminergic neurons, which play an important role in mediating reinforcing properties of abused psychostimulants like cocaine. The potential role of M5 receptors in the reinforcing effects of cocaine was investigated using M5 receptor-deficient mice in a model of acute cocaine self-administration. The M5-deficient mice self-administered cocaine at a significantly lower rate than wild-type controls. In the conditioned place preference procedure, a classic test for evaluating the rewarding properties of drugs, M5-deficient mice spent significantly less time in the cocaine-paired compartment than control mice. Moreover, the severity of the cocaine withdrawal syndrome (withdrawal-associated anxiety measured in the elevated plus-maze) was significantly attenuated in mice lacking the M5 receptor. These results demonstrate that M5 receptors play an important role in mediating both cocaine-associated reinforcement and withdrawal.

  8. Relationship between 17β-hydroxysteroid dehydrogenase 2 deficiency and changes of progesterone receptor isoforms in ectopic endometrium%异位子宫内膜17β-羟基类固醇脱氢酶2缺乏与孕激素受体亚型变化的相关性研究

    Institute of Scientific and Technical Information of China (English)

    张萍; 李笛悠; 惠宁

    2011-01-01

    目的 探讨子宫内膜异位症(EMT)病灶对孕激素不敏感是否由局部孕激素受体(PRs)亚型及173 -羟基类固醇脱氢酶2( 17β-HSD2)改变或功能缺陷所致.方法 采用Real-Time PCR检测36例EMT患者的卵巢异位子宫内膜(EMT异位子宫内膜组)和16例在位子宫内膜(EMT在位子宫内膜组)的PR-(A+B)、PR-A、PR-B及l7β-HSD2 mRNA的表达;免疫组织化学方法检测PR-(A+ B)、PR-B和17β-HSD2蛋白的表达.结果 EMT在位子宫内膜组PR-(A+B)、PR-B、PR-A mRNA增殖期较分泌期表达升高(P<0.05);增殖期子宫内膜腺上皮细胞及间质细胞都有PRs表达,在分泌期主要在间质细胞中表达;PR-A占优势,PR-A/PR-B比值在整个月经周期中保持相对恒定.子宫内膜间质细胞中PR-B与腺上皮细胞中17β-HSD2的表达一致.EMT异位子宫内膜组PR-A在整个月经周期中持续性低表达,在分泌期与在位内膜PR-A表达差异无统计学意义(P>0.05);PR-B在整个月经周期的表达明显低于在位内膜;PR-A及PR-B的周期性变化消失.与EMT在位子宫内膜组比较,EMT异位子宫内膜组PR-B表达相对降低,PR-A/PR-B值显著升高(P=0.001).EMT异位子宫内膜组间质细胞中PR-B明显下降;17β-HSD2也明显下降,其周期性变化消失.结论 异位子宫内膜的PRs亚型改变影响173-HSD2的表达,可能是EMT发生孕激素抵抗的分子机制之一.%Objective To investigate the mechanism of changes of isoforms of local progesterone receptors ( PRs) and 17β-hydroxysteroid dehydrogenase 2 (17JJ-HSD2) deficiency in insensitiveness of ectopic endometrium ( EMT) to progestin. Methods Ectopic endometrium samples of 36 cases of EMT (EMT ectopic endometrium group) and 16 samples of eutopic endometrium ( EMT eutopic endometrium group) were selected, the expression of PR-( A + B), PR-A, PR-B and 17β-HSD2 mRNA was detected by Real-Time PCR, and the expression of PR-( A + B), PR-B and 17B-HSD2 protein was determined by

  9. Lipodystrophy, Diabetes and Normal Serum Insulin in PPARγ-Deficient Neonatal Mice

    Science.gov (United States)

    O’Donnell, Peter E.; Ye, Xiu Zhen; DeChellis, Melissa A.; Davis, Vannessa M.; Duan, Sheng Zhong; Mortensen, Richard M.; Milstone, David S.

    2016-01-01

    Peroxisome proliferator activated receptor gamma (PPARγ) is a pleiotropic ligand activated transcription factor that acts in several tissues to regulate adipocyte differentiation, lipid metabolism, insulin sensitivity and glucose homeostasis. PPARγ also regulates cardiomyocyte homeostasis and by virtue of its obligate role in placental development is required for embryonic survival. To determine the postnatal functions of PPARγ in vivo we studied globally deficient neonatal mice produced by epiblast-restricted elimination of PPARγ. PPARγ-rescued placentas support development of PPARγ-deficient embryos that are viable and born in near normal numbers. However, PPARγ-deficient neonatal mice show severe lipodystrophy, lipemia, hepatic steatosis with focal hepatitis, relative insulin deficiency and diabetes beginning soon after birth and culminating in failure to thrive and neonatal lethality between 4 and 10 days of age. These abnormalities are not observed with selective PPARγ2 deficiency or with deficiency restricted to hepatocytes, skeletal muscle, adipocytes, cardiomyocytes, endothelium or pancreatic beta cells. These observations suggest important but previously unappreciated functions for PPARγ1 in the neonatal period either alone or in combination with PPARγ2 in lipid metabolism, glucose homeostasis and insulin sensitivity. PMID:27505464

  10. Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity

    NARCIS (Netherlands)

    Krabbe, Grietje; Matyash, Vitali; Pannasch, Ulrike; Mamer, Lauren; Boddeke, Hendrikus W. G. M.; Kettenmann, Helmut

    2012-01-01

    Microglia, the brain immune cell, express several neurotransmitter receptors which modulate microglial functions. In this project we studied the impact of serotonin receptor activation on distinct microglial properties as serotonin deficiency not only has been linked to a number of psychiatric disea

  11. Vitamin D deficiency and stroke

    Directory of Open Access Journals (Sweden)

    2012-12-01

    Full Text Available Vitamin D comprises a group of fat-soluble pro-hormones, obtained from sun exposure, food, and supplements, and it must undergo two hydroxylation reactions to be activated in the body. Several studies have shown the role of vitamin D in mineral metabolism regulation, especially calcium, phosphorus, and bone metabolism. Some factors such as inadequate vitamin intake and liver or kidney disorders can lead to vitamin D deficiency. Furthermore, vitamin D malnutrition may also be linked to susceptibility to chronic diseases such as heart failure, peripheral artery disease, high blood pressure, cognitive impairment including foggy brain and memory loss, and autoimmune diseases including diabetes type I. Recent research has revealed that low levels of vitamin D increase the risk of cardiovascular-related morbidity (Sato et al., 2004 and mortality (Pilz et al., 2008. Also, hypertension contributes to a reduction in bone mineral density and increase in the incidence of stroke and death. This article reviews the function and physiology of vitamin D and examines the effects of vitamin D deficiency on susceptibility to stroke, as a cardiovascular event, and its morbidity and subsequent mortality.

  12. Anaemia and iron deficiency anaemia among young adolescent girls from the peri urban coastal area of Indonesia.

    Science.gov (United States)

    Kurniawan, Yustina Anie Indriastuti; Muslimatun, Siti; Achadi, Endang L; Sastroamidjojo, Soemilah

    2006-01-01

    Anaemia due to iron deficiency is still a widespread problem. Among adolescent girls, it will bring negative consequences on growth, school performance, morbidity and reproductive performance. This cross sectional study aimed to identify the different nutritional and iron status characteristics of young adolescent girls 10-12 years old with iron deficiency anaemia and anaemia without iron deficiency in the rural coastal area of Indonesia. Anaemic girls (N =133) were recruited out of 1358 girls from 34 elementary schools. Haemoglobin, serum ferritin, serum transferrin receptor and zinc protophorphyrin were determined for iron status, whilst weight and height were measured for their nutritional status. General characteristics and dietary intake were assessed through interview. Out of 133 anaemic subjects, 29 (21.8%) suffered from iron deficiency anaemia, which was not significantly related to age and menarche. About 50% were underweight and stunted indicating the presence of acute and chronic malnutrition. The proportion of thinness was significantly higher (P < 0.05) among subjects who suffered from iron deficiency anaemia (51.7% vs. 29.8%). Furthermore, thin subjects had a 5 fold higher risk of suffering from iron deficiency anaemia (P< 0.05) than non-thin subjects (OR: 5.1; 95%CI 1.34-19.00). Further study was recommended to explore other factors associated with anaemia and iron deficiency anaemia, such as the thalassemia trait and vitamin A deficiency. The current iron-folate supplementation program for pregnant women should be expanded to adolescent girls.

  13. Multispectral Analysis of Color Vision Deficiency Tests

    OpenAIRE

    Sergejs FOMINS; Ozolinsh, Maris

    2011-01-01

    Color deficiency tests are usually produced by means of polygraphy technologies and help to diagnose the type and severity of the color deficiencies. Due to different factors, as lighting conditions or age of the test, standard characteristics of these tests fail, thus not allowing diagnosing unambiguously the degree of different color deficiency. Multispectral camera was used to acquire the spectral images of the Ishihara and Rabkin pseudoisochromatic plates in the visible spectrum. Spectral...

  14. Prevalence of Color Vision Deficiency in Qazvin

    OpenAIRE

    Mohammad khalaj; Ameneh Barikani; Mozhgan Mohammadi

    2014-01-01

    Background: Color vision deficiency (CVD) is an X chromosome-linked recessive autosomal dominant. Determine the prevalence of color blindness in Qazvin population. Materials and Methods: In a cross sectional study color vision deficiency examined in 1853 individuals with age 10-25 years old who participated in private clinics and eye clinic of Bu-Ali hospital in Qazvin in 2010. The screening of color vision deficiency was performed using Ishihara test. Data were analyzed by SPSS-16 with χP...

  15. Vitamin B12 deficiency and depression

    OpenAIRE

    Milanlıoğlu, Aysel

    2011-01-01

    Vitamin B12 deficiency may cause psychiatric manifestations preceding the hematological and neurological symptoms. Despite a variety of symptoms, data on the role of vitamin B12 deficiency in depression are sparse. We report a case with B12 deficiency that is diagnosed with psychotic depression and treated successively with vitamin B12 replacement instead of using conventional therapy. Future investigations should focus on the role of vitamin B12 status in depression and other neurops...

  16. Atypical B12 Deficiency with Nonresolving Paraesthesia

    OpenAIRE

    Haider, S.; Ahmad, N; Anaissie, E J; Abdel Karim, N.

    2013-01-01

    Vitamin B12 deficiency can present with various hematological, gastrointestinal and neurological manifestations. We report a case of elderly female who presented with neuropathy and vitamin B12 deficiency where the final work-up revealed polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS). This case suggests that, although POEMS syndrome is a rare entity, it can present with vitamin-B12 deficiency and thus specific work up for early diagnosis of P...

  17. Vitamin D Deficiency in Early Pregnancy

    OpenAIRE

    Flood-Nichols, Shannon K.; Tinnemore, Deborah; Huang, Raywin R.; Napolitano, Peter G.; Ippolito, Danielle L.

    2015-01-01

    Objective Vitamin D deficiency is a common problem in reproductive-aged women in the United States. The effect of vitamin D deficiency in pregnancy is unknown, but has been associated with adverse pregnancy outcomes. The objective of this study was to analyze the relationship between vitamin D deficiency in the first trimester and subsequent clinical outcomes. Study Design This is a retrospective cohort study. Plasma was collected in the first trimester from 310 nulliparous women with singlet...

  18. Vitamin D Deficiency in Children and Adolescents

    OpenAIRE

    Andıran, Nesibe; Çelik, Nurullah; AKÇA, Halise; Doğan, Güzide

    2012-01-01

    Objective Vitamin D deficiency is an important health problem in both developed and developing countries. Recent reports on the extraskeletal effects of vitamin D have led to increased interest in prevalence studies on states of deficiency/insufficiency of vitamin D. The aim of this study was to determine the frequency of vitamin D deficiency and insufficiency in children and adolescents residing in Ankara, Turkey and to investigate the factors associated with low vitamin D status. Methods: A...

  19. Abnormal modulation of reward versus punishment learning by a dopamine D2-receptor antagonist in pathological gamblers

    NARCIS (Netherlands)

    Janssen, L.K.; Sescousse, G.; Hashemi, M.M.; Timmer, M.H.; Huurne, N.P. Ter; Geurts, D.E.M.; Cools, R.

    2015-01-01

    RATIONALE: Pathological gambling has been associated with dopamine transmission abnormalities, in particular dopamine D2-receptor deficiency, and reversal learning deficits. Moreover, pervasive theoretical accounts suggest a key role for dopamine in reversal learning. However, there is no empirical

  20. Vitamin C deficiency in weanling guinea pigs

    DEFF Research Database (Denmark)

    Lykkesfeldt, Jens; Trueba, Gilberto Perez; Poulsen, Henrik E.;

    2007-01-01

    Neonates are particularly susceptible to malnutrition due to their limited reserves of micronutrients and their rapid growth. In the present study, we examined the effect of vitamin C deficiency on markers of oxidative stress in plasma, liver and brain of weanling guinea pigs. Vitamin C deficiency...... increased, while protein oxidation decreased (P¼0003). The results show that the selective preservation of brain ascorbate and induction of DNA repair in vitamin C-deficient weanling guinea pigs is not sufficient to prevent oxidative damage. Vitamin C deficiency may therefore be particularly adverse during...

  1. Genetics Home Reference: common variable immune deficiency

    Science.gov (United States)

    ... 2 links) National Institute of Allergy and Infectious Diseases: Immune System National Institute of Allergy and Infectious Diseases: Primary Immune Deficiency Diseases Educational Resources (8 links) Boston Children's ...

  2. The effects of in utero vitamin D deficiency on airway smooth muscle mass and lung function.

    Science.gov (United States)

    Foong, Rachel E; Bosco, Anthony; Jones, Anya C; Gout, Alex; Gorman, Shelley; Hart, Prue H; Zosky, Graeme R

    2015-11-01

    We have previously demonstrated increased airway smooth muscle (ASM) mass and airway hyperresponsiveness in whole-life vitamin D-deficient female mice. In this study, we aimed to uncover the molecular mechanisms contributing to altered lung structure and function. RNA was extracted from lung tissue of whole-life vitamin D-deficient and -replete female mice, and gene expression patterns were profiled by RNA sequencing. The data showed that genes involved in embryonic organ development, pattern formation, branching morphogenesis, Wingless/Int signaling, and inflammation were differentially expressed in vitamin D-deficient mice. Network analysis suggested that differentially expressed genes were connected by the hubs matrix metallopeptidase 9; NF-κ light polypeptide gene enhancer in B cells inhibitor, α; epidermal growth factor receptor; and E1A binding protein p300. Given our findings that developmental pathways may be altered, we investigated if the timing of vitamin D exposure (in utero vs. postnatal) had an impact on lung health outcomes. Gene expression was measured in in utero or postnatal vitamin D-deficient mice, as well as whole-life vitamin D-deficient and -replete mice at 8 weeks of age. Baseline lung function, airway hyperresponsiveness, and airway inflammation were measured and lungs fixed for lung structure assessment using stereological methods and quantification of ASM mass. In utero vitamin D deficiency was sufficient to increase ASM mass and baseline airway resistance and alter lung structure. There were increased neutrophils but decreased lymphocytes in bronchoalveolar lavage. Expression of inflammatory molecules S100A9 and S100A8 was mainly increased in postnatal vitamin D-deficient mice. These observations suggest that in utero vitamin D deficiency can alter lung structure and function and increase inflammation, contributing to symptoms in chronic diseases, such as asthma. PMID:25867172

  3. The Syk/CARD9-coupled receptor Dectin-1 is not required for host resistance to Mycobacterium tuberculosis in mice

    OpenAIRE

    Marakalala, Mohlopheni J.; Guler, Reto; Matika, Lungile; Murray, Graeme; Jacobs, Muazzam; Brombacher, Frank; Rothfuchs, Antonio Gigliotti; Sher, Alan; Brown, Gordon D.

    2011-01-01

    There is interest in identifying the pattern recognition receptors involved in initiating protective or non-protective host responses to Mycobacterium tuberculosis (Mtb). Here we explored the role of the Syk/CARD9-coupled receptor, Dectin-1, using an aerosol model of Mtb infection in wild-type and Dectin-1 deficient mice. We observed a reduction in pulmonary bacilli burdens in the Dectin-1 deficient animals, but this did not correlate with significant changes in pulmonary pathology, cytokine ...

  4. Mechanistic insights into the role of C-type lectin receptor/CARD9 signaling in human antifungal immunity

    OpenAIRE

    Drummond, Rebecca A.; Lionakis, Michail S.

    2016-01-01

    Human CARD9 deficiency is an autosomal recessive primary immunodeficiency disorder caused by biallelic mutations in the gene CARD9, which encodes a signaling protein that is found downstream of many C-type lectin receptors (CLRs). CLRs encompass a large family of innate recognition receptors, expressed predominantly by myeloid and epithelial cells, which bind fungal carbohydrates and initiate antifungal immune responses. Accordingly, human CARD9 deficiency is associated with the spontaneous d...

  5. Mechanistic Insights into the Role of C-Type Lectin Receptor/CARD9 Signaling in Human Antifungal Immunity

    OpenAIRE

    Drummond, Rebecca A.; Lionakis, Michail S.

    2016-01-01

    Human CARD9 deficiency is an autosomal recessive primary immunodeficiency disorder caused by biallelic mutations in the gene CARD9, which encodes a signaling protein that is found downstream of many C-type lectin receptors (CLRs). CLRs encompass a large family of innate recognition receptors, expressed predominantly by myeloid and epithelial cells, which bind fungal carbohydrates and initiate antifungal immune responses. Accordingly, human CARD9 deficiency is associated with the spontaneous d...

  6. Deficient approaches to human neuroimaging

    DEFF Research Database (Denmark)

    Stelzer, Johannes; Lohmann, Gabriele; Mueller, Karsten;

    2014-01-01

    Functional magnetic resonance imaging (fMRI) is the workhorse of imaging-based human cognitive neuroscience. The use of fMRI is ever-increasing; within the last 4 years more fMRI studies have been published than in the previous 17 years. This large body of research has mainly focused...... of the major conceptual and practical deficiencies in widely used brain-mapping approaches, and exemplify some of these issues by the use of imaging data and simulations. In particular, we discuss the inherent pitfalls and shortcomings of methodologies for statistical parametric mapping. Our critique...... emphasizes recent reports of excessively high numbers of both false positive and false negative findings in fMRI brain mapping. We outline our view regarding the broader scientific implications of these methodological considerations and briefly discuss possible solutions....

  7. B12 Deficiency with Children

    Directory of Open Access Journals (Sweden)

    Selahattin Katar

    2007-01-01

    Full Text Available Aim of the study: to rewieved the clinical and laboratory properties of seven cases with megaloblastic anemia. Clinical and laboratory findings of seven cases with megaloblastic anemia are described. İt is determined that all of the patients received little or no animal products by nutritional history. Clinically apatite, malasia, headeche, otism, and parestheia in the lower extremities and foods were present in patients. On physical examination; four patients had glossit, four had hyporeflexia, one had ataxia. Folat level was normal and B12 vitamin level was low in all patients. The MCV (mean corpuscular volume was normal in three patients. Hypersegmentation of neutrophil was observed in all patients, leukopenia in two, and trombocytopenia was observed in one patient.Conclusion: it is suggested B12 vitamin deficiency in the patients that received little or no animal products by nutritional history. However, hypersegmentation of neutrophil in peripheral blood sample is an important finding for diagnosis of megaloblastic anemia.

  8. [delta-Aminolevulinate dehydratase deficiency].

    Science.gov (United States)

    Fujita, H; Ishida, N; Akagi, R

    1995-06-01

    delta-Aminolevulinate dehydratase (ALAD: E. C. 4.2.1.24), the second enzyme in the heme biosynthetic pathway, condenses two moles of delta-aminolevulinic acid to form porphobilinogen. ALAD deficiency is well known to develop signs and symptoms of typical hepatic porphyria, and classified into three categories as follows: (i) ALAD porphyria, a genetic defect of the enzyme, (ii) tyrosinemia type I, a genetic defect of fumarylacetoacetase in the tyrosine catabolic pathway, producing succinylacetone (a potent inhibitor of ALAD), and (iii) ALAD inhibition by environmental hazards, such as lead, trichloroethylene, and styrene. In the present article, we will describe molecular and biochemical mechanisms to cause the enzyme defect to discuss the significance of ALAD defect on human health.

  9. Complementary signaling through flt3 and interleukin-7 receptor alpha is indispensable for fetal and adult B cell genesis

    DEFF Research Database (Denmark)

    Sitnicka, Ewa; Brakebusch, Cord; Martensson, Inga-Lill;

    2003-01-01

    Extensive studies of mice deficient in one or several cytokine receptors have failed to support an indispensable role of cytokines in development of multiple blood cell lineages. Whereas B1 B cells and Igs are sustained at normal levels throughout life of mice deficient in IL-7, IL-7Ralpha, commo...

  10. Pmch-Deficiency in Rats Is Associated with Normal Adipocyte Differentiation and Lower Sympathetic Adipose Drive

    OpenAIRE

    Mul, Joram D.; Eoghan O'Duibhir; Shrestha, Yogendra B.; Arjen Koppen; Peter Vargoviç; Toonen, Pim W; Eleen Zarebidaki; Richard Kvetnansky; Eric Kalkhoven; Edwin Cuppen; Bartness, Timothy J.

    2013-01-01

    The orexigenic neuropeptide melanin-concentrating hormone (MCH), a product of Pmch, is an important mediator of energy homeostasis. Pmch-deficient rodents are lean and smaller, characterized by lower food intake, body-, and fat mass. Pmch is expressed in hypothalamic neurons that ultimately are components in the sympathetic nervous system (SNS) drive to white and interscapular brown adipose tissue (WAT, iBAT, respectively). MCH binds to MCH receptor 1 (MCH1R), which is present on adipocytes. ...

  11. Vitamin D or hormone D deficiency in autoimmune rheumatic diseases, including undifferentiated connective tissue disease

    OpenAIRE

    Cutolo, Maurizio

    2008-01-01

    Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of autoimmune diseases. The presence of vitamin D receptors in the cells of the immune system and the fact that several of these cells produce the vitamin D hormone suggested that vitamin D could have immunoregulatory properties, and now potent immuno-mudulatory activities on dendritic cells, Th1 and Th17 cells, as well as B cells have been confirmed. Patients with undifferenti...

  12. Immunoglobulin G–mediated Inflammatory Responses Develop Normally in Complement-deficient Mice

    Science.gov (United States)

    Sylvestre, Diana; Clynes, Raphael; Ma, Minga; Warren, Henry; Carroll, Michael C.; Ravetch, Jeffrey V.

    1996-01-01

    The role of complement in immunoglobulin G–triggered inflammation was studied in mice genetically deficient in complement components C3 and C4. Using the reverse passive Arthus reaction and experimental models of immune hemolytic anemia and immune thrombocytopenia, we show that these mice have types II and III inflammatory responses that are indistinguishable from those of wild-type animals. Complement-deficient and wild-type animals exhibit comparable levels of erythrophagocytosis and platelet clearance in response to cytotoxic anti–red blood cell and antiplatelet antibodies. Furthermore, in the reverse passive Arthus reaction, soluble immune complexes induce equivalent levels of hemmorhage, edema, and neutrophillic infiltration in complement-deficient and wild-type animals. In contrast, mice that are genetically deficient in the expression of Fc receptors exhibit grossly diminished reactions by both cytotoxic antibodies and soluble immune complexes. These studies provide strong evidence that the activation of cell-based FcγR receptors, but not complement, are required for antibody-triggered murine inflammatory responses. PMID:8976192

  13. Genetics Home Reference: pyruvate kinase deficiency

    Science.gov (United States)

    ... National (UK) Information Centre for Metabolic Diseases National Organization for Rare Disorders (NORD): Pyruvate Kinase Deficiency Genetic Testing Registry (1 link) Pyruvate kinase deficiency of red cells Scientific articles on PubMed (1 link) PubMed OMIM (1 link) ...

  14. Growth hormone deficiency and hyperthermia during exercise

    DEFF Research Database (Denmark)

    Juul, A; Hjortskov, N; Jepsen, Leif;

    1995-01-01

    Sweat secretion is often disturbed in patients with GH secretory disorders. Hyperhidrosis is a classic feature of acromegaly, and it has recently been shown that GH-deficient patients exhibit decreased sweating capacity after pilocarpine stimulation of the skin. Thus, patients with GH-deficiency ...

  15. 30 CFR 57.5015 - Oxygen deficiency.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Oxygen deficiency. 57.5015 Section 57.5015..., Physical Agents, and Diesel Particulate Matter Air Quality-Underground Only § 57.5015 Oxygen deficiency. Air in all active workings shall contain at least 19.5 volume percent oxygen....

  16. Acquired Zinc Deficiency in an Adult Female

    OpenAIRE

    Mohanan Saritha; Divya Gupta; Laxmisha Chandrashekar; Devinder M Thappa; Nachiappa G Rajesh

    2012-01-01

    Acrodermatitis enteropathica is an autosomal recessive inherited disorder of zinc absorption. Acquired cases are reported occasionally in patients with eating disorders or Crohn′s disease. We report a 24-year-old housewife with acquired isolated severe zinc deficiency with no other comorbidities to highlight the rare occurrence of isolated nutritional zinc deficiency in an otherwise normal patient.

  17. Academic Deficiency: Student Experiences of Institutional Labeling

    Science.gov (United States)

    Barouch-Gilbert, Abraham

    2015-01-01

    Limited existing research examines how undergraduate students in the United States experience the process of being identified as deficient due to their academic performance. The purpose of this phenomenological study was to explore the lived experiences of college students on academic probation who were labeled academically deficient. Students…

  18. Short Stature and Growth Hormone Deficiency

    OpenAIRE

    Matemi, Sezer

    1994-01-01

    This paper summarizes the importance of measurements of height and weight in normal children and emphasizes the role of growth increments for the diagnosis of short stature Causes of short stature methods for diagnosis of GH hormone deficiency actions of growth hormone treatment of growth hormone deficiency and doses for biosynthetic GH treatment are described Key words: Short Stature Growth Hormone

  19. Growth Hormone Deficiency, Brain Development, and Intelligence

    Science.gov (United States)

    Meyer-Bahlburg, Heino F. L.; And Others

    1978-01-01

    Available from: American Medical Association, 535 N. Dearborn Street, Chicago, Illinois 60610. In order to determine what effect, if any, growth hormone (GH) has on human brain development, 29 patients (mean age 11.7 years) with GH deficiency were selected according to the following criteria: no evidence of reversible GH deficiency, onset of…

  20. Genetics Home Reference: complement factor I deficiency

    Science.gov (United States)

    ... the complement system decreases blood levels of another complement protein called C3, reducing the immune system's ability to fight infections. ... in my area? Other Names for This Condition C3 inactivator deficiency complement component 3 inactivator deficiency Related Information How are ...

  1. Breath hydrogen test and sucrase isomaltase deficiency.

    OpenAIRE

    Ford, R P; Barnes, G L

    1983-01-01

    Sucrose breath hydrogen tests were performed on 7 children with proved sucrase isomaltase deficiency. All children had raised breath hydrogen excretion. The amount of hydrogen produced and symptoms experienced increased with increasing sucrose loads. The sucrose breath hydrogen test appears to be a reliable indicator of sucrose malabsorption in sucrase isomaltase deficiency.

  2. How Best To Utilize a Deficiency.

    Science.gov (United States)

    Miller, Patricia H.

    2000-01-01

    Focuses on the importance and meaning of the degree of spontaneity in memory strategy production. Situates the concept of utilization deficiency within current work on memory strategy heterogeneity, contextual support, and situation-specific skills. Concludes that work on utilization deficiencies helps balance the focus on early emergence of…

  3. Reprint of "Vitamin D deficiency in pregnant women impairs regulatory T cell function".

    Science.gov (United States)

    Vijayendra Chary, A; Hemalatha, R; Seshacharyulu, M; Vasudeva Murali, M; Jayaprakash, D; Dinesh Kumar, B

    2015-04-01

    Regulatory T cells and IgE receptors (CD23 and CD21) on B cells were assessed in vitamin D deficient pregnant women. For this, 153 pregnant women were recruited from a government hospital and were categorized into three groups based on 25-hydroxyvitamin D3 (25(OH)D3) status. Regulatory T cell population (Treg cells) and CD23/CD21 expression on B cells were quantified by FACS ARIA II in maternal blood at third trimester; and the same parameters were evaluated in cord blood soon after delivery. In addition, TGF β and IL-10 were quantified in maternal and cord blood by using Milliplex kits. In a representative sample of eight women from each group (vitamin D sufficient, insufficient and deficient), placental tissues were processed for mRNA expressions of vitamin D receptor (VDR), retinoic acid receptor (RXR), vitamin D binding protein (VDBP) and vitamin D regulating enzymes. Of the 153 pregnant women, 18 were sufficient (≥30ng/mL), 55 were insufficient (20-29ng/mL) and 80 were deficient (≤19ng/mL) for 25(OH)D3 status. The maternal blood Treg cell population (mean (%)±SE) was lower (pTreg cell population (mean (%)±SE) was also lower (pasthma in neonates. PMID:25644204

  4. Vitamin D deficiency in pregnant women impairs regulatory T cell function.

    Science.gov (United States)

    Vijayendra Chary, A; Hemalatha, R; Seshacharyulu, M; Vasudeva Murali, M; Jayaprakash, D; Dinesh Kumar, B

    2015-03-01

    Regulatory T cells and IgE receptors (CD23 and CD21) on B cells were assessed in vitamin D deficient pregnant women. For this, 153 pregnant women were recruited from a government hospital and were categorized into three groups based on 25-hydroxyvitamin D3 (25(OH)D3) status. Regulatory T cell population (Treg cells) and CD23/CD21 expression on B cells were quantified by FACS ARIA II in maternal blood at third trimester; and the same parameters were evaluated in cord blood soon after delivery. In addition, TGF β and IL-10 were quantified in maternal and cord blood by using Milliplex kits. In a representative sample of eight women from each group (vitamin D sufficient, insufficient and deficient), placental tissues were processed for mRNA expressions of vitamin D receptor (VDR), retinoic acid receptor (RXR), vitamin D binding protein (VDBP) and vitamin D regulating enzymes. Of the 153 pregnant women, 18 were sufficient (≥30 ng/mL), 55 were insufficient (20-29 ng/mL) and 80 were deficient (≤19 ng/mL) for 25(OH)D3 status. The maternal blood Treg cell population (mean (%)± SE) was lower (pTreg cell population (mean (%)± SE) was also lower (pasthma in neonates. PMID:25448751

  5. Prevalence of Color Vision Deficiency in Qazvin

    Directory of Open Access Journals (Sweden)

    Mohammad khalaj

    2014-01-01

    Full Text Available Background: Color vision deficiency (CVD is an X chromosome-linked recessive autosomal dominant. Determine the prevalence of color blindness in Qazvin population. Materials and Methods: In a cross sectional study color vision deficiency examined in 1853 individuals with age 10-25 years old who participated in private clinics and eye clinic of Bu-Ali hospital in Qazvin in 2010. The screening of color vision deficiency was performed using Ishihara test. Data were analyzed by SPSS-16 with χP2P test with p<0.05. Results: Mean age of participant was 17.86±4.48 years. 59.5% of them were female. 3.49% of the total population had color vision deficiency that 0.93% and 2.56% were female and male respectively. Conclusion: color vision deficiency must be noticed by decision makers in health field for screen planning.

  6. [Vitamin B12 deficiency in the elderly].

    Science.gov (United States)

    Leischker, A H; Kolb, G F

    2015-01-01

    The prevalence of vitamin B12 deficiency increases with age. Patients with dementia and spouses of patients with dementia are at special risk for the development of vitamin B12 deficiency. In a normal diet this vitamin is present only in animal source foods; therefore, vegans frequently develop vitamin B12 deficiency if not using supplements or foods fortified with cobalamin. Apart from dementia, most of these manifestations are completely reversible under correct therapy; therefore it is crucial to identify and to treat even atypical presentations of vitamin B12 deficiency as early as possible. This article deals with the physiology and pathophysiology of vitamin B12 metabolism. A practice-oriented algorithm which also considers health economic aspects for a rational laboratory diagnosis of vitamin B12 deficiency is presented. In cases with severe neurological symptoms, therapy should be parenteral, especially initially. For parenteral treatment, hydroxocobalamin is the drug of choice. PMID:25586321

  7. [Vitamin B12 deficiency in the elderly].

    Science.gov (United States)

    Leischker, A H; Kolb, G F

    2015-01-01

    The prevalence of vitamin B12 deficiency increases with age. Patients with dementia and spouses of patients with dementia are at special risk for the development of vitamin B12 deficiency. In a normal diet this vitamin is present only in animal source foods; therefore, vegans frequently develop vitamin B12 deficiency if not using supplements or foods fortified with cobalamin. Apart from dementia, most of these manifestations are completely reversible under correct therapy; therefore it is crucial to identify and to treat even atypical presentations of vitamin B12 deficiency as early as possible. This article deals with the physiology and pathophysiology of vitamin B12 metabolism. A practice-oriented algorithm which also considers health economic aspects for a rational laboratory diagnosis of vitamin B12 deficiency is presented. In cases with severe neurological symptoms, therapy should be parenteral, especially initially. For parenteral treatment, hydroxocobalamin is the drug of choice.

  8. Immune deficiencies due to defects in cytokine signaling.

    Science.gov (United States)

    Kelly, John; Leonard, Warren J

    2003-09-01

    Severe combined immunodeficiency (SCID) represents a syndrome comprising the most severe forms of inherited immunodeficiencies. Defects in cytokine signaling pathways can result in impaired development of lymphoid cells and/or defective functioning of these cells, and most cases of SCID result from defective signaling through the common cytokine receptor g chain (g(c)) or associated molecules and signaling pathways. Studies of these patients and the analysis of gene-targeted mice provide insight into the underlying signaling defects in inherited immunodeficiencies. The identification of the genetic defects in humans with SCID provides the basis for future therapies for these patients. More subtle deficiencies in cytokine signaling have also been found as causes of other forms of immunodeficiency, and the knowledge learned could lead to novel approaches to antimicrobial therapy. PMID:12906775

  9. Opposing effects of CXCR3 and CCR5 deficiency on CD8+ T cell-mediated inflammation in the central nervous system of virus-infected mice

    DEFF Research Database (Denmark)

    de Lemos, Carina; Christensen, Jeanette Erbo; Nansen, Anneline;

    2005-01-01

    T cells play a key role in the control of viral infection in the CNS but may also contribute to immune-mediated cell damage. To study the redundancy of the chemokine receptors CXCR3 and CCR5 in regulating virus-induced CD8+ T cell-mediated inflammation in the brain, CXCR3/CCR5 double-deficient mice...... and therefore protect mice against the otherwise fatal CD8+ T cell-mediated immune attack. Contrary to expectations, the accumulation of mononuclear cells in cerebrospinal fluid was only slightly delayed compared with mice with normal expression of both receptors. Even more surprising, CXCR3/CCR5 double......-deficient mice were more susceptible to intracerebral infection than CXCR3-deficient mice. Analysis of effector T cell generation revealed an accelerated antiviral CD8+ T cell response in CXCR3/CCR5 double-deficient mice. Furthermore, while the accumulation of CD8+ T cells in the neural parenchyma...

  10. Complement component C7 deficiency in a Spanish family.

    Science.gov (United States)

    Vázquez-Bermúdez, M F; Barroso, S; Walter, K; Alvarez, A J; Alarcón, A; López-Trascasa, M; Wichmann, I; Aguilar, F; Núñez-Roldán, A; Sánchez, B

    2003-08-01

    Different genetic mutations have been described in complement component C7 deficiency, a molecular defect which is clinically associated with an increased susceptibility to neisserial recurrent infections, although some cases remain asymptomatic. In this work we report the genetic bases of C7 deficiency in one Spanish family. Exon-specific PCR and sequencing revealed a novel point mutation at nucleotide 615 (exon 6) leading to a stop codon (UGG to UGA) in the patient, his mother, and sister. This transversion causes the premature truncation of the C7 protein (W183X). Additionally, we detected a missense mutation at position 1135 (exon 9) located in the first nucleotide of the codon GGG (CGG), resulting in an amino acid change (G357R) in the patient, his father, as well as in his sister. This latter mutation had been previously described in individuals from Moroccan Sephardic Jewish ancestry. Since both heterozygous mutations were found in the patient as well as in his asymptomatic sister, we analyse other meningococcal defence mechanisms such as polymorphisms of the opsonin receptors on polymorphonuclear cells. Results showed that the patient and his sister bore identical combinations of FcgammaRIIA-H/R131 and FcgammaRIIIB-NA1/2 allotypes. Our results provide further evidence that the molecular pathogenesis of C7 deficiency as well as susceptibility to meningococcal disease are heterogeneous, since different families carry different molecular defects, although many of the C7 defects appear to be homogeneous in individuals from certain geographical areas. The missense mutation G357R would make an interesting topic of analysis with regard to meningococcal disease susceptibility in the Spanish population. PMID:12869030

  11. Vitamin D deficiency and childhood obesity: interactions, implications, and recommendations

    Directory of Open Access Journals (Sweden)

    Peterson CA

    2015-02-01

    Full Text Available Catherine A Peterson Department of Nutrition and Exercise Physiology, University of Missouri-Columbia, Columbia, MO, USA Abstract: Vitamin D deficiency and childhood obesity have been classified as epidemics throughout the world, and both share some common risk factors including poor diet and inactivity. Observational and clinical studies show that vitamin D status and fat mass are inversely correlated. It is not clear whether vitamin D deficiency contributes to, or is a consequence of obesity, or whether there are regulatory interactions between excess adiposity and vitamin D activity. The effects of this deficiency in childhood obesity appear to have negative influences on overall health, including insulin resistance, inflammation, and impeded bone mineralization, as well as increased future risk of type 2 diabetes, cardiovascular disease, and osteoporosis. The rather ubiquitous distribution of the vitamin D receptor and the 25-hydroxyvitamin D 1a-hydroxylase throughout the body, including evidence for a role of vitamin D in adipogenesis and adipocyte metabolism, may in part explain these widespread effects. Most of the findings to date suggest that the vitamin D needs of obese children are greater than the nonobese. Although ultraviolet B-induced skin synthesis is a main source of vitamin D, its use is neither feasible nor prudent due to limited sun availability for many and concerns for skin cancer. Likewise, obtaining adequate vitamin D from natural food sources alone is generally not achievable, and even in countries that allow fortification, vitamin D intakes are low. Therefore, in obese children, vitamin D supplementation is warranted. Weight loss interventions using energy restriction and physical activity may also improve the poor vitamin D status associated with obesity. More research is needed to define optimal vitamin D status in this vulnerable population, including investigations to determine the efficacy of vitamin D

  12. Epileptogenesis after traumatic brain injury in Plaur-deficient mice.

    Science.gov (United States)

    Bolkvadze, Tamuna; Puhakka, Noora; Pitkänen, Asla

    2016-07-01

    Binding of the extracellular matrix proteinase urokinase-type plasminogen activator (uPA) to its receptor, uPAR, regulates tissue remodeling during development and after injury in different organs, including the brain. Accordingly, mutations in the Plaur gene, which encodes uPAR, have been linked to language deficits, autism, and epilepsy, both in mouse and human. Whether uPAR deficiency modulates epileptogenesis and comorbidogenesis after brain injury, however, is unknown. To address this question, we induced traumatic brain injury (TBI) by controlled cortical impact (CCI) in 10 wild-type (Wt-CCI) and 16 Plaur-deficient (uPAR-CCI) mice. Sham-operated mice served as controls (10 Wt-sham, 10 uPAR-sham). During the 4-month follow-up, the mice were neurophenotyped by assessing the somatomotor performance with the composite neuroscore test, emotional learning and memory with fear conditioning to tone and context, and epileptogenesis with videoelectroencephalography monitoring and the pentylenetetrazol (PTZ) seizure susceptibility test. At the end of the testing, the mice were perfused for histology to analyze cortical and hippocampal neurodegeneration and mossy fiber sprouting. Fourteen percent (1/7) of the mice in the Wt-CCI and 0% in the uPAR-CCI groups developed spontaneous seizures (p>0.05; chi-square). Both the Wt-CCI and uPAR-CCI groups showed increased seizure susceptibility in the PTZ test (plearning showed a genotype effect, being more impaired in uPAR-CCI than in Wt-CCI mice (p<0.05). The findings of the present study indicate that uPAR deficiency does not increase susceptibility to epileptogenesis after CCI injury but has an unfavorable comorbidity-modifying effect after TBI. PMID:27208924

  13. Vitamin D deficiency in adolescents

    Directory of Open Access Journals (Sweden)

    Ashraf T Soliman

    2014-01-01

    Full Text Available The prevalence of severe vitamin D deficiency (VDD in adolescents is variable but considerably high in many countries, especially in Middle-east and Southeast Asia. Different factors attribute to this deficiency including lack of sunlight exposure due to cultural dress codes and veiling or due to pigmented skin, and less time spent outdoors, because of hot weather, and lower vitamin D intake. A potent adaptation process significantly modifies the clinical presentation and therefore clinical presentations may be subtle and go unnoticed, thus making true prevalence studies difficult. Adolescents with severe VDD may present with vague manifestations including pain in weight-bearing joints, back, thighs and/or calves, difficulty in walking and/or climbing stairs, or running and muscle cramps. Adaptation includes increased parathormone (PTH and deceased insulin-like growth factor-I (IGF-I secretion. PTH enhances the tubular reabsorption of Ca and stimulates the kidneys to produce 1, 25-(OH 2D3 that increases intestinal calcium absorption and dissolves the mineralized collagen matrix in bone, causing osteopenia and osteoporosis to provide enough Ca to prevent hypocalcaemia. Decreased insulin like growth factor-I (IGF-I delays bone growth to economize calcium consumption. Radiological changes are not uncommon and include osteoporosis/osteopenia affecting long bones as well as vertebrae and ribs, bone cysts, decalcification of the metaphysis of the long bones and pseudo fractures. In severe cases pathological fractures and deformities may occur. Vitamin D treatment of adolescents with VDD differs considerably in different studies and proved to be effective in treating all clinical, biochemical, and radiological manifestations. Different treatment regiments for VDD have been discussed and presented in this mini-review for practical use. Adequate vitamin D replacement after treating VDD, improving calcium intake (milk and dairy products, encouraging

  14. Folate deficiency affects histone methylation.

    Science.gov (United States)

    Garcia, Benjamin A; Luka, Zigmund; Loukachevitch, Lioudmila V; Bhanu, Natarajan V; Wagner, Conrad

    2016-03-01

    that the bound THF serves to protect the FAD class of histone demethylases from the destructive effects of formaldehyde generation by formation of 5,10-methylene-THF. We present pilot data showing that decreased folate in livers as a result of dietary folate deficiency is associated with increased levels of methylated lysine 4 of histone 3. This can be a result of decreased LSD1 activity resulting from the decreased folate available to scavenge the formaldehyde produced at the active site caused by the folate deficiency. Because LSD1 can regulate gene expression this suggests that folate may play a more important role than simply serving as a carrier of one-carbon units and be a factor in other diseases associated with low folate. PMID:26880641

  15. Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice.

    Science.gov (United States)

    Zhang, Jingyao; Song, Sidong; Pang, Qing; Zhang, Ruiyao; Zhou, Lei; Liu, Sushun; Meng, Fandi; Wu, Qifei; Liu, Chang

    2015-01-29

    Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH₂-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.

  16. SLAP deficiency decreases dsDNA autoantibody production.

    Science.gov (United States)

    Peterson, Lisa K; Pennington, Luke F; Shaw, Laura A; Brown, Meredith; Treacy, Eric C; Friend, Samantha F; Hatlevik, Øyvind; Rubtsova, Kira; Rubtsov, Anatoly V; Dragone, Leonard L

    2014-02-01

    Src-like adaptor protein (SLAP) adapts c-Cbl, an E3 ubiquitin ligase, to activated components of the BCR signaling complex regulating BCR levels and signaling in developing B cells. Based on this function, we asked whether SLAP deficiency could decrease the threshold for tolerance and eliminate development of autoreactive B cells in two models of autoantibody production. First, we sensitized mice with a dsDNA mimetope that causes an anti-dsDNA response. Despite equivalent production of anti-peptide antibodies compared to BALB/c controls, SLAP(-/-) mice did not produce anti-dsDNA. Second, we used the 56R tolerance model. SLAP(-/-) 56R mice had decreased levels of dsDNA-reactive antibodies compared to 56R mice due to skewed light chain usage. Thus, SLAP is a critical regulator of B-cell development and function and its deficiency leads to decreased autoreactive B cells that are otherwise maintained by inefficient receptor editing or failed negative selection.

  17. Iron deficiency in the elderly Deficiência de ferro no idoso

    Directory of Open Access Journals (Sweden)

    Sandra F. M. Gualandro

    2010-06-01

    Full Text Available Anemia is a common problem in the elderly and is associated with significant morbidity and mortality. More than 10% of all individuals above the age of 65 have anemia. Because an increasing proportion of the world's population is aged 65 and older, it is inevitable that the prevalence of anemia will increase in the future. Thus, early diagnosis of anemia is important to prevent the condition from worsening, to slow disease progression, and improve outcomes in patients. The WHO definition of anemia (hemoglobin concentration Anemia é comum em idosos e é associada a significante morbidade e mortalidade. Mais de 10% dos indivíduos acima de 65 anos tem anemia. Com uma proporção crescente da população mundial atingindo idade igual ou superior a 65 anos, a prevalência de anemia certamente aumentará no futuro. O diagnóstico precoce é importante para prevenir piora do quadro, diminuir progressão da doença e melhorar a evolução dos pacientes. Os critérios mais utilizados em estudos epidemiológicos para definir anemia em idosos são os da OMS (hemoglobina<12 g/dL para mulheres e hemoglobina <13 g/dL para homens. Aproximadamente um terço dos idosos com anemia tem deficiência de ferro, folato e/ou vitamina B12, um terço tem insuficiência renal e/ou inflamação crônica e o terço remanescente tem anemia inexplicada. A anemia ferropênica é microcítica e hipocrômica e caracteriza-se por baixos níveis de ferritina sérica, capacidade total de ligação de ferro do plasma aumentada, saturação da transferrina diminuída, concentração do receptor solúvel da transferrina elevada e ausência de ferro na medula óssea. É causada geralmente por perda de sangue pelo trato gastrointestinal devido a gastrite, úlceras, câncer de colo ou angiodisplasia. Anormalidades do trato gastrointestinal podem ser identificadas na maioria dos pacientes. Em alguns casos, ingestão ou absorção inadequada de ferro pode contribuir para a anemia

  18. Deficiency of RAMP1 attenuates antigen-induced airway hyperresponsiveness in mice.

    Directory of Open Access Journals (Sweden)

    Manyu Li

    Full Text Available Asthma is a chronic inflammatory disease affecting the lung, characterized by breathing difficulty during an attack following exposure to an environmental trigger. Calcitonin gene-related peptide (CGRP is a neuropeptide that may have a pathological role in asthma. The CGRP receptor is comprised of two components, which include the G-protein coupled receptor, calcitonin receptor-like receptor (CLR, and receptor activity-modifying protein 1 (RAMP1. RAMPs, including RAMP1, mediate ligand specificity in addition to aiding in the localization of receptors to the cell surface. Since there has been some controversy regarding the effect of CGRP on asthma, we sought to determine the effect of CGRP signaling ablation in an animal model of asthma. Using gene-targeting techniques, we generated mice deficient for RAMP1 by excising exon 3. After determining that these mice are viable and overtly normal, we sensitized the animals to ovalbumin prior to assessing airway resistance and inflammation after methacholine challenge. We found that mice lacking RAMP1 had reduced airway resistance and inflammation compared to wildtype animals. Additionally, we found that a 50% reduction of CLR, the G-protein receptor component of the CGRP receptor, also ameliorated airway resistance and inflammation in this model of allergic asthma. Interestingly, the loss of CLR from the smooth muscle cells did not alter the airway resistance, indicating that CGRP does not act directly on the smooth muscle cells to drive airway hyperresponsiveness. Together, these data indicate that signaling through RAMP1 and CLR plays a role in mediating asthma pathology. Since RAMP1 and CLR interact to form a receptor for CGRP, our data indicate that aberrant CGRP signaling, perhaps on lung endothelial and inflammatory cells, contributes to asthma pathophysiology. Finally, since RAMP-receptor interfaces are pharmacologically tractable, it may be possible to develop compounds targeting the RAMP1/CLR

  19. Infections Revealing Complement Deficiency in Adults

    Science.gov (United States)

    Audemard-Verger, A.; Descloux, E.; Ponard, D.; Deroux, A.; Fantin, B.; Fieschi, C.; John, M.; Bouldouyre, A.; Karkowsi, L.; Moulis, G.; Auvinet, H.; Valla, F.; Lechiche, C.; Davido, B.; Martinot, M.; Biron, C.; Lucht, F.; Asseray, N.; Froissart, A.; Buzelé, R.; Perlat, A.; Boutboul, D.; Fremeaux-Bacchi, V.; Isnard, S.; Bienvenu, B.

    2016-01-01

    Abstract Complement system is a part of innate immunity, its main function is to protect human from bacterial infection. As genetic disorders, complement deficiencies are often diagnosed in pediatric population. However, complement deficiencies can also be revealed in adults but have been poorly investigated. Herein, we describe a case series of infections revealing complement deficiency in adults to study clinical spectrum and management of complement deficiencies. A nationwide retrospective study was conducted in French university and general hospitals in departments of internal medicine, infectious diseases enrolling patients older than 15 years old who had presented at least one infection leading to a complement deficiency diagnosis. Forty-one patients included between 2002 and 2015 in 19 different departments were enrolled in this study. The male-to-female ratio was 1.3 and the mean age at diagnosis was 28 ± 14 (15–67) years. The main clinical feature was Neisseria meningitidis meningitis 75% (n = 31/41) often involving rare serotype: Y (n = 9) and W 135 (n = 7). The main complement deficiency observed was the common final pathway deficiency 83% (n = 34/41). Half of the cohort displayed severe sepsis or septic shock at diagnosis (n = 22/41) but no patient died. No patient had family history of complement deficiency. The mean follow-up was 1.15 ± 1.95 (0.1–10) years. Half of the patients had already suffered from at least one infection before diagnosis of complement deficiency: meningitis (n = 13), pneumonia (n = 4), fulminans purpura (n = 1), or recurrent otitis (n = 1). Near one-third (n = 10/39) had received prophylactic antibiotics (cotrimoxazole or penicillin) after diagnosis of complement deficiency. The vaccination coverage rate, at the end of the follow-up, for N meningitidis, Streptococcus pneumonia, and Haemophilius influenzae were, respectively, 90% (n = 33/37), 47% (n = 17/36), and 35

  20. Identification of Regulatory Mutations in SERPINC1 Affecting Vitamin D Response Elements Associated with Antithrombin Deficiency

    Science.gov (United States)

    Toderici, Mara; de la Morena-Barrio, María Eugenia; Padilla, José; Miñano, Antonia; Antón, Ana Isabel; Iniesta, Juan Antonio; Herranz, María Teresa; Fernández, Nuria; Vicente, Vicente; Corral, Javier

    2016-01-01

    Antithrombin is a crucial anticoagulant serpin whose even moderate deficiency significantly increases the risk of thrombosis. Most cases with antithrombin deficiency carried genetic defects affecting exons or flanking regions of SERPINC1.We aimed to identify regulatory mutations inSERPINC1 through sequencing the promoter, intron 1 and 2 of this gene in 23 patients with antithrombin deficiency but without known genetic defects. Three cases with moderate antithrombin deficiency (63–78%) carried potential regulatory mutations. One located 200 bp before the initiation ATG and two in intron 1. These mutations disrupted two out of five potential vitamin D receptor elements (VDRE) identified in SERPINC1 with different software. One genetic defect, c.42-1060_-1057dupTTGA, was a new low prevalent polymorphism (MAF: 0.01) with functional consequences on plasma antithrombin levels. The relevance of the vitamin D pathway on the regulation of SERPINC1 was confirmed in a cell model. Incubation of HepG2 with paricalcitol, a vitamin D analog, increased dose-dependently the levels of SERPINC1transcripts and antithrombin released to the conditioned medium. This study shows further evidence of the transcriptional regulation of SERPINC1 by vitamin D and first describes the functional and pathological relevance of mutations affecting VDRE of this gene. Our study opens new perspectives in the search of new genetic defects involved in antithrombin deficiency and the risk of thrombosis as well as in the design of new antithrombotic treatments. PMID:27003919

  1. 维生素D受体基因多态性与维生素D缺乏性佝偻病遗传关联性Meta分析%Assoiation between polymorphisms of vitamin D receptor gene and vitamin D deficiency rickets: a meta-analysis

    Institute of Scientific and Technical Information of China (English)

    李卫国; 刘丽君; 李湘津; 周晓菊; 杨慧; 李宇宁

    2011-01-01

    Objective To evaluate the association between vitamin D receptor( VDR ) gene polymorphsims and nutritional vitamin D deficiency rickets.Methods PubMed, Springer, Science Direct, Web of Science, China National Knowledge Infrastructure, VIP Chinese Periodical Database and Wanfang Chinese Periodical Database were searched for the case-control study on the association of VDR gene polymorphisms with rickets ( up to February 2011 ).Meta-analysis of all the eligible studies was performed, which focused on four most commonlv investigated VDR polymorphisms: Fok Ⅰ , Apa Ⅰ ,B.sm Ⅰ and Taq Ⅰ.The hest genetic model in pooled analyses was selected.Stata 11.0 software was applied for investigating the heterogeneity among individual studies and the pooled odds ratio( OR ) and 95% confidence interval( CI) were calculated.Sensitivity analyses were performed by excluding studies with controls inconsistent with Hardy-Weinberg equilibrium.Results A total of 19 eligible studies were included.①Codominant genetic model was used to analyze the Fok Ⅰ single nucleotide polymorphisms ( SNPs ).There was no heterogeneity among included studies.Subgroup analyses showed that Fok Ⅰ SNP was significantly associated with rickets ( FF vs ff : OR = 4.59.95% CI:2.98 - 7.07 ; FF vs Ff : OR = 2.58.95% CI: 1.79 - 3.73 ) in Asian population.However.the association was not significant in Caucasian population( FF vs ff: OR = 2.50, 95% CI: 0.76 - 8.19; FF vs Ff: OR = 1.18 , 95% CI: 0.66 2.10 ).②Dominant genetic model of A allele( AA + Aa v.s aa )was used to analyze Apa Ⅰ SNP.There was no significant heterogeneity among included studies.No significant association between Apa Ⅰ SNP and rickets was found in Asian population ( OR =1.04.95% CI: 0.72 - 1.49 ) and Africans ( OR = 0.98.95% CI: 0.57 - 1.71 ).But in Caucasian population,a study suggested that aa genotype was a protective factor for rickets ( AA +Aa vs aa.OR = 5.50, 95% CI: 1.22 - 24.75 ).③Dominant genetic model of

  2. GRK2 deficiency is a pain

    NARCIS (Netherlands)

    Kleibeuker, W.

    2007-01-01

    G protein-coupled receptor (GPCR) kinase (GRK)2 regulates the responsiveness of many GPCRS, e.g. CCR1, CCR2, CCR5, neurokinin-1 receptor, and metabotropic glutamate receptors, which are involved in the development of allodynia (pain due to a stimulus which does normally not provoke pain) and hyperal

  3. Genetics Home Reference: iron-refractory iron deficiency anemia

    Science.gov (United States)

    ... refractory iron deficiency anemia iron-refractory iron deficiency anemia Enable Javascript to view the expand/collapse boxes. ... All Close All Description Iron-refractory iron deficiency anemia is one of many types of anemia , which ...

  4. Genetics Home Reference: mannose-binding lectin deficiency

    Science.gov (United States)

    ... Health Conditions mannose-binding lectin deficiency mannose-binding lectin deficiency Enable Javascript to view the expand/collapse ... PDF Open All Close All Description Mannose-binding lectin deficiency is a condition that affects the immune ...

  5. Genetics Home Reference: ataxia with vitamin E deficiency

    Science.gov (United States)

    ... Home Health Conditions ataxia with vitamin E deficiency ataxia with vitamin E deficiency Enable Javascript to view ... boxes. Download PDF Open All Close All Description Ataxia with vitamin E deficiency is a disorder that ...

  6. Flu Vaccine Guidance for Patients with Immune Deficiency

    Science.gov (United States)

    ... Vaccine Guidance for Patients with Immune Deficiency Share | Flu Vaccine Guidance for Patients with Immune Deficiency This ... is the best tool for prevention of the flu, should patients with immune deficiency be given the ...

  7. Testosterone deficiency and cardiovascular mortality

    Institute of Scientific and Technical Information of China (English)

    Abraham Morgentaler

    2015-01-01

    New concerns have been raised regarding cardiovascular (CV) risks with testosterone (T) therapy (TTh). These concerns are based primarily on two widely reported retrospective studies. However, methodological flaws and data errors invalidate both studies as credible evidence of risk. One showed reduced adverse events by half in T‑treated men but reversed this result using an unproven statistical approach. The authors subsequently acknowledged serious data errors including nearly 10% contamination of the dataset by women. The second study mistakenly used the rate of T prescriptions written by healthcare providers to men with recent myocardial infarction (MI) as a proxy for the naturally occurring rate of MI. Numerous studies suggest T is beneficial, including decreased mortality in association with TTh, reduced MI rate with TTh in men with the greatest MI risk prognosis, and reduced CV and overall mortality with higher serum levels of endogenous T. Randomized controlled trials have demonstrated benefits of TTh in men with coronary artery disease and congestive heart failure. Improvement in CV risk factors such as fat mass and glycemic control have been repeatedly demonstrated in T‑deficient men treated with T. The current evidence does not support the belief that TTh is associated with increased CV risk or CV mortality. On the contrary, a wealth of evidence accumulated over several decades suggests that low serum T levels are associated with increased risk and that higher endogenous T, as well as TTh itself, appear to be beneficial for CV mortality and risk.

  8. Primary Immuno-deficiencies (PID

    Directory of Open Access Journals (Sweden)

    Javad Ghaffari1

    2009-01-01

    Full Text Available (Received 6 June, 2009 ; Accepted 22 July, 2009AbstractBackground and purpose: Primary immune-deficiencies (PID are associated with a wide range of clinical disorders along with variable symptoms. The aim of this study was to evaluate and improve our knowledge regarding PID from patients that were referred to Booali Sina Hospital.Materials and methods: We evaluated all of PID`s that were referred to Booali Sina Hospital from their data records. Demography, clinical and laboratory data were recorded and then analyzed.Results: In the duration of 3 years, we had 10 patients with PID (7 males and 3 females. Of these cases, 5 had hum oral (50%, 1case had phagocytic (10%, 3 cases had cellular (30% and 1 case had hyper IgE syndrome (10%. Many of them had respiratory and otitis media infections, while a few patients had adenitis, gastroenteritis, liver abscesses, bleedings and malignancy.Conclusion: PID is a diverse disorder that involves different immune systems. Knowledge from patient’s clinical symptoms and consideration in their differential diagnosis can be helpful in early diagnosis and an effective treatment.J Mazand Univ Med Sci 2009; 19(70: 76-80 (Persian

  9. Antibiotic prophylaxis in primary immune deficiency disorders.

    Science.gov (United States)

    Kuruvilla, Merin; de la Morena, Maria Teresa

    2013-01-01

    Long-term prophylactic antibiotics are being widely implemented as primary or adjunctive therapy in primary immune deficiencies. This practice has transformed clinical outcomes in the setting of chronic granulomatous disease, complement deficiencies, Mendelian susceptibility to mycobacterial disease, Wiskott-Aldrich syndrome, hyper-IgE syndrome, Toll signaling defects, and prevented Pneumocystis in patients with T-cell deficiencies. Yet, controlled trials are few in the context of primary antibody deficiency syndromes, and most of this practice has been extrapolated from data in patients who are immune competent and with recurrent acute otitis media, chronic rhinosinusitis, cystic fibrosis, and bronchiectasis. The paucity of guidelines on the subject is reflected in recent surveys among practicing immunologists that highlight differences of habit regarding this treatment. Such discrepancies reinforce the lack of standard protocols on the subject. This review will provide evidence for the use of antibiotic prophylaxis in various primary immune deficiency populations, especially highlighting the role antibiotic prophylaxis in primary antibody deficiency syndromes. We also discussed the relationship of long-term antibiotic use and the prevalence of resistant pathogens. Overall, examination of available data on the use of prophylactic antibiotics in antibody deficiency syndromes merit future investigation in well-designed multicenter prospective trials because this population has few other management options.

  10. Reticulocyte maturity indices in iron deficiency anemia

    Directory of Open Access Journals (Sweden)

    Muriel Wollmann

    2014-01-01

    Full Text Available Objective: The aim of this study was to analyze the reticulocyte maturity indices (low, medium, and high fluorescence ratios in iron deficient 1- to 6-year-old children, and identify the prevalence of iron deficiency anemia in this population. Methods: The present study included 39 subjects, divided into two groups: control subjects (n = 33, and subjects with iron deficiency anemia (n = 6. The results were analyzed by Student's t-test for comparison of means. Differences were considered significant when two-tailed p-value < 0.05. Results: Subjects with iron deficiency anemia presented increases in the proportion of mean (10.3 ± 4.7% vs. 6.0 ± 3.4%; p-value = 0.003, and high fluorescence reticulocytes (2.3 ± 0.87% vs. 0.9 ± 0.9%; p-value = 0.03 compared to the control group. The prevalence of anemia in this population was 15% (n = 6. Conclusion: The indices related to immaturity of reticulocytes are higher in the presence of iron deficiency, thus demonstrating a deficiency in the raw material to form hemoglobin and are, therefore, possible early markers of iron deficiency and anemia. We emphasize the need to standardize these indices for use in clinical practice and lab test results.

  11. Treatment of zinc deficiency without zinc fortification

    Institute of Scientific and Technical Information of China (English)

    Donald OBERLEAS; Barbara F. HARLAND

    2008-01-01

    Zinc (Zn) deficiency in animals became of interest until the 1950s. In this paper, progresses in researches on physi-ology of Zn deficiency in animals, phytate effect on bioavailability of Zn, and role of phytase in healing Zn deficiency of animals were reviewed. Several studies demonstrated that Zn is recycled via the pancreas; the problem of Zn deficiency was controlled by Zn homeostasis. The endogenous secretion of Zn is considered as an important factor influencing Zn deficiency, and the critical molar ratio is 10. Phytate (inositol hexaphosphate) constituted up to 90% of the organically bound phosphorus in seeds. Great improvement has been made in recent years on isolating and measuring phytate, and its structure is clear. Phytate is considered to reduce Zn bioavailability in animal. Phytase is the enzyme that hydrolyzes phytate and is present in yeast, rye bran, wheat bran, barley, triticale, and many bacteria and fungi. Zinc nutrition and bioavailability can be enhanced by addition of phytase to animal feeds. Therefore, using phytase as supplements, the most prevalent Zn deficiency in animals may be effectively corrected without the mining and smelting of several tons of zinc daily needed to correct this deficiency by fortification worldwide.

  12. Perinatal iron deficiency and neurocognitive development

    Directory of Open Access Journals (Sweden)

    Emily Clare Radlowski

    2013-09-01

    Full Text Available Iron deficiency is the most common form of nutrient deficiency worldwide. It is highly prevalent due to the limited availability of high quality food in developing countries, and poor dietary habits in industrialized countries. According to the World Health Organization, it affects nearly 2 billion people and up to 50% of women who are pregnant. Maternal anemia during pregnancy is especially burdensome to healthy neurodevelopment in the fetus because iron is needed for proper neurogenesis, development, and myelination. Maternal anemia also increases the risk of low birth weight, either due to premature birth or fetal growth restriction, which is associated with delayed neurocognitive development and even psychiatric illness. As rapid neurodevelopment continues after birth infants that received sufficient iron in utero, but that receive a low iron diet after 6 months of age, also show deficits in neurocognitive development, including impairments in learning and memory. Unfortunately, the neurocognitive complications of iron deficiency during critical pre- and postnatal periods of brain development are difficult to remedy, persisting into adulthood. Thus, preventing iron deficiency in the pre- and postnatal periods is critical as is devising new means to recapture cognitive function in individuals who experienced early iron deficiency. This review will discuss the prevalence of pre- and postnatal iron deficiency, the mechanism, and effects of iron deficiency on brain and cognitive development.

  13. Growth hormone deficiency and hyperthermia during exercise

    DEFF Research Database (Denmark)

    Juul, A; Hjortskov, N; Jepsen, Leif;

    1995-01-01

    Sweat secretion is often disturbed in patients with GH secretory disorders. Hyperhidrosis is a classic feature of acromegaly, and it has recently been shown that GH-deficient patients exhibit decreased sweating capacity after pilocarpine stimulation of the skin. Thus, patients with GH-deficiency ......Sweat secretion is often disturbed in patients with GH secretory disorders. Hyperhidrosis is a classic feature of acromegaly, and it has recently been shown that GH-deficient patients exhibit decreased sweating capacity after pilocarpine stimulation of the skin. Thus, patients with GH...

  14. C3 Deficiency – A Case Report

    OpenAIRE

    Carreiro-Martins, P; Gaspar, A.; Rosado-Pinto, J.

    2006-01-01

    O sistema do complemento é um componente essencial do sistema imunitário inato, pelo que as deficiências de proteínas da sua complexa cascata podem ter consequências mais ou menos graves, de acordo com a importância do factor afectado. As complicações mais usuais das deficiências do complemento são infecções recorrentes a bactérias encapsuladas e distúrbios autoimunes. Os autores apresentam um caso clínico de deficiência do factor C3, situação extremamente rara, discutindo a fisiopatolo...

  15. Nutrition and hair: deficiencies and supplements.

    Science.gov (United States)

    Finner, Andreas M

    2013-01-01

    Hair follicle cells have a high turnover. A caloric deprivation or deficiency of several components, such as proteins, minerals, essential fatty acids, and vitamins, caused by inborn errors or reduced uptake, can lead to structural abnormalities, pigmentation changes, or hair loss, although exact data are often lacking. The diagnosis is established through a careful history, clinical examination of hair loss activity, and hair quality and confirmed through targeted laboratory tests. Examples of genetic hair disorders caused by reduced nutritional components are zinc deficiency in acrodermatitis enteropathica and copper deficiency in Menkes kinky hair syndrome.

  16. The clinical spectrum of hexosaminidase deficiency diseases.

    Science.gov (United States)

    Johnson, W G

    1981-11-01

    Hexosaminidase deficiency diseases or GM2-gangliosidoses were originally described as infantile encephalopathies. Recently, hexosaminidase deficiencies have been found with different phenotypes, including juvenile and adult encephalopathies, cerebellar ataxias, and motor neuron diseases. Individual cases have resembled Ramsey-Hunt syndrome, olivopontocerebellar ataxia, Friedreich ataxia, amyotrophic lateral sclerosis, Kugelberg-Welander disease, Fazio-Londe disease, and Charcot-Marie-Tooth disease. Tremor, dystonia, spastic paresis, and psychosis have been seen. Since few diagnosable causes for these system atrophies are known, these patients should be tested for hexosaminidase deficiency. These recessive disorders fit a multiple loci/multiple alleles genetic scheme, and a clinical genetic classification is presented.

  17. Auditory Neuropathy/Dyssynchrony in Biotinidase Deficiency

    Science.gov (United States)

    Yaghini, Omid

    2016-01-01

    Biotinidase deficiency is a disorder inherited autosomal recessively showing evidence of hearing loss and optic atrophy in addition to seizures, hypotonia, and ataxia. In the present study, a 2-year-old boy with Biotinidase deficiency is presented in which clinical symptoms have been reported with auditory neuropathy/auditory dyssynchrony (AN/AD). In this case, transient-evoked otoacoustic emissions showed bilaterally normal responses representing normal function of outer hair cells. In contrast, acoustic reflex test showed absent reflexes bilaterally, and visual reinforcement audiometry and auditory brainstem responses indicated severe to profound hearing loss in both ears. These results suggest AN/AD in patients with Biotinidase deficiency. PMID:27144235

  18. Severe Vitamin D Deficiency Causing Kyphoscoliosis.

    Science.gov (United States)

    Singhai, Abhishek; Banzal, Subodh

    2013-01-01

    Vitamin D deficiency is common among Indian population. Women are especially at risk for severe vitamin D deficiency. The risk is higher for those who are multiparous and postmenopausal. Poor exposure to sunlight, higher latitude, winter season, inadequate diet, older age, obesity and malabsorption are also important risk factors. Symptoms of hypovitaminosis D, including diffuse or migratory pain affecting several sites (especially the shoulder, pelvis, ribcage and lower back) have also been misdiagnosed as musculoskeletal disorders, including fibromyalgia, polymyalgia rheumatica and ankylosing spondylitis. Here, we report two cases presented with kyphoscoliosis, diagnosed to have severe vitamin D deficiency. PMID:26664847

  19. The expression of the ACTH receptor

    Directory of Open Access Journals (Sweden)

    L.L.K. Elias

    2000-10-01

    Full Text Available Adrenal glucocorticoid secretion is regulated by adrenocorticotropic hormone (ACTH acting through a specific cell membrane receptor (ACTH-R. The ACTH-R is a member of the G protein superfamily-coupled receptors and belongs to the subfamily of melanocortin receptors. The ACTH-R is mainly expressed in the adrenocortical cells showing a restricted tissue specificity, although ACTH is recognized by the other four melanocortin receptors. The cloning of the ACTH-R was followed by the study of this gene in human diseases such as familial glucocorticoid deficiency (FGD and adrenocortical tumors. FGD is a rare autosomal recessive disease characterized by glucocorticoid deficiency, elevated plasma ACTH levels and preserved renin/aldosterone secretion. This disorder has been ascribed to an impaired adrenal responsiveness to ACTH due to a defective ACTH-R, a defect in intracellular signal transduction or an abnormality in adrenal cortical development. Mutations of the ACTH-R have been described in patients with FGD in segregation with the disease. The functional characterization of these mutations has been prevented by difficulties in expressing human ACTH-R in cells that lack endogenous melanocortin receptor activity. To overcome these difficulties we used Y6 cells, a mutant variant of the Y1 cell line, which possesses a non-expressed ACTH-R gene allowing the functional study without any background activity. Our results demonstrated that the several mutations of the ACTH-R found in FGD result in an impaired cAMP response or loss of sensitivity to ACTH stimulation. An ACTH-binding study showed an impairment of ligand binding with loss of the high affinity site in most of the mutations studied.

  20. Combined deficiency of coagulation factors V and VIII: an update.

    Science.gov (United States)

    Zheng, Chunlei; Zhang, Bin

    2013-09-01

    Combined deficiency of factor V (FV) and FVIII (F5F8D) is an autosomal recessive bleeding disorder characterized by simultaneous decreases of both coagulation factors. This review summarizes recent reports on the clinical presentations, treatments, and molecular mechanism of F5F8D. Genetic studies identified LMAN1 and MCFD2 as causative genes for this disorder, revealing a previously unknown intracellular transport pathway shared by the two important blood coagulation factors. LMAN1 and MCFD2 form a Ca2+-dependent cargo receptor complex that functions in the transport of FV/FVIII from the endoplasmic reticulum (ER) to the Golgi. Disrupting the LMAN1-MCFD2 receptor, complex formation is the primary molecular defect of missense mutations leading to F5F8D. The EF-hand domains of MCFD2 are necessary and sufficient for the interactions with both LMAN1 and FV/FVIII. Similarly, the carbohydrate recognition domain of LMAN1 contains distinct and separable binding sites for both MCFD2 and FV/FVIII. Therefore, FV and FVIII likely carry duel sorting signals that are separately recognized by LMAN1 and MCFD2 and necessary for the efficient ER-to-Golgi transport. FV and FVIII likely bind LMAN1 through the high-mannose N-linked glycans under the higher Ca2+ conditions in the ER and dissociate in the lower Ca2+ environment of the ER-Golgi intermediate compartment. PMID:23852824